Updated: Oct 21, 2020
Locoregional therapies for hepatocellular carcinoma (HCC) are utilized to bridge patients within Milan criteria to eventual transplantation, downstage more advanced disease for potential resection/transplantation, and control disease within transplant-ineligible patients to prolong survival. Controlling disease in transplant candidates during the waiting period for an allograft is critical to prevent drop-out. More robust disease response to liver-directed therapy may portend superior long-term outcomes after transplantation, as patients with complete pathologic response have demonstrated significantly improved survival and recurrence rates post-transplant. Transplant surgeon Dr. Jennifer Berumen and interventional radiologist Dr. Isabel Newton discuss current locoregional treatment options for HCC, the impact of the mandatory six-month waiting period before transplantation, and prognostic factors in determining suitability for transplantation.
We’ve provided the highlight reel below, but you can listen to the full podcast here.
The BackTable Brief
Since the UNOS adoption of Milan Criteria in 2002 for conferring listing status for liver transplant in HCC patients, organ allocation has been driven primarily by MELD score. In order to combat geographic disparities in transplant access, the UNOS instituted a mandatory six-month wait-time for all patients before consideration for prioritized allocation via MELD exception. Controlling disease during these prolonged waiting periods is essential to maintain a patient’s transplant eligibility.
Locoregional therapies play a critical role in bridging patients with HCC from time of listing to transplantation, and primarily include stereotactic body radiotherapy (SBRT), transarterial chemoembolization (TACE), transarterial radioembolization (TARE, or y90), and/or percutaneous ablation. The principal goals of these liver-directed therapies are to control and potentially eradicate disease in order to maintain eligibility for transplant candidates, to downstage disease in transplant-ineligible patients to meet Milan criteria, and to prolong survival and palliate symptoms in patients with advanced or otherwise unresectable disease. The degree of response to therapy may elucidate elements of tumor biology and long-term prognosis following eventual transplantation.
A thorough understanding of hepatocellular tumor biology is essential to the assessment of disease prognostication in HCC. Although pathological study of HCC tissue represents the gold standard for elucidating tumor biology, transplant surgeon Dr. Jennifer Berumen warns that percutaneous biopsy carries the risk of extrahepatic seeding of tumor cells. Surrogate indicators of tumor biology such as imaging features, radiologic response to therapy, and serum markers such as AFP provide valuable information to guide management. However, interventional radiologist Dr. Isabel Newton notes that these metrics are of limited reliability for predicting disease prognosis in individual patients.
Image Courtesy of Sabeen Dhand MD
Disclaimer: The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
Types of HCC Locoregional Therapies and Their Importance
The primary locoregional therapies for HCC (AKA liver-directed therapies) include stereotactic radiotherapy (SBRT), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and/or percutaneous ablation. Treatment selection and timing vary between patients based on a multitude of diverse factors, and may include numerous locoregional treatments, often in combination with systemic therapy. According to interventional radiologist Dr. Isabel Newton, the underlying goal of all locoregional treatment options for HCC is to eradicate as many tumor cells as possible. The degree of treatment response can help elucidate tumor biology and potentially predict long-term outcomes following transplantation. Although liver-directed therapy should ideally elicit at least partial pathologic and radiologic disease response, patients with stable or even progressive disease after treatment are not necessarily excluded from transplant eligibility. Similarly, a robust treatment response does not in itself guarantee a future transplant, particularly in patients with continued tobacco/other substance abuse, inadequate social support systems, and erratic attendance at scheduled follow-up appointments.
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?
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.
Jennifer, do you have any preferences or biases with regards to locoregional therapies?
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.
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?
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.
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?
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.
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?
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.
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.
Impact of Liver Transplant Wait Period on Use of Locoregional Therapies
Since the UNOS adoption of Milan Criteria in 2002 for conferring listing status for liver transplant in HCC patients, organ allocation has been driven primarily by MELD score. In order to combat geographic disparities in access to liver allografts, the UNOS instituted a mandatory six-month wait-time for all patients before consideration for prioritized allocation via MELD exception. According to Dr. Jennifer Berumen, this universal waiting period has afforded clinicians the opportunity for more reliable assessment of tumor biology in individual patients, facilitating stratification based on disease aggressiveness to prioritize candidates with more favorable tumor biology and resultant superior prognosis after transplantation. She also notes that in order to maintain disease status within Milan Criteria, the majority of transplant patients with unresectable HCC are now referred for locoregional therapy to bridge them to eventual transplantation.
There’s a mandatory six-month wait time for patients with liver tumors for liver transplant. Can you tell us a little bit about when this was instituted and how your practice changed from before the mandatory six-month wait time till after the six-month wait?
So when patients get listed for transplant in the past, if they have tumor, they're eligible for what's called tumor exception points. The waitlist is based on the MELD score, model for end-stage liver disease, which looks at the lab values with patients with cirrhosis and gives you a score. The list goes from zero to 40. When patients are at 40, they're really, really sick and the risk of mortality is about 80% within three months. So those patients are prioritized for transplant. The waitlist in [California] is one of the longest waitlists. Patients were getting transplanted with MELDs in the 30s to 40s. In other centers, like in Louisiana, the list tends to be shorter, and so it's actually easier to get a liver transplant with a lower MELD score. So there's a lot of variation in the country as to when you could actually get transplanted. In December 2017, they changed the tumor points to a six-month wait period, and there are a few different reasons behind that. One was that maybe if you waited six months, tumors that had really bad biology are potentially going to grow faster than other tumors and metastasize earlier. This would potentially be able to be picked out within that six-month wait period, and those are patients that shouldn't probably get transplants. The six months might help you decide who should actually get a transplant and to make sure that those patients are healthy enough and that their tumor is not going to grow out of the criteria for transplant. It actually seems to be a really good thing for the most part. But it does also mean that pretty much every patient who comes with a tumor now, is going to get referred to radiology for local-regional therapy in order to bridge into transplant, because no one wants to wait six months after you find a tumor to treat it.
So in 2017, they instituted the mandatory six-month wait period time for liver transplant for patients with HCC. It was to tease apart those patients who may have aggressive tumor biology. Basically, that six-month waiting period would give you a chance to evaluate the behavior of the tumor and tease out more aggressive tumors from less aggressive ones.
That's exactly right.
The wait to transplant is so long that it's not like we get so many patients achieving transplantation that it's an expectation that we're counting on. We're basically treating almost everyone like a bridge to transplant. And so perhaps in a state where it's easier to get a transplantation, I have certainly had patients who have moved to either Texas or Pennsylvania in order to have a higher chance of getting transplanted, and they did. Unless you're one of those patients, you're largely looking at a combination of therapies to try to treat your cancer so that we can extend your lifespan. Most of our patients fall in the intermediate stage category, so they're going to be looking at catheter-directed therapies, potentially in combination with other therapies as well. But that's been the mainstay of our treatment paradigm.
When the six-month wait happened, it didn't really change much for our patients in California because they were already waiting a year and a half, so they were already getting sometimes three and four TACE procedures. I think I've had one patient who had seven local-regional therapy treatments before he got transplanted.
Methods and Markers for HCC Prognostication
Dr. Isabel Newton believes that detailed study of HCC tumor biopsies will eventually replace current surrogate metrics used to reflect tumor biology by more reliably predicting tumor behavior, assessing response to therapy, and informing prognosis. Dr. Jennifer Berumen, however, warns that percutaneous biopsy of HCC carries the risk of extrahepatic seeding of tumor, which could eliminate the option for future transplantation. She states that, although state-of-the-art imaging and other parameters provide useful information, we’re unable to comprehensively characterize the tumor and expected outcomes until the liver has been explanted and studied by pathology.
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?
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.
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.
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.
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.
Dr. Jennifer Berumen is a transplant surgeon and assistant professor with the UCSD Department of Surgery in San Diego.
Dr. Isabel Newton is a practicing interventional radiologist at UC San Diego Health in San Diego, CA.
Host Dr. Christopher Beck is a practicing interventional radiologist with Regional Radiology Group in New Orleans.
Cite this podcast:
BackTable, LLC (Producer). (2020, May 21). Ep. 64 – Bridging to Transplant for HCC [Audio podcast]. Retrieved from https://www.backtable.com/podcasts
The Materials available on the BackTable Blog are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
Special thanks to our sponsor:
TriSalus Infusion Systems