Dr. Rilling: Hello, Isabel. It is great to be here with you today.
Dr. Newton: Great to be here with you, as well. Today we are discussing some of the changes to how we are taking care of our patients with liver cancer, in light of the new BCLC guidelines and some of the new therapies that are available. I wanted to run some patients by you and see, in your opinion, how you would treat them, what is happening at Medical College of Wisconsin (MCW), and how it differs to what is happening down here in San Diego, especially at the VA.
Dr. Rilling: Sure, that sounds great. It is an exciting time right now for HCC treatment, as you know. A lot of advances in systemic therapy for HCC and in liver-directed therapy, and a lot of shifting of the guidelines are going on, so it is a great time to have this conversation. Let's talk about some of your potential patients.
Dr. Newton: I have this one patient: he is a 67-year-old Hispanic male, and he has NASH cirrhosis and bilobar, multifocal HCC. His performance status is 1. We can talk about what that means. His total bilirubin is 1.8, INR is 1.2, albumin is 3.8, platelets are 120, and creatinine is 1. According to the new BCLC guidelines, he falls between an intermediate stage B and an advanced stage C. I am curious how you would approach him.
Dr. Rilling: A lot of interesting points about this patient: first, as you alluded to, the issue of performance status as a subjective assessment in BCLC is something that is pretty controversial. Remember that patients who have anything other than an ECOG of zero are automatically put into the advanced group, which, for an objective measure, is sort of over-staging. Certainly, some of these patients you and I have talked previously about, such as people with cirrhosis without liver cancer, often have some degree of fatigue, if you really drill down on it. So, do you count that if they have chronic fatigue? Because, if they have cirrhosis or other things going on with them, such as diabetes (which this patient probably has), it is hard to tease out the symptoms from these chronic diseases versus true cancer-related performance status changes. That whole conversation is challenging, and where you put these people, based on performance is obviously really subjective when compared to other measures in the BCLC, which are quite a bit more objective. I assume that this person is outside Milan criteria. He is not a transplant candidate right now but because he is a young man, if there is any chance to get into a curative-intent therapy, we would want to try to do that.
Assuming he is outside of Milan criteria, his liver function is not awesome, but it is not terrible with total bilirubin 1.8, and his albumin is down a little bit. What we do for this patient would depend purely on their tumor burden and the size of distribution of their tumor. With a bilirubin of 1.8, we certainly do not want to treat his entire liver. We want to be careful to try to preserve his liver function as much as possible. It has been suggested that regarding immunotherapy in a patient like this with NASH cirrhosis, his response to immunotherapy might be less robust than patients with hepatitis-related cirrhosis, so that plays into the decision-making process.
With this patient, we would probably try to do liver-directed therapy, and, if we could treat most of the tumor burden with only a couple of segments, then we would probably do Y90. If it was more widespread, then, in the interest of trying to make sure we do not hurt his liver function, we might do TACE as a starting point.
Then we would have follow-up discussions based on his response and tolerance to that sort of treatment around where to go next. The best goal would be to downstage him to be within Milan if there is any way to do that.
What are your thoughts?
Dr. Newton: All that sounds concordant with what we would do.
You mentioned that NASH as a driver of cirrhosis might lead to a poorer response to immunotherapy. Let’s say he has hepatitis C driven cirrhosis instead, or if his disease was not located in discrete segments that you could just take off, are those the factors that would push you towards atezolizumab and bevacizumab?
Dr. Rilling: Those are great points. Certainly, if it is hepatitis C cirrhosis, that pushes us a little bit more towards immunotherapy. If there is tumor in every segment where you are not going to be able to treat him without treating the whole liver, that is another factor in favor of systemic therapy.
The biology of these BCLC-B patients is all over the map. BCLC-C by tumor burden, not by performance status - the biology is also quite variable. We often first meet these patients with just a single data point of their scans and their alpha-fetoprotein, and then you're going to be learning about their tumor biology as you go forward. Some of these patients have a fair amount of tumor, but it is not rapidly progressive. So you treat them, and you see the next scan, and you either get a response or not, but you are not seeing a bunch of new tumors.
Then there are other patients, where every time you scan, there is disease progression in various segments. Those patients are on a completely different path than the patients where you are treating the same lesions without progression elsewhere in the liver.
If I see a patient who has a couple of new tumors, even if they are really small on every scan, that is a patient I want to get on systemic therapy sooner rather than later. You have more of a field effect going on, and I think it is important to try to get other therapies on board.
Dr. Newton: That is such a good point. Whenever I am establishing care with an HCC patient, I tell them first that we're in it together for the long haul and second, I tell them that our first treatment is the "getting to know you" treatment. I see how you tolerate things, how your tumor responds, how you respond and we'll go from there. The decision tree is wide in the beginning and then you will tell me how we narrow it at the next step.
The point you made before about performance status, a lot of times when we have these patients in our office we get a gestalt kind of a feeling of what they could tolerate. You can assess if are they pretty strong or are they feeble, and all that kind of stuff.
That was really helpful. I appreciate your parsing out of how you would make that decision.
Dr. Rilling: The point you just made about seeing these patients in-person is really critical. With patients, the way they look on their scans or on paper and based on their labs can be completely different from the way they look when they're sitting in front of you.
Literally, you can’t tell. You obviously know their labs are their labs and their scans are their scans, but when that person is in front of you in the clinic, there is so much more information.
We are in the age of virtual visits, and, I don't know about you, but I don't get as much from a virtual visit as I do from having the patient right in front of me. Being able to look them in the eye and ask them questions about what their daily life is like, what is limiting them, and how things are going is invaluable.
Dr. Newton: And you hear and notice the other things they have too, right?
Dr. Rilling: Right, because they usually have comorbidities too. So, I think that point that you made is critical.
Dr. Newton: Alright, I have another patient for you. He is a 55 year old, Caucasian man, and he has alcoholic cirrhosis, so not NASH, and he has HCC that is pretty advanced with portal invasion. His performance status is zero. This patient passes the eyeball test. He does not look sick. He looks great; in fact, he is a muscular guy. He came in, he drove himself and he is fine.
But, his total bilirubin is 2.5. His INR is creeping up, it is 1.8, and his albumin is 3.3. He had some reserves to be able to now have an albumin of 3.3 and look as good as he does. His platelets are 85 and his creatinine is 1.5.
In your experience, how would you approach this patient?
Dr. Rilling: Boy, this is a challenging patient as well. It is tough to see these young patients with a terrible problem like this. These patients who present with vascular invasion are in a tough situation.
First of all, this patient is obviously in the BCLC-C category, by definition, with the portal invasion.
I think it is worth discussing a little bit that one portal invasion is not exactly like another portal invasion. The branch PVT are different than a main right or all the way into the main portal vein. In our practice, how we approach these patients and definitely the degree of portal invasion is taken into consideration along with, obviously, hepatic reserve here, which is a big problem with this patient. What you would really like to do differs from what you will end up having to do because of concerns of his hepatic reserve. The portal invasion is really rough and, by definition, a bad marker for tumor biology for this patient.
Even though he is a young person and, by looking at him, you could be aggressive, we have to be concerned. When we see an elevated bilirubin, we always make sure we get direct and indirect bilirubin to make sure it is not Gilbert syndrome that is artificially making the bilirubin look worse and it is actually not a synthetic problem. This ensures that the synthetic function is fine, even though the bilirubin is so elevated. This gentleman, by the guidelines, would get systemic therapy first line, probably atezolizumab and bevacizumab.
The thing that you are worried about is if he does not respond, you have a narrow window in these patients. While his liver function is not great, if he progresses, you may lose the window to be able to try to do some locoregional therapy. The discussion we would have at tumor board would be, if we start systemic therapy, he would get a couple of cycles, and we would check very early to get a sense for whether this is working or not working. We would be very quick to switch gears in a young healthy patient like this if it is not working right away.
Dr. Newton: That is an interesting approach to be very vigilant. Other institutions would just go straight to Y90 with a patient like this and leave the systemic for in case he progresses, which is not entirely in line with these new guidelines, but it is kind of the local practice.
What are your thoughts on that given his age? If he were 85 years old or 70 years old it would be different, but he is 55 years old.
Dr. Rilling: Yes, and again I think the degree of portal invasion is important.
We struggle with this at our tumor board honestly, which way to go in the order of therapies. At the end of the day, a lot of these patients end up getting both locoregional therapy and systemic therapy. I don't think we know at this point in time, from a data standpoint, which one of those is better and which to start with and exactly how to integrate them in an optimal way. That is obviously going to be the subject of a lot of research over the next couple of years.
The other thing, as you are well aware, is looking at the Y90 dosimetry in a patient like this. If you have one of the personalized dosimetry platforms, to determine based on Technetium MAA scan if you can get over 200 Gy into the tumor and not hit much of his background liver, then, by DOSISPHERE data, you would be on good standing to treat this patient with Y90 with a very high response rate to start off. If you find out in your Y90 mapping and dosimetry that you're not going to be able to get 200 Gy or you can't isolate the tumor, then that's another story for this patient in terms of which direction to go.
Dr. Newton: Right. With the data, I think everybody's wondering about the order in which to do it, as you discussed. When you treat with Y90, you are releasing so much tumor antigen that could potentiate or help the systemic therapy. It is going to depend on how the data plays out, but that is certainly the hypothesis that's emerging. Hopefully, we can have more guidance in terms of how to combine these things or the order to do it in.
Dr. Rilling: Yes, and I think if we are going to combine we need to first show safety. I mean there's not a lot of reasons to suspect that there would be significant cumulative toxicity from, say, atezolizumab and bevacizumab and Y90, but it has not been really well studied up to this point in time, to my knowledge.
Just showing that it can be combined, that it's safe to put them together, is an important thing for us to do. Right now, we are not, in our practice, doing them right on top of each other. Especially for bevacizumab: if they have that on board, we're waiting four to six weeks from last dose to do Y90, so that's important. I think we still have a lot to learn about combining these treatments.
Dr. Newton: We have the same practice exactly. At the VA, we don't have Y90 yet, so we send our patients to the university or up to one of the other VAs that has it, and so there is this inherent delay that comes with the bureaucracy of sending a patient.
That's something else I wanted to bring up. Each place locally has its own challenges. You mentioned that with your gastroenterologists being very backed up and how that is impacting how you are practicing. Can you talk about that a little bit?
Dr. Rilling: Sure. For the patients that are going to start atezolizumab and bevacizumab, if they have portal hypertension, they generally have to get an endoscopy to look for high risk varices. Right now, our GI service is scheduling three or so weeks out for an outpatient upper endoscopy.
It's interesting, some of the knock on Y90 has been the delay from when you see a patient in clinic until you are treating them. We actually can get a patient seen in clinic, mapped and treated oftentimes within a week. We can do it very fast, and we prioritize these patients in our clinic and in our scheduling. We have a coordinator who does a fantastic job expediting the process. We can treat oftentimes less than a week from the time we're doing the mapping.
I think if a new patient comes in, who is going to be waiting a month until they can legitimately get on atezolizumab and bevacizumab, that is a great opportunity if they are eligible for locoregional therapy to do that up front. Then, you're doing something to the tumor while you're waiting for the patient to be able to get started on their systemic therapy. This would be a great patient to do that on.
Dr. Newton: Yes, I agree. Alright, I have my last patient I would like to pick your brain on. He is a 72-year old, Filipino male who has HCV cirrhosis, and his HCC is infiltrative. He is one of those people who, when you look at his MRI, it looks awful. Then you look at his labs and you look at him, and he looks fine. He has preserved liver function and total bilirubin is 1.3. INR is 1, albumin is 4, platelets are 145, creatinine is 1.1. His performance status is zero. He is still gardening and volunteering at his church.
What would you recommend for this patient?
Dr. Rilling: This is an interesting patient, as well.
This guy, by BCLC, would be sort of an advanced B because of the infiltrative of tumor morphology. As you and I were discussing earlier, one of the big changes in the revised BCLC guidelines is subdividing the Bs. This patient would be more of a high-risk B patient.
There's a lot of discussion out there now about whether the high risk B patient should be getting on systemic therapy as their first line of therapy or after liver-directed therapy, because traditionally the BCLC-B patients have had TACE as the standard of care.
So this patient has many options because of his good performance status and good liver function. I would just say that I get really, really worried about the infiltrative tumors. I think it is almost a worse prognostic sign than PVT. I haven't seen good data to compare those two, but it is a really bad biomarker of how this tumor will act. We try very hard, if we can, to treat these infiltrative tumors with Y90.
Again, this would be a great patient to see what the dosimetry looks like. Some of these infiltrative tumors are sort of hypovascular sometimes.
If you see that you're not going to get a good dose into the tumor, this helps guide our decisions. Obtaining this additional information to triage therapy is extremely helpful. These infiltrative tumors are really tough. You want to be as aggressive as possible with them right away.
Dr. Newton: That is really, really helpful, thank you. You have so much more experience than me, and I respect you so much, I appreciate your insights.
Dr: Rilling: Yeah, I’m just older than you.
Dr. Newton: Well, we do have something in common, which I just found out. We both started our liver tumor boards, and we both run our liver tumor boards, which is not typical that it is IR- run. It is a great advantage. For anybody who's considering starting a liver tumor board, it is some work, but there is a lot of advantage to being at the helm. You see all the patients who go through, you have an opportunity to refine these algorithms to understand the nuances, and that's what we talked about today. I really appreciate your input. Thank you so much.
Dr. Rilling: Thank you as well, this is a great conversation and always fun talking to you.
Dr. Newton: Likewise.