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Dr. Ahmed: It’s great to be here with you today. Both of us have probably been practicing long enough to have lived in an era where for HCC, interventional therapies were the main treatments offered almost all the time with very few systemic therapy options available. In recent years, that has definitely changed. Can you reflect on how that changing landscape is starting to influence how we practice clinically and where newer data fits into your practice?

Dr. Toskich: Yes, so how has changing systemic therapy changed interventional practice?

Dr. Ahmed: Exactly.

Dr. Toskich: When I first started, the thought was treat as much HCC as you can within IR, and when there were no options left, patients would transition to Sorafenib. The perception of the interventional radiologist at that time for systemic therapy, was – well, “let's just delay progression as long as we can.”

Ever since the advent of immunotherapy, systemic therapy now means something different to the interventional radiologist. The notion that current systemic therapy efficacy is being largely driven by the immune system is of great interest to the interventional radiologists, because it is the patient's body as opposed to a synthesized agent that is attacking the tumor. Many interventionalists I speak with are open to the addition of immunotherapy with local therapy earlier in the disease process because it is generally well tolerated and not mutually exclusive. In fact, combination therapy may provide additive and even potentially synergistic benefits to patients, and - and when this connects - we provide something far better than "let's keep this from progressing."

These changes have brought cooperation, inclusivity, and a combining of forces amongst disciplines that was organic – no one ever told us to do this – but people believe in the concept. It has certainly raised a ton of new questions as well. It's going to be a long time before we answer them, but I think they're good questions and represent progress.

Dr. Ahmed: I think that's a great answer and a great overview of many of the things in the changing perspective of interventional radiologists. You highlighted one in particular to touch on which is that in an earlier generation, there was a definitely a push to do as much locoregional treatment as possible, with less emphasis on patient characteristics and / or liver function, because the alternatives really had very little potential improvement on outcome. Therefore, the need to think about that point at which locoregional therapy starts to do maybe more harm even than good was much farther out than it is now, potentially. There is a shift and there will continue to need to be a shift to think about how we are administering interventional therapies and saying, “What is that threshold where should we be layering in these other therapies?” 

The other point you made well is because they are immunotherapies there is a difference in tolerabilities, risk profile, and time to efficacy, effectiveness, and other things that are just different than some of the conventional systemic therapies, or even TKI and other types of molecular therapies. We don't necessarily understand all of that, as we interweave all these treatments together, but I definitely think it is changing the perspective, and will continue to change the perspective, of the interventionalist to say, “How do we bring these systemic therapies in sooner? How can we use them potentially together or who are the right patients for that?”

The other thing I would note is that the staging systems are continuing to evolve. The one that is used for liver cancer, the Barcelona Clinic Liver Cancer staging system (BCLC) is a great example of that. They updated this year their guidelines and recommendations. One of the things that they highlighted is this concept of tumor stage migration and untreatable progression where conventional therapies assigned to specific tumor stages might need to be used at differently (i.e., in earlier or later stages) based on how tumors and patients' characteristics are on the ground, so to speak, and in the tumor board.

What are your thoughts on how that is incorporated into your multidisciplinary tumor board and clinical practice?

Dr. Toskich: There are two points here to comment on. Firstly, I believe that liver preservation should be paramount to any interventional oncologist. There's no point in making all the tumor stop enhancing if the liver stops working, or if you box out future options for a cancer that has up to a 50% recurrence rate at two years after resection. HCC is a disease that, outside the of a liver transplantation, many patients will face on a recurring basis and liver function is their lifeline.

When considering the new BCLC recommendation for systemic therapy in patients with more advanced presentations of intermediate stage disease, my sense is that most providers have been intrinsically accepting of the guideline, despite the absence of positive phase 3 randomized data against the gold standard of TACE, if decisions are made with multidisciplinary consensus. Why? Because as IRs, we have all been there, when we see patients with intermediate disease that are probably not going to respond well to transarterial therapy. Whether it's extensive or infiltrative disease, whether it's a high AFP, we've been accepting of the addition or migration to systemic treatments because we see the potential benefit, particularly with immunotherapy. The acceptance of systemic therapy for intermediate stage disease by the greater oncology community without trial supported evidence does beg why the same consideration does not exist for the addition of local therapy in select patients with advanced disease, where there has certainly been positive signal.

As interventional radiology matures as a separate medical specialty, so does our clinical prowess and patient selection. Local therapy is no longer and order, it is a consultation in clinic. BCLC is a very useful foundation, but our hepatobiliary team is phenotype focused and considers more granular patterns of presentation – again, patient selection is paramount. For example, do you offer ablation to every single 2 cm HCC? Do you apply only systemic therapy to every single patient with vascular invasion? There are a lot of overlapping good options, along with healthy debates, and that's a positive for patients.

The bigger issue at hand is that more personalized we get in oncology, the less likely we'll be able to power studies with 500 patients per arm to meet an endpoint. We will have to become increasingly reliant on well-designed, smaller, study outcomes that move oncology forward incrementally. In the meantime, most decisions will to come to local multidisciplinary expertise until we get more comprehensive recommendations. It's the most challenging portion of our practice - to compartmentalize, to formulate, to boil down to an algorithm. However, I do think tumor boards work when disciplines are well educated with each other's data and have the same mission, the needs of the patient. Irrespective of new drugs or devices, this level of collaboration is probably what generates the biggest impact in our practice.

Dr. Ahmed: I could not agree more, and I think that really is where multidisciplinary collaboration both needs to go and where it is going, because you can't really interweave these different therapies without that discussion.

In our tumor board I'm probably one of the biggest advocates for use of first line systemic therapy and atezolizumab and bevacizumab. In particular in cases that might have traditionally come without question to interventional radiology, but based on, as you noted, the phenotype and the experience of knowing what would be the likelihood of success, starting systemic therapies earlier in situations less suited for interventional treatments.   The strategy you're talking about it also points to situations where interventional therapies are being introduced potentially later or they're being interleaved in a way where a patient gets systemic therapy first and then gets interventional therapies later to treat bulk disease or tumors that don't seem to respond.

There's an ability to mix and match that comes from that discussion. One of the other points you made as well is what the impact of combination effects are and how there is a lot of unknown in the biology of immunotherapy combined with interventional therapies and how they influence the immune system. One of my own points of passion is that it's unclear as to whether one should get immunotherapy first or after a neoadjuvant therapy.

In reality, immunotherapy given first might actually be advantageous in terms of priming the tumor that then may also be responsive to local effects from various local therapies, of which there are many choices, all of which have different immune effects as well. There is so much unknown in all of that space, which is a great opportunity to continue to study as well.

Can you talk a little bit about specific scenarios where you see the most change in your practice? You mentioned phenotype a little bit if we were to talk through scenarios where that plays out most commonly. In my mind, maybe it'll be the intersection of different stages, or certain phenotypes definitely where we see that kind of influence more often.

Dr. Toskich: Sure. If a patient comes with metastatic or extensive bilobar disease, the backbone of treatment is clear – systemic therapy. But, what may be nice us to discuss are the instances where interventional radiology raises the notion of systemic therapy for their patient. It seems to come down to three basic categories.

The first one is the patient with "early advanced disease." They have macrovascular invasion, but it's limited to a lobe or a segment and we can treat their disease locally without compromising liver function. Many IRs, surgeons, and radiation oncologists offer local for high-risk disease and adjuvant studies are underway, but most see no reason why systemic therapy should exclude other effective treatments. There are numerous other GI malignancy precedents which offer local therapy and systemic therapy as guideline supported protocols – this is not a novel concept. Our group has published on successful downstaging to transplant with a similar combination approach resulting with complete tumor pathologic necrosis and the potential warrants exploration.

The second one, as mentioned earlier, is the patient who you think is not going to respond well to your treatment, or local therapy is going to be unsafe. A classic example is the patient with intermediate stage disease that has milliary subcentimeter lesions and nearly the whole liver is restricting diffusion. Yes, technically speaking there is no vascular invasion, there is no disease outside of the liver, but you cannot provide selective therapy to that patient. Our group support those as first line systemic therapy scenarios, and it does not mean that IR has not future role. We've performed local therapy as a salvage to failed systemic treatment in rare cases which ignited systemic response. It's case reportable, but that doesn't mean that we stop investigating how it happened, or stop trying just because we cannot predict who will benefit at this time.

Finally, I refer to this one as the “discordant presentation”: this is a patient who has a three and a half centimeter tumor, but the AFP is 4,000. This is someone who we know is going to have bad biology, is high risk for local recurrence and metastases. While we are essentially using a serologic marker as a surrogate for microvascular invasion, this could be applied to any concerning phenotype, such as patients with disrupted pseudocapsules, large tumors, or in the presence of satellites. Ultimately, this disease presentation is where we are interested bringing bringing systemic therapy to BCLC A, because as good as the BCLC staging system is at unifying and trying to get the world to practice with some commonality, it's very difficult to have all those patterns in an algorithm. To help standardize this more granular approach, we are currently developing AI to identify high risk phenotypes as part of a transforming liver transplant initiative that has the potential to reproducibly identify risk outside of tumor size and number alone.

I think those three are some of the strongest current reasons for IRs to knock on systemic therapy's door and say "come on in and help out!"

Dr. Ahmed: Yes, we practice in a very similar fashion. In all of those instances, we practice almost identically in where we think about interweaving systemic therapy early or perhaps outside of the standard study-based parameters.

I’d say that the other cohort are people who have liver-dominant disease and a few sites of oligometastatic tumor outside of the liver. For example, the patient that has a a few metastatic lymph nodes at one or two sites, but has an eight centimeter tumor in the liver, where penetration of systemic therapy and the effect of that may not be as robust for the dominant liver tumor.  This is where we might combine therapies even though they fall conventionally into in a later stage grouping or category, particularly if we're concerned about the rate of growth or intrahepatic progression, which is its own predictor of mortality and outcome in these patients.

Then you have the last group, which is interesting too, where the medical oncologist brings a patient back to us as there has been oligoprogression. This where the patient is on a systemic therapy regimen and has two small sites or three small sites that are growing. By the conventional medical oncology review, one would say that they have disease progression, and need to be switched to something else, but all the other sites seems to be well-controlled. So we have those instances as well, where we are treating them on a case by case basis to allow the systemic therapy agents to continue to be used for a longer period of time.

That is another hot area of interest because there is now data across other cancer types as well around this concept of immune escape in lesions and the value of potentially treating some of those with local therapies as well.

Dr. Toskich: Yes, the concept of immunologic compartments being different in your nodal basin, as compared to your liver, lungs, or bone, is a great additional point.

The notion of trying to separate all hands on deck sequentially may not necessarily be the best way to fight cancer. As mentioned, there are so many examples in GI oncology where you have “chemorads” protocols. I see similarly in the liver, particularly when using radioembolization for more advanced disease, I see no reason why you can't explore “immunorads” in the liver.

It all comes to addressing the individual aspects of any given patient's condition that presents a hazard to life – and doing it with agility. Is it their liver function over time? Is it the systemic taxation of chronic disease burden? Is it local hazard such as biliary or portal obstruction? Do we have an opportunity for transplant? I think these are all worth engaging in real time and may uncover benefits of not treating everything with a solitary hammer, whether it's infused through a catheter or through an IV.

I honestly think we're getting there. I am impressed by how many people can quote other disciplines data in depth at my tumor board these days. We're co-educating each other and it’s really an exciting time to help patients with HCC. As matter of fact, I recently had to unexpectedly cancel a scheduled interventional oncology talk at the last minute due to an emergency. I reached out to my medical oncologist at the time and asked if he wanted to give the talk instead. He not only agreed, but knocked it out of the park. That was a great litmus test for multidisciplinary communication. 

I believe this is the way forward. Ridiculous turfs are set aside, and we start thinking about how we generate durable responses with low adverse events in parallel. Overall survival data is great, but it's going be really hard to get when we have a million permutations of therapy. Despite the amazing advancements of systemic treatment, tumor response is still not greater than 50%. If patients are interested in rolling the dice for immune activation in addition to concurrent local therapy, with the potential for a favorable DOR/AE ratio, why not try? That is why we are seeing interest in local and systemic therapy trials for even early stage disease, and patients are equally invested.

Dr. Ahmed: You made a lot of excellent points. The nuance that is now in place in making actual treatment decisions is really both quite interesting and exciting. It really does speak to all the different treatment options and choices that people have. You outlined a really great example of the engagement of the different oncology treatment communities. On the ground, on a daily basis, and with each other is really a point of collaboration that is just going to be a great example of where medicine should go in a multidisciplinary way. HCC is an evolving entity itself, in part because of advances in liver disease. The overall development of fatty liver disease and its implication in HCC development is a different biology so there's a lot of different sort of changing pieces as well makes the space very interesting.

Do you have any advice for people coming into practice? You and I both have very robust training programs. When I have fellows and trainees, the complexity of some of the discussion at multidisciplinary conferences can be overwhelming sometimes because of the rising amount of data and treatment options and patient considerations.

Is there any perspective or advice that we should offer people who are earlier in their careers on how to think about engaging with their medical oncologists to understanding key elements to data, practicing in real time, as you alluded to?

Dr. Toskich: The best way I would approach that question would be what would I have wanted to know when I was finishing my fellowship. The first thing to realize is that you're not going to be successful alone.  You need to team up with good hepatologists, oncologists, surgeons, and a transplant team with whom you can foster a mutually respectful relationship. That's so important because it’s the human element that cannot be protocolized.

People who get along, who respect each other...that benefit translates to better patient care. I believe in that. So start early, start from day one, be humble. Learn from these people, they can teach you amazing things. My passion was HCC since I was a resident, and yet the knowledge and experience blind spots I had in my first years as an attending were massive. Be aware of those blind spots and rely on people you trust to help you eliminate them.

That brings me to my next point which is, a lot of people within interventional radiology, (although I do think this is changing) are overly focused on the technical aspects of therapy. What is a harder and more fruitful question is “should I intervene?” and “when?” Patient selection is key. That is what people should be asking when they call their mentors, not to find out what catheter they use or some awesome tricks to perform with it. You will develop your own tricks one day, that's going to come naturally.

Collecting and communicating your outcomes is next most important step. Most people have adopted and the advances of systemic therapy, but I think that it's human nature experience a pendulum swing and forget established treatments that are effective. Think about the patients who are coming back transarterial therapy for neuroendocrine disease who were poor responders to theranostics. Embolization never went away, it was merely a pendulum swing and having your local data will help keep the best options for a patient at the forefront. This is human nature and it is normal. But it is up to the interventional radiologists to champion what we know does well for patients, what is it that is the crown jewel of our practice that needs to be protected. The best way to do that, if you're in academics or private practice, is to continuously know your outcomes and hold others to that standard. This will also allow you to identify which aspects of your practice are worth preserving and aspects that maybe aren’t working as well and consider moving on to the next opportunity.

Now I have a question for you. If you incorporate an aspect of your practice into a nonexistent guideline right now that works well for your multidisciplinary team, what recommendation would you make?

Dr. Ahmed: I would say, not something that we necessarily do well in our practice, but what I would like to see more broadly is the incorporation of biologic data more aggressively in both studies and ultimately in treatment guidelines. I do believe that in HCC because the imaging has become, and has been for a while, so accurate in the diagnosis of HCC against non-malignant entities, that the perception of not needing biopsy data and/or biologic sampling is very heavily embedded as a culture within the treatment of HCC.

Actually, what we're appreciating now, whether it's in these aspects of HCC, and also in liver disease in general, is that our stratification needs to be much more nuanced. We are not going to be able to do that, particularly on the immunotherapy front and on the locoregional therapy front, without some additional sampling of tumors, acknowledging the limitations of what that sampling entails. We are starting to see some of these studies for locoregional and interventional therapies, where the peripheral blood is sample to look for secondary signals of response after local treatment, or to help stratify patients who to predict response or progression.  There is quite a lack of that in the HCC space compared to other GI malignancies, lung cancers, and other sort of cancer types where correlated genotype or phenotype by sampling to radiological imaging and response is farther along.

I'd love to see that culture expand in HCC, and we actually can be strong proponents of that because we are the people doing the biologic sampling. To your point, if one thinks about the patient, then the treatment biopsies have added value and we can be strong advocates of incorporating that into studies and clinical practice.

Dr. Toskich: I agree, and that is what I was hoping you would say, because biomarkers exist in so many other malignancies, but HCC biomarkers have shown potential but have not panned out. That doesn't mean we should stop trying.

I think being smarter in our approach – whether combining systemic and local treatments – for a particular patient’s pattern of diseases earlier in their diagnosis is going to provide oncologic leverage. And that's really where I am hopeful of our upcoming biggest strides.

Dr. Ahmed: Great. This has been a great discussion, thank you for speaking with me today and sharing your insights.

Dr. Toskich: Likewise, thank you.

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.