Podcast Transcript: Immunotherapy & TACE in HCC Treatment

[Dr. Christopher Beck]
All right. Very nice. Julius, also thank you for coming on the show. Richard and Julius, you guys may or may not know, but we've covered a lot of this stuff in the topic. I want to at least give you guys just both open mic as to set the table about HCC, and just introduce the topic to the audience. Then we'll jump into the real meat and potatoes of it. Richard, do you want to start?

[Dr. Richard Finn]
Yes, sure. From the oncology standpoint, liver cancer is fairly unique. We know what causes it, chronic liver disease in 90% of patients, where most cancers we don't. I sometimes make parallels to lung cancer because it's a malignancy that's occurring in a very critical organ. Usually, that organ is sick. In the context of lung cancer, it's COPD and lung disease. In the setting of liver cancer, it's cirrhosis. How we approach patients is really not only dictated by the tumor characteristics, but the characteristics of the patient and their underlying physiology.

It's very different to have a two-centimeter tumor in someone who is well-compensated, child PUA, no portal hypertension, as compared to someone with a two-centimeter tumor with a bilirubin of eight, renal failure, and bedbound. Two very different scenarios, and by the TNM staging system, they're the same. Stage one tumor. Obviously, their prognosis is very different. That's where a system like TNM fails our patients with liver cancer, because it ignores this fundamental underlying risk of outcome and death, which is their liver function.

That is why I think largely the Barcelona system has been adopted. There's many very good staging systems globally. In the modern age, most of them try to capture the liver function as well as tumor characteristics. It has served to be prognostic for its various stages. It really has been the backbone for clinical drug development and clinical trials. We can all speak the same language across disciplines and across regions. I could go on for an hour, but I'll let Julius chime in as well.

[Dr. Christopher Beck]
Julius?

[Dr. Julius Chapiro]
Yes, definitely second all these comments from a master. I will say, from a radiological perspective, liver cancer is a bit unique in that it's one of the very few cancers that can actually be diagnosed in non-invasive fashion. In my view, this comes both as a blessing as well as a curse, because as a scientist, I always want tissue and I want to understand the biology of a tumor. Liver cancer is extremely heterogeneous because it's very poorly understood in terms of its molecular bioprofile, mutational map.

Because it has been diagnosed using LI-RADS in these patients and because we were blessed to have amazing diagnostic tools like the MRI and a triphasic CT that in many of these cancers gives us the diagnosis just by imaging features. At the same time, we've, I think, for a long time missed an opportunity to understand these cancers and to map them out with retrospective and sometimes even perspective data from a biological and pathological perspective.

IR has, once again, a very important role here, not only from the side of local regional therapies where, of course, we're represented, but also from obtaining samples, I think. I think this conversation is picking up a lot right now in light of the so many upcoming drugs and trials.

(2) HCC Referral Patterns and Multidisciplinary Care

[Dr. Christopher Beck]
Well-said. All right. I just want to talk about some boring stuff first, but they're a little bit necessary. Richard, we'll kick it over to you. I want to know, in the UCLC system, particularly with your practice, what are the referral patterns for HCC? How do they get plugged in with oncology?

[Dr. Richard Finn]
Yes, that's a very good question. Look, I'm at a large tertiary center and I've been here a while and I'd say historically and probably still the backbone of a successful program is going to be driven by transplant. That puts you on the map because that is the backbone of cure. When I say transplant, often that's associated with hepatobiliary surgery. The reality is most patients are not going to be surgical candidates. At a large health system, we control a lot of patients because they're part of UCLA Health and they get referred in either to hepatology with a liver mass. Some of them will be referred to from hepatology to then the liver cancer center. I'm part of that.

At the same time, they see me, they might see the surgeon, or maybe they'll just see me first, and I'll let Julius speak to this. I'm speaking a little bit for my IR colleagues at UCLA, they have a big presence and they probably get direct referrals themselves from outside UCLA and within. I think most of the referral pattern comes through internal medicine in some way, whether hepatology or directly to oncology.
Surgery will see patients and unless they're directly a resection candidate-- which few are in the US because our patients generally have some degree of portal hypertension from hep C or metabolic liver disease, NASH, MASH, unlike the East where hepatitis B dominates and those patients are not as cirrhotic and they do have more resections. Patients will come in and they can't get a transplant right away. As part of their evaluation, they see medical oncology or the liver cancer program to help manage them while they're waiting for transplant. Also weigh in on their candidacy.
I, in my practice, are involved with patients of all stages. That's different than in the community where someone with liver cancer might just see the oncologist when they have metastatic disease or they're not part of a very active multidisciplinary program. Things are fractured a little bit more in the community. Maybe the hepatologist might send someone to IR. When IR is done, send them back to hepatology or oncology and it's a little less organized. At our center, I'm seeing patients' direct referrals to me because I'm known in the community, in the cancer community, direct referrals to hepatology and then to me or even from surgery.
[Dr. Christopher Beck]
Is it a fair statement that even if patients are referred directly to you, outside of the liver program, is it a multidisciplinary approach where if you see somebody, then you're like, "Well, we really need to touch base with hepatology," or something like this, Richard?

[Dr. Richard Finn]
Yes, these are good questions because the multidisciplinary program is just one half day for me, because it's hard to have that five days a week. I do see patients on other days, some off-site. Main campus is in Westwood, I have a very busy oncology practice in Santa Monica, or other part of our health system. Certainly for patients that are not advanced, I will bring them to the tumor board. I see plenty of patients that are intermediate, liver-confined, and I'll bring them to the tumor board to get them tied in with a plan on how we will manage them.

I focus a lot on research, and obviously try to prioritize patients for research studies, but I'll see patients who I think are resectable. They come in for a second opinion, and someone recommended medical treatment, I'll slow down. You might be resectable, or a transplant candidate. That's very important for transplant, especially because the guidelines are changing so frequently as far as size criteria, downstaging criteria, and there's plenty of data that has shown that patients managed at a multidisciplinary program tend to do better.
Certainly for patients that I don't really think are appropriate for anything other than medical treatment, I don't feel obligated to bring to the tumor board. At the same time, some patients come back, meaning they're large, infiltrative tumors, they've had a great response to treatment, and maybe now they are candidates for a more definitive approach. Especially in the modern age of the drugs we have with immunotherapy, we see significant responses.
I have patients who have been unresectable that then get Atezo/Bev and continue to shrink and eventually, nadir, and will go on to receive a surgical procedure or definitive, maybe, radiology procedure. Eventually, I think many patients do go to the tumor board, certainly all of the early and intermediate, and increasingly some of the advanced.
[Dr. Christopher Beck]
Julius, same question, referral patterns and how your practice looks as far as where you fit. I'm sure you guys have a multidisciplinary approach also, but just paint a picture of what y'all's practice looks like.

[Dr. Julius Chapiro]
Yes, I work as part of the liver cancer program here at Yale, right now under the leadership of hepatology. I would say that it's a very evenly distributed practice in terms of how decisions are made. Obviously, we see a variety of different referral patterns. Some of the patients that I see and find are just patients who really appear through the emergency room and are incidentally found to have tumors or admitted for decompensation of their cirrhosis. Then we got a referral for biopsy and biopsy is an important tool for us to just diagnose HCC.

Then sometimes we are the first to see these patients in a health system. Then I tend to, I would say, almost always bring the patients to the multidisciplinary tumor board, simply because I feel as though while the BCLC of the past and the treatment patterns of the past would allow, in certain cases, an IR alone decision, now in a day and age where we have combination therapies, even if I think that a patient is a great candidate for TACE, I do want our medical oncologist to chime in. I do want our hepatologist to tell me whether they believe this patient is a good candidate for locoregional therapy or not, and whether from their perspective, this patient is compensated enough to tolerate it.
I want to second what was said there about transplant and sometimes downstaging or bridging. I think trying to bring cure to every single patient that we see is a fundamental mission, no matter what specialty we have. If there is someone who can be bridged or downstaged, yes, I do want our transplant program to know about this, so I think multidisciplinary care is really important.
[Dr. Christopher Beck]
Okay. Well-said. Just a quick question, a quick aside. Richard, how many of your patients with suspected HCC?

[Dr. Richard Finn]
Yes, it is still a minority, I think, because they're suspected and diagnostic. For someone who is clearly cirrhotic with a LI-RADS 5 lesion, hypervascular with washout in the right clinical setting, generally, we do not biopsy them. Now, with that being said, for patients who go for ablation, the radiologists do tend to do a biopsy at the time of ablation, just by practice pattern. There are patients in the context of research studies now which do want tissue for either biomarkers or confirmation of diagnosis, but I think the majority are not being biopsied outside of those scenarios.

Julius brings up an excellent point in many ways. How much of liver cancer progress has been delayed by the lack of tissue available? I think there's two ways that we think about that. One is to understand tumor biology and identify new targets or approaches for treatment. The other part of that, which is increasingly important, is linking some biomarker in a biopsy to a therapeutic, a predictive marker, which we lack dramatically in liver cancer. The only drug that is associated with a predictive marker benefit is AFP, and that's for ramucirumab in the second line setting.
No other drugs have been developed with a companion diagnostic. That's the term we use in medical oncology, something that you need to test whether positive or negative tells you how to treat patients. That is an important part of our mission in cancer medicine and getting the right drug to the right patients. Especially now that we have several choices that all have positive data, how do we decide which is best for the patient in front of us? That's an ongoing translational effort.
[Dr. Christopher Beck]
Julius, I saw you nodding your head for part of this. Anything to add as far as from the biopsy component, biopsy question?

[Dr. Julius Chapiro]
Yes, well, obviously, as a scientist who's trying to develop biomarkers and thinking about molecular imaging or even machine learning approaches and how to identify what kind of tumor we're dealing with and whether or not this is an immunologically hot disease or whether or not this even is going to be predictive for a good response to immunotherapy or which particular drug, I understand when someone tells me that biopsy is going to be risky or there is a risk of seeding, which I think is more or less theoretical. Even some IRs will say if you biopsy a tumor and then you have to do an embolization, then you're going to create possibly a shunt or a fistula.

I just feel as though we've probably missed an opportunity to investigate this cancer better. I think as I'm discovering and understanding the system more with the years that I do research on these patients, I think that the resected samples are a great treasure for us to better understand. Although most of these patients don't undergo immunotherapy before, but some now have and I think the dose samples are going to be more and more important for us to understand really what is going on in these tumors.
[Dr. Richard Finn]
Just for the discussion, because like you, I have no fear that biopsy is dangerous in these patients, I know experienced IRs can do this. There's no real risk of seeding. You burn the track, you go through a cannula. The issue is, LI-RADS, when you have a LI-RADS 5 lesion in the right patient, it's pretty diagnostic. That's been the challenge to overcome for us, I think. You've done yourselves very good at radiology, better imaging, better protocols. Then it's like, now we don't need to do it because we need tissue, but I agree, biopsies are really important for us to move forward.

(3) TACE Procedure & Role in HCC Treatment Strategy