Recent Advances in Systemic Therapy for Hepatocellular Carcinoma

MedPage Today brought together three leaders in the field to discuss the latest research and clinical advances in the field of liver cancer. In this first of four exclusive episodes, moderator Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City, is joined by Amit Singal, MD, of UT Southwestern Medical Center in Dallas, and Peter R. Galle, MD, PhD, of Mainz University Medical Center in Germany, for a roundtable discussion on the advent of new systemic therapies available for advanced liver cancer.

Following is a transcript of their remarks:

Abou-Alfa: Hello everybody, and thanks for joining us on this roundtable on liver cancer. It’s a great pleasure to have you on board and my name is Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center, New York. I’m joined today by dear colleagues Dr. Peter Galle from University in Mainz, Germany, as well as Dr. Singal from University Texas Southwest in Dallas.

A lot going on in that disease and a lot for us to talk about. And if anything, no doubt that the advent of systemic therapy in regard to liver cancer is relatively new in the big scale of things. And I’ll start by asking Dr. Singal, what do you think systemic therapy and the oncologist’s role came into play from your perspective as an oncologist?

Singal: Yeah, Ghassan, to your point this is all something relatively new. We went from having no therapies that were shown to be effective in the advanced-stage setting to now having multiple therapies. And this really started around 2008 with the introduction of the SHARP trial, which showed the benefit of sorafenib in the advanced-stage setting. And I remember when sorafenib came about, we thought we had finally unlocked the secrets to advanced-stage HCC [hepatocellular carcinoma] and we would have a flood of new therapies.

And as you know, we had multiple negative trials over the subsequent 10-year period. And it wasn’t until recently that we’ve seen more first-line and second-line therapies coming to market.

But to your point, this is all relatively new, happening in the last 15-year period, where we’ve now had an introduction of first-line and second-line therapies in the advanced-stage setting.

Abou-Alfa: That’s great. Thanks so much, Dr. Singal.

And Dr. Galle, again, with the same expertise and broader experience in regard to HCC and you’ve been on the stage from like day zero, I have to tell you that a patient used to come to us with the perception they’re gonna get a local therapy intervention; systemic therapy was not there. How do you see a change in the trend?

Galle: Yeah, it really started with surgery and interventional radiology and it’s actually interesting that at that time it was also defined that we can rely, in respect to diagnosis, making on radiographic imaging and don’t need biopsy. And the reason was because we had nothing to offer which would in any way be influenced by biopsy. This has totally changed.

We now have a plethora of therapies, many options, and it’s absolutely clear that the old tendency to TACE [transarterial chemoembolization] and to over-TACE has dramatically shifted in the BCLC [Barcelona Clinic Liver Cancer] scheme to the left. And now we offer much earlier the systemic intervention.

One aspect which nicely underlines this is actually the fact that the outcome with systemic therapies is getting better almost every year. And this is probably at least to some part because we are getting these patients earlier on systemic therapy. So in 2022 systemic therapy is reality.

Abou-Alfa: That’s very important to hear. And back to that, Dr. Singal, no doubt that a very important component that we need to relate to our colleagues is that liver cancer, after all, is two problems in one: the cancer itself and liver function. Please teach us, especially our audience, which mainly could be oncologists, appreciation of liver function or dysfunction. And how do you assess it and how does it intervene in regard to therapy?

Singal: It’s a critical point when you think of HCC. This is a cancer, to your point, it’s a disease within a disease. So we know that over 90% of HCCs develop in the setting of chronic liver disease, if not in the setting of advanced chronic liver disease — i.e., cirrhosis. And so one of the things that actually drives prognosis in these patients is the health, or lack thereof, of the underlying liver.

And so when we think of this, it’s important for us always to assess the health of the liver, and we typically use the Child-Pugh scoring system. This has been the traditional system that we’ve used in terms of assessing the health of the underlying liver.

When we think of systemic therapies, most of the systemic therapies — well, all the systemic therapies — have really been evaluated predominantly in the setting of good liver function — i.e., Child-Pugh A disease.

And to Dr. Galle’s point, this is why it’s so critical that we don’t TACE and TACE and over-TACE people before they go onto systemic therapy. Because all of the therapies that we do at an earlier stage can impact the health of that background liver, and patients can enter into this systemic therapy eligibility realm in a worse-off position and may not be eligible for these exciting systemic therapies that we have available.

Now, the one other thing that we should remark on, Child-Pugh is the historic way that we’ve assessed the health of the liver function. And this is what’s been traditionally built into treatment allocation systems and staging systems like the BCLC. However, I think as a sort of organization and multiple disciplines working together, we are starting to become more nuanced in terms of our assessment of liver function, including other objective scoring systems such as the ALBI [albumin-bilirubin] score based on albumin levels, bilirubin levels. We know that these things can be additive to this sort of “simple” Child-Pugh scoring system.

Abou-Alfa: No, that’s extremely helpful. So to just re-collect all the important thoughts that we just heard from our dear colleagues here: number one, systemic therapy, yes, has a role in regard to liver cancer. There’s been a lot of advances in regard to that disease; as we heard from Dr. Singal, it started with one drug being sorafenib.

It’s not like we’re not doing anything — there were really serious efforts to try to enhance on that activity. And enough that, as Dr. Galle said, I love what he mentioned, is that, in 2022 systemic therapy, exactly, solid — has a role in regard to treatment of patients with liver cancer.

We’re gonna go over a lot of the choices of therapy in a second. But more importantly though, as Dr. Singal mentioned and reminded us that liver cancer is a disease within the disease. Because liver functionality is key. As we heard Child-Pugh scoring, it’s really by default. We know the story, some of us, and Peter might remember a while ago, like more than 20 years ago, we had a discussion and we settled on Child-Pugh not for any scientific reason, but this is the only thing we could agree to.

Ironically, Child-Pugh was not even assessed in patients with liver cancer to begin with. But at least it is a good norm to use simply because all the studies on the reference points are from the Child-Pugh scoring system: “A” being like the least cirrhotic, “B” middle cirrhosis, and “C” most advanced.

And very importantly, it’s not really as I always like to jokingly say, it’s not an ice cream flavor. It really is a trend that happened from A to B to C. And at the same time it is really not a linear curve. It’s really an exponential curve. I kind of would say it’s from where I am in New York to where Dr. Singal is in Dallas to around the world to where Dr. Galle is in Germany and back to New York … And please, very important take care of our patients when they are in Child-Pugh A. Exactly as Dr. Galle told us, patients are coming earlier and earlier and that’s why our role as medical oncologists to be on the table, to be at the tumor boards early in the game, because of where we can help the most.