Transitioning to Systemic Therapy in HCC


Richard S. Finn, MD: Locoregional therapy, I think, is very well defined in Barcelona stage B. An area that I think, in the community and even in academia, has become a little gray has been patients who have tumors in the liver that are growing into some of the vasculature; not necessarily the main portal vein, but we see a branch of the right portal vein or something like that. By the Barcelona Clinic Liver Cancer criteria, those patients are stage C. That’s a group where systemic therapy has been proven to improve survival. There’s a sense that, “Oh, it’s just in the liver. We should do locoregional therapy.” What’s your take on that, Dr. Marshall? That’s probably the group that was studied in the Y-90 literature. They got TACE, it didn’t work, and then we had those negative studies. Should they even get TACE in the first place?

Richard H. Marshall, MD: Well, we have seen patients with extrahepatic disease do better with locoregional therapy, but locoregional therapy does not target the extrahepatic disease. I think we still need to learn a lot more about how to best treat these patients. We’re going to see, in the future, combinations of systemic therapy and locoregional therapy much more frequently than I think we do now. But we don’t have enough data to say that we should not give patients locoregional therapy.

Richard S. Finn, MD: Amit, if we stick strictly to guidelines, these patients with vascular invasion are not ones that should necessarily get locoregional therapy. There are phase III data with sorafenib, and now noninferiority data with lenvatinib, that show that this group of patients probably benefits from systemic therapy. It has proven overall survival. I wouldn’t even say, “Probably.” It’s level 1 evidence. So, if we have a patient who has TACE, does not have vascular invasion, doesn’t have a car accident, and doesn’t die of some other disease, how do we know when locoregional therapy is no longer working and it’s time to transition to systemic treatment?

Amit Singal, MD, MSCS: That’s a good question, and I think it’s something that we really need to be better at defining—TACE failure. What is TACE failure? If you surveyed 100 different hepatologists or interventional radiologists, you’d probably get about 50 different answers. There’s huge variation. The field has become better at defining this and says when you should transition. I can tell you, at our center, we do something similar in terms of we treat TACE a couple times, and if you don’t respond and you continue to have progression at that point, we transition to systemic therapy.

Richard S. Finn, MD: When you say, “Don’t respond” or “Progress,” say they have a solitary lesion, because I think there’s 2 types of progression. There’s a solitary lesion that gets treated, and then they develop a lesion on the other side of the liver versus that 1 lesion that keeps getting bigger.

Amit Singal, MD, MSCS: Yes. I think, honestly, both are worrisome. What we will do is, if you have progression in that lesion that you have been treating—suggesting that it is not responding to TACE—we will definitely switch over to systemic therapy or if you have a couple of TACEs and it grows. If you have a new lesion on the other side that has not been attempted to be treated, then we will attempt locoregional therapy there. However, once again, when you take a look at that tumor biology, it shows that you are having intrahepatic metastatic spread. It does suggest, with that tumor biology, that you are at higher risk of once again continuing to have progression despite treating with locoregional therapy. It will lower our bar to switch to systemic therapy if you have either form of progression.

Richard S. Finn, MD: I think that’s a great word, this intrahepatic metastatic spread. It’s still the same organ, but it’s spreading within the organ and you don’t need to have spread outside of the liver to be considered advanced.

Amit Singal, MD, MSCS: But once again, it goes back to the idea that you can’t take anyone at 1 snapshot. You can’t just say, “The tumor is within the liver, I’m going to follow the BCLC.” Or “They’re at BCLC stage B, I’m going to go down to TACE.” You really need to take a look at what the natural history of this person is. They’ve started. You’ve treated them. They’ve progressed, and they’ve progressed. Even though you could, theoretically, do something like another chemoembolization, you should consider something else. The line that I use in our tumor board a lot is, “The definition of insanity is to do the same thing over and over again and expect a different outcome.”

Richard S. Finn, MD: Albert Einstein, I think?

Amit Singal, MD, MSCS: Yes. We need to be better at this. In our center, we’ve become more cognizant of this. And despite the interventional radiologist saying, “I can do this,” we say, “Just because you can, doesn’t mean you should.” We have transitioned those people over to systemic therapy, earlier.

Richard S. Finn, MD: Like here, I’m sure there is a very lively discussion at your tumor board, right? Arndt?

Arndt Vogel, MD, PhD: If you have progressive disease, either of the treated lesion or of the untreated lesion, I think it’s pretty clear to switch. You have a good argument. I think it’s more difficult to decide how to proceed with patients that have stable disease. And I think, in general, we have accepted, in oncology, stable disease as an acceptable outcome for systemic therapies, for example. But in hepatocellular carcinoma, we cannot accept stable disease as an efficient outcome when we treat patients with local therapies.

Progressive disease is, clearly, a failure of TACE, but I also think that stable disease is also an indication of TACE failure. We really have to double-think, many times, how many times we should treat our patients. I agree that we can treat patients twice. I think that’s okay if you have additional vessels that can be successfully treated. But after that, if you do not get a response after 2 treatments with TACE, I think you should be very careful to continue with TACE.

Richard S. Finn, MD: Richard, you have a patient in the interventional radiology clinic. You did a chemoembolization. They come back with a good result. A few months later, they now have a new tumor on the other side. How are you approaching that patient?

Richard H. Marshall, MD: Well, whenever I see something that I would define as a treatment failure or new disease or expanding disease, I always have to ask, “Why?” In particular, did the treatment that I do miss something? Did I embolize only part of the tumor and leave some behind? These are questions that I need to answer before I decide what the next step is in treatment of this patient.

In a patient who has a new tumor at a distant site, if it’s something that I think is really a new tumor, then I like to reset the clock for that patient and start treating it as a brand new single site, if it’s possible to do that. Now, this is reading between the lines in what the guidelines are and what recommendations are, but it’s very important to know that a TACE failure or a treatment failure is because it’s a real failure, not a miss.

Richard S. Finn, MD: In your opinion, when does someone transition from locoregional therapy to systemic therapy outside of metastatic disease? Intrahepatic progression, when would you say to your colleague or to the patient, “I can’t help you anymore”?

Richard H. Marshall, MD: This is a complex question. I think 2 TACE failures is, certainly, a good time to move to systemic therapy, but it depends on multiple things. If this is a patient who has got really good liver function and could still stand another treatment, and the tumor biology is good, then it may be time to have a discussion with that patient and say, “I would like to offer you this additional therapy. This is not what I typically do, but given that you have good liver function and very good tumor biology, I think we have some time to do this.” However, there are other patients with bad tumor biology that we know are not going to respond to TACE very well.

Richard S. Finn, MD: Let’s be a little more specific. Bad tumor biology?

Richard H. Marshall, MD: Patients who don’t respond to 2 TACE procedures, I consider that bad tumor biology, provided the procedure has gone very well.

Richard S. Finn, MD: What about vascular invasion? This is where I see a knowledge gap in the community, and, obviously, there’s a lot of opinion and debate. A patient has a tumor that’s in the liver, but now it’s progressing into the portal vein. Is that a patient in whom you ask, “You need more locoregional therapy?” or do you say, “We need to put you on systemic treatment”?

Richard H. Marshall, MD: That’s a patient who I’m going to give systemic treatment to fairly quickly. There’s not a whole lot that I can do to control that portal vein invasion. Again, we need to use our diagnostic radiologists to define these things prior to starting treatment or immediately after treatments. It’s imperative that we look at these signs—nodularity around the periphery of the tumors, invasion into vascular structures, intrahepatic metastases—to help triage these patients into better treatments.

Transcript Edited for Clarity

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