Locoregional Therapy for Liver-Confined HCC

Transcript: Ghassan K. Abou-Alfa, MD: Let’s talk more about locally advanced disease where the tumor is not deemed resectable, but at the same time it’s not yet metastatic, or disease has not spread outside liver. Katie, I’ll start with you. So you have that patient with tumors that are not amenable for any of the interventions that we spoke about that’s curative, but at the same time it’s not metastatic. What should we do with that patient? Here’s an example: 6 cm lesion; close but not really invading, but very close to vascular involvement with a Child-Pugh A score. What do you want to do with that?

Katie Kelley, MD: Right. So, as you said, the first step always is to make sure we’ve reviewed with our multidisciplinary team and confirmed for ourselves that they’re eligible for a downstaging approach or transplant or surgery. But I’d say, assuming we have a case other than the one you presented, that the historic standard has been liver-directed therapies through arterial therapy, such as chemoembolization or radioembolization. For larger tumors, we may favor radioembolization. Occasionally, these patients can be downstages or converted if they have a favorable biology, as we talked about earlier. So again, right now for solitary of a couple lesions confined within the liver without vascoinvasion, our go-to therapy is liver-directed arterial therapies.

Ghassan K. Abou-Alfa, MD: Fair enough. Farshid, what’s chemoembolization?

Farshid Dayyani, MD: Chemoembolization utilizes the anatomic fact that the tumor is fed through the hepatic artery, but the majority of the normal parenchyma of the liver is coming through the portal vein. And what it does is interrupt the blood supply to the tumor locally and induce necrosis, consequently damaging the liver. You can do that by also trying to deliver high-dose chemotherapy specifically to the tumor through the arterial hepatic artery to improve it. So there’s different ways of embolization, bland or with chemotherapy. And both are initially very highly effective, but unfortunately the recurrence rates are high.

Ghassan K. Abou-Alfa, MD: Amit, I remember that the data, when it was first published on chemoembolization back in 1999, was something that we all got excited about. But at that time there was a clarity that patients need to have chemoembolization. There was an arm where they did the embolization without any chemotherapy—what we call bland embolization—but it was kind of a stop in that study that carried on with the chemoembolization. Do we really need the chemotherapy?

Amit Singal, MD: I think it really depends on who you talk to. There have been cohort studies that showed similar outcomes of bland embolization versus chemoembolization. It really depends on who your intervention radiologist is in terms of how much they believe in the therapy, and the effect of chemotherapy from that embolization, versus just the embolic effect.

When you take a look at the chemotherapy that’s loaded in those beads, you’ll see that they actually have minimal effects when used systemically. If you ask me, I think the vast majority of this is probably embolic effect, and the chemotherapy may be a cherry on top. It really depends on who you talk to in terms of their belief between chemoembolization versus bland embolization. I think, as the data has evolved, they’re probably more similar than disparate.

Ghassan K. Abou-Alfa, MD: Katie, we get those questions quite frequently. Patients love their chemoembolization or their bland embolization, or some form of it. You get a procedure. Maybe you are sick for a few days, and then you move on with life. You don’t have to take anything else. How many times can we embolize a patient? When do we say enough is enough?

Katie Kelley, MD: That’s a great question because I think the answer is different for different patients, of course, and this comes back to the topic we had earlier on about the underlying liver disease and the cancer being 2 separate diseases that we’re unfortunately dealing with. And so in part it depends on how healthy the underlying liver is. In part it depends on how big and disseminated the tumors are. How much are we treating at a time?

If patients have tiny, indolent tumors that popup 1 at a time, 6 or 12 months apart, they can have multiple embolization, meaning, on occasion, double-digit treatments over multiple years. The reality is that we don’t know if it’s the same cancer coming back. It’s probably, in some cases, a field effect where, one year, they had a tiny tumor and received a new, biologically distinct tumor.

Other patients, though, will have a large or infiltrative tumor in an important part of the liver, or very bad fibrosis or cirrhosis. And every insult that we give them, whether it’s beads of chemo-laden beads in a TACE [transarterial chemoembolization] therapy, or bland embolization, it will affect their normal liver function, killing a bit of that remnant liver around the edges of the tumor. That can trigger decompensation even after just 1 or 2 TACE treatments. It’s really a clinical call: how did the patient respond to the taste? How is their liver function performing? Did they get ascites? Is their bilirubin or AST [aspartate aminotransferase] or ALT [alanine aminotransferase] levels okay? Those are all signs that the liver may not tolerate additional TACE treatments.

Ghassan K. Abou-Alfa, MD: Fair enough. Farshid, you spoke about chemotherapy. You introduced us to bland embolization and radioembolization. Tell us about that.

Farshid Dayyani, MD: Radioembolization is mostly done with Y-90 particles which, again, utilizes the fact that the tumors are preferentially fed through the hepatic artery. The main effect is thought to be through selective injection of Y-90 particles—glass or resin—into the tumors. Here you try to rely on the radiation effect and the radio killing effect of these particles, rather than just bland embolization as we have done with TACE therapy.

The response rates have been high. You can use tumors that are not eligible for TACE therapy, such as larger or multifocal tumors. At you center, we usually divide the lobes in between therapy—left and right. That’s obviously one of the options that we use at our center.

Ghassan K. Abou-Alfa, MD: Amit, back to you. We spoke about chemoembolization and bland embolization. What about radioembolization? Why don’t I just radiate the liver? What do we know about radiation therapy to the liver?

Amit Singal, MD: There’s more data coming out in terms of external beam radiation, as well—so stereotactic body radiation therapy. We use this a lot, actually. UCSF [The University of San Francisco] Medical Center uses this a lot. There’s more data showing that you can have very good outcomes. Historically, we’ve been limited because, even though the tumors have been radiosensitive, you actually saw high toxicity to the background liver. You weren’t able to deliver high doses using conventional radiation delivery techniques. When you use this in a stereotactic manner, you’re able to concentrate the radiation doses into these tumors and spare the background liver. You see excellent results with this. There was an analysis comparing this to TAS [tipiracil hydrochloride] treatments and oblation. You can actually see, in some studies, superior results with SBRT [stereotactic body radiation therapy] compared to oblation, for tumors over 2 centimeters.

Ghassan K. Abou-Alfa, MD: Fair enough. Katie, back to you. Sometimes we hear this scenario from some of our colleague: “Well I have this patient, I’m going to do embolization, but what about adding some systemic therapy with that embolization?” What do you know about that?

Katie Kelley, MD: So far the studies combining systemic therapy with chemoembolization or liver-directed therapies in general have not yielded positive results. I speak mostly of studies combining tyrosine kinase inhibitors [TKI] with chemoembolization, or TAS therapies, where over multiple randomized trials there have not been survival benefit. In some studies, there may be a decreased eligibility for further TAS, meaning patients who are on systemic therapy have worse liver function or performance status when combining these modalities such that they end up getting less of the treatment over time.

Right now, I think the jury is out, as we talk more about the new systemic therapies, on whether these newer therapies such as immunotherapy [I/O] will have a role in combination with liver-directed therapy earlier in disease progression, because there may potentially be more favorable tolerability or antigenicity that could be synergistic. That’s all completely speculative, however, as of now. We need the clinical data to know how to use these therapies together.

Ghassan K. Abou-Alfa, MD: That’s right. Admittedly, this is a rather complex subject, and there are a lot of opinions as to what the proper methods are. If anything, embolization, which means targeting the tumor that’s localized to the liver, can be done with chemoembolization—and this is really the standard we’ve seen most of. In addition to that, we can see a bland embolization. I would say that the data, as Amit mentioned, really has shown that they are most likely equivalent. Actually, this is data that we reported from Memorial Sloan Kettering Cancer Center with a randomized trial that looked at chemoembolization versus bland embolization.

Interestingly, that data brought up an important concept, which is the perception that we all had, that embolization having a prolonged median survival [MS] is not necessarily true. The reason is because, in the early days, we embolized relatively small tumors, whereas now we’re embolizing very large tumors, but we’re using the old data. This is really important to put into perspective.

A patient who has metastatic disease—let’s say, which is mainly driven by disease in the liver—with some small-lung lesions or bone metastases, they will most likely receive local therapy of embolization. I would say this is really something we have to be careful not to do because there are systemic options for those patients. At the same time, we are not necessarily addressing correctly by only addressing what’s happening in the liver.

Transcript Edited for Clarity