Metastatic HCC: Locoregional to Systemic Therapy



Ghassan K. Abou-Alfa, MD, MBA: I would like to jump to systemic therapy. Usually when we talk about this, we say local disease, embolization of some form. I totally agree; there is no question about it.

But I’m going to jump to systemic therapy, and I might get a little feeling from the different experts. Let’s ask Dr Frenette. As a hematologist, if you had a patient with really extensive disease but still limited to the liver, it’s a little dicier: no vascular involvements, no metastatic disease, but it required endless numbers of embolization to be able to control the disease. Do you think it’s crazy if you say, “I have systemic therapy that can help you”?

Catherine T. Frenette, MD: I don’t think that’s crazy. In fact, as more and more data come out with systemic therapies, we’re getting overall survivals that are rivaling our local regional therapy, especially for those patients that have an extensive burden of disease. I heard 1 of the IRs [insulin receptors] describe it as a “pepperoni pizza liver,” where you’re going to need more than 2, 3, 4, or 5 TACEs [transarterial chemoembolizations] or Y90s to be able to control this disease. You also want to protect the liver function so you can benefit from systemic therapy. In those cases, it’s absolutely reasonable to proceed to systemic therapy first.

Ghassan K. Abou-Alfa, MD, MBA: It sounds like music to my ear.

Anthony B. El-Khoueiry, MD: Absolutely.

Ghassan K. Abou-Alfa, MD, MBA: Anthony, have you had a situation where there is a patient with locally advanced disease and they were on some form of systemic therapy, and they did very well?

Anthony B. El-Khoueiry, MD: Oh, absolutely. In our clinic I think the parameters, if we really cannot treat the entire disease with an average of 2 to 3 TACEs, we usually go to systemic therapy. We know from the TACE data that the larger the lesions are, the more multiple lesions there are, the less the chance of long-term benefit from TACE anyway. It’s important to keep that in mind.

At this meeting, at ASCO GI [Gastrointestinal Cancers Symposium] 2020, there is a poster from Japan reporting an experience that with patients with BCLC-B [Barcelona Clinic Liver Cancer stage B], meaning liver limited—this is not a randomized trial—but they looked at patients who got TACE versus lenvatinib, for example, with BCLC-B disease, which was quite multifocal and extensive. The group that got lenvatinib actually tended to do better from a survival and response perspective. Again, we need more data in this front, but I think the trend is that we will take the higher risk BCLC-B patients and start systemic therapy going forward.

Ghassan K. Abou-Alfa, MD, MBA: Ahmed, along those lines, as we both know, there have been attempts to try to combine therapies for the sake of enhancing the outcome from the local therapy; ie, add the systemic to the local therapy for the patient’s local disease. As you know, there is the TACE study of TACE plus sorafenib. Your thoughts on that.

Ahmed Kaseb, MD: There have been several attempts to do that, and the early results are very significant. Some of them did it in adjuvant manner—you do TACE, and then you start randomizing treatment. Other studies looked into combining them from day 1 or doing systemic followed by local. In my mind, I really think that if you cannot manage your patient in the least number of sessions for local therapy, it’s just a marker with disease prognosis and biology itself.

If you have multifocal bilobar disease, from the oncology standpoint that’s an aggressive disease. In these cases my purpose is to start with systemic therapy. In some cases we use local therapy as a kind of salvage or combination strategy down the line. If the patients are responding in all lesions except 1 small lesion, that grows a little bit tolerating the treatment well. I like the importance of multidisciplinary care with our team, and also our hepatologist who, as Dr Frenette said, has to make sure that we don’t damage the underlying chronic liver disease.

Ghassan K. Abou-Alfa, MD, MBA: Pierre, the perception that we heard is that this is where most of us were adding systemic therapy for local disease. But Ahmed already alluded to this. I have to say that I would not necessarily say that we have the data for that, and I might not necessarily agree on the idea of combining things until we have data. Nonetheless, there was a report that came out in 2018 in JAMA Oncology that spoke about adding local to systemic therapy for systemic disease. It came out that you can combine the local therapy with systemic therapy, but for metastatic disease we need to really focus on the liver disease, while of course taking care of the metastatic side. Do you think there’s a behavior difference between the liver disease in the liver versus metastases?

Pierre Gholam, MD: The paper you alluded to is part of a small body of evidence that suggests that maybe achieving disease control beyond the liver is of some value. For the most part the evidence that is indeed the case, at least in my mind, is not quite there. So we don’t routinely offer patients local regional therapy on top of systemic if they have microvascular invasion or extrahepatic spread.

As systemic therapy improves in terms of providing better outcomes from a disease-controlled overall survival perspective, it becomes less and less attractive to combine both, at least in my mind. Indeed, even from the BCLC-B patients, the locally advanced disease patients, it becomes increasingly attractive to offer them systemic therapy, especially if they have what we colloquially call “bad B disease,” right? Where they have fairly diffused multinodular disease, which realistically local regional therapy might not effectively treat.

Ghassan K. Abou-Alfa, MD, MBA: What we’re hearing here—and this is very important; I very much like what we’ve heard—is that it’s a multidisciplinary team approach. And to please make sure that when you have a tumor board, be there.

This opportunity to really learn about our colleagues and experts in other parts of managing HCC [hepatocellular carcinoma]—ie, the interventional radiologists, the surgeon, the transplant surgeon, the hepatologist, and of course us medical oncologists—is all there on the table. And No. 2, make sure we get the input from everybody about what’s the best approach to treat a certain patient.

Interestingly, and this was something we brought up almost 10 years ago, and wrote that editorial in JCO [Journal of Clinical Oncology]. We said that local systemic therapy isn’t really a marriage. Maybe it is.

At that time I wanted to write it as marriage or divorce, and the suggestion from the editor was to keep it as marriage. And you know what? In retrospect, it was absolutely right.

What we heard from Dr Gholam, after all that discussion, might lead to a certain potential further evaluation of the combination of therapy that we are all obligated to do together. At this point, though, local disease, and as Dr El-Khoueiry said, there’s a certain effort to try to control it with local therapy. If it remains local but it becomes a little uncomfortable, and recurrences happen quick, or there are too many recurrences, it’s time to move to systemic therapy.

On the other hand, I like what Dr Frenette said. A systemic disease might come back a little and some further control locally, even though it might be “out of the book.” It does not mean that, but to be sure we keep all options open. I always tell the patients with HCC everything that with HCC remains on the table. We cannot say, “Oh, you’re done with local, now it’s time for systemic.” You have to make sure that you keep mobilizing things as appropriately needed for a specific patient.

Transcript Edited for Clarity

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