Case 3: Downstaging and Increased Survival in HCC



Ghassan Abou-Alfa, MD, MBA:I’ll go back to Farshid. Sadly, we can see that this is not a good story. It really makes us wonder if things could have happened relatively earlier rather than pushing for one intervention after the other, watching the liver functioning worsening. What would have been your ideal approach with this situation with regard to systemic therapy intervention? What would you have done?

Farshid Dayyani, MD:In this period of multidisciplinary clinics, if that patient had presented to our institution today, we would have tried to harness the benefits of all liver-directed therapies, systemic therapy, by putting him on the trial where we do locoregional treatment and combining it with deepening the response by giving an anti-VEGF agent and making it durable by giving a checkpoint inhibitor. I think this would have been my ideal before the patient progressed to that stage.

The other avenue that’s opening now with more effective treatment, systemic treatments that actually give us a response, is now something like lenvatinib that gives us 40% response by modified RECIST. If you look at the waterfall plot, many more patients will have tumor shrinkage that is reflected in the RECIST criteria. We would use this as an adjunct or as a systemic treatment to try to cytoreduce this patient, downstage to see whether this patient might become a transplant candidate, for example. The data are not here. We need to generate the data. We have to see whether it will hold up to what we know with locoregional treatment and downstaging and going to transplant. But certainly, now we have the tools to start asking those questions and to try to more aggressively manage these patients.

Ghassan Abou-Alfa, MD, MBA:What we heard so far is that, sadly, this patient who Riad has presented came with a rather relatively advanced cirrhotic component and was treated with embolization on more than 1 occasion while sadly the liver functionality continued to worsen. We’re not necessarily saying this could have happened, but naturally this is really what occurred at the end of the day. Already as we can see on the table, there are other options that could have been there, including what Riad mentioned: going to radioembolization that probably could have controlled disease in a more expansive way than the localized chemoembolization. We heard about potential for certain further intervention, now that the responses are available, starting with lenvatinib but also with the checkpoint inhibitors, as we mentioned, pembrolizumab and nivolumab.

In addition, we have data that suggested that we could also bring in a great response. Among which, as we all have seen, there was a press release—we don’t know the data yet—of the combination of atezolizumab plus bevacizumab. We have also the data that were reported on lenvatinib plus pembrolizumab. Also we have the durvalumab plus tremelimumab, the anti­—CTLA-4 plus PD-L1 [programmed death-ligand 1] inhibitor strategy. There’s quite a bit going on, as Farshid already mentioned. But 1 thing that all 3 of my colleagues have brought up—and I have to admit that I don’t have full understanding of this and I’m going to go back to Riad on this—is downstaging. What’s that?

Riad Salem, MD:In general,downstagingis a term that’s used in the transplant context. While we know that patients who present within Milan criteria for liver transplantation have a certain 5-year survival, is it possible that if you take somebody outside those criteria and shrink them and make them within those criteria, and then demonstrate that the biology is there to support that, can you impart the same type of benefit? More recently that concept has been expanded to the surgical side in cirrhotics. Can I downstage somebody who’s initially inoperable for whatever reason—size, for example, or location of the tumor—into somebody who’s more operable?

The idea here is that you take a patient who’s otherwise not transplantable, not resectable, and you downstage them; that’s the term. You potentially make them transplantable or resectable to a possible cure by using a locoregional therapy. That’s what we have traditionally enjoyed in interventional radiology with the locoregional therapies, where you have this. But with the advent of some of these therapies, like lenvatinib with 40.9% response rate or so by mRECIST [modified RECIST], now that narrative is there in level 1 evidence, can we use mRECIST criteria to support that? I think that narrative is being expanded.

Ghassan Abou-Alfa, MD, MBA:I can see you’re ready to give your view. And you know, I’m very eager. I was going to ask you because I’m not sure I buy this.

Amit Singal, MD:Oh, no, I completely agree with Riad, actually. But there are data that show that if you actually get downstaged, you have equivalent survival as those who start with the Milan criteria.

Ghassan Abou-Alfa, MD, MBA:Interesting.

Amit Singal, MD:This started from the University of California, San Francisco group. There were actually data from Texas and Oklahoma as well, and now this is national policy.

Ghassan Abou-Alfa, MD, MBA:Amazing.

Amit Singal, MD:I think this really is important for everyone who treats HCC [hepatocellular carcinoma] to know, because you started by describing the Milan criteria, which is the traditional criteria that were described by Vincenzo Mazzaferro and has been the standard for years. Downstaging now means that for anyone who has locoregional disease, you have to consider, can I downstage this patient and make them a transplant candidate? This is an important concept because those patients then have 5-year survival that exceeds 60%. This is a cure for their liver disease. This is a cure for their HCC.

Farshid, you mentioned that when we think about systemic therapy options, we can use the tyrosine kinase inhibitors and immunotherapy. But I think it’s important that these patients are discussed in a multidisciplinary fashion, because if you treat that patient with locoregional disease with immunotherapy, at this time we don’t know if that affects post-transplant outcomes—and if so, how it impacts post-transplant outcomes. And so if you treat a patient like this, who has liver dysfunction and locoregional disease, with 1 of the checkpoint inhibitors, you may be impacting their chance of getting a transplant and their post-transplant outcomes. I think that’s where early referral and discussion in a transplant setting, a multidisciplinary setting, is critical for these patients.

Transcript edited for clarity.

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