Comprehensive insight on the role of locoregional therapies in early- or intermediate-stage HCC, alone or in combination with systemic agents.
Josep Llovet, MD: My first question will be for Amit. How do you decide on early stage cases, what to do, when to treat the patients with resection, and [when to] transplant local ablation?
Amit Singal, MD: First, when we can do curative therapies, we should. If somebody is noncirrhotic, we have to think of resection first. Resection is the standard of care for most patients with HCC [hepatocellular carcinoma] in the absence of cirrhosis. In the Western world, most patients present in the setting of cirrhosis. You really need good liver function to be considered for surgical resection, including Child-Pugh A and the absence of portal hypertension. Although with laparoscopic and robotic procedures, we’re seeing an expansion, so you can do this in patients with mild portal hypertension. This is now incorporated into both the EASL [European Association for the Study of the Liver] and AASLD [American Association for the Study of Liver Diseases] guidelines. If 1 has mild portal hypertension, you’re able to do a minor resection, particularly if it’s able to be done laparoscopically or robotically, you can still consider surgical resection.
If you’re not able to do this, if somebody presents with more advanced liver dysfunction, then liver transplantation is the key in those patients because it’s a cure for the HCC as well as the underlying liver dysfunction. In those patients, liver transplantation is the key. We used to be restricted to the Milan criteria, but now we have expanded criteria, like the UNOS [United Network for Organ Sharing] downstaging criteria. For example, if somebody who responds to locoregional therapy has a decrease in their tumor burden and falls within Milan, those patients can be listed for transplantation and receive exception points, as if somebody presented within Milan criteria.
Furthermore, if somebody presents beyond UNOS downstaging and has a rigorous response to locoregional or even systemic therapies, they can also be transplanted, but they just won’t be awarded MELD [Model for End-Stage Liver Disease] exception points. This would typically be done by a living donor pathway. The nice thing is that from an agency perspective, we’ve seen expansion of our curative therapies to more patients, which is what we want to see because these therapies can afford median survivals in well over 10 years. If somebody isn’t eligible for those curative therapies, then you can consider surgical curative therapies. One can consider ablation if you have lesions less than 3 cm, which have a high response rate. If you’re not eligible for any of those therapies, that’s where locoregional therapies come in.
As you mentioned, most data—including the data you’ve generated over the last several years—has been for chemoembolization, which significantly prolongs survival but isn’t regarded as curative. We’ve seen more data come out for radioembolization, which is well tolerated and offers higher time to progression but similar overall survival. We’ve seen adoption of that in many US centers. That’s the landscape for HCC, but these silos are breaking down. We’re getting into combination therapies as well as competing therapies as we start to see all the notable advances in the systemic therapy space.
Josep Llovet, MD: Thank you very much for this overview. Radioembolization with Y90 is considered more for early stages. Segmental chemoembolization is quite effective. Particularly in the United States, it’s also considered as an alternative to TACE [transarterial chemoembolization]. Let’s talk a bit about intermediate HCC. I’d like to talk about the patients who are suitable for TACE and then the patients who are unsuitable. Let’s talk about patients who are suitable. Andrea, who is an ideal candidate for TACE?
Andrea Casadei-Gardini, MD: A good candidate for TACE is a patient with intermediate-stage [disease], with tumor size not more than 5 cm. It’s more important to perform a very selective TACE for dysfunction of the liver, because we have more options for patients with intermediate-stage [disease]. For example, it’s important for our patient to be treated in 1 or 2 steps and to be downstaged. It’s important to have a partial response or complete response after TACE. Another good candidate is a patient with good or very good liver function. The problem with locoregional therapy, particularly TACE, and not super-selected TACE, is the liver dysfunction after the procedure.
Josep Llovet, MD: Eventually, for the upper boundary, 5 cm is quite strict. There’s no hard-core role in guidelines, but up to 10 cm is considered acceptable. The other thing with liver dysfunction is patients with Child-Pugh B, ascites, and so on are formal contraindications for TACE. The recommendation is not to do more than 3 TACEs per year, but these are not hard rules. In these patients, should we use systemic therapies in combination? Do we have evidence? As you know, several trials are published, and other trials are coming. How do you see that?
Arndt Vogel, MD: I can briefly comment on the first point regarding the TACE candidate. What we need to indicate is that patients should be discussed in a tumor board. Sometimes, it’s not just size. We try to figure out, but there’s no definitive size. It could be 7 or 10 cm, but we’ve also seen complete responses with 15 cm. In my experience, in the discussion with the tumor board, the radiologist says, “We have a feeding artery. We can do a super selective TACE.” Then we can go for it. I do it once, twice, maybe 3 times. If you see a good response, everything is good. If not, it’s time to switch. The tumor board is most important. We have so many systemic therapies, and we shouldn’t miss a potentially curative approach. I see more doctors in the community who start patients with intermediate-stage [disease] with atezolizumab-bevacizumab. This is good in principle, but sometimes you miss the chance of transplantation. The tumor board is important, and then we can decide who is a candidate for TACE.
Coming back to your question, I don’t think it’s time to do combinations outside clinical trials. There’s a strong argument to do it within clinical trials. I’m happy that we have so many ongoing studies to better understand whether there’s a meaningful addition in overall survival for the combination compared with the sequential approach. In the end, we want to spare our patients as much toxicity as possible. If you get a good response with TACE, maybe an almost-complete response, why should we add some potentially toxic drugs? Therefore, we’ve seen initial data, but nothing convinced me. There were a lot of negative phase 3 studies…. We have good evidence that, in terms of overall survival, even the TACTICS study wasn’t positive in terms of overall survival. Therefore, in our center, we use a sequential approach, not a combination.
Josep Llovet, MD: This is also in the guideline: to use TACE as a single agent. The trials have been negative with suboptimal end points.
Transcript edited for clarity.