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Hepatocellular Carcinoma: Switching to Systemic Therapy

Insights From: Anthony El-Khoueiry, MD, USC Keck School of Medicine; Richard Finn, MD, UCLA Geffen School of Medicine
Published: Friday, Mar 22, 2019



Transcript: 

Richard Finn, MD: It’s very interesting if we take an historical perspective of liver cancer. Before sorafenib in 2007, systemic drugs didn’t have activity. By default, doxorubicin took on this first-line treatment, but there were no data to justify that. So, I think interventional radiology expanded to fill a void, in that studies did show, in selected patients, chemoembolization improves outcome, in selected groups. And, in practice, that’s been applied a little more broadly. The question becomes now that we have more drugs available for liver cancer, how do we triage patients for chemoembolization versus systemic treatment? And you touched on it in the context of the Barcelona Clinic Liver Cancer criteria, which you and I are very familiar with. To the points we’ve talked about before, unlike other cancers where tumor node metastases, the TNM system, has good prognostication, it ignores the competing risk of liver dysfunction. Whereas, the Barcelona criteria include that as represented by Child-Pugh score.

So, let’s walk through a typical scenario. A patient comes in, they’ve had known hepatitis for a long time, and maybe haven’t been screened so adequately. It could be hepatitis B or hepatitis C for that matter. They start having some abdominal pain. They come into the clinic and they’re evaluated, and they have a tumor on both sides of the liver but no invasions in the vasculature, no extrahepatic spread. I think a lot of us would say this is an intermediate patient, probably beyond transplant or curability. And therefore, they get chemoembolization. How do you follow these patients? You alluded to the fact that these patients will eventually progress to advanced disease because we don’t cure them with chemoembolization. When do we make that switch?

Anthony El-Khoueiry, MD: So, the trigger for switching from locoregional TACE [transarterial chemoembolization] to systemic therapy is a bit tricky because there are not necessarily standardized or agreed upon criteria. I think in Japan, they follow certain criteria, which are probably the most used in a systematic fashion—at least in Japan—and reported on. But, generally, there is agreement that if a patient doesn’t achieve a good response, meaning either a complete response or a very solid partial response in the treated lesion after 2 TACEs, then this is a patient who is not going to benefit significantly from additional TACE.

Richard Finn, MD: Even though they don’t have disease outside the liver, right?

Anthony El-Khoueiry, MD: Even if they don’t have disease outside the liver. So a patient like this who hasn’t achieved a deeper response or who’s actually just had stability of disease after 2 TACEs, I think these are patients who would be very fair to switch to systemic therapy, especially now that we have multiple options available, so we can maximize their exposure to sequential therapy and hopefully have their biggest impact on survival. The other concern that you may be alluding to in your question is that locoregional therapy can take a toll on liver function. So additional TACEs can compromise liver function, which then prevents the access to maybe systemic therapy.

Richard Finn, MD: Sure, especially as we’ll talk later about second-line, third-line options. When we’re talking about systemic treatment, the newer player on the block has been lenvatinib. The REFLECT study was a noninferiority study that took patients with advanced liver cancer, so patients who had progressed on TACE either where, as you described, they didn’t have good TACE control or they had extrahepatic disease, or even vascular invasion within the liver. Patients who had main portal vein invasion, in the study, were excluded. And it met its endpoint of noninferiority. It had some improvement on secondary endpoints, response, PFS [progression-free survival], TTP [time to progression]. But now you have a drug that you’ve been working with for a decade and now a drug that’s relatively new. So this patient of yours who is getting a chemoembolization now has vascular invasion in the liver. What’s your decision process?

Anthony El-Khoueiry, MD: So, as you alluded to, vascular invasion or the development of extrahepatic metastases is a reason to switch to systemic therapy. So now, we have 2 first-line options. We have sorafenib, which we’ve used for a long time, and lenvatinib, which is a newcomer based on a noninferiority study. So I consider these as 2 options for patients. In this noninferiority trial, the overall survival was comparable between the 2. So, in theory, physicians can choose either one based on preference. If we look at adverse event profile, they tend to overlap quite a bit with a couple of distinctions that we see higher frequency of hypertension with lenvatinib and higher frequency of hand-foot skin reaction with sorafenib. So these are things that one could take into account when choosing.

Richard Finn, MD: For example, in a patient with baseline hypertension, maybe that would shy you away from lenvatinib.

Anthony El-Khoueiry, MD: Sure, and I think that’s fair. In regard to the secondary endpoints of higher PFS, higher response rate, in the context of similar overall survival, it’s hard to know what to do with that. However, as practitioners, we tend to believe at times that maybe a higher response rate or higher PFS is important for patients who present with symptomatic disease or patients who are ill enough where we’re concerned whether they may make it to second- or third-line. So an agent that gives us a bigger punch, as far as response in the front line, may be favorable in such a setting. But this is really clinical practice. It’s not hard scientific evidence at this point.

Richard Finn, MD: It’s not data driven.

Transcript Edited for Clarity
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Transcript: 

Richard Finn, MD: It’s very interesting if we take an historical perspective of liver cancer. Before sorafenib in 2007, systemic drugs didn’t have activity. By default, doxorubicin took on this first-line treatment, but there were no data to justify that. So, I think interventional radiology expanded to fill a void, in that studies did show, in selected patients, chemoembolization improves outcome, in selected groups. And, in practice, that’s been applied a little more broadly. The question becomes now that we have more drugs available for liver cancer, how do we triage patients for chemoembolization versus systemic treatment? And you touched on it in the context of the Barcelona Clinic Liver Cancer criteria, which you and I are very familiar with. To the points we’ve talked about before, unlike other cancers where tumor node metastases, the TNM system, has good prognostication, it ignores the competing risk of liver dysfunction. Whereas, the Barcelona criteria include that as represented by Child-Pugh score.

So, let’s walk through a typical scenario. A patient comes in, they’ve had known hepatitis for a long time, and maybe haven’t been screened so adequately. It could be hepatitis B or hepatitis C for that matter. They start having some abdominal pain. They come into the clinic and they’re evaluated, and they have a tumor on both sides of the liver but no invasions in the vasculature, no extrahepatic spread. I think a lot of us would say this is an intermediate patient, probably beyond transplant or curability. And therefore, they get chemoembolization. How do you follow these patients? You alluded to the fact that these patients will eventually progress to advanced disease because we don’t cure them with chemoembolization. When do we make that switch?

Anthony El-Khoueiry, MD: So, the trigger for switching from locoregional TACE [transarterial chemoembolization] to systemic therapy is a bit tricky because there are not necessarily standardized or agreed upon criteria. I think in Japan, they follow certain criteria, which are probably the most used in a systematic fashion—at least in Japan—and reported on. But, generally, there is agreement that if a patient doesn’t achieve a good response, meaning either a complete response or a very solid partial response in the treated lesion after 2 TACEs, then this is a patient who is not going to benefit significantly from additional TACE.

Richard Finn, MD: Even though they don’t have disease outside the liver, right?

Anthony El-Khoueiry, MD: Even if they don’t have disease outside the liver. So a patient like this who hasn’t achieved a deeper response or who’s actually just had stability of disease after 2 TACEs, I think these are patients who would be very fair to switch to systemic therapy, especially now that we have multiple options available, so we can maximize their exposure to sequential therapy and hopefully have their biggest impact on survival. The other concern that you may be alluding to in your question is that locoregional therapy can take a toll on liver function. So additional TACEs can compromise liver function, which then prevents the access to maybe systemic therapy.

Richard Finn, MD: Sure, especially as we’ll talk later about second-line, third-line options. When we’re talking about systemic treatment, the newer player on the block has been lenvatinib. The REFLECT study was a noninferiority study that took patients with advanced liver cancer, so patients who had progressed on TACE either where, as you described, they didn’t have good TACE control or they had extrahepatic disease, or even vascular invasion within the liver. Patients who had main portal vein invasion, in the study, were excluded. And it met its endpoint of noninferiority. It had some improvement on secondary endpoints, response, PFS [progression-free survival], TTP [time to progression]. But now you have a drug that you’ve been working with for a decade and now a drug that’s relatively new. So this patient of yours who is getting a chemoembolization now has vascular invasion in the liver. What’s your decision process?

Anthony El-Khoueiry, MD: So, as you alluded to, vascular invasion or the development of extrahepatic metastases is a reason to switch to systemic therapy. So now, we have 2 first-line options. We have sorafenib, which we’ve used for a long time, and lenvatinib, which is a newcomer based on a noninferiority study. So I consider these as 2 options for patients. In this noninferiority trial, the overall survival was comparable between the 2. So, in theory, physicians can choose either one based on preference. If we look at adverse event profile, they tend to overlap quite a bit with a couple of distinctions that we see higher frequency of hypertension with lenvatinib and higher frequency of hand-foot skin reaction with sorafenib. So these are things that one could take into account when choosing.

Richard Finn, MD: For example, in a patient with baseline hypertension, maybe that would shy you away from lenvatinib.

Anthony El-Khoueiry, MD: Sure, and I think that’s fair. In regard to the secondary endpoints of higher PFS, higher response rate, in the context of similar overall survival, it’s hard to know what to do with that. However, as practitioners, we tend to believe at times that maybe a higher response rate or higher PFS is important for patients who present with symptomatic disease or patients who are ill enough where we’re concerned whether they may make it to second- or third-line. So an agent that gives us a bigger punch, as far as response in the front line, may be favorable in such a setting. But this is really clinical practice. It’s not hard scientific evidence at this point.

Richard Finn, MD: It’s not data driven.

Transcript Edited for Clarity
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