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HCC: The Criteria for Adjuvant Therapy

ASCO HCC Global PX
Published: Friday, Aug 10, 2018



Transcript: 

Ghassan K. Abou-Alfa, MD: And this, if anything, brings me to the next point of discussion, which is like, how we do treat. And we kind of suggested already that for early stage disease that is possibly resectable, let’s take it out. And the question is, if it’s really probably still locally advanced and really limited to a potential resectability but the liver is not good, we’ll probably do transplant. There’s a big debate. It’s a little bit out of the context of what we’re going to talk about today, about the difference and the applicability between transplant and surgery. But nonetheless, there’s a key question that we’ll come to ask, probably from the perspective of oncology and hepatology, and that is, do we have a role in regard to those patients, especially in regard to neoadjuvant or adjuvant therapy. Let me start by asking our colleagues about at least some of the thoughts in regard to adjuvant therapy. And I’ll start with Dr. Kudo, because if we know that a lot of the adjuvant work was reported from Japan initially in regard to the different work that was at that time. Can you tell us a little bit about the experience of Japan in regard to the adjuvant therapies?

Masatoshi Kudo, MD, PhD: Yes. For adjuvant therapy, there were 2 trials only in Japan. The one is a Vitamin K2 trial and another is retinoid. But both of them failed. And a third global study was the STORM trial with sorafenib.

Ghassan K. Abou-Alfa, MD: Correct.

Masatoshi Kudo, MD, PhD: All 3 adjuvant trials failed. So, I don’t think there is no adjuvant agent with evidence.

Ghassan K. Abou-Alfa, MD: Fair, fair. In other words, we really don’t have standard of care at this point in time in regard to adjuvant therapy. Let’s kind of dissect that a little bit scientifically. Why would sorafenib not do the job in regard to adjuvant therapy? Antiangiogenesis is like really driven at the time of the surgery. What do you think, Rich?

Richard S. Finn, MD: Well, I think if we look at other cancer types, a drug that is active in metastatic disease does not automatically mean it’s going to work in early-stage disease. And I think there is precedent for that; bevacizumab in colon cancer, for example. The drug ultimately is cytostatic, and it’s not necessarily cytotoxic or cytocidal, so it doesn’t kill cells. And that might be an important thing in the adjuvant setting.
The other thing is, we have a field defect, and we’re not only preventing maybe the tumor that was taken out from coming back but de novo recurrence. And that’s the problem with resection in liver cancer is that you still leave behind a diseased organ. And the analogy I like to use with patients is you have bad soil, we take out a weed, but the bad soil is left behind, and it can give rise to new tumors, new weeds. And a drug like sorafenib just might not be potent enough to prevent that.

We’re now seeing a new study being launched with nivolumab in the adjuvant setting. Obviously, its readout in a randomized study has not read out. But maybe that will be an approach that might be more important. There is an interesting… I think it was a randomized phase II study out of Asia that used a vaccine approach in the adjuvant setting and did show a very dramatic benefit. It was, I think, a cellular-based vaccine after resection, but that never got pushed forward.

Ghassan K. Abou-Alfa, MD: Of those that you brought up, let me ask Arndt. Let’s start this way. You can choose anything you want to do a clinical trial in regard to adjuvant therapy for HCC. What would you pick?

Arndt Vogel, MD: When we look at the drugs that are available, we have a lot of TKIs. We have these antiangiogenic drugs that not only have failed in HCC but also in colorectal cancer. I’m not so sure whether I would pick any of those, and so I would probably also go for the immunotherapy.
Ghassan K. Abou-Alfa, MD: You’d go for checkpoint inhibitors, interesting.

Arndt Vogel, MD: I’m not really sure whether they would be the perfect choice, but we have to see it. At the moment, I think that would be probably my best pick. And maybe just one other point. If you talk about adjuvant therapy, we still see a lot of patients with hepatitis C infection, and they’re only diagnosed very late maybe, only diagnosed when they have the first diagnosis of the tumor. And I think this is something we should still keep in mind and oncologists should also always remember, that once they have curative treatment for the tumor, I think that’s a better candidate for also antiviral treatment and that should be done. It should not be done immediately after surgery, and there are some discussions on the effect on recurrence of the tumor after HCV treatment. So, this is still a matter of debate, and I think it’s not very clear that it does not increase the incidence. But there are some data that suggested tumors might be more aggressive. So, there should be a time between antiviral treatment and the curative tumor treatment. But this is something that should not be forgotten. So, if you have hepatitis C patients, they should get treatment for their hepatitis C after curative treatment.

Ghassan K. Abou-Alfa, MD: Hold that thought. I would love to touch on this first, but let’s finish first what we’re discussing in regard to the adjuvant. And I have a question to you, Rich. You mentioned the nivolumab study in the adjuvant setting. Is there any scientific reason why checkpoint inhibitors will do a job in regard to adjuvant therapy or we are just doing it because of what we just heard from Arndt? Like really what’s exciting these days to use checkpoint inhibitors?

Richard S. Finn, MD: Well, I think, for one, the data in metastatic disease single-arm studies are impressive, very robust. So, it does have a role in treating the disease, at least it would appear based on the single-arm phase II study. I think there has long been a sense that preventing recurrence after resection, there is a role for immune surveillance. And I think that is the strongest rationale, that by altering the immune milieu, so to speak, in the microenvironment in the liver, the liver historically is an immune-tolerant organ. The function of the liver is to detoxify the bowel. That’s one of the main functions. A lot of antigens come in, so the native environment of the liver is immune tolerant, and perhaps that allows recurrence after resection. And if we’re reversing that immune tolerance, so to speak, to some degree, with checkpoint blockade, I think again that’s a strong rationale to move them into the early-stage setting.

Ghassan K. Abou-Alfa, MD: Of course. And yes, this is still to be proven.

Transcript Edited for Clarity 

Brought to you in part by Eisai

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Transcript: 

Ghassan K. Abou-Alfa, MD: And this, if anything, brings me to the next point of discussion, which is like, how we do treat. And we kind of suggested already that for early stage disease that is possibly resectable, let’s take it out. And the question is, if it’s really probably still locally advanced and really limited to a potential resectability but the liver is not good, we’ll probably do transplant. There’s a big debate. It’s a little bit out of the context of what we’re going to talk about today, about the difference and the applicability between transplant and surgery. But nonetheless, there’s a key question that we’ll come to ask, probably from the perspective of oncology and hepatology, and that is, do we have a role in regard to those patients, especially in regard to neoadjuvant or adjuvant therapy. Let me start by asking our colleagues about at least some of the thoughts in regard to adjuvant therapy. And I’ll start with Dr. Kudo, because if we know that a lot of the adjuvant work was reported from Japan initially in regard to the different work that was at that time. Can you tell us a little bit about the experience of Japan in regard to the adjuvant therapies?

Masatoshi Kudo, MD, PhD: Yes. For adjuvant therapy, there were 2 trials only in Japan. The one is a Vitamin K2 trial and another is retinoid. But both of them failed. And a third global study was the STORM trial with sorafenib.

Ghassan K. Abou-Alfa, MD: Correct.

Masatoshi Kudo, MD, PhD: All 3 adjuvant trials failed. So, I don’t think there is no adjuvant agent with evidence.

Ghassan K. Abou-Alfa, MD: Fair, fair. In other words, we really don’t have standard of care at this point in time in regard to adjuvant therapy. Let’s kind of dissect that a little bit scientifically. Why would sorafenib not do the job in regard to adjuvant therapy? Antiangiogenesis is like really driven at the time of the surgery. What do you think, Rich?

Richard S. Finn, MD: Well, I think if we look at other cancer types, a drug that is active in metastatic disease does not automatically mean it’s going to work in early-stage disease. And I think there is precedent for that; bevacizumab in colon cancer, for example. The drug ultimately is cytostatic, and it’s not necessarily cytotoxic or cytocidal, so it doesn’t kill cells. And that might be an important thing in the adjuvant setting.
The other thing is, we have a field defect, and we’re not only preventing maybe the tumor that was taken out from coming back but de novo recurrence. And that’s the problem with resection in liver cancer is that you still leave behind a diseased organ. And the analogy I like to use with patients is you have bad soil, we take out a weed, but the bad soil is left behind, and it can give rise to new tumors, new weeds. And a drug like sorafenib just might not be potent enough to prevent that.

We’re now seeing a new study being launched with nivolumab in the adjuvant setting. Obviously, its readout in a randomized study has not read out. But maybe that will be an approach that might be more important. There is an interesting… I think it was a randomized phase II study out of Asia that used a vaccine approach in the adjuvant setting and did show a very dramatic benefit. It was, I think, a cellular-based vaccine after resection, but that never got pushed forward.

Ghassan K. Abou-Alfa, MD: Of those that you brought up, let me ask Arndt. Let’s start this way. You can choose anything you want to do a clinical trial in regard to adjuvant therapy for HCC. What would you pick?

Arndt Vogel, MD: When we look at the drugs that are available, we have a lot of TKIs. We have these antiangiogenic drugs that not only have failed in HCC but also in colorectal cancer. I’m not so sure whether I would pick any of those, and so I would probably also go for the immunotherapy.
Ghassan K. Abou-Alfa, MD: You’d go for checkpoint inhibitors, interesting.

Arndt Vogel, MD: I’m not really sure whether they would be the perfect choice, but we have to see it. At the moment, I think that would be probably my best pick. And maybe just one other point. If you talk about adjuvant therapy, we still see a lot of patients with hepatitis C infection, and they’re only diagnosed very late maybe, only diagnosed when they have the first diagnosis of the tumor. And I think this is something we should still keep in mind and oncologists should also always remember, that once they have curative treatment for the tumor, I think that’s a better candidate for also antiviral treatment and that should be done. It should not be done immediately after surgery, and there are some discussions on the effect on recurrence of the tumor after HCV treatment. So, this is still a matter of debate, and I think it’s not very clear that it does not increase the incidence. But there are some data that suggested tumors might be more aggressive. So, there should be a time between antiviral treatment and the curative tumor treatment. But this is something that should not be forgotten. So, if you have hepatitis C patients, they should get treatment for their hepatitis C after curative treatment.

Ghassan K. Abou-Alfa, MD: Hold that thought. I would love to touch on this first, but let’s finish first what we’re discussing in regard to the adjuvant. And I have a question to you, Rich. You mentioned the nivolumab study in the adjuvant setting. Is there any scientific reason why checkpoint inhibitors will do a job in regard to adjuvant therapy or we are just doing it because of what we just heard from Arndt? Like really what’s exciting these days to use checkpoint inhibitors?

Richard S. Finn, MD: Well, I think, for one, the data in metastatic disease single-arm studies are impressive, very robust. So, it does have a role in treating the disease, at least it would appear based on the single-arm phase II study. I think there has long been a sense that preventing recurrence after resection, there is a role for immune surveillance. And I think that is the strongest rationale, that by altering the immune milieu, so to speak, in the microenvironment in the liver, the liver historically is an immune-tolerant organ. The function of the liver is to detoxify the bowel. That’s one of the main functions. A lot of antigens come in, so the native environment of the liver is immune tolerant, and perhaps that allows recurrence after resection. And if we’re reversing that immune tolerance, so to speak, to some degree, with checkpoint blockade, I think again that’s a strong rationale to move them into the early-stage setting.

Ghassan K. Abou-Alfa, MD: Of course. And yes, this is still to be proven.

Transcript Edited for Clarity 

Brought to you in part by Eisai
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