Update on Treatment of Advanced Liver Cancer - Episode 8
Transcript:Ghassan K. Abou-Alfa, MD: I want to go back to the biopsy question because that’s a really very important component. And, maybe, I’ll start the story with Amit. You have your patients in your clinic with hepatitis C on what we call a screening program. And, please tell us what the screening program is and then tell us what might happen when something erupts in the liver; what do you do about it?
Amit G. Singal, MD: So, anyone who has cirrhosis should be entered into an HCC screening program. The screening program should consist of at least an ultrasound done every 6 months. It can be supplemented with alpha-fetoprotein (AFP), which is a serum biomarker to be done every 6 months as well. And that decision really depends, in my mind, on the quality of your ultrasound. Although ultrasound can be efficacious when done by high-quality ultrasonographers, there’s variability in terms of the ultrasound quality that you see in clinical practice. And, so, if you’re not sure about the quality of your ultrasound, I think it should be ultrasound plus AFP. If you have good quality ultrasounds, then it can be ultrasound again. But, nonetheless, patients with cirrhosis should be entered into a screening program every 6 months. If they have any abnormality on the ultrasound, so a lesion greater than 1 centimeter or an elevated alpha-fetoprotein greater than 20 ng/mL, then they should be going on to a diagnostic evaluation. And that diagnostic evaluation can be a multiphase CT or a contrast-enhanced MRI.
And I think, going to your point, if they have that diagnostic evaluation and they have characteristic appearance on the CT or the MRI, then you can make a diagnosis of HCC without doing a biopsy. That characteristic appearance—as you started to say, Richard—was arterial enhancement, so enhancement on the arterial phase and then what we call delayed washout. It’s darker than the appearing liver either on the portal venous phase or the delayed phase. And what we’ve seen is that you can actually make a diagnosis of HCC with about 95% to 97% specificity, so it’s really good. However, we may have shot ourselves in the foot because now we have very little tissue on HCC, which has hampered our understanding of the cancer. And so, you can make a case, that all of the failed clinical trials that we’ve seen, failed in part because we’re taking a stab in the dark, instead of really saying that we have a good understanding of the tumor biology. That may be hepatologists’ fault because we’ve been making this diagnosis radiologically instead of pathologically.
Ghassan K. Abou-Alfa, MD: This is like music to our ears. If we did this program 10 years ago, we’d be spending half an hour discussing that subject. And there would be a great debate about if we need to get tissue or no tissue. But, to hear it from the hepatologist, that’s really fascinating because it appears—in all fairness, we’re all on the same page—we got to have the tissue. Because, now, what we’re going to discuss next, not only from the diagnostic standpoint, but even from the biomarker standpoint, is systemic therapy.
With this said, we’re going to go back to this question of systemic therapy. Obviously, we kind of dissected which patients are going to go on treatment, those with a reasonable performance status. We’ll dissect that a little bit in detail, not necessarily only metastatic disease, but maybe patients with locally advanced disease and not amenable to some form of local therapy, which is of course based on some discussion. Sorafenib has been the standard of care. It was, if anything, tested and reported and approved all in 2007. It showed an improvement in survival by more than 10 months, 10.7 months to be specific, versus 7.9 for placebo. Clinically and statistically significant, one of the fastest approval of drugs in the FDA, and then there’s the great lull from 2007 till now. What’s going on?
Richard Finn, MD: Yes, it’s been a little disappointing to say the least. I think that none of us would have expected us to be here almost 10 years without another approved drug. Let’s look at the drugs that have gone, in the frontline setting at least, because still in the second-line setting we don’t have anything to prove. But, in the frontline setting, the majority of the drugs that went up against sorafenib were very similar compounds. There was sunitinib, brivanib, linifanib, a lot of small molecules multikinase inhibitors. And the decision to go forward was not based on strong data. Most of it was based on single-arm, small, phase II studies. The combination of erlotinib and sorafenib, the SEARCH study—which was one of the first studies to go forward—had no real clinical data supporting it.
So, when you take 40 patients and say we treated them all with a given agent—and we get a survival that’s 15 months or 16 months, and say, hey, that’s better than 10.7 months with sorafenib—then it’s not that hard for people to convince themselves that they have something to move forward with. And all these studies were very, very large—at least 900 patients, some over 1000—because they were looking at fairly small improvements, and they were not based on any strong biologic rationale. I think a lot of us, looking back now, could say some of those failures could be limited by the idea of a randomized phase III, at least, where we could get a signal of whether or not this was just a patient selection or a real activity of the drug, as well as the idea that was touched on before: whether or not we can select patients with a given therapeutic that do better than others. Is there a biomarker for response?
Still, I think with a lot of these multikinase therapies, it’s going to be hard to identify that. And, so far, most of the drugs that have gone forward in the frontline setting and, for that matter, in the second-line setting, have been empiric. We’re now seeing that change a little bit. But, to answer your question, I think a lot of us got too excited based on small, phase II studies.
Ghassan K. Abou-Alfa, MD: Fair enough. But, nonetheless, we’re going to dissect a little bit more in the future because obviously, even though we have those negative studies, it does not imply that we’re not going to try in different approaches. And, we have fascinating data and fascinating thoughts we’re going to share with you in a minute.
Transcript Edited for Clarity