Ghassan K. Abou-Alfa, MD: Peter and Riad, you are mentioning a very critical point over here, which is, again, related to endpoints. Interestingly, there are 2 schools of thoughts. One of them is, if I’m having therapy X, whatever that is, and, if, for whatever reason, the survival is influenced by therapy Y, which is to follow therapy X, then you wonder, is the survival really due to therapy X? That’s 1 school of thought, and I think Riad presented on that nicely.
On the other hand, there’s another school of thought. If a patient was on therapy X and they go to therapy Y and they say survival is extended further, what is therapy X’s contribution here? How can I tell? Interestingly, the argument is given that a patient who ended up going on therapy Y did not succeed because they got therapy X. We are not really looking at therapies in isolation. They are really being looked at as a continuum, per se.
These 2 schools of thoughts are going to go back and forth all the time, but I would say until that day comes, looking at survival is still really the ultimate reference point for us. We were discussing local therapy. If, for example, we embolize a tumor in the liver and something happened, or a new tumor emerged in the lung, technically it is part of the process. It’s not like something independent. This is where TTUP [time to untreatable progression] comes into play. It’s a bit of a debate right now. It’s not necessarily specific to liver cancer, but to many other cancers. For now, we look at things as not being independent. At the same time, survival is really understood as being the ultimate endpoint.
I have 1 last question. Riad mentioned the decision making, planning, and sequencing of the embolization. If you recall, there was the OPTIMIS study. Tell us more about it. What is OPTIMIS?
Amit Singal, MD: OPTIMIS is a multinational observational study looking at locoregional therapies and how they’re used in practice. There are a couple key points that you can take from this observational study. The first is that TACE [transcatheter arterial chemoembolization] is used in many patients for whom it’s not typically recommended. It’s used, for example, in patients with more advanced tumor burden. At most centers, we would not be treating with chemoembolization. The second thing is that what you see is even after you have progression—and this gets to what Peter was talking about in terms of actually figuring out when you would get off that track and go to sequential therapy—we see people who receive multiple TACE therapies, potentially more than they should. When you take a look at the data from OPTIMIS, you start to see a couple trends. The more TACE treatments you receive, the less likely it is that you’re going to have a response. Each of these TACE treatments is associated with the risk of liver dysfunction. And so, you could argue that the value, this risk-benefit ratio, changes over time.
You really have to reassess, and, after each chemoembolization, ask, “What’s the response?” “How is that patient tolerating it?” “Is it the appropriate time for me to move to systemic therapy?” That’s really key, particularly as we have more and more options that provide good benefit for systemic therapy. I think we really need to define when that optimal time is to move to systemic therapy. Then we can get the maximum benefit from both locoregional therapy and systemic therapy.
Ghassan K. Abou-Alfa, MD: That’s a great point. Riad, since you are an interventional radiologist, what do you hear from patients? When do you think patients should move from local therapy to systemic therapy? At the same time, do patients ask you, “Maybe I should look into systemic therapy?”
Riad Salem, MD: That’s a great real-life scenario that you present. As Peter was mentioning, the reality is that when I meet with patients, all of these things come into play. It’s my belief that the combination therapy should be closer together, rather than further, apart. There are data and we’ve written on this before. If you do a local therapy and you wait until patients progress, about half of them have decompensated liver dysfunction because of natural progression, because of disease progression, and because of treatment toxicity. My belief, although this is not evidence based, is that the optimal thing to do is give locoregional therapy and, at day 30 or 60, implement systemic therapy. They still have good liver function. They still have a good performance status and can tolerate the benefit of the two. If you wait too long, there’s dropout. That’s why not all patients that progress on locoregional therapies go on to a systemic drug. They can’t tolerate it.
So I think the ideal strategy is to use a local therapy and then a systemic therapy. Even in patients who have no systemic disease, with sort of bulky disease, I think that’s the optimal combination. I don’t believe in waiting that long. That’s my personal opinion, and it would be interesting to do a study like that. We’ve done some retrospective analyses that support this position. If you wait too long, you’re not going to tolerate the therapies.
Transcript Edited for Clarity