So John, we wanted to talk a little bit about actually as we learn more about this disease, as we have more options, we may not be using our scalpel as much. So wanted to talk to you a little bit about the next steps in terms of the non-surgical treatments. Let's focus on non-muscle-invasive bladder cancer first. We've got some medications, a lot of them have been FDA approved and maybe some that will change what we do for these non-muscle-invasive bladder cancer patients. So tell me your thoughts.
John Sfakianos: Sure. Thank you for your kind words, by the way. I think that the field is definitely evolving. We are at this next phase where I think we're taking some risks and hopefully that they pay off. I think not so much in the non-muscle-invasive cohort of patients. So chemoablation I think has been a concept that actually if you look back in the literature in the 1980s and '90s, there were studies done with aqueous solutions. We left a marker lesion. We tried to destroy it with chemo alone. And the main issue was always I think more the technology or the tools that we were using. So the aqueous solutions, a lot of our patients didn't have good dwell times. They peed it out right away. And so it was challenging to overcome that until now where I would say that we're in this innovative technology phase.
We see this with a lot of the other specialties, subspecialties in urology. And things like Zusduri from UroGen, which is a technology, a reverse thermal gel that actually allows us to destroy the tumor rather than having to go to the operating room. And I think it's really exciting. I've incorporated it into my practice and I'm actually shocked with the results we're seeing. And the hypotheses and the theories we've had in the past are actually living up to it now because we have the tools to be able to do that.
Sam Chang: Yeah. I think it's a really important point, John. A lot of people have a lot less gray hair than me and they don't know even about early studies from the '70s, late '60s, early '80s that looked mainly in Europe, some in the US looked at exactly that, of let's put a medicine in, let's see what happens to the tumor. And then as I went through training, that was like, "Oh, you can't do that. It's not safe." And now we're shifting back and realizing that for this big group of patients that have low-grade disease, specifically, and recurrent disease, that now you have a treatment option that can actually obviate the need for a TURBT, but actually eliminates the tumor. So tell me your real-world experience with that.
John Sfakianos: Sure. I think there's a couple of important concepts with this intermediate-risk, low-grade, non-muscle-invasive bladder cancer. We know these patients recur. Historically we have the data. We also know that it's likely a field effect in this disease. So multifocal tumors, large tumors, often the recurrences are in other areas. And so for me, it was always that it was frustrating. I would joke with my patients like, "Okay, you have low-grade disease, you're going to put my kid through college," because I knew they were going to come in all the time, cystoscopies, follow-ups. And for me, what was most impressive from the ENVISION trial was really the durability of response. If you respond, you respond. And when we think about it, if we put on the scientific hat a little bit and think about it, it makes sense because as you're destroying a tumor, the immune system is what's destroying that tumor.
The chemotherapy that we're placing is killing the cells, but then the immune system has to come in and clear it. So it's developing that sort of vaccine-type, I know that's a hard word to use right now, but it's building that memory and allowing, I think, what we've always wanted to do with things like BCG, build that memory, train our bladders and our immune system. And I think with doing the chemoablation, we're really doing that. And so I've completely incorporated it into my practice. I offer it first-line now for all my recurrent low-grade intermediate-risk patients. And I think it's been on both angles. So from the patient's perspective, they're so much happier not having to go to the operating room.
Sam Chang: Yeah, absolutely.
John Sfakianos: Of course, you do have some patients who still choose to go to the operating room, which is fine. I think from a durability of response where it's shocking. You see all these tumors, six treatments, you come back six weeks for your cysto and the bladder's like nothing ever happened.
Sam Chang: Yeah. I think it's the outline that you placed in terms of, okay, the cytotoxic effect followed by the immune system clearing basically what was killed by the chemotherapy. But then understanding that when we do for these patients this field defect of these small tumors, honestly, that we're not seeing. And then we go and we treat. Oh yeah, we think we got them all. And the aqueous treatments we have are effective, but they don't eradicate the dwell time, et cetera, I think has really shifted things dramatically. And similar to you, as we started using this medication is the fact that it does eliminate tumors, which it took me some time to wrap around. But I think the long-term durability, it makes sense. It makes sense.
John Sfakianos: They have the 24-month, the 36-month durability. Still what they're reporting are more than half the patients have not recurred, which is crazy. When you think about...
Sam Chang: The normal, just so you see the majority of these patients will recur. And then once they recur, they start recurring again, again, again, again.
John Sfakianos: Yeah.
Sam Chang: All right. So let's switch gears from the non-surgical management for non-muscle-invasive. I can tell you right now, our medical oncologists, they aren't there yet in terms of invasive disease, the treatment paradigms with enfortumab vedotin and pembrolizumab and the complete pathologic response we've had. Are we really not going to be doing cystectomies in the future? Tell me how you think about the current situation, where we're moving to and what you all do at Mount Sinai now.
John Sfakianos: So this is a topic that I think I have slightly shifted my thoughts on. And I'll tell you why. Because I am on my third systemic only bladder trial, bladder trial now. So we started with gem/cis/nivo with Makowski and then we went to pembro alone and now we're at EV pembrolizumab. So I've seen the shift from one to the other. I have to say that I was extremely enthusiastic. I'm okay not having to do a cystectomy again, even though I'm probably doing more complicated and more aggressive, more difficult ones. And so I think there's a couple of things that have evolved. One is the traditional therapies I don't think were strong enough, if I can use, or had the efficacy that we were looking for to truly give a complete response in the bladder and maintain that response.
Sam Chang: Over time. Yeah.
John Sfakianos: Over time.
Sam Chang: That's a good point. I think that's a key point. Yeah.
John Sfakianos: I think that's the important part. What we've seen with the initial is yeah, about a quarter, a third of patients will continue having their bladder. Some will have non-muscle-invasive recurrences. So showing you that the field effect, the cancer is still going to be there. But can you control it for metastasizing, is really going to be the goal if you're going to maintain your bladder because of that field effect.
When you think about the idea of this, you really have to eradicate all the cancer cells, but you also have to eradicate all the cells that have dysplasia, metaplasia, or have that...
Sam Chang: Ready. Yeah.
John Sfakianos: That are ready to eventually...
Sam Chang: Exactly. Yeah.
John Sfakianos: And that's why the maintenance therapy in a lot of these trials is important, but for how long are you going to treat these patients? And so I think select patients, I think it's great. My concern now as we're moving to the EV pembrolizumab world, we're probably shifting one set of adverse reactions for another. And while I think the cystectomy adverse events are mostly not long-term and we can know how to manage and get patients through them, now we're getting to a little bit more of a permanent...
Sam Chang: Neuropathy.
John Sfakianos: Neuropathy and rashes and other things. And so we're giving better therapies to try to spare bladder, but they're not necessarily better for the patient. And so that balance, I think, needs to be identified, which is not where we are yet.
Sam Chang: Yeah. I think that's the key point that you raised is balance. And I understand that a big anti-cystectomy sentiment raised by patients, by oncologists, by understanding the... And we're as responsible as anyone at Vanderbilt reporting on all the complications we have, et cetera. And all true. But I think your point regarding many of the complications or issues we can overcome, we can improve. We've got quality of life data that shows in many of our patients conduit, neobladder, whatever type of diversion that actually quality of life can stabilize, can even improve compared to what they have. And you trade that to possibly permanent neuropathy, issues with skin, all these types of things. We're going to have to figure that out. What trade-offs we accept, what we don't. Where we need to interact. And I don't think cystectomy is gone forever at this point.
John Sfakianos: No. We're still going to have a lot of patients that are going to require cystectomies. Like I said, I do worry that we're shifting now where we're going to make the cystectomy complications worse because these are going to be these advanced bladders that come back with this fibrosis and all this other challenging inflammation for the actual operation. And we do see some of that.
Sam Chang: Oh, for sure.
John Sfakianos: And so that is a little bit of a concern, but we won't know. My biggest concern with these trials, and I agree with you, cystectomy is not ideal for every patient, of course. It does carry risks. But like you said, quality of life data from multiple institutions, even the CISTO trial shows us long-term that within six months to 12 months, the patients go back to baseline and continue functioning really well. The majority of the patients.
And so why is cystectomy so bad? I don't know when that happened or why it happened. And my other concern was really that we're doing these bladder-sparing trials with what preliminary data. We've never shown that pathologic complete response is a surrogate for survival. So why are we doing this now without really truly...
Sam Chang: Having evidentiary support that...
John Sfakianos: And is two years enough? Probably not. What happens five years?
Sam Chang: With the bladder intact. Exactly, right. So I think that as we look at non-surgical interventions for non-muscle-invasive bladder cancer, I think we've done a very good job in terms of monitoring, understanding, and we're going to have more and more options. As we look at invasive disease, I think the jury is still out and there is... I think there will be patients that we will not remove their bladders for different reasons. Understood. But there are going to be those that we continue for many reasons that we'll need to actually proceed with cystectomy. And then teasing out which of the populations really fits in which bucket I think will be something that we'll continue to need to study and that's why we need surgeon scientists just like yourself. So John, thanks so much and look forward to catching up with you again soon.
John Sfakianos: Awesome. Thank you, Sam. That was great.