The Evolving Role of Radical Cystectomy in the Era of Bladder-Sparing Therapies - Sima Porten & Roger Li

May 17, 2024

Ashish Kamat hosts Sima Porten and Roger Li to discuss the management of BCG-unresponsive bladder cancer. They emphasize personalized patient care, starting by understanding patients' goals and risk tolerance. Dr. Porten highlights the importance of discussing radical cystectomy as the gold standard while also considering bladder-preserving treatments depending on the patient's disease characteristics and preferences. Dr. Li stresses the advancements in treatment options, such as pembrolizumab, Adstiladrin, and Anktiva, and the need for effective sequencing of these therapies. They both acknowledge the need for vigilant monitoring and the role of clinical trials in providing more treatment options. They agree that despite new therapies, radical cystectomy remains a primary recommendation, but personalized approaches considering the patient's overall health and treatment preferences are crucial.


Sima P. Porten, MD, MPH, Urologic Oncologist, Department of Urology, University of California, San Francisco, CA

Roger Li, MD, Urologist, Moffitt Cancer Center, Tampa, FL

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX

Read the Full Video Transcript

Ashish Kamat: Hello everyone and welcome to UroToday's Bladder Cancer Center for Excellence. I'm Ashish Kamat, and I'm here in San Antonio for AUA 2024. It's a pleasure to welcome to the URO Today Studios, Sima Porten and Dr. Roger Li, who are no strangers to this forum. So welcome back.

Roger Li: Thanks for having us.

Sima Porten: Thanks for having us.

Ashish Kamat: So I hope you're having a great AUA, and of course, we have the debate that you are participating in tomorrow at the forum where it comes to BCG-unresponsive disease and how much therapy is safe for the patient, how long we can wait, et cetera, et cetera, right? And that's a debate tomorrow. Today, let's hear both of your thoughts on how you approach your discussion with a patient that has BCG-unresponsive disease when you see him or her in your clinic. So Sima, if I could ask you, here's a patient with BCG-unresponsive disease, fits all the FDA-required definitions as closely as possible, and is asking you, "Hey, Dr. Porten, do I need a radical cystectomy? Can I try something?" What's your thought process when you're counseling this patient?

Sima Porten: Yeah, I think I start with something from the patient about what's their big goal? What's their life look like? What are they looking forward to? What are they into? What are they doing? And that kind of helps the conversation of figuring out, because when you ask if something is safe, it's really about trying to estimate risk for somebody. And everybody has a different line or threshold for that risk, each person, each physician. And so I think that sets the stage with looking from the patient perspective where they kind of fall along that continuum. And then I think you can look at some disease characteristics. You can look at not all BCG-unresponsive recurrences or created equal. There's your small high-grade Ta, and there's your high-volume, high-grade T1, which you in your own mind would risk stratify a little differently as a clinician and try to put that in perspective for a patient. So I think by and large, you can start the conversation by saying that radical cystectomy is considered the gold standard for these reasons because it's definitive and can be curative. However, bladder preservation I know is important for a lot of reasons, and I do think we can try something else safely, but let's talk about that and define what safe means to you.

Ashish Kamat: And that's a great point you bring up because every patient has a different threshold. Some patients are like, "I just want to get this bladder out if you tell me that's the only safe thing." And some patients are like, "Dr. Porten, if you tell me this is safe for me, I'm willing to try X, Y, Z things." So Roger, when a patient comes to you and says, "Well, I have this disease, my referring doctor has told me I need a radical cystectomy." How do you go about resetting that expectation in the patient's mind? That the radical cystectomy, yes, it's in the guidelines. It's something we all recommend, but it's not the only option.

Roger Li: Right, yeah. So first of all, I'm so glad to see so much activity that's being done in the BCG-unresponsive setting. Just over the last few years, as you know, there's so many different agents that are not only being investigated but also being approved by the FDA now. So as you know, we have three different approved agents in this disease phase, pembrolizumab, Adstiladrin, and also now ANKTIVA, and with a lot of other agents that are right on their tails as we witnessed from the plenary session yesterday with the TAR-200 product and also cretostimogene following very closely on their heels. So I think it's a very exciting time for patients, but also for us as their treating physicians to have such a plethora of different options to offer patients. The other thing that I wanted to mention is as we're kind of treating this BCG-unresponsive disease, as urologists, we're really becoming more familiar with this disease entity. Whereas before, we were always taught that once patients have high-grade recurrence after BCG, then the next step really is cystectomy and there are no other options. We're beginning to understand that with some of these diseases, as Sima had pointed out, you can potentially treat them with additional bladder-sparing agents. And I think from the patient's perspective, certainly to hear that is very welcome because, for obvious reasons, they want to keep their bladders.

Ashish Kamat: Yeah, so the point there is really, it goes back to the trial design with pembrolizumab and nadofaragene. At that time, when the BCG-unresponsive paradigm was adopted by the FDA, and of course Merck and Ferring at that time or FKD were developing these trials, we, as a community, did not feel that safe about sparing the bladders. We knew you could do it, but it wasn't safe, which is why if a patient had a recurrence or did not respond, they came off the study, they couldn't get re-dosed, right? But then we've learned that it is safe. These patients are not at harm if you try something else. And obviously, on the other trials with CG, for example, they get re-induced or they get more treatment. Has that changed the way you counsel patients just learning that this re-induction or re-dosing is appropriate? Are you thinking about it differently now, Sima?

Roger Li: To some degree, right? I think those trials showed that trying something else is safe when you look at the cystectomy rates and the rate of muscle-invasive disease, and then more importantly, cancer-specific survival. And so all those were very favorable. And so you're like, okay, well one thing was safe, now can I do another thing? So now we're getting into the sequencing question and how would you intelligently sequence this? And because the biomarker aspect is not really there, you're using experience gestalt, you're using things like does somebody have a good enough bladder capacity to even tolerate this next thing? Because if you can't hold the drug, then maybe it's not so safe because it's not being delivered. And so you're trying to now factor in all these other things to help you make a decision on this. But there's no way to tell somebody in, if we treat 100 more patients with the second-line therapy, we'll lose a curative window in X. That number, a lot of people want that, and we don't have that yet.

I do think that the data is showing, okay, well we can reinduce, kind of like with BCG, maybe if it didn't work quite as well as you hoped after induction, you can reinduce for certain patients. We're sort of seeing that now in this very different setting. And so I think there is more and more comfort around that. But I also think there's, and I think Roger actually, maybe the two of you actually, have published some of these studies looking at if the patient crosses the line to muscle-invasive disease and then you do the cystectomy, we know that definitely maybe we could impair oncologic outcome there, but where is that line that you step over into muscle invasive all of a sudden? That part is hard to estimate, and I think I'm more comfortable with it, but I also end up being very vigilant on cystos. You see a flat mound, you're like, maybe that's CIS. Maybe there's something deeper. Making sure you sample that right. I worry a lot about upper tract. I mean, I call it, it's not a term, upper tract creep. I worry about that a lot, particularly tumors of the trigone doing that aspect. And so I do image a little more frequently, but I think I'm slowly becoming more comfortable. I still worry.

Ashish Kamat: Yeah, no, worrying is important, right?

Roger Li: Still worry.

Ashish Kamat: And you're referring to the MD Anderson paper that Pat Hensley put out that showed that if a patient gets muscle-invasive disease, progression from non-invasive to invasive, that's worse than the novel muscle-invasive disease. And that's something we all worry about. And that's, I think, why the whole initial trials were so strict. So Roger, share with me your thoughts on how we, as urologists, have become better at TURBTs, at using appropriate urinary markers, whether it's cytology or whatever, at better imaging, our higher definition of scopes. Do you think the BCG-unresponsive disease that we are seeing today in 2023, 2024 is the same as what was looked at in historic data?

Roger Li: Yeah, no, absolutely. That's a great point. I think a lot of our fear towards BCG-unresponsive disease is derived from historical data where we don't have the enhanced cystoscopy. We don't have the, even the cross-sectional imaging may be suboptimal. When the disease does come back after BCG, when BCG fails, it's very likely that the patients will actually have progressive disease. And I certainly agree with Sima that preventing progressive disease to muscle invasion and metastatic disease is the number one goal. But in addition to that, I feel like the toxicity, the cumulative toxicity for all of the different lines of treatment is something that we have to keep in mind too.

We talk about sequencing because we now have a variety of different agents, and I think, as you know, Ashish, from the IBCG meeting over the last summer, the one thing that did emerge from that was toxicity needs to be front and center in choosing some of these bladder-sparing agents. In that light, pembrolizumab, because it's given IV and because it causes the 15% SAE rate, it's thought to be a little bit less optimal than some of the intravesical agents, and I think that's the way that it should be sequenced in that case. Certainly, we're going to be working on biomarkers that can tell us which patients to use, which agents to choose, and hopefully in the future, we're going to be able to have this paradigm where you're going to have a disease, you're going to have a biomarker, and you're going to have a hunch as to what the biomarker indicates the optimal treatment will be. I think we're going to be closer to that than many of us think.

Ashish Kamat: Yeah, I think biomarker-driven identification of which patient and which drug can be matched together is critical. I mean, there's a lot of work going on. You both are leading work in that area, and that's really where we need to go, but we're not there today.

Roger Li: Right.

Ashish Kamat: So if you have, say, and we didn't talk about gemcitabine and docetaxel, so we have to bring that into the mix because that's what most of us use currently. So let's go on hypotheticals, and I'll ask both of you this and you can agree or disagree, or we could go into nuances. Say you have a Ta high-grade patient that is CIS high-grade with a large tumor, not huge, say three centimeters CIS, and it's BCG-unresponsive and you have, at your disposal, gemcitabine, docetaxel. Let's assume you have no problem with your medical oncologist and pembro is not an issue. Let's assume you have nadofaragene or Adstiladrin as it's called, and let's assume because now it's approved and available that you also have NAI or ANKTIVA, which is its trade name. What's your first choice, second choice? How do you go about that choice as to which drug you would use for a particular patient? Sima?

Sima Porten: Yeah, so for the ANKTIVA, I'm going to assume that I don't have a BCG shortage, which is not true because that's going to be my biggest barrier for using that. I would say that in terms of choosing next steps for that patient, I think it will depend a large part on the current state of their bladder and their other comorbidities. So if BCG led to a lot of side effects or they had trouble with tolerance, I'll likely switch to something like gemcitabine-docetaxel probably to begin with, unless their bladder capacity is such that using Adstiladrin would be a better first line because of the very favorable dosing, the once every three months and the volume is less, and so I'll likely use those smaller clinical factors to kind of help decide what should be the front-line treatment.

The other really interesting thing with do you do BCG again, plus something kind of comes into play with some interesting data at the EAU from Amanda Myers in your group looking at re-challenge with BCG. I'm not sure how comfortable I would be with re-challenging with BCG, but I certainly would with ANKTIVA if I had the BCG to do so. And so I think it's going to be those small, smaller clinical factors that likely will help me choose therapy. It will be probably the rare patient that would get pembrolizumab as an upfront drug that would probably be at the bottom of the list for me, just because of that AE profile, particularly now that we have three other intravesical options, which have some great results.

Ashish Kamat: Yeah, no, I mean again, you're using clinical factors to do the biomarker replacement and personalizing to patients. Do you have a different paradigm? What's your thought process?

Roger Li: Yeah, no, I agree with a lot of the things that Sima said, but I think even though we have a lot of options, what we have to keep in mind is that patients are coming in trying to save their bladders in the long term. They're not looking at three-month complete response rates as their end of treatment goals. They're looking at two years, three years, four years, keeping their bladder intact and also disease-free. So I think we have to assess all of the reports and the results from all the ongoing clinical trials and also the previously ran clinical trials in that light. And I think when looked in that light, there really isn't an option currently that has really shifted the paradigm. So I would still say that again, radical cystectomy is the frontline option. For myself, I think I would also try to encourage patients to enroll in clinical trials if it's available because there are a lot of different, very exciting agents that are coming on in the clinical trial space that we can enroll patients on and still have really great efficacy from.

Outside of that, I think still gemcitabine and docetaxel, even from the retrospective data, have shown results that are on par with many of the newer agents. And because of the cost to not only the healthcare system but also to the patients themselves. I just found out the other day that one single dose of nadofaragene costs $61,000. And even if the patient's insurance is able to cover 80% of that, that's still a significant amount of money on a quarterly basis that they still have to pay towards their treatment. So especially pitted against the results from those trials, again, I just don't think that the paradigm has really shifted. And so for that reason, I think gemcitabine-docetaxel still might be the de facto treatment to use in that setting.

Ashish Kamat: You both raised great points. You have to personalize with the patient and all those factors, and you're absolutely right. Patients don't care what's going to happen in three months. I mean, they want to know at a year, at two years what's going to happen. And if you look at that tail, NAI plus BCG has a nice long duration of response of more than 26 months. Gem Doce has very durable data as well. And of course, the newer drugs, which I didn't mention because they're not approved yet, also look like they have a long duration of response. I think it's wonderful that it's May, it's Bladder Cancer Awareness Month, and we're at the AUA talking about so many drugs. We didn't talk about others, right? Lengene, the non-viral delivery system, I mean, there are so many new agents being looked at and all that. It's just an exciting time for us in the bladder cancer community. In closing, I want to leave you with the opportunity for final closing thoughts on this matter for our audience. I'll let you go first, Roger, and then Sima, you'll have the last word.

Roger Li: Thank you. So I think it's exciting times. I totally agree with you, Ashish, that we are really kind of in the beginning of this personalized medicine era in non-muscle invasive bladder cancer. It's up to us, Sima, myself, and yourself, to try to figure out which biomarkers fit with which treatment, and for us to also be able to counsel our patients towards the best treatment that's best for them.

Sima Porten: Really exciting time, particularly for urologists. We have treatment options for patients and we have tools, good tools in terms of, even though I know it sounds boring, but like a good TURBT, right? That's all in our realm and arena. And I think this is a great time because we, as urologists, get to make an impact in a space where we didn't have a lot of options before. And so I think it's really exciting being able to partner with patients, partner with organizations, bring awareness, and I think it's really going to move the field forward and might help people, which is why we all are doing what we're doing.

Ashish Kamat: Absolutely. Thank you again for taking the time, spending it with us today, and thank you to UroToday for giving us this opportunity.

Roger Li: Thank you.

Sima Porten: Thanks.