Bladder Preservation for High-Grade NMIBC: Eligibility & Treatment Approach

[Dr. Aditya Bagrodia]
We've set the patient. Now we're going to dig into the pathology report and walk us through what that's like from your lens. Importantly, in today's day and age, with all the tools that we have, where you may be thinking the next intervention for this patient may be cystectomy, for instance.

[Dr. Ashish Kamat]
Yes, great question. When you're looking at a pathology report and we're looking at it, we're looking for clues from our pathologist. Obviously, knowing how our pathologist reports is important. If they don't report all the points that you and I are going to talk about in the next few minutes, I think the listeners should go to their pathologist and say, "Hey, I need all this information," right?

The pathology report should clearly state the grade and the stage of the tumor. It should clearly state if there's invasion of X, and that X is either lamina propria or muscle, because oftentimes you'll see the pathology report just say papillary high-grade tumor, but there's no mention of does it invade the lamina propria, yes or no. It's important to know that it doesn't invade the lamina propria, because that's a different beast, right?

Lymphovascular invasion, very important to state if lymphovascular invasion is present. If there's any histologic subtype, what we used to call variant histology, micropapillary disease, small cell carcinoma, neuroendocrine features, et cetera, et cetera, they need to be mentioned, and ideally the percentage of that histologic subtype needs to be mentioned. If there's muscularis mucosa present, mention it. If it's involved, mention it. If it's muscularis propria, present or absent, it's really important, right?

Because what you and I are trying to do now is figure out is it safe to give a particular patient the opportunity to save his or her bladder? Is it something you would recommend to your brother or uncle, or father, right? Would you say, "No, this tumor is really, even though it's non-invasive, it's aggressive enough that, hey, either we really embark on a experimental journey or a clinical trial to try and save the bladder, or I really should be telling you need a cystectomy up front."

If someone's got T1B disease, widely invasive, lots of disease in the bladder, LVI, micro-papillary. You and I know that if we try to save that patient's bladder, they could metastasize while you're working to save the bladder, right? Even though now we have EV Pembro, which has given you 30 months, it's still only 30 months. It's less than three years once the tumor metastasizes.

[Dr. Aditya Bagrodia]
I think it goes back to what the bladder looks like. I feel like we all have a sense, and sometimes it is challenging to verbalize, but if it is multifocal, multinodular, extensive carcinoma in situ, certainly, it's just a bladder worth saving. Sometimes when the disease is that bad, it doesn't really make a lot of sense. I do find, just to be totally honest, that it's harder and harder to have the conversations of you need a cystectomy because we may miss a window of an opportunity for a cure in the next three months.

There are patients that I'm worried about, and there's always this catch-22. It's the younger patients that you don't want to get it wrong at all because the opportunity cost of that three years of life with EV Pembro versus 40 years of life with a neobladder or a conduit, that's high stakes. In the same breath, this is precise to the person that you want to maintain their urinary function and sexual function. We'll jump into this, but how do you think about that?

[Dr. Ashish Kamat]
Yes. Obviously, it's been 20 plus years that I've been doing this. Initially, just like you mentioned, you try to be more forceful with the patient, more aggressive because you're like, "Okay, let's do the cystectomy. Let's get you cured." Patients don't want that. What I've evolved into educating my patients over the years is I say, "Hey, your safest course of action is a radical cystectomy. Do you want it? Yes or no."

About 10% of patients that come to see me will, in fact, jump on an initial radical cystectomy if I counsel them on it. It's probably a higher number than many you would see because 1 out of 10 is still a large number of patients wanting cystectomies. Let's assume most patients don't want a cystectomy. Then what I tell the patient is, "Okay, anything we're going to try is to try to avoid that cystectomy. At any point of this tumor does not behave well, if our treatments don't work, then we are back to square one talking about the cystectomy."

That helps me and the patient because at the back of their mind, they know they have to keep the appointments. They have to be particular about their BCG schedule. I know we'll talk a little bit about that. They have to be particular about their cystoscopies. They can't just say, "I'm a busy executive and I can't come in for six months for my check," right? Also, if the tumor comes back, at that point, it's not a surprise to the patient if we bring up a cystectomy. Because otherwise, oftentimes they're like, "Wait a minute, why are we talking about cystectomy again? I thought we were doing intravascular therapy and that would be it."

I tell the patient cystectomy is always on the cards. We're trying to avoid that. I've found that makes that subsequent conversation as to a clinical trial, if you have a recurrence or cystectomy, or what have you, a lot more palatable to the patients.

[Dr. Aditya Bagrodia]
Yes. I find like one of the more challenging thing is that the idea of cystectomy being a part of your management either now or down the way has never been brought up when they come to you. It's like a jaw dropping experience that I was never told that my bladder might ever have to come out.

[Dr. Aditya Bagrodia]
Perfect. Comprehensively, again, in my mind, it's cystectomy, clinical trials, Adstiladrin, EV Pembro, those are our workhorses, FDA-approved. We have GemDoce, definitely use a lot of it here as well, again, for the folks that I'm not worried about. We'll talk a bit about sequencing, but another maybe underutilized tool, chemoradiation. Any opinions on that, Ashish?

[Dr. Ashish Kamat]
Yes, a lot of strong opinions on that. we've had debates on multiple different stages. I'm a big proponent of bladder sparing. I'm a big proponent of allowing our patients to spare their bladders. If a patient has appropriate T2 disease, appropriate T3 disease even, I think there's a role for chemoradiation for selected patients. I think when it comes to the non-invasive setting, the clinical trials that are currently being done are great because we're looking at IO plus or minus chemoradiation, et cetera, and they'll answer that question.

I think people forget that CIS does not respond to radiotherapy, and a lot of our patients that are BCG unresponsive have CIS, right? Now you're taking a entity that doesn't respond to radiation, and you're trying to force radiation on it. I don't think that's a good option for patients. Needs to be studied. I have nothing against clinical trials there, but it's always been a factor that even our radiation oncology colleagues say, "Hey, don't put this patient on radiation if they have CIS." We've got to keep that in mind.

The other thing is that heavily pretreated bladders, which don't exist in the T2 population but do exist in the non-muscular invasive population, patients already are having irritative voiding symptoms. We need to be cognizant of that before we send the patient to our radiation oncology colleagues because our poor rad-on colleagues will see the patient, start radiation, and the patient just is so miserable to send them right back to you, right? We are the urologist. We have to educate the patient better as to the nuances and the implications of radiation therapy.

Short answer, I think there's a role, but it's going to be in very selected patients.

[Dr. Aditya Bagrodia]
Yes. I appreciate that. The idea that it's got to be a bladder worth saving is always, I think, one to keep front and center when thinking about bladder sparing approaches. All right. You touched on it a little bit. If you're worried, maybe that could be a patient who really is pushing for bladder sparing. If you're worried about micro-metastases, Pembro could be a good option. Intravesical therapy.

Well, let me just back up. Maybe if they've had a really gangbusters recurrence, multifocal, nodular, CIS, T1 high-grade, that's a patient that probably really needs a cystectomy as long as they're fit and willing to receive that. Adstiladrin, GemDoce, intravesical sequencing, any opinions at all there?

[Dr. Ashish Kamat]
Yes. If you look at the data, right, and you look at what matters to the patient, is what is the chance that he or she will be free of disease at 12 months, 18 months, 24 months, et cetera? That three months, six months, probably most patients don't care about. If you look at the numbers there, Adstiladrin has prospectively collected data that suggests about 24% at 12 months. GemDoce has retrospectively collected data that suggests it's 55%, 60% at 12 months.

With the caveat that one is retrospective and one is prospective, but recognizing that even Adstiladrin was not a randomized study, I think when it's up to us to offer that education to the patients and help them make an informed decision. Most patients tend to want to go with the treatment that has a higher number, and hence, GemDoce jumps up.

I think at Adstiladrin has a really good role to play in patients that have access issues, right? Patients that are driving three hours, they can't come to see you. They're having to have their grandchild or someone take time off to drive them to see you. They might be better served by an agent that, yes, it's lower efficacy rate, but it's once every three months. It's not every week for six weeks, right?

In those patients, you can say, "Well, let's try this drug. It's only once every three months. If you have a recurrence, we can go to this more intensive therapy." Then at the same time, you and I have to be better stewards of healthcare dollars. We have to factor in the cost of each treatment. It's a very nuanced discussion. Again, all of what you and I are talking about right now is what I discussed with the patient, and we come to a shared decision as to the next steps.

[Dr. Aditya Bagrodia]
Couldn't agree more. I think there are so many things to consider when making these decisions. I was actually just trying to think about, say, an ideal state study, and you've got your BCG refractory patients, and they get, let's just say today, and in six weeks, it's going to get infinitely more complex. They start out with either Adstiladrin or GemDoce, or Pembro. If they recur, they get randomized to X, Y, or Z. You've got these three arms with all these different crossover options, and they're probably not realistic in the short term.

Of course, with biomarkers, as you mentioned, maybe we could do a better job, like we've seen in prostate cancer, for instance, of how to sequence these. Right now, I think you captured it really well. Here's the data. Here's the quality of the data. Here's some logistical concerns. Here's some use-specific concerns. Here's some tumor-specific concerns. What do you think? It's turning into shared decision-making, as opposed to your option of another course of BCG, valrubicin, which is not going to work, or cystectomy, go ahead and take your pick.

Well, there's not going to be a clear cut. Here's a neon sign that pops up that says, "Here's the next best option for you." That becomes abundantly clear. We've got options, and we didn't used to.