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BackTable / Urology / Podcast / Transcript #177
Podcast Transcript: Latest Approaches to Treat High-Risk NMIBC
with Dr. Ashish Kamat
Dr. Ashish Kamat discusses contemporary management of high-risk, non-muscle-invasive bladder cancer (NMIBC) and his thoughts into the future of this arena. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) TURBT Planning & Technique
(2) Recurrence & Progression: Key Considerations for Patient Counseling
(3) Bladder Preservation vs. Radical Cystectomy
(4) Reassessing Risk in High-Grade Bladder Cancer
(5) Emerging Therapies for High-Grade Bladder Cancer
(6) BCG Dosing Strategies
(7) Evaluating Cytology in the Context of BCG Therapy
(8) BCG-Refractory Disease: Defining Failure & Reassessing Treatment
(9) Chemoradiation, Intravesical Therapy, & Clinical Trials
(10) The Future of Bladder Cancer Management
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[Dr. Aditya Bagrodia]
…I feel like this is a conversation with a true living legend in urology, particularly as it pertains to bladder cancer, clinical management, translational management, really driving the next generation of treatment. A lot of it's really come out of your lab.
[Dr. Aditya Bagrodia]
Today, the focus of our conversation is going to be on high-risk, non-muscle-invasive bladder cancer. Ashish, maybe I'll ask you to just take a walk down memory lane. Ten years ago, what did this conversation look like when you met somebody with newly diagnosed high-risk, non-muscle-invasive bladder cancer?
[Dr. Ashish Kamat]
Aditya, it's interesting you ask that, right, because 10 years ago, there wasn't that much activity in the world of bladder cancer. We had BCG, and we had maybe a little chemotherapy here and there we could trickle in. The conversation with patients really was more about, okay, let's try A. If A doesn't work, let's try B, and then move on, right? In some ways, it made that conversation with the patients simple, but a little too simple.
I'm glad that things have evolved. The understanding of bladder cancer, the understanding of risk stratification, what exactly is high-risk, what's intermediate risk, what's lower risk, and how do we actually tailor and personalize treatment to the individual patient is really a fascinating evolution in a very relatively narrow subset of patients that we treat in neurologic oncology. It's been a remarkable improvement in everything that we've seen, and you've been part of it too, over the last 10 years.
(1) TURBT Planning & Technique
[Dr. Aditya Bagrodia]
Couldn’t agree more. Obviously, that's a nuanced question in and of itself, but let's jump on into it. Obviously, you're at a quaternary referral center. You're probably not seeing tons of microhematuria, gross hematuria. Just so we can level set new diagnosis, whether that's suspicious imaging, staging for somebody that you're even remotely thinking that they could have a high-grade bladder cancer.
[Dr. Ashish Kamat]
Yes. Like you alluded to, most patients that come to see me already have a good set of workup being done, right? What does that workup consist of? Clearly, nowadays, most people default to CT urogram as a workup for hematuria. Patients have CT urograms. They have usually a UA that shows blood and urine, and if they don't, I think a cytology is critical before you take the patient to the OR because it helps us know before we go in, does the patient have high-grade or low-grade, right? If it's a high-grade positive cytology, you tend to think of the TURBT a little bit differently.
The TURBT is one of these really under-appreciated and under-recognized nuanced procedures that we tend to leave to junior residents, rightfully so because they need to learn how to do it. It's the first and most important step in the management of every bladder cancer patient. Knowing what you're going to do when you go in there, having a game plan. If it's high-grade disease, it's likely to be high-risk disease, resect the tumor, get muscle, send a separate specimen off the base of the tumor, maybe do some directed biopsies or blue-light directed biopsies. It really helps to have that cytology before you go in as well.
[Dr. Aditya Bagrodia]
Whether it's an initial or a restaging and you're with the fellows and the residents, what is the ‘this is what an Ashish Kamat TURBT should look like’, these are the critical elements of the operative report. Can you walk us through that a bit?
[Dr. Ashish Kamat]
It's a game plan, Aditya. You've got to have a game plan, right? Whether it's doing it with me, doing it with someone else; develop a game plan, refine it, and stick to it. That game plan should pretty much involve some of the elements that we talked about already, knowing what the cytology is, knowing the location of the tumor, because it starts with that communication with the anesthesiologist. This tumor is lateral. I think I'm going to have to go deep. I might get that obturator reflex kicking me and then causing a perforation. Let me get the patient paralyzed, right? The positioning, all of that goes into play.
The actual TURBT, you need to-- and again, we know this, you and I know this, but for the residents and the fellows, they need to know the nuances of the energy device they're using. I tend to prefer bipolar, nothing against monopolar, I tend to prefer bipolar. Even within the bipolar machine, there are nuances of settings that allow you to do a little bit more, a little bit less, do like an on block versus a non-on block resection. That game plan needs to be developed before you actually put the scope in.
Once the scope's in, have a plan to map the bladder. Locate the different areas of the bladder, know where the tumors are, and then develop a plan for resecting the tumor that's going to give you the most information first, knowing that you're going to do a complete TURBT. If something happens, right, anesthesia-wise or bleeding-wise, or something, know that the best bang for your buck tumor is the one you should get out first.
[Dr. Aditya Bagrodia]
Yes, I love that. I love that. I think it really behooves us. I always tell the residents, especially when they're in scenarios that are resident-dominant, let's just say, the basics, the size, the focality, did you visibly resect everything? Did there appear to be any carcinoma in situ? Because our pathology colleagues, by all means, they're trying their best, but these can be challenging situations. Are you using blue-light generally in the operating room for your resections?
[Dr. Ashish Kamat]
I use blue-light quite a fair amount, but selectively, right? Because if you look at the studies that we and others were part of, the original studies in 2008, really the indication was for anybody with suspicion of CIS or papillary disease. The indication was papillary, but we use it for anybody with suspicion of CIS as well. That's a little bit of an oversimplification, so I tend to use it a good amount, but it's not a 100% penetrance in the TURBT, because you don't really need it for every patient.
You made a really good point, which I want to bring up. Those points that you mentioned, focality, number of tumors, location of tumors, I think it's crucial, whichever record-keeping system you use, and by you, I mean the audience that's listening, whether it's Epic or otherwise, develop a template that mandates that the operative note has all those elements, right?
Did I get muscle? If I didn't get muscle knowingly, why not? There might be a reason. If I didn't go deep on purpose because, for example, I thought it's a low-grade disease, that's fine. Did I use perioperative chemotherapy? Yes/no. If no, why not, right? Was it too close to the UO? Et cetera. Did I use blue-light? Yes/no. If no, why not? Those should be just part of our routine checklist that we have in our operative note template. You can't get away by not documenting them, right? If it's in the template, it forces you. It's a hard stop. You have to fill in those boxes.
(2) Recurrence & Progression: Key Considerations for Patient Counseling
[Dr. Aditya Bagrodia]
Perfect. I love that. I love that. You've done the TURBT. TURBTs, I tend to agree with you. They're such an incredible piece. They're fascinating. The tips and tricks are abound. Let's say, the patient's in your office in a week or so. The pathology's back. They're doing fine. Let's focus our conversation on patients with high-grade disease. The low grades, we'll just if this is okay, put those in a separate category as a little bit of a different beast here. Walk us through how this conversation starts with you.
[Dr. Ashish Kamat]
Again, I want to compliment you for saying high-grade and not high-risk, because if you really look at the risk classification, the AUA includes high-grade disease as intermediate risk, right? The International Bladder Cancer Group doesn't do that. CITSI doesn't do that. You also said high-grade, implying high-risk. Right off the bat, I think any high-grade tumor should be considered high-risk. That's how I have my conversation with the patient, right?
Because if the tumor is high-grade, and we nowadays talk about low-grade and high-grade, we've gone away from the nuances of Grade 1, 2, and 3, even though there's a push now to go to 1, 2, 3, and 4. Let's assume your pathology does high-grade, low-grade, and the patient is high-grade disease. What you are worried about on behalf of the patient is not just the potential for recurrence, but for progression of disease. Progression of disease, under-staging of disease.
It's a conversation that starts educating the patient that, okay, we're going to work towards recurring the number of times this tumor comes back. At any given point, we have to worry that this tumor is going to progress. If it progresses, either in grade from low-grade, which I know we're not talking about, but goes to high-grade, or stage from TA to T1, and definitely T1 to T2, we've got to have a trigger to go to a treatment that's going to avoid the morbidity of metastatic disease and the mortality that accompanies that.
That's where I level set with my patients going in, because otherwise, too many patients come to see me, and I'm sure they come to see you from sometimes referring centers, where they're told, "Oh, it's just a superficial tumor. Don't worry about it, we got it." I think that term superficial is a misnomer, especially for T1 disease. It's very important to set expectations in the patient's minds as to what the journey is going to entail.
[Dr. Aditya Bagrodia]
Perfect. That's about it. We've got two outcomes of interest here, recurrence and progression. Recurrence is oversimplified or inconvenient. Progression events, these are life-altering interventions, a threat to your life, and these are the ones that we really are trying to ward off here. We've had that conversation, and I will say that creating some of this patient education on the front end, where I tell them, once your pathology is back, I'm going to share that with you so you can educate yourself.
BCAN is a wonderful resource, of course. I've also created a couple of videos that I share with patients. By all means, this podcast is going to go on there, so patients can think about how physicians are thinking about it. When they come in, we can really start having a conversation, not just about grade and stage, and muscle, and LVI, and variance, and all of that, but let's you and I have that conversation.
(3) Bladder Preservation vs. Radical Cystectomy
[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]
Absolutely. 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.
(4) Reassessing Risk in High-Grade Bladder Cancer
[Dr. Aditya Bagrodia]
A couple of quick questions. High risk T1 high grade, whether the high risk is LVI or sub-histology, et cetera. Are you taking those patients back for a resection to confirm that they don't have muscle invasive bladder cancer would benefit from potentially neoadjuvant chemotherapy? Or if you've got muscle high risk T1, are you typically, okay, going to cystectomy, in that case?
[Dr. Ashish Kamat]
Yes. Again, that's a very nuanced question, right? At MD Anderson, we don't offer neoadjuvant chemotherapy to everybody with T2 disease. We only offer them to patients with T2 disease with histologic subtypes, T3B, hydronephrosis, LVI, et cetera. If they're T1 disease and they want to have a radical cystectomy, I would not take them back for a re-TUR unless imaging or something else suggests that they might've been under-staged.
On the other hand, if they want to save their bladder, I definitely take them back for a re-TUR because the risk of under-staging a T1 disease, especially if it has all those nuances you talked about, is 40% in the best of hands, right? Even if muscle's present, it's at least 20%. If a patient wants to embark on the journey to save his or her bladder, absolutely do a re-TUR for any T1 high-grade disease, even if I've done it myself because that 20% incidence does exist. MRI, VI-RADS, all of that are just adjuncts. They cannot replace a good quality repeat evaluation of the bladder and a re-TUR. Hope that answers your question.
[Dr. Aditya Bagrodia]
Totally. The T1 high-grades that are getting cystectomy, they're one path. The T1 high-grades, they all get a re-TUR. Are there any TA high-grade sub-scenarios where you really like to get another TUR before you commit them to management strategy A, B, or C?
[Dr. Ashish Kamat]
Yes, we put on the guidelines that patients with high-grade disease should be considered for re-TUR, and that's where that TA disease comes in. If a patient's TA high-grade and an expert such as yourself has done the resection, I don't necessarily take the patient back for re-TUR. If the patient's referred to me by someone, and I don't know that person, right, that person may be a phenomenal urologist, but I just don't know that person. I would prefer to go back and look again just to make sure that nothing was missed and that the resection in these was complete.
If the tumor is multifocal and even if I did the resection but I'm not 100% sure I got it all, then yes, I would go back. No, I don't routinely take every TA high-grade patient back to the OR for repeat resection and most of us don't.
[Dr. Aditya Bagrodia]
Okay, so now we've got our patient with or without a repeat TUR as clinically indicated. Are you using risk calculators? Do you sit down with EORTC risk calculators, CUETO tables or is this 20 years later, I've got a pretty good sense of how you're going to do with respect to recurrence and progression?
[Dr. Ashish Kamat]
I'm glad you brought that up, right? If you look at the risk calculators, and we published on this several times, they give you the risk of the patient's prognosis and outcomes without treatment. I don't think there's any patient that you and I are going to talk to that has high-grade, high-risk disease that we're going to say, "Okay, just go home, we're not going to treat you," right? If that patient asked me, "Hey, what if I have no treatment?" Then, sure, I'd plug them in the calculator. Those calculators are not useful for counseling patients that are actively pursuing treatment.
No, I don't use them as a matter of routine. I know our numbers. I know the current data. I'll tell the patient, I'll give them the numbers, but those calculators overestimate the risk of progression. In fact, in the EORTC most recent update, if you plug in the numbers for a patient that's very high-risk, it quotes you a 40% risk of progression and people get scared. We know that's without any treatment, right? You give them BCG, and we published on this too, the risk of progression is in the low teens, if not single digits. Got to keep that in mind.
[Dr. Aditya Bagrodia]
Perfect. I think in certain contexts, patients that are a little bit skeptical or maybe on one end of the spectrum where you're entertaining, deescalating, it makes some sense. In the garden variety patient, I think it's more just knowing the data. All right. High-grade, let's just say by definition, high-risk bladder cancer, generally speaking, they're getting something, not nothing. Is that fair?
[Dr. Ashish Kamat]
Absolutely. Absolutely. In the US, unfortunately, a large percentage of patients still get nothing. If you look at this year and the Medicare reporting, et cetera, but obviously, every patient should get some treatment.
(5) Emerging Therapies for High-Grade Bladder Cancer
[Dr. Aditya Bagrodia]
What does that look like? Maybe we could just throw it out there. Is everybody getting BCG? Are you putting patients on trial? How do you think about this for your newly diagnosed treatment, naive, high-grade, nominally sublateral cancer?
[Dr. Ashish Kamat]
Yes. It's been 40 plus years and the reigning king of the treatment, the best immunotherapy we have for cancer across all cancers, right, is still BCG. The response to BCG in bladder cancer is much better than immunotherapy for lung cancer or melanoma, or what have you. Yes, BCG is still the reigning king, the number one recommendation, but there's a global shortage.
In the era of global shortages, Mike O'Donnell and his group, and then all of us subsequently have adopted gemcitabine and docetaxel as a very reasonable alternative. Because of that, we have Max Kates leading the BRIDGE study, which is GemDoce versus BCG. I will offer that study to my patients because we have it here and say, "Hey, would you like to enroll in the study? We think they're two equivalent arms," but if the patient says, "What's current standard of care " It is BCG, induction, and then the SWOG protocol maintenance.
[Dr. Aditya Bagrodia]
I really appreciate you sharing that because it was something I thought about and honestly struggled with a little bit. We have this study open here as well. When you're talking to patients, I absolutely think there's equipoise. We've got our workhorse BCG, we've got a newcomer that has retrospective data suggesting it. To make the study appealing without imbalancing, I think is a bit challenging. I like that. We've got two good options here. One's a workhorse, one's a newer kid on the block, so to speak. Could there potentially be some theoretical benefits other than the population level shortages of GemDoce as it?
[Dr. Ashish Kamat]
It's, a lot of this is hypothesis generating, right? Because one of the things is, would it make sense to use GemDoce first and then would the rescue with immunotherapy BCG be better, or is it better to do BCG first and rescue with GemDoce? We don't know. That's why the trial is good to answer that question.
The other thing is, are you going to combine a checkpoint inhibitor or some other immunological agent with GemDoce, or are you going to combine it with BCG? We have, of course, N803, which is in combination with BCG. For the BCG-unresponsive patients, it's IL-15. With Pembro and BCG, those studies, is that going to show an efficacy with GemDoce? There's a lot of data to be gained from the clinical study that I think will really help us inform the next generation of treatments for patients and even how to sequence these treatments.
[Dr. Aditya Bagrodia]
Yes. Honestly, that's the whole second half of this conversation. As we're get more and more tools in our toolkit, it's going to-- I can envision a day where in the not too distant future, we're going to be like in kidney cancer world where it's crossover designs and so forth. We'll get there, of course. You all have published on this with the shortages. This is something front and center for us. Literally, it's like, who can get what? It's so frustrating. I know it's a reality for so many people.
(6) BCG Dosing Strategies
[Dr. Aditya Bagrodia]
The induction for BCG, really try to get a full dose in there, is that something that you think is important? Then maintenance, how much and what type of dilutions, if any, are acceptable?
[Dr. Ashish Kamat]
Yes. I'm going to be controversial with my response to that question, right? Because, yes, as a society, we put out guidelines to recommend at least full dose induction and then maintenance can be done at one third dose, so that you can give three patients a treatment on each vial. If you really look at the way BCG is manufactured, whether it's the most common manufacturer in North America or if it's any other manufacturer, there's a hundred-fold variation in the colony forming units from each vial of BCG from batch to batch.
One of my former fellows, Nate Brooks, he did the study and we published on it. If you look at a vial of BCG and compare it to the next vial of BCG, and the next one, you could have a hundred-fold variation. If you take a vial that has one hundredth the CFUs and give a patient a full dose, you're giving that patient one hundredth of somebody else. If you take someone that has a hundred times the CFUs and give them one third, they're still getting 30 times this patient, right?
That's why all the studies suggest that reduced dose BCG is just as efficacious. It makes perfect sense because we can't control for a hundred-fold variation. That's why I think this whole thing about full dose and one third dose, which one is better was answered very eloquently in the EORTC study that showed that dose really doesn't matter that much. It's duration that's important. Because of that, I always, always, always stress that if you can give less dose but longer duration, do it, right?
Try to get your patients to three years, especially the T1s and the CIS. TAs, if you don't have enough BCG and you have to stop at a year, that's okay. You can stop at a year. They will have higher recurrences, but as we know, a TA recurrence is not as dangerous as a T1 recurrence and a CIS clearly, it's even worse than a TA. That's what we do. No, at MD Anderson, we don't do full dose induction. We do one third induction right off the bat and very able to give more patients BCG that way.
[Dr. Aditya Bagrodia]
I appreciate you sharing that. There's obviously some different takes on this. Where I trained at Memorial, it was a little bit more induction forward, if you will. Then the duration of maintenance deprioritized a bit, however you want to phrase that. I do know for the BRIDGE Study that they do need to get a full dose induction as a thing just to standardize that and maybe get away from some of that variability. That's what I love about these conversations, is because you get all the different perspectives.
All right. If you've gotten their induction course of BCG or maybe GemDoce if they're on trial and their three-month Cysto rolls up, maybe we can think about the starting being papillary disease with or without CIS. Then this first month Cysto, we can run through it starting out with totally clean normal cytology, atypical cytology, suspicious cytology, high-grade cytology, and then papillary tumor with or without CIS. This is a lot to, I guess, unpack here, but maybe how I'm thinking about it.
(7) Evaluating Cytology in the Context of BCG Therapy
[Dr. Aditya Bagrodia]
Let's just start out with the bladders. Okay. Cytology is not normal, worried, not worried. How do you approach that scenario?
[Dr. Ashish Kamat]
Aditya, if the patient has CIS, like you mentioned, I don't even get a cytology at the first cystoscopy, right? Because it's really a piece of information that ends up being non-informative because the cytology is positive. Is it positive because of CIS? If so, you're not going to do anything anyways, right? You don't really care if the CIS is there at three months because you haven't given BCG time to work. If there is CIS, I wouldn't get a cytology. Let's assume there was no CIS and then the cystoscopy is completely normal and the cytology is negative. That patient's currently NED, so I'd continue on maintenance therapy.
[Dr. Aditya Bagrodia]
Okay. Cytology positive, no initial CIS?
[Dr. Ashish Kamat]
Yes. If there's no initial CIS and the cytology is positive, then I'm worried. I'm worried that I'm not seeing something in the bladder. I presume that I have already imaged the upper tracts just three months ago, but if I hadn't, I would worry there's something in the upper tracts. I'd also worry there's something in the prostatic urethra in men because that's a site that might not have been sampled early on.
The bottom line is this is a patient I would take to the OR for blue-light cystoscopy. If I don't see anything in the clinic and the cytology is positive, that patient is getting counseled by me that, "Hey, we need to go back to the OR, use blue-light. If I don't see anything with the blue-light, then I'm going to look in the prostate, upper tracts, what have you. If I see something with the blue-light, I know what I'm looking at and we'll do some biopsies there."
[Dr. Aditya Bagrodia]
Okay. Do you do much office flexible blue-light or is this primarily in the operating room for you?
[Dr. Ashish Kamat]
We used to, Aditya, but then STORZ withdrew the support for the Office Tower and we no longer have the Office Tower anymore. I know some places were allowed to keep their office towers if they had them, and some places weren't. We don't have an office tower anymore and STORZ is not going to provide any more equipment.
[Dr. Aditya Bagrodia]
Okay. Prosthetic urethra, upper tracts, if the bladder is looking okay, warrant a little bit of additional work. All right. Erythematous patch, even on Flexistol in the office, concerning for CIS, positive cytology in a patient that previously didn't have CIS.
[Dr. Ashish Kamat]
That's worrisome. If CIS is developing on BCG immunotherapy, that's actually worrisome, right? If the patient had CIS previously that was missed and now you're seeing it, but you said it's visible, so it's actually getting worse, that's worrisome. That patient, we would all consider being BCG unresponsive.
You would document that on a biopsy, but giving the patient the benefit of the doubt and knowing that roughly 65% of CISs take six months to respond, I would still give that patient the opportunity to get another course of BCG, a maintenance course, or a re-induction, depending on if they did not get the full induction first for the CIS to see if it goes away at that six-month cystoscopy. That's a patient I would file at the back of my mind as being high risk potentially for being BCG unresponsive, but hasn't met that criteria yet.
[Dr. Aditya Bagrodia]
Yes. I think this is all-- every one of these times that there's a recurrence in my mind, it goes back to, am I potentially putting this patient at risk of a missed opportunity of a wonderful cure if we wait three months? A patch here or there with a bladder doesn't look awful. The short answer is I don't think I'm putting that patient at risk and we can try something in the interim. Again, though, that conversation about if this starts really progressing and heading in the wrong direction, we may be looking at more involved treatments. Okay. TA high-grade, BCG, TA high-grade.
[Dr. Ashish Kamat]
That patient really is BCG unresponsive, but BCG refractory, right? That patient now gets that conversation about, hey, standard of care, radical cystectomy, but do you have TA high-grade disease? I think it's safe to try and save the bladder. We have a clinical trial and we do. If you didn't have a clinical trial, then we have GemDoce, which is a great non-approved off-label option, or we have some approved drugs that could also try, right? Those are Pembro and Adstiladrin, which is now actually available and ready to be used.
[Dr. Aditya Bagrodia]
Then for the sake of completeness, T1 high-grade, BCG, T1 high-grade, are these-- well, I don't want to color your comments here.
[Dr. Ashish Kamat]
No, feel free to color it, because I think you and I, we're going to say the same thing, right? Again, that patient also falls in the bucket of being BCG unresponsive, but that's a patient that is at a higher risk of having T2 disease that's not recognized. We're only trying to convince that patient, "Hey, remember we talked about cystectomy when you had that initial T1? We're talking now, and I'm really telling you that my primary recommendation still is a radical cystectomy. Do you want to go for it or not?"
If a patient still says no, then I would. I don't think it's unsafe. Even at this point, I don't think it's really unsafe, so long as that patient is willing to go on treatment X, whatever that is, and be closely monitored. Come back for that three-month cystoscopy. Do whatever needs to be done, not like just disappear. I think it's okay to give the patient at least one more shot, even with T1 disease, but if they ask me point blank, what's the safest oncologic option, it is a radical cystectomy.
(8) BCG-Refractory Disease: Defining Failure & Reassessing Treatment
[Dr. Aditya Bagrodia]
Okay. A couple of terms that you and I are familiar with that you mentioned, BCG refractory, we didn't really touch on BCG intolerant. Maybe a couple of the terms that you find yourself using and how you explain them to patients while we're talking about this disease state now.
[Dr. Ashish Kamat]
Yes. I brought up the term BCG unresponsive, right? That was a term that a group of experts, the International Biotic Cancer Group, and then the GU-ASCO group led by Seth Lerner, along with the FDA and the AUA, like different iterations came together mainly to create the definition to help clinical trials. That's not and never was meant to be a terminology to be used in the clinic. I know a lot of people use it in the clinic, and you and I have been talking about it in that term, but it was never meant to say that that patient is BCG unresponsive, and hence you should do this treatment.
It was merely to tell the FDA, and the FDA to then, in turn, tell pharma companies and investigators that, "Okay, you can enroll that patient in a single-arm study, and we will consider the data to allow the drug to be approved." The other terms are something that really make a lot more sense when we're thinking about and talking to the patient. Any patient who has a tumor despite BCG essentially falls in the category of BCG having failed in that patient, right?
Then is that BCG intolerant? Patient could not get adequate BCG at all, so that's BCG intolerant. Did the tumor ever go away and then come back? That's BCG relapsing because there was a disease-free interval. Did the tumor never go away? That's BCG refractory. There's enough evidence in small retrospective series, including some of ours, to suggest that the refractory patients tend to do a little bit worse than the relapsing patients, especially if the relapsing patients had a more than 18- to 24-month interval where they were disease-free.
That's what I will use to let the patient know what risk bucket they fall into, even within this, BCG failure bucket. Yes, it's a nuanced discussion. Some patients don't want to hear all this, right? Then just tell me, what are my chances? Some patients are like, "Well, what exact bucket do I fall in?" I think we have to tailor our discussion according to how much the patient wants to know, too.
[Dr. Aditya Bagrodia]
Absolutely. I can't help but chuckle. I see patients in a lot of different contexts, a lot of different backgrounds, and I think, it's absolutely incumbent on us to be able to have that conversation and in as much detail as the patient wants. With more and more information out there, they're coming in well-educated, no question about it. Maybe let's just talk about how you think about the comprehensive armamentarium of tools in your toolkit today when you have a patient that essentially has BCG refractory disease.
[Dr. Ashish Kamat]
Yes. If a patient has BCG refractory disease, right, that is pretty much the big unmet need several years ago where there was nothing really happening. We had one approved drug, valrubicin, which had a 4% two-year disease-free survival, and then we had nothing else. Now we have a whole bunch of drugs out there, some that are approved, some that are likely to be approved by the time this podcast is released, and some that are on their way to being approved in clinical trials. There's a lot of different moving parts here.
I think the unfortunate thing for us still is that there is no predictive marker, and maybe we'll have some, but we just did a retreat here in Houston last year at the International Bladder Cancer Group, spent a whole day and a half dissecting exactly this question. Which agent to use at what time after BCG? Do we have markers, not? The bottom line is, no. There's no predictive marker at this point that helps us predict which salvage treatment is appropriate for which patient.
At this point, it's a discussion with the patient. It's, okay, we have these three things available right now for use in the clinic. One is pembrolizumab, which is approved. Adstiladrin approved. GemDoce, non-approved, but like the de facto standard in the US. We have clinical trials that we could enroll you in. Then that question comes up from the patient, right? Well, what would you do? That's where you and I have to figure out, what would we do if we were in the patient's shoes?
Personally, if I had a patient in front of me that had BCG refractory disease and had a high likelihood of having micro metastatic disease, I think that's a patient whom I would lean more towards Pembro because it has some systemic activity. Short of that, my current recommendation outside of a clinical trial for patients is gemcitabine and docetaxel.
[Dr. Aditya Bagrodia]
Yes. I think, it's a little hard for me to, I guess if I'm worried, then it's going to be more, of course, cystectomy is a part of this conversation. Pembro, if I'm less worried, it's going to be more intravascular disease. I don't do a lot of reinduction BCG for BCG refractory disease. Maybe get your opinion on that before we put a nail in that coffin or resurrect it.
[Dr. Ashish Kamat]
Yes. I don't think we're going to put a nail in that coffin, right? Because what's happened is exactly because of the misconception that BCG and responsive terminology means it's a clinical definition, a lot of people think that if a patient is BCG unresponsive, it means you should never do any more BCG. That's not true, right? Again, most patients will not do well with BCG, but we actually looked at this and one of our fellows presented the data at the EAU recently and got an award for it.
If you select our patients appropriately, and again, there's no real way to select it other than the nuances that you and I have been talking about. With repeat BCG in our series of patients that were BCG unresponsive, the CR at 3 months was 73%, duration of response 80 months, right? Clearly, BCG does have a role to play in selected patients. It's not for everybody. It's something just to have a discussion with the patient.
I know the folks in New York use reinduction much more than we do or other people do as well, but there is a role for more BCG, but it's not something where we would tell everybody to get more BCG. Because if they have not responded to BCG and we have other options, why not try something else and then come back to BCG if you need to in the future?
(9) Chemoradiation, Intravesical Therapy, & Clinical Trials
[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. Maybe I'll ask you a couple of questions down the way. Clinical trials, you mentioned the definitions put together by the International Bladder Cancer Group for single-arm studies. Single-arm studies, are those even going to be a part of how we manage this disease? Is that going to work anymore?
[Dr. Ashish Kamat]
I've been a strong proponent of vocally saying that we need to get away from single-arm studies, right? The whole reason that the groups and the FDA adopted that BCG-unresponsive definition was because nothing was happening. Now, a lot has happened. We've talked about the drugs that are approved, but of course, there are other agents, such as N803 plus BCG, which has its PDUFA coming up. There's CG oncology's drug, Cretostimogene, which has really good results. Johnson & Johnson's agent R200, which has good results. The N-gene trial.
There's lots of good agents that potentially could be approved. Are we just going to stick-- well, for those that have already started the trials and are almost finishing, sure, let them finish out their single-arm studies. Let the FDA be true to their letter. I think we need to now require a control arm, right? We need to have a control arm against something, because we can't continue to go on these single-arm studies giving these hugely variable numbers.
Is it because patient selection has gotten better that we are seeing better results with the newer drugs? Are you and I recognizing that a particular type of tumor is better responding? Are we allowing re-induction, right? With Pembro, if a patient recurred, they came off steady. With Adstiladrin, if they recurred, they came off steady. With all the other drugs, if they recurred but then progressed, they were allowed the option of repeat treatment. Is that what's driving the response rates? We don't know. I think it's high time we start saying, let's do good quality trials, and a good quality trial requires a control arm.
(10) The Future of Bladder Cancer Management
[Dr. Aditya Bagrodia]
Yes, I appreciate you sharing that, and I tend to agree. I also think it's important, we have made tremendous strides. It's easy enough to play Monday morning quarterback, and sit back and judge, but it is really nice to see that now we do have, I would say, more robust controls than existed. In my show notes here, I had, what are you most excited about? You named, this is amazing, four studies just off the cuff that are going to be reading out in the next four to six months, and that could be practice changing, J&J, CG oncology, ImmunityBio with the IL-15 superagonist.
Earlier, you talked about a day and a half discussing biomarkers and predictive. We've got new drugs coming through the pipeline, work to be done on biomarkers. What else makes you optimistic and excited about the future?
[Dr. Ashish Kamat]
When it comes to bladder cancer, you mean, right?
[Dr. Aditya Bagrodia]
Yes. We'll stay on topic. Otherwise, it could be another hour.
[Dr. Ashish Kamat]
It's an exciting time to be in bladder cancer for us, right? For us that have seen not much happening and now so much happening, I think markers, right? Predictive and prognostic, and companion diagnostic markers are really where we need to focus our energies, and people are doing that. There's urinary CTDNA. It's like we've used fish for many years, and fish is coming back to see whether we can actually couple that with response to some of these newer agents.
I think the ability to allow us to figure out which drug for what patient, I think, should be the next goal for everybody doing research in this field, because like you said, there's no clear winner, right? It's going to be, yes, the response rate is X, and you're going to offer the patient the different treatments. Each patient is going to look at us and say, "Well, what should I get?" Then we're going to have to go back to stage, grade, nuances.
Which, again, don't get me wrong, they're great clinical parameters that allow us to make decisions to patients, but we're in a modern era. We have machine learning tools. We have the ability to do AI on pathology. We have the ability to do genome sequencing, which we do, but we haven't yet come upon a signature that predicts response to any of these agents, so we need to, right? The bottom line is that's what I'm excited about, finding someone that comes and does the data, or us, you or I doing it, and figuring out what's the marker that lets us predict what drug for which patient.
[Dr. Aditya Bagrodia]
I love that. Ashish, I've learned a tremendous amount over the course of our time together. Thank you. Thank you for sharing your insight and your expertise. As we come across an hour here, and I really do think I could talk to you another hour about this, what are some parting thoughts for the listenership?
[Dr. Ashish Kamat]
Parting thoughts for listenership, since we're talking about high-grade disease, is make sure you diagnose high-grade disease, assign it the appropriate risk category, which is high-risk, make sure the patient's not under-staged, make sure the patient understands the importance and the aggressiveness of the disease, because the biggest disservice we can do our patient is give them a complete false sense of security that lulls the patient into not wanting or not being able to be motivated enough to do the treatment right, right?
Then after that, it's standard of care, which is currently BCG immunotherapy, GemDoce is an option, but on a clinical trial, and then it's all these other agents that are available. It's up to us to be better stewards of not only the response rate discussion with the patient, but also remember, healthcare dollars, right? They're precious. We need to make sure we don't waste resources, which is dollars, but also don't waste resources, which is a patient's lives. We have to recognize that window of opportunity for cure.
If we think, you and I, that a patient in front of us is not going to have a good outcome as far as morbidity and mortality is concerned from the bladder cancer, pull the trigger and reinforce the bladder should come out at this point, right? The whole journey that we talked about in a nutshell.
[Dr. Aditya Bagrodia]
Well, thank you. Thank you, Ashish. Congrats on the work that you've done in this field, really across the spectrum and ultimately, of course, benefiting our patients who are True North. All right. We'll look forward to seeing you at the AUA here in San Antonio, and keep it up.
Podcast Contributors
Dr. Ashish Kamat
Dr. Ashish M. Kamat is a professor of Urologic Oncology and Cancer Research at M.D. Anderson Cancer Center in Houston, Texas.
Dr. Aditya Bagrodia
Dr. Aditya Bagrodia is an associate professor of urology and genitourinary oncology team leader at UC San Diego Health in California and adjunct professor of urology at UT Southwestern.
Cite This Podcast
BackTable, LLC (Producer). (2024, July 9). Ep. 177 – Latest Approaches to Treat High-Risk NMIBC [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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