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High-Grade BCG-Unresponsive Bladder Cancer: Management & Therapeutic Recommendations

Author Devante Delbrune covers High-Grade BCG-Unresponsive Bladder Cancer: Management & Therapeutic Recommendations on BackTable Urology

Devante Delbrune • Jan 19, 2023 • 34 hits

When a patient presents to the clinic with recurrent high-grade bladder cancer following Bacillus Calmette-Guerin (BCG) therapy, urologists work through a series of clinical questions to determine proper management of BCG-unresponsive disease. They may ask, “What is the subsequent management for these patients and what treatments are available?” and “Does the patient undergo cystectomy or additional BCG courses?” Dr. Aditya Bagrodia, Dr. Tim Clinton, and Dr. Eugene Pietzak answer these questions, provide recommendations for first-line therapy and alternative treatment options, and address promising future therapeutic agents for the management of high-grade BCG-unresponsive disease.

We’ve provided the highlight reel in this article, and you can listen to the full podcast below.

The BackTable Urology Brief

• Patients with high-grade BCG-unresponsive bladder cancer first undergo tissue biopsy which is then followed by treatment with TURBT. This procedure utilizes either blue light or narrowband imaging depending on pathology (e.g. Ta high-grade bladder cancer).

• Cystectomy is considered a last resort option unless patients are considered high risk based on factors such as increased age, high morbidity, or extensive nodular multifocal LVI pathology.

• Intravesical gemcitabine and docetaxel are first-line alternative therapies to cystectomy for BCG-unresponsive bladder cancer. Second and third-line alternative therapy recommendations are pembrolizumab and valrubicin, both of which are FDA-approved agents.

• Promising clinical trials for new therapeutic treatments for high-grade BCG-unresponsive disease include therapies that utilize CD20 agonists and N803 with BCG therapy. However, these therapies are still in their single-arm phase and require further comparison to other clinical trials.

Histology of high grade bladder cancer

Table of Contents

(1) High-Grade BCG-Unresponsive Bladder Cancer Management

(2) Alternatives to Cystectomy in High-Grade BCG-Unresponsive Bladder Cancer

(3) Promising Therapeutics for BCG-Unresponsive Bladder Cancer

High-Grade BCG-Unresponsive Bladder Cancer Management

Managing patients with BCG-unresponsive disease who present with CIS (carcinoma in situ) or Ta high grade bladder cancer have very similar management. In both instances, the patients undergo biopsies to establish cytology. For patients with CIS cytology, if there are no major concerns, they are started on BCG maintenance therapy. If a patient has already completed BCG maintenance therapy, they will undergo an additional maintenance therapy course, with an expected 50% rate of clinical response. For patients with Ta high grade bladder cancer, the next step is a transurethral resection of bladder tumor (TURBT) with blue light cystoscopy or narrowband imaging. Following cystoscopy and resection, maintenance BCG therapy begins. Maintenance therapy follows unless the patient is deemed high-risk or has no response to BCG maintenance therapy, in which case cystectomy is pursued.

High-risk patients are those with increased age, morbidity, unresectable cancer or concerning extensive invasion (e.g. sarcomatoid). Cystectomy may be considered earlier for patients with extensive nodular multifocal LVI. In high-risk patients, staging should be done and an initial CT scan should be obtained to identify any regional metastasis. Otherwise, cystectomy should be utilized as a last resort following other bladder-saving interventions.

[Dr. Aditya Bagrodia]
Great. CIS biopsy-proven basically gets a second induction of course if there's anything remarkably concerning that can be tailored. If it's a positive cytology without biopsy-proven continuum with maintenance, the patient could be counseled that if they're getting a second maintenance instead about a 50% response rate. That sounds about spot on. What if they've got something papillary and it's a Ta high-grade?

[Dr. Tim Clinton]
After BCG, I think as I mentioned earlier, I do all of these with blue light cystoscopy. Now we don't have it available in the office, but I think we're talking about already in the OR. This is where I would do a blue light transurethral resection of a bladder tumor to ensure that I get all of that papillary tumor out and anything surrounding it. I routinely see that there's either other tumors that were not seen on the white light cystoscopy in the office on the surveillance cysto. I do think there is added benefit and has been shown as well with blue light cystoscopy.

Or if you alternatively don't have that available and you utilize narrowband imaging, I think that's equally acceptable. It's your enhanced cystoscopy of choice, if you will, I think are very, very important. For these patients, if they're recurring already after BCG, you want to be as thorough as possible getting all of that papillary tumor out. If it's just Ta high-grade, again, we proceed with a second induction course at this point.


[Dr. Eugene Pietzak]
Yes, I would agree with what Tim said. In terms of some high-quality TURBT using enhanced cystoscopy. I'm a little bit more selective in blue light and the patients that I do that in routinely, but typically will do narrow band imaging just to, in my own personal experience out of 50 or 60 initial patients assessing blue light the clinical benefit of it. I didn't find to be any better than narrow band imaging but with that aside, I think doing a high-quality to TURBT identifying additional papillary tumors. Then once that is fully resected, then I would definitely retreat them with BCG if they have non-invasive disease. I think that's consistent with the AUA guidelines.

[...]

[Dr. Tim Clinton]
I typically would counsel I don't think that's a treatment failure by any accounts for BCG. I typically just try to explain to them that at the BCG is really good at eradicating high-grade disease and the biology of a low-grade tumor is a little bit different. Those patients, if they demonstrate that they have a low-grade recurrence, at least the initial one, I will typically post BCG do in the operating room. If they continue to have low-grade recurrences, which some patients do, those are things that I worry a little bit less about in terms of managing that in the office potentially with full duration if they're pretty small. Always try to do a biopsy on those patients if they had a high-grade Ta tumor at initial diagnosis or so. I worry a little bit less about those patients that have these low-grade recurrences post-BCG.

[...]


[Dr. Tim Clinton]
If this is a situation where I'm truly worried about these patient's concerns. I think there are a lot of factors that go into it. Both the tumor characteristics, multifocal, extent of lamina propria involvement. Is it multifocal? Is it extensive or is it minimal invasion? Is there associated CIS. All those tumor factors go into it, but also patient factors are very important. Is this a young and healthy male or is this a very comorbid individual that may be not the best cystectomy candidate? I think a lot of that goes into those discussions.



[Dr. Eugene Pietzak]
Yes, I would agree, and LVI is so uncommon in high-grade T1. That's a patient that I'd be really worried about and potentially even counseling that they may have nodal involvement and may need systemic therapy typically. At least in my experience, that would be after cystectomy verifying the pathology stage, verifying the nodes, but I know that there are some centers that advocate potentially for systemic therapy, even for these very high-risk T1 patients. I don't know if that's necessarily indicated or beneficial and I think the data is weak overall on that. Whenever you see a variant histology LVI, these very high-risk features, I think definitely counseling those patients towards cystectomy. I just worry we have very few effective bladder-preserving options after BCG has failed, and I think it's such a major unmet need and cystectomy is curative in the majority of these patients.


[Dr. Aditya Bagrodia]

I definitely think it's a good idea to stage them. I would get a CT scan chest, abdomen and pelvis personally if they've got persistent high-grade disease, T1, high-grade disease after induction BCG because you can have lymph node metastases or so forth in that clinical setting. By all means, Tim we didn't even have the upfront cystectomy conversation. T1 high grade with LVI sarcomatoid features, variant histologies, unresectable, et cetera, but totally point taken. It sounds like the preference would be cystectomy and totally agree with that. Now, what if the patient's unwilling or unfit to receive a cystectomy, what's your next go-to option here?

Listen to the Full Podcast

Management of BCG-refractory NMIBC with Dr. Timothy Clinton and Dr. Eugene Pietzak on the BackTable Urology Podcast)
Ep 64 Management of BCG-refractory NMIBC with Dr. Timothy Clinton and Dr. Eugene Pietzak
00:00 / 01:04

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Alternatives to Cystectomy in High-Grade BCG-Unresponsive Bladder Cancer

Not all patients with high-grade BCG-unresponsive bladder cancer are willing to undergo or qualify for cystectomy. For these patients, alternative treatment options are available. First-line recommendations for alternative interventions include intravesical gemcitabine and docetaxel. Second and third-line interventions include pembrolizumab and valrubicin, respectively, both of which are approved by the FDA. Limitations of pembrolizumab are its response rate (40% in 18 months), effectiveness (20% of patients disease-free following treatment), and increased drug toxicity. The major limitation for valrubicin is that, although it is approved for utilization, it is oftentimes not readily available for administration.

[Dr. Tim Clinton]
Yes, for us with these recurrent T1 high grades after BCG unwilling or unfit for a cystectomy, this is where you're looking at other alternative options now. If they're meeting the criteria here for BCG-unresponsive disease, you have a couple of different options. Our current preference at this point is the utilization of gemcitabine and docetaxel intravesical. FDA approval currently is just for valrubicin and pembrolizumab.

[Dr. Aditya Bagrodia]
Yes, comprehensively, the way I think about it is we have cystectomy, we have pembrolizumab, we've got Gem/Doce, we've got of course clinical trials. Valrubicin is an FDA-approved agent that I don't even really bring into the conversation. Then there's the stuff that's coming through the pipelines I think is exciting. Again, second induction course of BCG would be of those, and this is an opinion in this patient with large volume recurrent T1 high grade. While I am generally a fan of Gem/Doce, to me, I'm not super keen on another intravesical option, necessarily, if they've got a lot of early recurrent tumor. I would actually maybe lean towards pembro, but I'm curious to see what you all think.

[Dr. Eugene Pietzak]
If we're talking about our super high-risk, very high-risk T1 patient here, I think another potential option because this is a patient we're concerned that may have clinical under staging. I would completely agree that I would be uncomfortable with an intravesical option in this, although it's only been published in abstract form at this point. There is the chemoradiation potential option for some of these patients. I do discuss that for patients that I feel that they probably do have muscle-invasive disease even though clinically they're T1 and I counsel them as such.

Whether your early T1 post BCG would behave differently I think is a little bit unknown. but I do think that's an option for these very high-risk T1 patients for sure. For your run-of-the-mill high-grade T1 with BCG-unresponsive disease without significant multiple risk factors.

[...]

[Dr. Tim Clinton]
Any amount of a high-grade recurrence after adequate BCG is certainly concerning. I think it's never too early to start engaging in the idea of early and timely cystectomy just to put it on the table. For somebody who maybe it was difficult for them to get through those, just an induction and a maintenance course at BCG, the thought of undergoing any further intravesical therapies is pretty dissuading to a patient. They're ready to just get everything out. I don't think that's unreasonable.

If it's really just superficial single Ta lesion or something like this, now we're talking about really more second-line intravascular options. I tell them that, while the first-line option was BCG and unfortunately, they've had a recurrence, we have some other options available that seem to have pretty promising data. For us, we do lean on gemcitabine and docetaxel, and we've had pretty good success with it. Again, it's all based on retrospective data, so we do have to take that into consideration. At this time, these are easy drugs to get. They're cheap. In the absence of other clinical trials, which I also would get into, that's our second-line therapy at the moment.


[Dr. Eugene Pietzak]
I think, early on, having a discussion and introducing the concept of radical cystectomy in these patients that you're worried about, I think that's pretty important. I think emphasizing a lot of the quality of life data that is now emerging, suggesting that patients do go on to live healthy, fulfilling lives after cystectomy, and it is at this point in time, in 2022, the only real curative option after BCG fails. I think introducing that idea early on is important.

What I like about non-muscle invasive bladder cancer is you tend to develop relationships with patients as they go through multiple lines of therapy, et cetera. At least putting that on the back table, so to speak, as you go through the different bladder-preserving options, but my typical approach is BCG. If BCG is not working, then typically clinical trials, and if there-- well, cystectomy discussion versus clinical trials, and based off how worried I am about that patient.

If they're not eligible or not excited about the clinical trial options that are available to them, then our default option has also been the gemcitabine-docetaxel combination as well. I think I share both of your feelings that although it does seem promising, the data, the evidence is pretty weak and retrospective to support it.

I do worry that maybe this combination of gemcitabine and docetaxel may not be that much better than single agents. I think the science behind it, or the combination makes sense to me, and that's what we do for metastatic and muscle-invasive disease, but it will be nice to get some high-quality data to support what we're doing clinically.

[…]

[Dr. Eugene Pietzak]
I think it needs to be discussed with every patient because it is, besides valrubicin, which isn't really that readily available, it is the only FDA-approved drug. I think, at least in my practice, it always comes up in a discussion, mostly as an option. But because we have the availability to enroll in clinical trials with a component that has intravascular gemcitabine, I do send my patients with BCG-unresponsive disease to meet with a medical oncologist. They'll discuss pembrolizumab as a monotherapy.

Very rarely does the patient actually opt to go on that, but it's more for the discussion of pembrolizumab within the context of a clinical trial, or any immune checkpoint inhibitor within the context of a clinical trial. I think the data isn't very compelling. It's great that it was FDA-approved, but you know, it's a 40% response rate at three months, and beyond 12, 18 months or so, only about 20% of patients remain disease-free. I have a slide with a table on it that basically, with the expected response rates for the various options that are available to patients. Many patients will even decline meeting with a medical oncologist because neither one of us is very enthused about the potential results with pembrolizumab monotherapy.

Promising Therapeutics for BCG-Unresponsive Bladder Cancer

The current approved primary management methods and alternative therapies for BCG-unresponsive disease are the most studied therapeutics. However, there are equally as promising and potentially more effective medications currently undergoing clinical trials. The general approach to these clinical trials is investigating agents that are effective and biomarker-driven. The Bernie Bochner trial is one of the highlighted clinical trials which looks at utilizing CD20 agonists. Another promising clinical trial is testing the efficacy of N803 immunotherapy in conjunction with BCG. While initial data from trials appear to have clinical benefits in their current single-arm phase, the definitive efficacy of treatment should be determined via direct efficacy comparison.

[Dr. Aditya Bagrodia]
Yes, I think you're absolutely right. At this point, I'll typically start looking into things like tumor sequencing when I'm getting worried, and we can certainly envision a day where ultra patients would go on to something like erdafitinib. It's exciting, right? It's exciting that over the course of our careers, and we're not 1000 years old, we've seen these new changes, new options. I remember being at a dinner during residents with the Valstar people and just being like, "Oh, my gosh, I wouldn't even off this." It's disappointing, we get 10% response rate.

At least we have some other options now. We're coming on about an hour. It's been an amazing conversation. Clinical trials have come up, and I don't think we're going to be able to comprehensively run through all of them. Eugene's mentioned of IO, intravesical therapies, which I think are exciting. There's novel treatments, instiladrin, and things along those lines, there's the devices. Maybe I could just ask both of you all to share a couple of thoughts on what you're excited about.

[Dr. Tim Clinton]
You're right. There's so many options coming down the pipeline. There was even Vicinium, of course, which I think failed to get FDA approval. Now, with adstiladrin coming on, and I think they're seeking FDA approval. There's so many agents that are looking to advance in this space. I do think that there's a lot of renewed excitement, maybe is the idea, of some of the agents that you can put into the bladder. The pretzel, I think was popularized for a while there, and coming back online. There's just so many different agents, so I'll be interested to see what ultimately wins out.

To echo some of what Eugene said as well, I think the biomarker-driven strategy, whether it's a urinary-based assay, or if it's truly tissue-based, both would be exciting as far as helping guide maybe a little bit more precision-based treatment options for a lot of these patients, because I think there is a heterogeneous mix, even in the non-muscle invasive space.
[...]

[Dr. Aditya Bagrodia]
Have you ever heard of a CD20 agonist?

[Dr. Tim Clinton]
This is the Bernie Bochner trial.

[Dr. Eugene Pietzak]
It's anti-CD40 inside of Rockefeller. It's a clinical trial that we're running in Phase I. The preclinical data looks very promising.

[Dr. Aditya Bagrodia]
I agree with both of you in terms of there's a lot of things coming down the pipeline, and I think that is exciting, but it also presents challenges to us as a community as well. I think when you have almost a limitless number of agents and potential combinations, I think we as a community need to be thoughtful how we're going to do this. I think it's important to generate high-quality data that we can potentially assess. I completely agree with the idea that a lot of this should be biomarker-driven, within high-grade T1, within CIS, et cetera.

There's a lot of tremendous heterogeneity in terms of the biology of the tumors themselves. I think there's only a limited number of patients, it's certainly those that are going to be enrolling on clinical trials. I think some of these larger, more ambitious trials, unfortunately, are closing because failure to accrue. I think we need to be pretty thoughtful in how we develop these clinical trials or assess these drugs or combinations more quickly and more accurately. Whether that's a urine-based approach using urinary tumor DNA, et cetera, whatever it may be.

Get an idea, "Is this drug or this combination promising or not? Or, is the toxicity acceptable?" Because some of these systemic therapies are acceptable and patients with metastatic disease are going to be very willing to accept some of these toxicities. Someone with non-muscle invasive disease, when cystectomy is curative for these patients, they're going to be less tolerant of some of these immune adverse events like we have been discussing. I think moving forward being able to rapidly assess these drugs and combinations is going to be even more important.

I think in terms of therapies that should be readily available in the near future. I think the N-803 combination with BCG, that data looks fairly promising. Maybe this is just the skeptic in me in total. You got to wonder since BCG-unresponsive disease is just based off expert opinion, we actually don't know how the BCG alone would perform in some of these patients. I think some of these patients may derive benefit from BCG, not suggesting that they receive it, but I wonder how much of that efficacy we're seeing is from the actual IL-15 superagonist versus from the BCG retreatment. Not to end on sort of a down note, but I think a lot of that data may be generated in this BCG naïve trial that they're running comparing this combination versus BCG.

[Dr. Tim Clinton]
Yes, I think you brought up a good point was just that as we're looking at all of these trials that are coming down the line, ultimately we'll have to compare them head to head. We keep using these tables and looking at response rates at 3 and 12 months. We have to actually compare these head to head ultimately in sort of better trial designs ultimately. I think you're exactly right.

[Dr. Eugene Pietzak]
Yes, 100% agree with you. I think BCG unresponsive criteria is very helpful in sort of building some momentum to these single-arm trials and coming up with things to potentially test. Cross trial comparisons are fraught with a lot of issues. Again, not to end this on a downer, but I also do worry that like some of the data that we're seeing may be more of a natural history type of situation with BCG-unresponsive disease. The fact that instiladrin, the fact that pembro, insineum, et cetera, we're seeing like a 40 to 50% initial response rate.

Then seems to all drop down to about 20% beyond 12-18 months or so. That has me a little bit worried. Some of that may be therapeutic effect from TUR as suggested a believer in that. That's why I think the N-803 plus BCG data, that seems more promising. Maybe there is a little bit more activity there than elsewhere, but I agree 100% that the only way to know that is to compare some of these agents head to head. It's just if you were a patient or for your own patients, like would you really want to be randomized to pembrolizumab? I think investigator choice randomization is also a little bit challenging or presents some challenges.

Podcast Contributors

Dr. Timothy Clinton discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

Dr. Timothy Clinton

Dr. Timothy Clinton is a urologic oncologist with Brigham and Women’s Hospital in Boston, Massachussetts.

Dr. Eugene Pietzak discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

Dr. Eugene Pietzak

Dr. Eugene Pietzak is a urologic oncologist with Memoral Sloan Kettering in New York City.

Dr. Aditya Bagrodia discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

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). (2022, November 9). Ep. 64 – Management of BCG-refractory 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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