.png){kind=small}
.png){kind=small}
BackTable / Urology / Article
Bladder Cancer Treatment After BCG Failure
Sophie Frankenthal • Updated Apr 4, 2025 • 31 hits
High-risk non-muscle invasive bladder cancer (NMIBC) is an aggressive and often recurring form of bladder cancer that is confined to the inner lining of the bladder. Treatment decisions are complex, with the primary consideration being whether to pursue radical cystectomy or explore bladder-sparing alternatives. Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk NMIBC. However, when BCG fails – whether due to intolerance or resistance – it presents a significant challenge, necessitating alternative treatment options.
Urologic Oncologist Dr. Ashish Kamat covers the various subsets of BCG failure, explaining how it is identified through cytology and offering valuable insights into bladder cancer treatment options after BCG failure. This article features excerpts from the BackTable Urology Podcast. You can listen to the full episode below.
The BackTable Urology Brief
• Accurate classification of BCG failure (refractory, relapsing, intolerant) is important for prognosis and treatment decisions. BCG-refractory disease has worse outcomes than relapsing disease, making this distinction especially important.
• Positive cytology during BCG treatment requires careful evaluation. Although new-onset Carcinoma in situ (CIS) may resolve with further treatment, persistent or worsening CIS raises concern for BCG failure.
• Radical cystectomy is often the safest option for BCG-refractory disease, especially in the case of T1 high-grade disease. Bladder-sparing options like Pembrolizumab, Adstiladrin, or off-label Gemcitabine/Docetaxel may be considered for select patients.
• Reinduction BCG may be effective in certain cases, but alternative treatments like Pembrolizumab are preferred for patients at high risk of micrometastatic disease.
Table of Contents
(1) Defining BCG Failure
(2) The Role of Cytology in Identifying BCG Failure
(3) Bladder Cancer Treatment After BCG Failure: From Salvage Therapies to Radical Cystectomy
Defining BCG Failure
Precise classification of BCG failure is essential for guiding treatment decisions and determining eligibility for clinical trials. While “BCG unresponsive” is a regulatory term used for trial enrollment, clinicians must distinguish between BCG-refractory, relapsing, and intolerant disease to assess prognosis and guide therapy. BCG-refractory disease refers to a tumor that persists despite adequate BCG treatment. In contrast, BCG-relapsing disease describes a tumor that recurs after a disease-free interval. BCG-intolerant patients are those unable to tolerate BCG due to toxicity or other reasons. Refractory disease is associated with worse outcomes than relapsing disease, especially when recurrence occurs shortly after a disease-free period, making this distinction essential for both prognosis and treatment decisions.
[Dr. Aditya Bagrodia]
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.
Listen to the Full Podcast
Stay Up To Date
Follow:
Subscribe:
Sign Up:
The Role of Cytology in Identifying BCG Failure
Positive cytology during BCG treatment can indicate recurrence, prompting further evaluation. If there is no prior CIS, positive cytology should be followed by a thorough workup, including blue-light cystoscopy and assessment of the prostatic urethra and upper tracts. In cases where CIS was previously identified, however, early positive results may not influence management, as persistent CIS does not always indicate treatment failure. The emergence of new-onset CIS during BCG treatment raises concern, but it may still resolve with extended therapy, typically within six months, before being categorized as BCG-unresponsive. High-grade recurrence – whether Ta or T1 – suggests BCG unresponsiveness, particularly when tumors persist despite adequate BCG treatment.
[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.
Bladder Cancer Treatment After BCG Failure: From Salvage Therapies to Radical Cystectomy
BCG-refractory disease presents significant treatment challenges and often requires radical cystectomy. Specifically, the presence of T1 high-grade disease in the context of BCG failure raises concern for undetected muscle-invasive disease, in which case radical cystectomy is the safest option. However, bladder-sparing approaches such as clinical trial participation or off-label therapies like Gemcitabine/Docetaxel, may be considered for high-grade Ta disease.
FDA-approved therapies such as Pembrolizumab and Adstiladrin are also options, with Pembrolizumab preferred for patients at high risk for micrometastatic disease. In the absence of predictive markers, treatment decisions are largely based on clinical judgement.
Although reinduction BCG is not universally recommended, it may still be effective in select patients, underscoring the need for individualized treatment plans.
[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.
…
[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?
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.
Podcasts
Articles
Bladder Preservation for High-Grade NMIBC: Eligibility & Treatment Approach
Blue Light vs White Light Cystoscopy in Bladder Cancer
Blue Light Cystoscopy in Bladder Cancer: A Research-Based Perspective
High-Grade BCG-Unresponsive Bladder Cancer Management & Alternatives