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BackTable / Urology / Article
Recommendations for BCG-Unresponsive Bladder Cancer
Devante Delbrune • Updated Jan 19, 2023 • 129 hits
Bacille Calmette-Guerin (BCG), a commonly utilized treatment for nonmuscular invasive bladder cancer (NMIBC), is not 100% effective. When treatment fails, cancer can recur and is then classified as BCG-refractory bladder cancer. Due to previously undefined diagnosis criteria, these patients have been inconsistently further categorized as having BCG-unresponsive disease. These inconsistencies lead to incorrect patient communication and treatment recommendations. Urologic oncologists Dr. Aditya Bagrodia, Dr. Tim Clinton, and Dr. Eugene Pietzak explain specific diagnostic criteria and the overall framework and hierarchy of treatment for BCG-unresponsive bladder cancer.
This article features excerpts from the BackTable Urology Podcast. We’ve provided the highlight reel in this article, and you can listen to the full podcast below.
The BackTable Urology Brief
• If a patient receives 5 out of 6 BCG induction doses with 2 out of 6 second induction doses or 2 out of 3 maintenance doses it is considered adequate BCG therapy.
• The FDA criteria for a diagnosis of BCG-unresponsive bladder cancer indicates that a patient must have a T1 high-grade tumor after an induction BCG course, a recurrent Ta/T1 tumor within 6 months, or CIS with or without T1/Ta within 12 months following adequate BCG treatment.
• Patient counseling for BCG-refractory disease or initial BCG consultation includes a discussion of the treatment time course, side effects (e.g vestibulodynia, dysuria, etc.), and the likelihood of treatment success (upwards of 80% in patients following the induction course).
• BCG dosing resources are limited and typically patients undergo an induction treatment followed by maintenance dosing administered at 3, 6, and 12 months, but this can vary based on the grade of the recurrent disease.
Table of Contents
(1) Defining BCG-Unresponsive Bladder Cancer
(2) Patient Counseling & Treatment Induction for BCG-Unresponsive NMIBC
(3) BCG Prioritization & Maintenance Dosing Recommendations
Defining BCG-Unresponsive Bladder Cancer
Patients with BCG-refractory bladder cancer who present to the clinic are often inconsistently labeled as having BCG-unresponsive disease following BCG treatment. It is imperative there is a standard for this label, but the definition seems to vary based on the diagnosing urologist. The official definition created in 2018 by the Food and Drug Administration (FDA) defined BCG-unresponsive disease based on distinct criteria following adequate BCG therapy. Adequate BCG therapy is classified as the administration of 5 out of 6 induction doses plus 2 out of 6 second induction doses or 2 out of 3 maintenance doses. According to the FDA, a patient meets the criteria if they present with a T1 high-grade tumor at first evaluation following BCG induction course, recurrent Ta/T1 disease within 6 months, or CIS with or without Ta/T1 disease within 12 months following adequate BCG therapy. These distinct criteria provided by the FDA are based on expert opinion as opposed to clinical data. This definition provides uniformity and consistency for patient classification. When assessing a patient, it is essential that the patient meets these baseline criteria before further classifying them based on others, such as the criteria of a proposed clinical trial.
[Dr. Aditya Bagrodia]
This is a topic that I think can be confusing in my experience. As an academic urologist, a lot of mismanagement can take place for this group of patients, but maybe let's just start out with some definitions. When you're thinking about BCG-unresponsive bladder cancer, can you just walk us through the lexicon of pertinent terminology?
[Dr. Tim Clinton]
Sure, I can start. I think BCG-unresponsive disease has been a difficult one to characterize, and I think the best definition these days and the most widely accepted has been defined by the FDA in 2018, with their BCG-unresponsive criteria for clinical trial design. They've really defined this as folks who have had adequate BCG, which includes five of six induction courses, and two or three maintenance doses of BCG, or five of six induction BCG doses, as well as, I believe two of six of a second induction course as well. If they've undergone adequate BCG and have persistent or recurrent CIS within 12 months, recurrent high-grade Ta or T1 within six months of adequate BCG or T1 at the first evaluation, and this is what we now define as BCG-unresponsive disease.
[Dr. Aditya Bagrodia]
When you say T1 at the first evaluation, patient comes in, T1 high grade, you do your resection, you do repeat resection, they don't have any pressing indications for a upfront early, timely cystectomy. You do induction BCG, and then you take a look in their bladder and there's T1 high-grade recurrence. How would you define that patient?
[Dr. Tim Clinton]
I think this is exactly what we're talking about as far as unresponsive disease. Now, this is somebody that I'm worried about. They had their first induction course of BCG, you're starting to talk about invasive disease that's still present. Now, I'm starting to talk about early cystectomy and possible alternative therapies at this point.
[Dr. Aditya Bagrodia]
Technically, per the FDA, does this patient have BCG-unresponsive disease? They've just received their induction course not a five plus two, or you're saying just after the very first induction here?
[Dr. Tim Clinton]
Yes.
[Dr. Aditya Bagrodia]
Oh, right. right. Yes, exactly. First evaluation after adequate BCG for T1. This is somebody-- but I still am worried about it. They still have T1 disease, now we're looking at, is this someone who's still going to potentially respond to a second induction course or not.
[Dr. Tim Clinton]
Yes, I guess what I'm getting at is, to me, the FDA definition is interesting in some ways. It's these patients that you really worry about that they get their induction course and they've got persistent or worrisome disease multifocal T1 high-grade, or diffuse carcinoma in situ. I feel like, in my mind, I think of them ultra high-risk players that should be eligible, say, for like a clinical trial, or something a little bit more involved. These patients specifically, I would counsel them towards a cystectomy. Eugene, what do you think? Is that patient unresponsive per the FDA definitions?
[Dr. Eugene Pietzak]
Yes. Per the FDA definitions and for clinical trial purposes, they certainly do fall into that category of BCG-unresponsive disease, just of induction course only, and then having on your first three-month assessment high-grade T1, that would meet the criteria. I agree with both of you, this is definitely a concerning situation that we run into, but I think a lot of us at academic centers, I think the FDA criteria provides a very good framework and tries to develop this more homogeneous cohort for which we could do clinical trials.
I think we also need to be mindful that the BCG unresponsive criteria is really just based off of expert opinion, it wasn't super data-driven. There's been some post-hoc analyses to validate it, but you think if we've been using BCG since 1976 or so, there's over 40 years of data. I think it would have been nice if we would have got together, pool their data sets and come up with a more evidence-based definition. I think the framework that we have now is helpful, and we're not going to go back, we're going to go forward.
Pembrolizumab is FDA-approved. There's a handful of other agents that I'm sure we're going to talk about that will likely get FDA-approved. I think when you're faced with that patient in clinic, though, you have to think about where his initial treatment was. Where were the TURBTs performed, because there's tremendous variability. The BCG-unresponsive criteria for clinical trials doesn't factor in that initial tumor management, whether or not a restaging TURBT was actually performed or not. I think that's very relevant when you're in that three-month assessment.
I think it's hard to tell, is this biologically resistant disease, or was this patient that just had disease that went unresected, because they didn't have a restaging TURBT locally, and now you're seeing this patient post-BCG. I'm still worried about that patient because as Tim had mentioned, these are early invasive changes, and this can be a very biologically aggressive tumor. What we see in clinical practice and what the clinical trial criteria are, may not necessarily always merge.
[Dr. Tim Clinton]
Totally. I think this is a role for the enhanced cystoscopies, whether it's enhanced cystoscopy in the office or the blue light TURBT. At the time of your repeat resection here, I think that plays a role too. The initial management was as a blue light or enhanced cystoscopy at the time of the TURBT. Certainly, if you're doing it now, post-BCG, I think this all helps you just make sure that you've had a thorough analysis and all tumor was resected.
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Patient Counseling & Treatment Induction for BCG-Unresponsive NMIBC
Regardless of if it is an initial visit or a follow-up for patients with BCG-unresponsive or refractory bladder cancer, patient counseling needs to be clear and transparent. Proper counseling covers the time course of induction treatment which consists of BCG treatment once a week for 6 weeks, followed by a rest period, and re-evaluation at 12 weeks.
Counseling should also include the common side effects of treatment including dysuria, polyuria, flu-like symptoms, and vestibulodynia. Side effect management is simply symptom management. It should be highlighted that vestibulodynia, an often overlooked side effect, is effectively managed with vaginal estrogen. Although most symptoms are self-limiting, these symptoms may worsen, making BCG unmanageable. Patients who cannot tolerate the side effects or have ineffective symptom management classify as BCG-intolerant. It is important to note that these side effects may be worth it, as some physicians will quote that up to 80% of patients will experience clinical benefit following BCG induction. The remaining 20% of patients will go on to require additional induction courses or receive maintenance doses. With clear communication upfront, physician’s set clear expectations for treatment which leads to higher rates of adherence to treatment.
[Dr. Aditya Bagrodia]
Yes. We've jumped on into it, and I had an outline and I think this is just great. We've covered some definitions. BCG intolerance, is this something that you guys encounter? I get calls from our infusion center that patient X was only able to hold their BCG for 10 minutes, and they're having significant frequency and urgency bladder spasms. Is this a common clinical scenario? Well, actually, what do you tell your patients that are about to start their first course of BCG? What's the probability that this is going to work, and then what does BCG look like?
[Dr. Tim Clinton]
Sure, I think when I'm talking to folks who have had their initial TURBT, and I think you had your initial podcast with Dr. Sam Chang there who did a really nice job of discussing what constitutes an adequate evaluation and adequate transurethral resection of a bladder tumor. I think that's probably the most important thing as we've alluded to already. After that, now they have some amount of high-risk or intermediate-risk, non-muscle invasive bladder cancer and you're discussing the options for BCG.
I tell them that we're going to start with an induction course of BCG, which will be given once a week for six weeks, followed by a rest period and then an evaluation usually about 12 weeks after the initial resection. That BCG is a medication here that's instilled into the bladder and it's truly an immunostimulatory agent here, and so because of that, your body has a systemic immune response as well and can actually induce changes within the bladder, but also some systemic side effects as well.
I tell a lot of folks that I expect some amount of dysuria urinary frequency urgency shortly after the administration and there can even be flu-like symptoms for about 48 to 72 hours after the administration of BCG but in general, these are self-limiting and should resolve. Additionally, these side effects can sometimes be a little bit worse after the first couple of doses for BCG. It'll get a little bit worse during the treatment while they're undergoing treatment with BCG. But then after that, we'll assess their bladder. There are certainly some folks who can't tolerate BCG. I think you're mentioning someone gets the BCG and it's just too painful or the side effects are too much and they can't tolerate further doses despite local control. Then there are the folks who you, you can subsequently deem BCG-intolerant.
[Dr. Aditya Bagrodia]
Eugene, when they say, "Doc, what's the chance that this is going to work for me? How do you have that conversation? Maybe we could start out with patients that have papillary high-grade tumors and then patients that have CIS and then combination patients. You've done their most recent TURBT and feel like you've cleaned them out.
[Dr. Eugene Pietzak] Yes, I think as you alluded to, I do give a stage-specific or disease-specific estimate based on the data, at least the way that I interpret it. Someone who has say high-grade T1 multifocal disease with diffuse CIS, those patients, I counsel and emphasize that there's a little bit of concern depending on whether or not you're worried about potential clinical under-staging. Potentially even if you're doing it yourself, et cetera. For those patients I'll counsel the chance that they would derive clinical benefit from BCG may be as low as 50% sometimes.
Certainly, that's an opportunity for clinical trials of BCG plus initial agent, like an immune checkpoint inhibitor in that case if they have early invasive changes, et cetera. For a patient with papillary high-grade Ta-only disease, those patient's chances of response I typically quote them is at least 80% or so. Those that don't initially respond, may be able to be re-challenged with a second induction course or again, a clinical trial opportunity. Those patients may still derive clinical benefit from BCG that can be long-lasting.
I do counsel patients though that even if they have an initial response, even with maintenance BCG, there's still a chance that they could recur. Typically I say somewhere around 20 to 30% chance within the first few years. Again, I try to individualize it a little bit more for patients with multifocal disease, even if it's high-grade Ta, I worry more about those patients with larger tumor burdens overall. Even if they're fully resected using enhanced cystoscopy techniques, et cetera, compared to a patient with a small solitary tumor. I think risk-stratified my estimates to them.
[Dr. Tim Clinton]
Yes, that sounds spot on or consistent with what I do. If it's the favorable end solitary Ta, high grade, less than three centimeters in that 80% range. Now you're getting on the other end of the spectrum T1 high grade. Usually, if they have LVI, I'm super worried but if it's T1 high grade and not chock-full unresectable early cystectomy candidate closer to about 50%.
[...]
[Dr. Aditya Bagrodia]
I think I've got a good sense of how you counsel patients on what your likelihood is of responding and what BCG looks like. A number that stuck out of my head for the three-year maintenance program. The SWOG trials that only about 20% of people actually completed that. Now whether that's they lost interest or it was persistent side effects, it does seem that there are two camps like there are for so many things. People that do just fine with BCG, no issues, no problems.
Then the other end of the spectrum is going to be the people that really have the fatigue, the systemic symptoms, the pelvic pain discomfort. One of the things that I've started doing is actually for all my female patients that are getting BCG is starting them on vaginal estrogen. I feel like their vestibulodynia and discomfort have improved. I think that might be something that could be beneficial. Then I've also had a handful of patients with extreme, what I would consider BCG cystitis.
BCG Prioritization & Maintenance Dosing Recommendations
Currently, a shortage of BCG exists and thus, dosing should be prioritized for patients who would benefit most from treatment. According to clinical trials, only about 25% of patients ultimately benefit from a maintenance course of BCG, so administering induction courses takes precedence over administering maintenance courses. Those that receive priority for maintenance courses are individuals with a high degree of disease (e.g. CIS or T1), and the initial courses should be prioritized over subsequent rounds. The dosing duration for a maintenance course is one year with BCG therapy at 3, 6, and 12 months. This treatment course can be repeated for some patients for up to 3 years based on BCG availability. BCG is the first-line therapeutic agent, but for those who do not qualify for maintenance dosings alternative treatments, such as gemcitabine and docetaxel, exist.
[Dr. Aditya Bagrodia]
A couple of questions. Both in terms of tolerance of BCG maintenance regimens and our ongoing BCG shortages, that's certainly something we're affected by. We get a weekly email and it's like, "Oh my gosh, like we're about to run out of BCG." The first question on that first counseling session, how are you advising your patients in terms of duration of maintenance BCG, and then do you ever use dose reductions, and what are your opinions on that?
[Dr. Tim Clinton]
I think you're exactly right. We're all plagued by this BCG shortage right now, which is really become terrible as far as patient expectations with regards to especially to maintenance BCG. Here, we're certainly keeping a list of everybody who's eligible for BCG treatments, whether it's induction or maintenance, and priorities given to those who need induction courses. Certainly, if you have T1 or CIS disease, these men and women are at the top of the list for that induction course.
I tell everybody that that's the most important course of the treatment and maintenance if we have extra available will be given. Again, preferences are given for those for the first maintenance course and the second maintenance course but it really is dependent on what our shipment is for the month there. We've been doing one-third dose reductions based on a couple of different studies and I think MD Anderson and Ashish Kamat's group have done a nice job of showing the efficacy of one-third doses as well.
[Dr. Aditya Bagrodia]
Eugene, how long is a patient in your practice typically going to get maintenance BCG?
[Dr. Eugene Pietzak]
I typically give or try to give at least one year of SWOG protocol maintenance, BCG 3, 6, and 12 months. Then depending on the availability of BCG at that point in time we may go to try to go for the full three years. I think as Tim had said, it's more important to prioritize the induction and we typically will prioritize full-strength induction course BCG rather than one-third dosing. With a caveat that some of my partners with discussions with their patients often will not give maintenance BCG.
I think if you go back to the original studies of that and look at that, not everyone necessarily derives clinical benefit from the maintenance BCG. There's probably about a 25% benefit in recurrence-free survival, potentially a benefit for progression-free survival, but at least the SWOG clinical trial uses that composite point of disease worsening. I think ideally patients will receive maintenance BCG and it's supported by the guidelines, but I think if you have a limited supply of BCG, that should definitely be allocated for induction courses.
If I could go off script just for one second and put a plug for an upcoming ECOG study, The BRIDGE trial, that's going to be randomizing patients with newly diagnosed NOMI invasive disease, high-grade disease between BCG versus gemcitabine and docetaxel. I think as a community, that's going to be such a critical study to support such an important trial to support as a bladder cancer community since BCG has been the first-line option for over 40 years. Gem/Doce as we'll probably discuss later on has some promising data.
This is an ECOG-led study by Max Kates at Hopkins that should hopefully be opening within the next few months.
Podcast Contributors
Dr. Timothy Clinton
Dr. Timothy Clinton is a urologic oncologist with Brigham and Women’s Hospital in Boston, Massachussetts.
Dr. Eugene Pietzak
Dr. Eugene Pietzak is a urologic oncologist with Memoral Sloan Kettering in New York City.
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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