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Matthew Mossanen: So, we're going to move on to case two. So this is a patient of mine. She's a retired nurse. She has urinary frequency and urgency. It led to a workup. The relevant past medical history is, she smoked also two packs per day for 30 years, a BMI of 39. And she had a prior sacrocolpopexy for prolapse many years ago. She had high-grade urothelial cancer. MR urogram was fine. PET-CT was okay. She underwent induction BCG. She did not tolerate it that well. A repeat TURBT after she was done showed high-grade bladder cancer. At that time, we were struggling with BCG availability, which Dr. Yates will talk about in a little bit, so we did gemcitabine and docetaxel. I put her on some medications to help her tolerate the therapy; she was on trospium and mirabegron. She had another TURBT and still had high-grade disease. We restaged her and her PET-CT was negative.


So, I think this is an interesting case because it'll help us talk a little bit about BCG refractory, BCG-unresponsive. We'll talk a little bit about definitions and alternatives. We're lucky enough to have a patient with bladder cancer here today that we're going to interject the session with a mini interview and get her thoughts on all of this, which I think will be very valuable. Second line agents, and then again, the role of radiation in this challenging population.

So, the FDA put out something very useful a couple years ago, developing drugs and biologics for treatment, guidance for industry. I think of it as 3, 6, 9. So, T1 after induction within the first three months, at your first evaluation. Six months, so if you have a current high-grade or T1 six months after adequate BCG, or recurrent CIS within 12 months. So, that's what I talk to the residents about. 3, 6, 12. Adequate BCG. We're all familiar with the definitions; they're up there.

One of the lines that's interesting inside this PDF, and it's really not that long, you should take a look at it if you're interested, is sponsors may have some flexibility in the use of 6 and 12 months to define BCG-unresponsive disease. So, we've done our best to define it, but I bet if everybody out here filled out an index card with the definition, it would vary. So, I'm going to invite Dr. Yates up here to talk a little bit about some of her perspectives when you're managing patients with recurrent high-grade bladder cancer.

Jennifer Yates: Thank you Dr. Mossanen. So, first I want to point out that I think we should always keep in the back of our mind guidelines-based, and also I'm sure everybody's had this experience of the patient who recurs in their bladder, and we are so focused on the bladder and we're so focused on the BCG-unresponsive nature of their bladder cancer, that sometimes it's easy to forget the upper tracts. So, I think pointing out this patient did not have upper tract disease, this is one of my patients that did, so I think it's very important for us to keep that in mind whenever we're seeing these bladder recurrences, before we start talking about salvage regimens and cystectomy, to take a look at the upper tracts.

In low-risk patients, and if you look at the sources here, this is a little bit older data, so we have to keep in mind that low risk, intermediate risk, high risk don't necessarily correlate with our more recent AUA guidelines. But generally speaking, low risk remains low-grade Ta in these earlier cohorts. So you can see the risk is quite low in the low-risk, in the intermediate risk starts to increase a little bit, and then we get to the high risk and it can be as high as 10% in these patients. So, we always want to keep that in mind, that before we commit to anything with lower tract that we've at least surveilled the upper tracts in the recent past, with AUA guidelines of course supporting imaging about every one to two years.

What about patients treated with BCG? This is a small series that indicated that 13% of these patients, so speaking to the higher-risk nature of this patient cohort, had upper tract de novo disease. All of them were asymptomatic, which is a little terrifying. We often assume, I think, that gross hematuria or some sort of symptom will herald the development of upper tract urothelial cancer, and that's not always the case. And that absence of ability to detect it from a symptom standpoint also speaks to the finding of 7 of 11 patients had metastatic disease, presumably from their upper tract, since their lower tract was still superficial or non-muscle invasive disease.


So moving on, this is a lot of information in one slide, but I will cover it very quickly. I think a lot of us already know most of this information, so I won't perseverate. The strategies that we've had to deal with the BCG shortage have been well identified in the 2020 communication, and it was a combined declaration from many of our organizations that gave us some guidelines of how to manage our patients in the era of the shortage. Some institutions I know are still struggling with the shortage, and that has actually, I think it's kind of exciting, in the sense that it's really inspired a lot of innovation. What can we do as far as dosing, as far as regimens, and what other alternatives can we look at? We may have just continued in a BCG era at a very slow rate, trying to find novel alternatives, and this has really stimulated us to work a little bit more quickly.


So, question of whether we can reduce the dose, whether we can change the dosing regimen. There's been data that tells us that we can decrease the dose, but not necessarily does that change the overall tolerance of the BCG. So, a little disappointing in our hopes that we can get some of our patients to tolerate the treatments better. I'm sure many of you are using gemcitabine, mitomycin, docetaxel, valrubicin in the setting of BCG shortage, and also sharing that same space with BCG failures.


I did want to mention the reduced frequency dosing trial of NIMBUS indicated that decreasing the amount of BCG, this was full-dose BCG, it was inferior to standard regimen of BCG. So we need to keep that in mind, that even though this is arbitrarily chosen BCG doses and regimen years ago, there are criteria that keep us really having the optimal patient outcomes.


So, looking at the BCG shortage, there's some interesting literature out there in the lay press about what's going on with Merck. They were the single producer and remain the single producer of our strain of BCG. So, that's where the struggle came; it's actually quite challenging to produce the BCG as far as the timeline goes. They're building another facility to help meet this demand, but it's not anticipated to be completed for several more years. Hence, the innovation for new treatment options. On the right of the screen here is a SWOG trial that is looking at a different strain, the Tokyo strain comparison, so we may have some more availability, not only of our Merck product of TICE but also Tokyo in the future.


I want to speak a little bit about intravesical gemcitabine and docetaxel, gem/doce. So there are a couple of populations of patients, and I'll speak to both of those briefly, where this is a relevant treatment option. And I'm sure all of you have tried this regimen, and it's remarkably well-tolerated by the patient, so that's definitely in favor of this treatment for both the salvage and for the BCG naive population.


So, the paper that I present here was a series; it was a retrospective review of their entire series of intermediate and high-risk, and a cohort within their institution received—this was predating our BCG shortage era—but they received upfront, so BCG naive, gem and doce as treatment for intermediate and high-risk disease. And you can see that the vast majority of patients tolerated the full induction, which I think, if you compare that to BCG induction therapy, that's a big difference. So the toxicity, the side effects, the ability for patients to make it through their induction was quite remarkable. And compared to, admittedly this was a shorter maintenance regimen, and SWOG was a three-year maintenance regimen, but more patients were able to complete their entire maintenance schedule compared to BCG maintenance. So, really encouraging data here for our BCG naive population.


And then in the salvage setting, I think we've all been using this for quite a while; this is a multi-institutional study, and fairly encouraging one- and two-year recurrence-free survivals. So definitely something to keep in our armamentarium in both spaces, the BCG naive and BCG refractory.


I use this slide with the permission of Dr. Kates, who is spearheading with the other folks in the upper-left corner there, this study; it's called the BRIDGE trial. It is accruing, and it's looking at patients having upfront gem/doce. So this is a prospective trial, and they're currently enrolling, and we should have some results from this in a couple of years. So this is very exciting to be looking at this in the BCG naive space, and as a prospective trial with a comparison to BCG.


Other investigational treatments, I won't go into great detail on this, but just to make mention of all the exciting research that's being done in this area. We've heard a lot about intravesical chemohyperthermia, not ready for prime time; there's been some mixed data about that. Don't really have time to go into all that data, but it's very interesting and has some potential there. And this is an Australian and New Zealand clinical trial that is also accruing, combining intravesical chemotherapy with intravesical BCG. So, all kinds of different opportunities to combine agents in the intravesical and systemic setting, to try to improve our outcomes in this patient population.


I also want to make mention of this trial from several years ago, nab-paclitaxel, based on some prior data in the systemic therapy space. And it's kind of interesting; a nanoparticle albumin-bound, so it increases uptake. And this is a Phase II trial. The recurrence-free survival was 18%. So, one other option that's being evaluated as well, and we're also going to speak about some other options in a moment.


I'm going to turn this over to Dr. Mossanen and to speak a little bit about the cost of bladder cancer surveillance and treatment.


Matthew Mossanen: It is very exciting that there are so many treatments emerging. As they start to gradually diffuse their way into our clinic, it's important to take just one moment to think about some of the other things that relate to the treatment of bladder cancer, such as the cost. This was a project I did as a fellow, where we did a little bit of modeling. And I think the take-home point is that there are cumulative costs that add up when you're taking care of patients with non-muscle invasive bladder cancer. And based on the intensity of cystoscopies and cytologies and what treatments those patients receive, the costs can be substantial. This is old data, and now there has been, I would say, an explosion of new treatments; a lot of the cost for patients with non-muscle invasive bladder cancer typically relates to progression.

In a lot of ways, the cost of bladder cancer I think of in two categories: direct costs, money, and indirect costs. And we often don't just take one moment to think about what those indirect costs might be. People like to say bladder cancer is one of the most expensive cancers to treat on a per-person basis, which it is, but there are indirect costs, there are missed workdays, interference with the patient's quality of life, sexual function, body image, psychosocial impact, quality of life, etc. And so it's very important to just remember that there's another aspect of this entire talk that we're barely scratching the surface of. We just want to plant the seed.

I have a patient who has recurrent high-grade bladder cancer, and she used to be a medical illustrator, so I said, "It's confusing, isn't it?" And she's like, "Yeah." And I asked her to draw a picture. I think this is perfect. This is exactly what patients feel, sometimes even myself. There are so many treatment options. The definition of BCG-unresponsive disease is a little bit of a fluid definition. We'll just say BCG is not working anymore. And so, just keeping in mind that the patient is an important part of this entire conversation, is, I think, a step in the right direction.

I borrowed this slide from John Gore. The CISTO trial is a national study that we're participating in, and just wanted to put a little plug for it. The data is on its way, but they looked at patients with non-muscle invasive bladder cancer who had a BCG failure. It's an observational study, so some patients underwent radical cystectomy, other patients underwent bladder-sparing therapy, and they looked at their primary outcome of generic health-related quality of life and a number of other secondary endpoints. And I think this will actually be very important once the data comes out to guide us when we're studying this complicated population.

So, we're lucky today because Lydia's with us. I'm going to sit over here and basically talk to her for 10 minutes, and I think it's helpful to get the patient perspective in all of this, because we don't often do that. So... Give you this mic. Take this mic. So, this is meant to be sort of an informal conversation to really drive home the point that the patient is at the core of all of this. If it's all right with you, would you mind telling us a little bit about who you are? And we'll start maybe with the diagnosis of bladder cancer.

Lydia Saravis: Okay. Hi. Thank you, Matt and Kriti, for inviting me here. So, my name is Lydia Saravis. I was diagnosed eight years ago, had an episode of blood in my urine, and went to my primary, then was sent to a urologist. And when I went to see the local urologist, because of my age, I was 55, no history of smoking, he said, "I'm not concerned." So we did a CT scan and we did a scope, and I clearly had bladder cancer. He referred me, fortunately, to... I lived in Los Angeles at the time. He referred me to USC and Dr. Daneshmand. And at the time I didn't realize how fortunate I was to have landed there.

Dr. Daneshmand wanted to do a TURBT, which he did, and he said I had a tumor in over 50% of the bladder. And at the time, the pathology came back that it was stage one, and he was recommending bladder removal. So here I was, 55 years old, in great shape, felt great, and they wanted to take my bladder out, and I thought that was a little hokey. So I got a second opinion at UCLA, and a third at City of Hope. And UCLA suggested a trial of BCG, and City of Hope said, "Your bladder's coming out." So we went back to Dr. Daneshmand, and that's where I was there.


Matthew Mossanen: Can you talk a little bit about the decision that you were confronted with? You had the choice of, I think, was it BCG or up-front cystectomy?


Lydia Saravis: One of the opinions suggested BCG, but two had suggested bladder removal. And so we did go back to Dr. Daneshmand, and that was his recommendation. And at the time he gave me a study to read that he had written, that argued for radical cystectomy at the point that I was at, being multifocal and tumor greater than three centimeters; that was his recommendation.


Matthew Mossanen: Pretend for a second that you had a choice between cystectomy and one of these newer agents. I know it's hard to ask you this question, but what are some of the factors that you think about if I say, "Our choices are, we can take out your bladder, or I can give you therapy X, Y, or Z?"


Lydia Saravis: Right. So at the time, the reason I chose not to do BCG was based on my reading that there was a chance of progression during that time. And for me personally, I was more afraid of chemo than surgery. I felt that I would heal from surgery; I've always healed well from things. But the chemo scared me, just in terms of the lasting side effects.

Matthew Mossanen: Where were you going for information at that time?

Lydia Saravis: Dived deep into medical journal articles, which I then followed up with many discussions with my surgeon. Did read the BCAN website, did talk to some patients. But I think for me, what guided me were the numbers. So, I'm not a medical professional, but I would read the journal articles, and then I would go to my surgeon with questions. And the way he framed it for me that was really helpful was percentages. In terms of complications, yes, that can happen 2% of the time, that might happen 20% of the time, but we have a remedy. And so he was very reassuring.

Matthew Mossanen: When you were deciding on urinary diversion options, did you speak to any patients who had undergone the surgery?

Lydia Saravis: Yes. It's really complex to choose a diversion, because you don't get a trial run. So, I had the choice of all three, and I initially actually committed to the Indiana pouch, because with the neobladder, the concern was about incontinence and possible cathing. But it didn't sit right with me. And so I spoke to a lot of patients that I met through... BCAN has a page on Inspire, which most of you may be aware of; it's like a shared space for discussion. And I was able to speak to several women who had the Indiana pouch. But ultimately, a week before surgery, I met with the ostomy nurse to be marked for the ostomy, and I told her my concerns, and she said, "You know what? They all leak at some point or another, so choose what you want." So I chose the neo, and I'm really fortunate that my neobladder works incredibly well and I am fully continent.

Matthew Mossanen: You are an overachiever in bladder cancer, and so we did bring you here for that reason. Your health literacy is in the top one percentile of all bladder cancer patients on Earth, but not all patients are as lucky as you, and it can sometimes be hard to help patients navigate to resources that are helpful for them, because there is an indirect cost. I think one of the most important things that you've done is generate this support group, so I think it would be very helpful for you to just share it, because a lot of people in the audience might actually have patients who could benefit from this sort of valuable resource.

Lydia Saravis: Right. Thanks. So, six years ago I started the Neobladder Support Group. We meet monthly by Zoom. We were Zooming before COVID. I guess the reason for starting the group is, there's a fair amount of isolation with a neobladder. Your friends and family have never heard of it. Your regular physicians like your primary or my gastroenterologist or my dentist, nobody had ever heard of it; so you're really educating a lot everywhere you go. And there's a little bit of isolation within the bladder cancer community, because I think the ileal conduit is the most well-known, so even when you meet other bladder cancer patients, they're not really familiar with the neobladder.

So, just for a lot of different reasons, I started the group. It's been very successful. I have a very large group now. We just did a survey in the group of the things that they liked about... What do they like about the group? And the common theme was just having an opportunity to share with other people who get it, just being with other people who understand and share the same experience, and we also share a lot of tips and tricks for living with a neobladder. Not everybody's neobladder functions as well as mine does, and so there's a lot of discussion on how you handle the different issues that come up.


Matthew Mossanen: And any patient can join after they get a neobladder.

Lydia Saravis: Right. So the group is open to anyone who has a neobladder or is scheduled for neosurgery, or their caregiver. We're not the best place for shopping diversion choices. I think BCAN's page on Inspire is a larger opportunity for that.

Matthew Mossanen: Can you say what Inspire is?

Lydia Saravis: Oh, I'm sorry.

Matthew Mossanen: In a sentence or two, just in case some in the audience might not know.

Lydia Saravis: Yes. So Inspire, I guess, is an organization; they have several hundred pages for different health issues. BCAN has a page on Inspire. I guess it's an online support community, but you can be anonymous; you don't have to use your name on there, you can use another moniker. And it's a place where you can ask questions, there's discussion, and I think BCAN monitors the page.

Matthew Mossanen: I send 100% of my bladder cancer patients to bcan.org, so I highly recommend it if you're not already referring your patients to that resource. I could probably talk to you for another hour. I do want to be mindful of the time, so reluctantly, I'll ask you the last question, which is, in this room are a lot of people who treat bladder cancer, or are on the front lines of developing new therapies, or treating patients with complicated stages of disease. Any wisdom, advice, last words?

Lydia Saravis: So, I really encourage any physician who is involved with bladder cancer patients to support Dr. Sarah Psutka's work. She's trying to develop a dedicated program for prehab and rehab, which is really important, I believe, for outcome after radical cystectomy, and especially for neobladder patients. Having access to PT with pelvic floor training makes a huge difference. Unfortunately, there's just not a lot of PT out there, even with pelvic floor training, who are familiar with the neobladder surgery. But in any case, I was just really impressed with what she spoke about at BCAN Think Tank, and I agree that being in your best shape before and having help after with PT, nutrition, and even emotional counseling, goes a long way to recovery, because it is a long recovery.

Matthew Mossanen: I just want to thank you for coming all this way, and sharing all of that.

Lydia Saravis: Thank you.