Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston, and I'm joined today by Dr. Sima Porten, Associate Professor of the Department of Neurology from UCSF California, San Francisco, and Dr. Josh Meeks, Assistant Professor of Urology at Northwestern in Chicago. Thank you so much, guys, for taking the time to join me today.

Joshua Meeks: Thanks for having us.

Sima Porten: Thanks for having us.

Ashish Kamat: So both of you have the task at the AUA, which obviously this year is virtual, of talking about guidelines-based management of bladder cancer patients. And we thought here that will be great for you to discuss some of that with our audience and give your unique perspectives on guidelines and the specific management of bladder cancer patients. Sima, do you want to take it away?

Sima Porten: Sure. So this case really focuses on treating patients with carcinoma in situ. So real quickly, this is a 79-year-old gentleman who presented with microscopic hematuria and irritative lower urinary tract symptoms. He definitely has some comorbidities, has some renal dysfunction, and didn't have any upper tract disease on a CT urogram. In the office, we confirmed two papillary lesions, and we went to the operating room with blue light for his TURBT. And on blue light, which is the picture over on the left side of the screen, he had a carcinoma in situ in a blue light only positive lesion. This is where I think that it's exceptionally helpful to use blue light in this situation. He also did have those two other papillary lesions that were high-grade TA and low-grade TA.

He then underwent the SWOG protocol with BCG induction and maintenance. He had about 12 total treatments. We did have to dose reduce his 12th treatment because he was having a lot of lower urinary tract symptoms. However, on the next surveillance cystoscopy, which is shown over on the right-hand side of the screen, we did it with blue light in the clinic and we saw an area that lit up again. A biopsy was performed in clinic showing carcinoma in situ in that area. So he definitely has a BCG unresponsive carcinoma in situ.

There are a couple of points that I want to make with this case. The first one is when to use blue light cystoscopy. So this is our AUA guidelines statement stating when blue light might be useful. I really find it useful to look for these hidden carcinoma in situ lesions. And then in follow up on surveillance, I alternate between white and blue light in patients who have had a blue light only illusion to, again, look for any of these types of carcinoma in situ recurrences.

So when you look at the guidelines, he did get BCG like he was supposed to, because he has high-risk, nonmuscle-invasive bladder cancer. However, I would say, right now, many of us are experiencing a shortage. We've had alternating BCG supply and then also lack of BCG. So, these are some tips that we sort of discussed in what to do during the shortage, if you happen to be experiencing it in your area of practice. So you can address modifiable risk factors for recurrence, like smoking cessation. So kind of getting back to the basics, you could do a really good TURBT, which is always helpful. There are strategies to ration BCG and focus on patients who derive the most benefits, such as those with carcinoma in situ, or other high-risk patients.

You can also consider proceeding to cystectomy in patients who have very high-risk disease. Those with high-grade T1 with carcinoma in situ and those with variant histology. You can use other intravesical combination therapies, and where I sort of focused on really was looking at gemcitabine and docetaxel because retrospective data does suggest fairly good results. When you use gemcitabine and docetaxel with maintenance with an 81% one-year recurrence-free survival and a 59% two-year recurrence-free survival that has been reported by multiple institutions. And you can always enroll in clinical trials, primarily SWOG 1602, which is looking at the Tokyo strain of BCG. So, there are many strategies for what you do during the shortage. I also put a link here which is from the AUA that kind of outlines these in a little bit more detail.

So what do we do now in a gentleman who has BCG unresponsive bladder cancer, primarily carcinoma in situ, and really the guideline-based answer or the gold standard is radical cystectomy. If someone is unfit for cystectomies, this gentleman has many, many comorbidities, or unwilling to undergo surgery, they do have some options such as clinical trials, as well as other intravesical treatments, primarily intravesical chemotherapy.

So when you look at these other ways of going about treating a BCG unresponsive carcinoma in situ, similar to the BCG-naïve space where we're getting creative in what we can use, there are single-agent chemotherapy and double-agent chemotherapy. And again, gemcitabine and docetaxel are what I favor the most based on this data shown here with a one-year complete response rate around 54% and a two-year complete response rate around 42%. That again is with maintenance. For single-agent chemotherapy, I don't think that the long-term complete response rates, despite valrubicin being FDA approved, are good enough, honestly, to justify the use of this. That is also similar to the BCG-naïve space, where for a high-risk patient I don't use a single-agent chemotherapy to replace BCG, and I only do that for intermediate-risk patients.

So what are other options? There is a new systemic option for recurrent carcinoma in situ after BCG. And that is with pembrolizumab, and this was recently FDA approved. There was a good complete response rate at three months, approximately 40%. However, right now we don't know the longterm durability of this response. So I think that remains to be determined, but it can be a useful strategy for certain patients with recurrent carcinoma in situ. I tend to refer patients for this when they have a lot of lower urinary tract symptoms that would preclude the use of something like gemcitabine and docetaxel.

Then you can't always forget about all of the wonderful clinical trials we have going and potentially upcoming approvals. Mainly, I want to focus on Adstiladrin®, which is a recombinant adenovirus that induces cell death. So the Phase III data was pretty good in this situation, so when you look at patients with carcinoma in situ, there was a 53% complete response rate by three months, and with a mandatory biopsy at 12 months, which I think is really important, about 45% of patients were disease-free in terms of high-grade disease. So, I think this is going to be a really great option in the future for patients.

When you look at carcinoma in situ, there are a couple of key points to make. Although BCG is guideline-recommended therapy, a tenuous supply does necessitate alternatives. And primarily this is in the form of intravesical chemotherapy with a doublet like gemcitabine and docetaxel. When you look at the BCG refractory or unresponsive state, there are a lot of options available to patients. Our guidelines really support a radical cystectomy, but alternatives are, again, doublet intravesical chemotherapy, pembrolizumab, as well as other future intravesical agents.

Don't forget that a diligent TURBT is necessary, and consider enhanced cystoscopy for patients in which either you have a cytology that's not matching with what you see in the bladder, or to look for these hidden carcinoma in situ lesions.

Ashish Kamat: That was a great, Dr. Porten. A couple of key questions if I may. So when you talk about the guidelines and you talk about the use of blue light cystoscopy, do you have any points of advice for the audience that is thinking, "Well, I want to use blue light cystoscopy, but the flow in my clinic is such that if I used it in everybody, it would just clog up my day." How would you recommend people kind of parse out their patient flow? And who would you recommend they use it in for surveillance in the office?

Sima Porten: Yeah. For surveillance in the office, I use it for patients within whom I was able to see a blue light lesion only in the operating room, such as this patient. I actually don't do every single cystoscopy with blue light for that patient, and it is for that reason. To improve clinic workflow I alternate for those patients. I also really like using it for patients who have recurrent low-grade disease, especially those that I'm managing with fulguration in the clinic. The blue light flexible system has a suction capability. So, it's easy to do multiple biopsies and multiple fulgurations, and very easy to fill and empty the bladder as well as go for complete clearance each time I do that.

I think part of it also I use for patients that I'm worried that are in their high-risk period, primarily within the first two years of diagnosis, but you're correct. I don't use it for everyone because honestly, we don't have enough scopes to use it on every single person, and it's likely not going to be useful for every single person. So I really limit it to that group where I find it the most helpful.

Ashish Kamat: Right. I think as you say, the patients in whom it will actually make a difference to their disease or management is where we should use it. Dr. Meeks, is your practice similar? Do you have any additional pearls with blue light or narrow-band imaging, for example?

Joshua Meeks: No, very similar. I mean, we don't have flexible blue light for the office. Nearly every patient gets a blue light cystoscopy, even if it's a first time mass. I find that it can be very helpful to see the carcinoma in situ that moves out from it and to make sure that the TUR is a complete TUR.

I think that one of the key things about Dr. Porten's talk is that there's a difference in CIS recurrence between what we saw there and someone whose whole bladder is covered. That's kind of where the shades of gray come in. So, that patient, that's potentially resectable CIS. Actually, they've not responded to BCG and I'd probably move them on ... I tend to use gemcitabine docetaxel, but it's different than if the entire bladder is covered and it's more of a field effect rather than surgically resectable. But those are all great points and I agree completely with what Dr. Porten expressed.

Ashish Kamat: So you raised an interesting point, which I was going to bring up, if you detect carcinoma in situ using blue light or narrow-band imaging, for example, and you see a discreet path, such as what you have there, that might be disease, that as you said, you could completely resect, you can fulgurate, get rid of. Do you differentiate between those patients in your recommendation for follow-up therapy? In other words, would you use something like that to decide between say intravesical gemcitabine, or intravesical Adstiladrin® if it's approved or pembrolizumab? Sima, if you want to take that?

Sima Porten: Yeah. So I would say, for that gentleman, we actually moved on to gemcitabine and docetaxel a little bit for that reason is that was the only site. And actually I was able with two biopsies with the flexible scope and fulguration to kind of blast away that whole area. And that was the only place. And there is a part of me that wonders and suspects that that is much different than what Dr. Meeks was talking about, a full bladder that's completely all carcinoma in situ. And for that situation, I kind of push a little more for something like a radical cystectomy. I also notice that when that happens, people do have some pretty debilitating urinary symptoms that kind of go along with complete involvement with carcinoma in situ.

For this gentleman, I didn't push for radical cystectomy number one, because in speaking with him, it didn't really align with his goals of care based on his comorbidities and a little bit on his frailty. But also part of me was wondering, "Do I do something like a radical cystectomy for that?" So he's been on intravesical chemotherapy now for maintenance. He's almost finishing a year and it's been, again, a completely silent bladder, no issues. And he was able to tolerate the gemcitabine and docetaxel a little better than actually he did with that last bit of BCG. So, I don't think I have a really great answer. What about you, Josh?

Joshua Meeks: Yeah, I mean, I think you both have sort of really contributed to this literature. I think one of the challenges we've had with BCG unresponsive bladder cancer is that it's at least three different diseases, right? So it's CIS, it's papillary cancer, and then it's invasive cancer, and they're all lumped as one group, but we treat them differently and we know that their prognosis is different. We're just coming off the heels of ASCO with the KEYNOTE-057 update. And I think I'm, again, impressed by the lack of progression in those patients.

So for example, if it's a T1, BCG T1, if the patient doesn't want a cystectomy I'm much more likely to consider pembro, because again your goal is survival. And I think if the progression continues to stay as low as it is on pembro, that certainly may be something to consider longterm for those more invasive cancers that I put almost into a different risk group than someone with a small amount of CIS or papillary disease.

Ashish Kamat: And I would agree with the points that both of you raised. I mean, if you look at, for example, Adstiladrin®, the three-month CR's about 53%, and then 48% of those are durable to 12 months. That's about 24% at 12 months. That's very similar to what pembro had, which is about 40.2%. And then at 12 months, if you kind of round it up, it's about 20%. So when you have similar percentages, how do we pick amongst the patients and the points that both of you raised, which is if you're concerned more about potential micrometastatic disease, maybe consider a systemic agent. If you are concerned more about local recurrences and not so much progression, then maybe consider intravesical therapy such as gem/doci or Adstiladrin®. I think those are great points. I could chat with you guys about this topic forever, but in the interest of time, I think maybe we could move on to Dr. Meeks?

Joshua Meeks: Great. So I'm talking more of a case of a stage I bladder cancer. And I think that that's ... managing patients with early invasive bladder cancer is one of the real challenges for us as urologists, and a good amount of that is trying to figure out what are the cases that tend to act more like noninvasive tumors and what are the ones that are going to be more aggressive and we truly have to worry about progression.

So this is a case of a patient that I'm sure Dr. Porten, Dr. Kamat, you folks have seen many patients like this. So he was 82 years old. He actually came to me for a cystectomy consult. He had a bladder mass and was found to have a T1 high-grade bladder cancer. A little bit of hydronephrosis on his left side, and the tumor was right near the ureter orifice.

So this is one of those ones where you ask, is it T3 cancer where there's invasion, or is it just kind of blocking the flow of urine? It wasn't clear. He clearly had a scan with some mild hydro and a bladder mass there, and his outside urologist put a perk in and told me he needs a cystectomy, so he came to see me for this discussion.

My thought was, "Well, let me take a look." Because again, he wished to keep his bladder if he could, and it's hard for me to really recommend a cystectomy for a T1 patient without any kind of early adverse features. I could tell that there are folks who had reviewed the path. There was no lymphovascular invasion, there was no variant histology. It wasn't really clear that he had a T3 tumor.

So I said, "The best advice I could give you would be after a surgery where I could take a look at your bladder." So he had a re-TUR. And again, he was a T1 high-grade on, on that re-TUR, and that was it. His bladder actually looked really pretty good. Again, we sampled muscle and there was no muscle invasion. Took him back actually a third time just to really make sure, and he had it just a little low-grade cancer. So we thought this was probably pretty good. We enrolled him in 1602. He got induction and then two episodes of maintenance therapy of BCG. Then he was found to have a new small bladder mass. When we went to the OR, actually it was a muscle-invasive bladder cancer.

I had a discussion with them at that time, and so really that was his best option was a radical cystectomy. He ended up being a T2 N0. So this was a patient that is one of those rare patients that you think you're doing the best job you can, you try to keep them a bladder sparing approach, and they ended up having a muscle-invasive bladder cancer. So looking at the AUA guidelines, this is from 2016, so he was a high-risk tumor and he underwent a re-TURBT. He did get BCG and got good BCG. He had a recurrence that ended up being a higher risk tumor, ended up with a cystectomy. So we think we followed the guideline-based care there, and the real question is, why does that happen?

And I think one of the real challenges, again, with these T1s, and we think he got, let's see, ended up being 12 doses. Should we have pulled the trigger and done his surgery much earlier? I think one of the challenges is really trying to figure out why these cancers are so challenging, and some of them are because they just started a very small amount of invasion. Other tumors have a good amount of invasion where the tumor's almost into the muscle. And then, of course, there are ones that are in the muscle. And for whatever reason, they're classified as T1s because the pathologist misses it, or we do too much cautery and you just can't see the muscle invasion.

Then you ask these patients when they progress, what really happened? And I do think there are at least two mechanisms there. The first would be we under staged them. And again, that's because of cautery, because the urologist doesn't get muscle when we should. Or there are some cancers that just come back and are just aggressive and they come back and they progress to a muscle-invasive tumor. It's interesting that in his case is that the tumor seemed to be in another area. So I tend to favor, it was just more of a field effect, or honestly, we could have missed it the whole time.

Now, the way that I tend to approach T1 tumors is that, again, there are high-risk tumors and they're almost all high-risk tumors by the AUA guidelines. Any T1 is really a higher cancer if it's high grade. And most of those patients are going to go on to get BCG, but there are some patients that are not just high-risk patients, they're actually very high-risk patients. We right now classify them as those that have lymphovascular invasion, those with variant histology, bigger tumors, or those with carcinoma in situ.

And for them, they're probably going to go on to get a radical cystectomy, or at least we're going to talk about that because the risk of having a recurrence is very high. So I tend to start the discussion with radical cystectomy right at the time of diagnosis because if they end up there, I think it's a little bit easier to get to that point if it's something that we've brought up previously.

The challenge with the radical cystectomy, and my concern is that if you get a T0, so you do a cystectomy and there's no cancer there, I'm not sure that that's a good answer. I mean, again, that's the safest answer, but at the same time, we probably over-treated that patient. Alternatively, the patient who's got a muscle-invasive tumor or lymph node involvement, again, we've probably missed the boat on that one as well. So it's one of these things where it's hard to do the right thing at the right time and you just don't have all the data.

So we've tried to figure out, are there any molecular markers? I know you folks are working on very similar questions and some of us are all working together, but trying to figure out, is there anything about these cancers that we can get a little glimpse of the biology that can help us make a better guess or better consultation with our patients? So for example, we've done sequencing to try to identify those patients. And interestingly, there are gene mutations that come up when a patient progresses, but we never have really found anything consistent. One thing that we're pretty interested in is the thought of total mutation burden, because this is a reflection of neoantigen burden, and perhaps that's involved in the response to BCG.

So for example, we found that if you look at tumors that get BCG, and these are all T1s, we found that patients that progress versus those that don't have a lower total mutation burden. Then after BCG, when they progress they have an even lower total mutation burden. So they seem to be dropping TMB, which is essentially dropping neoantigens.

This is not too different than what's been found with the immunotherapy literature. This is the data from the PURE-01 cohort, again, showing that patients who have residual cancer after pembro tend to have a lower total mutation burden. Again, the tumor seems to be dropping mutations as a way to escape immunotherapy.

So this is kind of to summarize, I wish there were a lot more cutting edge stuff in T1 and how we manage T1s, but I think the very standard things of a TUR followed by a re-TUR is still, I believe the standard of care. I have a lot of concerns for patients with variant histology, and some are more aggressive than others. Lymphovascular invasion is clearly a concern, and I worry about metastatic disease in those patients.

Ultimately, early cystectomy is something that we should consider and probably talk about with nearly all patients that have a T1 tumor. Then I tend to support BCG maintenance. I know our guidelines do as well. They try to give it as long as we can, if we can go three years, we have BCG. So we try and go give it to patients as long as they're able to tolerate it. Then if they have a T1 that recurs as a T1, again, I tend to favor early cystectomy. And if they're not able to or willing to do that, we'll move onto a clinical trial or new agents.

I'm excited about the future of this field. I think this is a part of nonmuscle-invasive bladder cancer that there's going to be a lot of innovation in the next five to 10 years, and hopefully, we'll be able to guide our patients a little better with some molecular markers.

Ashish Kamat: Thank you. A very, very nice summary of the T1 high-grade conundrum that we often face. Let me ask you a couple of questions, Josh. So when it comes to T1 high-grade bladder cancer, the AUA guidelines essentially put T1 high grade in the high-risk category along with the other qualifiers that you mentioned. The European guidelines then stratify them based on high-risk, which is what you showed, and the very high-risk, which is also what you showed. So what do you think about having them lumped together versus separated out? Do you think that's something that we should be doing and considering when we actually counsel the neurologic community at large?

Joshua Meeks: Yeah. I mean, I think the 2016 guidelines is a huge job. And as far as thinking about low, intermediate, and high. I think the other big part of the guideline is the discussion of radical cystectomy. And there's a lot of early radical cystectomy in that guideline, and I think that's very favorable. I think those of us who, as you know, see patients and have this discussion with them, we don't think that T1 high-grade is going to be the same as T1 high-grade, for example, with sarcomatoid features, right? We already kind of do that, right. Those are mentioned as different guideline points in there, but we don't have an extra category for them, even though we kind of treat them differently.

I guess the benefit of keeping them all together is they're all going to get BCG, right, and they're all going to get maintenance therapy. So in some ways, the bladder sparing approaches are the same, but we do in our guideline kind of call those out later on down as far as exceptional patients that we should have a low threshold to consider early cystectomy for.

Ashish Kamat: And I think one good guiding principle is that, in the academic centers, yes, we clearly parse those out, but sometimes in a busy practice where someone's not necessarily focused on cancers or not bladder cancer, it might be nice for them to actually have those separated it out because we really shouldn't be seeing any patient dying of nonmuscle-invasive bladder cancer, right? In T1 high-grade disease, you should really have a cancer-specific mortality that's in low single digits. That's my view, at least. Sima, do you have any variance in how you handle your T1 high-grade patients from what Dr. Meeks was talking about? Any coastal differences or philosophical differences?

Sima Porten: No. I mean, I pretty much also in my mind, probably reclassify high-grade T1 patients to very high-risk with those features. I think LVI sometimes is hard because of how our pathologists call LVI and what the fidelity of that is across different groups, I would say. So I find that one a harder one to put weight behind. I mean, we have a consensus re-review with our GU pathologist, which I think is really helpful, but even they also will say that sometimes it's very difficult to call an entity like that.

So it does make me worry though if you have high-grade T1 mild hydro CIS and LVI, I almost kind of conglomerate that as saying that is so many equivalents to muscle-invasive disease. That's what I would define that as. The ones that I actually struggle with the most are high-grade TA with CIS because technically CIS should respond quite well to BCG. And although I know that that denotes a more aggressive entity in terms of recurrence and in progression on studies, I still sometimes will give people a little bit of a pass if the carcinoma in situ is not extensive in that case. And I still tend to try to favor a bladder sparing approach if I can. But I do start with always saying the word "cystectomy" when I talk to patients with high-risk nonmuscle-invasive bladder cancer, because like what Dr. Meeks said, it can set the stage and potentially make it a little bit more acceptable to patients down the road if that's the way the disease decides to behave.

Ashish Kamat: Thank you. One closing question, just in the interest of time. Josh, what is your response to people who've been clamoring to get rid of the re-TUR claiming there's a large series by Paolo Gontero. I think that's the one most people referencing. Re-TUR it really doesn't matter if you do it before you start BCG or do it at the three-month setting. What's your viewpoint and counterargument, if you have one to that.

Joshua Meeks: I will admit that I've rarely seen the kind of original Dr. Herr data where 20% of T1s have muscle-invasive cancer if you re-TUR them. It's been pretty rare that I've seen muscle-invasive disease on a re-TUR from someone who had T1 and was high-grade with muscle. So I think of it less as I'm trying to make sure my staging is good, but I do think it contributes to our surgical contribution to treating nonmuscle-invasive bladder cancer, going back and re resecting that area, really making sure that as much carcinoma in situ and cancer is gone I think can only help, it can contribute to the patient's longterm success.

So I think of it more like that. Many of those folks, that's the first time I'm meeting them is the re-TUR, so it gives me another opportunity often to do a blue light and also to take a look at their bladder, and again, to resect that. There is good prognostic data, at least old data, that a negative TUR is a good sign. So I still think there's value to it. If they have CIS, I'm going to go back in six months at their six-month and do biopsies anyway, to make sure they've cleared that. But I do think there's a value to that still.

Ashish Kamat: Yeah, I couldn't agree with you more. I think it's playing with fire not doing a complete TUR after T1 disease, and however good we think we are, it's not worth the 10%, 12%, or 15% risk of having a patient that has missed invasive disease. And I consider T1 high-grade to be invasive, it just hasn't gotten into the muscle yet. Right? So we need to make sure we give our patients the best chance of not only preserving their bladders but also saving their lives. Thank you, both of you. This was very informative and our audience will really, really enjoy this. I hope you guys are staying safe and well during these crazy times.

Joshua Meeks: Thank you.

Sima Porten: Thanks.