Around the Practice July 21, 2021: Bladder Cancer Cases

This installment of Around the Practice focused on the multidisciplinary approach to bladder cancer care.

Dr. Jason Hafron: Hello, everybody and welcome to this month's installment of Around the Practice, a live interactive event, featuring the multidisciplinary approach to challenging cases in your logic oncology. This event is hosted by Urology Times and LUGPA. My name is Dr. Jason Hafron. I'll be hosting, uh, tonight's live event. It's my pleasure to be joined by Dr. Steven Finkelstein from Florida Cancer Affiliates, the US Oncology Network. And then Dr. Michael Bivins from Urology Centers of Alabama will hopefully be joining shortly. Before we get started... before we get started, uh, uh, there's a couple housekeeping notes. Um, there's a Q&A box, um, down in the left pant... in the left part of your screen. If you have any questions, just submit those and we will get to those at the ends of the case. Um, so let's get started with our first, uh, case, Case number 1. Our first case will be a BCG Unresponsive, Non-Muscle Invasive Bladder Cancer. Uh, as we know, bladder cancer continues to afflict more than 80,000 patients in the United States. And, uh, most recent data shows that approximately 75 to 80 percent of patients with bladder cancer present with a disease as combined mucosa stage TA, carcinoma and Sci-Tech, or submucosa T1. Although the management of non-muscle invasive bladder tumor has significantly improved over the past years, it remains difficult to predict the heterogeneous outcomes of such tumors.

With this is in mind, let's get into the first case and, and, uh, let's talk about this. Uh, let me just get this a little bit bigger. Um, so this is a case, it's a 64 year-old male. This was submitted to us African-American male without significant past medical history who presents the urology office with asymptomatic gross hematuria. CT urogram was negative for upper tract lesions, um, bladder and enlarged lymph nodes. An office flexible cystoscopy was performed, and that, um, showed an erythematous area in the posterior bladder wall and a one centimeter papillary tumor in the right lateral wall.

The patient, uh, subsequently underwent a transurethral resection of the bladder tumor, TURBT. Pathologies showed carcinoma In Situ in the posterior bladder wall. And then the papillary legion was TA high- high-grade on... in the right lateral wall. Um, we... before we get into the management, you know, I just want to ask, you know, Chris in, in up, you know, an AMP, you know, what... are you guys using enhanced visualization CIS view or, or a narrow band imaging? What's, what's your group's philosophy, or what's your philosophy on this?

Dr. Chris Pieczonka: Um, so we do have narrow band imaging available on each one of our clinics. I think we have 11 offices. We have access to CIS view really, in two of the facilities, um, that are, you know, hospital-owned. Our group does not have an ambulatory surgery center as of yet. Um, so from time to time, we will sort of do the, um, CIS you, if there was a sort of an extraordinary case. But quite honestly, um, I think that the timing and the logistics of doing that is cumbersome to us because it's not really in our home. It, it'll be... where the CIS view system is located is not in the place where we do the bulk of our outpatient operative procedures. Um, so mostly for us, it's narrow band imaging for our surveillance cystoscopy.

Dr. Jason Hafron: Yeah, I think you know, obviously, there's issues upfront costs and logistical things. So I think I would agree with that, you know, CIS view, when it's available, when it's easy, it makes, you know, it logistically possible. It's definitely an advantage. And when you look at the data, especially the CIS view registry study, um, you know, more than... over 3,500 lesions, 23% were only detectable by blue lights. Now, obviously, it's... it can be cumbersome. It can be costly, but if it's available, it can be helpful. And that's how we feel. So moving with the case, the patient had basically CIS high grade TA. He underwent six rounds of BCG intravesical therapy. Uh, a cystoscopy at three months, um, basically, and, uh, was performed with a bladder biopsy and it showed carcinoma In Situ in the posterior bladder wall.

This leads us to our first poll question, and this will launch a poll. The cool part of these live events is we can poll the audience and see how they would manage it. But I... you know, Chris, I'm going to pick on you because, you know, this is a little bit out of Steve's wheelhouse, is how would you classify this BCG recurrence? Would you classify this as BCG refractory, BCG relapsing, BCG unresponsive, or not a recurrence because the patient has had adequate BCG?

Dr. Chris Pieczonka: Um, so I, I, I think that the, the terminology that you put up there, I think is really meant to engender the discussion that the FDA has. The FDA has got pretty specific guidance about what defines BCG unresponsive disease or not. Um, and that could be in a couple of different ways. Um, and I don't know if we want to kind of go through that now as the, as the audience doing the questions. Uh, but I'll just kind of keep rolling unless you'd tell me otherwise.

Dr. Jason Hafron: No, keep rolling. I think it'd be a good idea to go through definitions or, or how you... you know, and then we'll, we'll go, go back to what the audience said.

Dr. Chris Pieczonka: So this particular patient had recurrent CIS, so he did not have a, a recurrence post initial induction of T1 disease. So, uh, you know, that would sort of categorize the patients being essentially BCG unresponsive right away. In this particular case, the patient really is not necessarily, um, uh, unresponsive to BCG because the FDA really looked at a five plus two schema, um, for defining on responsive disease, which would effectively be that you would have had to have gotten at least five, if not six weeks total on BCG, and then have gotten at least two more weeks worth of a maintenance regimen. Or you could have been defined as having unresponsive disease if you had six weeks induction plus another six weeks of induction and then recurrent cancer. So, so, you know, in my mind this patient is certainly not as, according to the FDA definition, is not BCG unresponsive. Um, I guess I would say that probably I would go with D, for my answer. Um, what, uh, just based on the fact that he hasn't taken the next step in terms of getting re-exposed to traditional BCG.

Dr. Jason Hafron: Yeah, Chris, I kind of agree with you too, because, you know, he really hasn't had adequate BCG/. And the FDA guidelines are, or, or their definitions adequate. BCG would be greater than equal to five doses of induction, and plus, you know, two greater than equal to two or three out of maintenance. So, um, you know, our audience is split here, but I think the correct answer, using these FDA definitions was he... this is not a recurrence because patients not had adequate BCG yet. He hasn't had his maintenance. So technically, you know, he, he's still... it wouldn't be a progression or relapse. Um, he just, you know, he's, he just hasn't had enough treatment. Um, the other thing to keep in mind too, is that the only way you could say that he's definitely BCG-refractory is if he had progression of disease at his three months cysto though. Um, so that's the only time at this three months first cysto after induction, if he... if he became T1 or obviously T2, but if he was T1, then we could say he's truly BCG refractory. But I agree with you, Chris that, that he's just, uh, not had adequate BCG, um, you know, based on the FDA recommendations. And we would just have to continue with therapy.

Um, so with that being said, let's just see what happened next. So he had his, uh, three months, um, what? I missed a slide, hold on. Sorry. So then he... oops. Trying to work with us, give me a... sorry. So he, he basically went on to his maintenance, um, BCG, and then had a nine months cysto that showed erythema at the right h- hemitrigone and posterior wall positive cytology, BCG... or biopsy was taken on pa- pathology demo- demonstrated recurrent CIS. So had maintenance, had adequate BCG, six cycles of induction maintenance therapy. So with... by FDA definition and still has CIS present. So that being said, that brings you to those to, to our second poll question, is how would you manage this p- patient with recurrent CIS after one course of induction, BCG and maintenance BCG? And I'll just read these and, and, uh, you know, and we'll ask that, you know, discuss this for a second is would you do a second course of induction BCG, would you offer him a radical Cystectomy?

Would you consider pembrolizumab or Keytruda? Would you consider an alternative che- uh, chemo regimen of gemcitabine docetaxol, or would you do BCG interferon? Just for the sake of, of discussion, I'm going to add, um, a second, um, question is, would you consider radiation? And I'll ask Steve that for recurrent superficial disease. I know there's been some, some work done there. Um, I guess I'll start... let's go to Steve. Steve, you know, talk to us about, you know, where we are today with, you know, not ETub, but superficial bladder cancer, as far as you know... is there any trials or in anything that you've done in the past? W- would you consider radiation in this, in this patient?

Dr. Steven Finkelstein: So the first thing I would say is that radiation is not the go-to move for superficial bladder cancer, right? So if you look at the NCCN guidelines, uh, the version 3, 2021, so March of 2021, for patients with stage TA T1 or TIS, external beam radiation therapy is rarely appropriate alone. If a, if a patient has recurrent TA, T1 disease, usually following BCG therapy, but without extensive TIS who are not candidates for cystectomy, concurrent chemo radiation therapy could be considered as a potentially curative, um, alternative to radical cystectomy. But that is the standard treatment by the NCCN guidelines.

Dr. Jason Hafron: No, that's good information. So, Chris, you know, what would you... you know, how would you answer this question? What would you do with this patient? How would you manage this patient with recurrent CIS after induction, after med- um, one round of maintenance?

Dr. Chris Pieczonka: So I think that this patient probably does the criteria for saying that the patient is the BCG-unresponsive. So that changes the game a little bit, it gives you a couple more options. I think that, um, what I would do is I would... I don't do cystectomies in our practice. We have a high volume bladder cancer surgeon that this patient at least get a surgical consult to have a conversation about that. Um, that patient, if, uh, if it was not going to go for a cystectomy, probably would be offered pembrolizumab in our practice. Um, at least, if I was seeing the patient. Now, we do not have a well-developed bladder cancer clinic in our practice. So this really is the wild west. I would say that most of the time, what would happen in this practice for our patients, perhaps for some of the folks who are not doing as much oncology work is they would probably either give them repeat BCG or switch to another intravesical agent. Um, and they probably wouldn't be as quote-unquote, "aggressive" is what I just suggested to you. So I think the vast majority of times what you find at this patient in our practice amongst our roughly 40 providers would be another course of something intravesical.

Dr. Jason Hafron: Yeah. And that... and if you look at the, the poll, the poll data is basically... that's essentially what the... I'm trying to pull it up. That's essentially what... no, this thing's jumping on me. Sorry. Gees. Th- that's what the audience recommended is, 50% of the audience recommended a second course of induction BCG. Um, 12.5% recommended a radical cystectomy, 12.5 recommended, uh, Keytruda, 25% did, uh, uh, chemo regimen, gemcitabine, docetaxol, and no one, you know, thankfully recommended BCG plus interferon. I think that, you know, these are all possibilities. I think it's important to have that discussion with the patient. Obviously, the patient's a candidate for cystectomy, um, um, reality, as we know that most patients won't go for it, you know. Uh, induction BCG is, is an option. Um, pembrolizumab obviously is an option. Um, but obviously, it's a discussion with the patient, but all of those kinds of what you said, Chris, are on the table and all, you know, essentially within guidelines to treat.

Getting back to the case, um, basically, the guy, um, did ano- did another course of induction BCG kind of what, you know, you would see in our group, in your group, kind of what we'd seen our group got a second six cycles of BCG. And then had a 12 month cystoscopy with again, recurrent CIS. Um, so we're seeing CIS again, which leads us to our, our third poll question, is now that he's had two courses of induction, BCG and maintenance, BCG, what, what would you recommend? Um, again, you know, Steve, obviously, radiation's not ideal. Um, candidates, not within the guidelines. Um, Chris, I think your answer probably will be the same, you know, all from cystectomy and then probably pembrolizumab, is that what you would say?

Dr. Chris Pieczonka: Yeah, but I would be very strong and not doing more BCG. Yeah. I think that kind of the... for previous, um, you know, step would have been, you know, maybe, you know, kind of try it again, you know, bide your time. But, but I, I definitely would say for me, that choice would be, you know, a third course of BCG would not be something that would be within, um, would be something I would recommend. But, uh, but other than that, you know, I still think this patient needs a cystectomy. If not, the patient could get, uh, pembrolizumab on label. Essentially if they were ineligible for cystectomy or they're surgically ineligible, or if they made themselves ineligible because they didn't want to do it.

Dr. Jason Hafron: Totally reasonable. So let's talk about the data for pembrolizumab. It was trial, it was keynote 057. Um, it's FDA approved for recurrent CIS in, in eligible, uh, patients for cystectomy, you know, what, what is, what do you like about the data? What, what stands out for you and, and why Chris, would you consider an option in this patient?

Dr. Chris Pieczonka: I think a couple of things. I mean, first and foremost, the 057, um, study had two different arms and we only know the results of one of the arms, which is the CIS arm. So really, in order to get a medicine... you know, although might be tempting to have this conversation about patients who don't have CIS, that would be off label. Um, and to the best that I understand that data is going to be presented soon. So just to kind of level set that. So this is really about CIS patients with recurrent CIS. Um, the thing I think that's pretty intriguing about the pembro thing is that, you know, their complete response rate was on the order of like 42 or four. I mean, I think it was 43%, you know, at three months. And essentially, uh, if you had a response within, and this was presented at ASCO, um, a couple of months ago that response, then it turned out to be very durable.

So you kind of would know right away with pembro, if you're going to use it, I would use it, um, uh, probably, uh, uh, you know, and then you would, re-scope the patient. And if you get a response at three months, you can probably get in front of that with the patient, and say, "This is going to probably be pretty durable. So that's really what I like about it. There are some other agents, none of which are FDA approved that have been, you know, gone through some phase three studies that, you know are kind of pending on the horizon. And it's interesting because their complete response rate, you know, it was a little bit different in terms of, of potential durability and when they get the complete response. So I think at a high level view, you know what you're getting into very quickly on this 'cause I think that a lot of these patients are probably going to opt for pembrolizumab rather than cystectomy.

And, you know, you've got to make sure that you kind of close the deal on that and just sit your patient down. And if they're failing pembro and say, "Listen, now it's really time. You know, you're really playing with fire."

Dr. Jason Hafron: And then on the keynote, 057, they were giving pembro, uh, 200 milligrams every three weeks for two years, um, or until a recurrence. What are you guys doing in New York? Are you doing through... every three weeks or are you... have you switched to every si- six weeks? Wh- where are you at with that?

Dr. Steven Finkelstein: I think all of our commercial patients, um, are being done every six weeks. It's interesting because, uh, you know, I think there's pretty good data that Merck has. It says that the side effect profile and efficacy is the same by extending it out, essentially doubling the dose and doubling the interval. Um, but that's not the way that the studies were done. Um, but from kind of our convenience standpoint, and honestly, one of the biggest reasons for me is nursing availability in New York. The needle that has to be put in the arm and this infusion needs to be done by a registered nurse. And that, that's a very, um, that resource is a very precious commodity. So if I can kind of extend that month, that actually kind of helps my clinic days, uh, you know, from an infusional standpoint. But what I'll do is I'll have those patients come in as though they were going to get an infusion every three weeks, because although I have experience with pembro for clinical trials, my experience is not hundreds of patients. So I'm pretty fastidious about more... the more touch points, the better with patients, although they're only getting the infusion every six weeks, I do like to have them get blood work, uh, you know, on that, uh, on that every three weeks.

Dr. Jason Hafron: So Chris, you guys been a pioneer, you know, a thought leader and kind of at the edge of urology. Just for the audience sake, who may not have the experience with pembro that you have in clinical trials or even clinical practice. Tell me what labs you're drawing every, you know, basically every three weeks. Um, what are you drawing? What are you checking how you're monitoring these patients?

Dr. Chris Pieczonka: Oh, yeah. That's a good question. So, you know, in my world, those patients are getting a complete CBC with diff to make sure that there's no hematological abnormalities. They're all getting a CMP, typically speaking. Then I usually order a thyroid profile on these patients, um, barring there being anything unforeseen or, or different than that. I don't go into any of the other endocrine type of testing as a routine thing. Um, so usually, CBC CMP, thyroid profile testing, you know, you capture most of the highlights of the things that are going to capture the blood sugar and whatnot. The other thing that I would make mention of is going to start a patient on pembro because one of the side effects for pembro is that you get, you know, an overzealous immune response and you can get an itis or an inflammation of just essentially anything in the body. It's not a bad idea to have a baseline hemoglobin A1C, just to kind of know what you're getting into, you know, 'cause some people might be chugging along and be pre-diabetic maybe they saw their primary care physician or not. Maybe they're not that well-manage. So it's probably a little bit better, uh, kind of longitudinal, you know, data point, uh, then just kind of grabbing that random blood sugar, uh, the CMP.

Dr. Jason Hafron: No, that's good. That's good. That's good advice because I think a lot of urology groups around the country are just getting their, their, their pembro program started. And then you still keep them on the, uh, Q3 months, surveillance, cystoscopy, um, watch them like you would normally, and then, like you said, if they have a recurrence, you- you're going to try to, you know, you're going to revisit that conversation with, with about radical cystectomy?

No, that's grea- that's great insight. And the other thing I just want to, you know, expand upon a little bit is what's coming down the pipe, you know? We, we got... uh, you mentioned there's been some very favorable trials, and I think it's important for the audience to kind of be on the lookout, um, for pending FDA approvals. Um, what- what's kind of peaking your interest, you know, that's potentially going to be approved or, or, you know, the trials that you have seen-

Dr. Chris Pieczonka: I think too, um, most of us as urologists are familiar with Ferring pharmaceuticals. You know, those are the people who give you, um, the, um, uh, the [inaudible 00:21:32]. And they had an offshoot, a company called Fergene F-E-R-G-E-N E. And their product is something called INSTILADRIN, and they have very favorable kind of similar phase three, uh, studies. And it actually is going to be a gene therapy. Um, but from what I understand is that, uh, they had some manufacturing issues, um, because of manufactured overseas and the FDA essentially really put a halt on this. So to the point that they laid off most of their staff, and I don't think that that's going to be on the commercial horizon, sort of soon-ish. Maybe in a year or two. What is on the commercial horizon is a compound called Presidium.

Um, so Presidium is, is actually a pretty interesting thing. It's a... it's a fusion protein that has a specific antibody fragment fuse to a pseudomonas exotoxins. And, um, and it's really being developed to treat these patients with BCG unresponsive disease. Um, they have a phase three study. The now the high level view... uh, high-level results have been announced. To the best that I understand, it hasn't been published yet, but they have pretty similar, complete response rates at three months around the 40% range. Um, and they... uh, that particular drug, I think has a Paducah date in mid-August. So it's possible that by the time the AUA rolls around that we might have another tool in our toolbox. Um, this is a, uh, medicine that would be an intravesical agent. So it might be more potentially within the wheelhouse of the, uh, maybe the urologists that are not doing a lot of immunotherapy.

Dr. Jason Hafron: Yeah. It's exciting to see that there is, you know, you know, that there's, you know, development going on in, in, in bladder cancers, non-muscle invasive bladder cancer. I mean, we've essentially had BCG for 30 or 40 years with no innovation. Here we have two pro- you know, now three potential products, one approved, one close to approval, and one co- coming, that there's, there's opportunity for these patients alternative to, to, to radical, um, you know, surgery, which we know that all patients, um, you know, really want... you know, it's hard to get a patient to go for a cystectomy. Um, so, you know, we have alternatives. Um, I jus-

Dr. Chris Pieczonka: Can I just add one other thing, Jason, just real quick?

For, just for the audience, you know, Pfizer also has a subcutaneous checkpoint inhibitor called Sasanlimab. And they just announced that they're changing their phase three around actually look at this exact patient population. And interestingly, the, the kind of the patients that are enrolling in that clinical study were doing a lot of that medicine in conjunction with BCG. And, uh, the, the cohort that they're going to be opening up soon is going to be for BCG unresponsive patients using this... uh, it's a subcutaneous injection, um, as monotherapy. So, so I think kind of the technology on that advancing to the point that, you know, like in my clinic, you know, where, uh, you know, IV infusion to kind of finding a chair and it kind of a time, to me that's attractive. Obviously, that's sort of down the road horizon-wise, but you know, that, that might be a very intriguing thing that we might, you know, as your role... as we're pulling out of riff, you know, you know, off the shelf and the blue prawns off the shelf, we might be able to have a checkpoint inhibitor that we pull off the shelf as an injection.

Dr. Steven Finkelstein: Yeah, and I wanted to make one additional comment as we think about what's coming down the horizon. You now, the data from keynote 057 is very exciting. And, you know, you asked me the question earlier about the use of radiation oncology. The ability to give immunotherapy coupled with radiation, uh, opens up potential ideas for RDI or radiation driven immunotherapy, the idea that we're radiating a specific area and that the immunotherapy could potentially work better because of it. That obviously is data that needs to, to be, uh, tested and generated. Uh, I want to give, um, uh, a props to my, uh, friend and colleague, Jason Staffie at Harvard who is doing that trial, uh, within the context of muscle invasive bladder cancer, uh, within SWOG. And I think that will be a very interesting trial as we look at a future. If that is, is positive in the muscle invasive space, you could see how this could potentially trickle down to the, uh, noninvasive space.

Dr. Jason Hafron: No, it's a good point. Thanks, Steve. So patient refused cystectomy, and was started on pembroluzimab, uh, every three weeks. They did three week dosing, and then the three months his Cystoscopy was negative. Just to close out this... this is the end of the case. I'm just going to do rapid fire questions, um that came in with BCG shortage is mytomycin C for high risk. Non-muscle invasive, a good alternative?

Dr. Chris Pieczonka: I think so. I mean, I think that, you know, depending on where you're located, we, you know, we, we have some trepidation about splitting the viral BCG and kind of extending it out, but, you know, mytomycin, mytomycin C, you've got, you've got to do something in these patients. That's certainly very, very very reasonable.

Dr. Jason Hafron: Yeah. It was challenging times. That's why it's exciting to see that they're all are, are alternatives being developed because we know the BCG shortage is not going to be resolved anytime soon. So no, that was a great discussion. Let's go to the second case. Um, we got more questions for you, so don't... I got... we'll get the more involved and more involved. So the second case is interesting. Is muscle invasive bladder cancer treated with neoadjuvant therapy, and it basically node positive disease at cystectomy? So let me just run through the case so we can understand. 51 year old male with past medical history presents with gross hematuria, no surgical history. Father with prostate cancer denies any to- uh, tobacco use, but parents smoked in the house so secondary. And he basically underwent a CT urogram, which you can see, um, there's blood... orange bladder mass about sticks, uh, at about 6.4 centimeters [inaudible 00:27:29].

Um, patient then subsequently went for a TURBT. There was extensive disease at the bladder neck with numerous lesions in the poster and dome. Pathology revealed non-invasive papi- papillary urothelial carcinoma, low grade. Um, based on guidelines, patient underwent a repeat, uh, TURBT, not only based on guidelines because all visible disease wasn't possible at the time of the initial resection. Basically, pathology revealed high-grade papillary, urothelium noninvasive. So high-grade TA muscularis, propria is present and not involved by tumor. Based on this, patient underwent induction BCG. Three months surveillance cystoscopy showed a two centimeter bladder neck lesion, high-grade TA. The surgeon at the time questioned whether this was residual versus recurrence, but based on our previous discussion, this is not progression... this is not progression, nor is it adequate BCG.

Um, so three months maintenance BCG, which I feel is appropriate was, uh, was given. [inaudible 00:28:38] is not really clear why that was ordered, but a CT urogram was ordered. And what's interesting is they found, it's hard to tell them this image, but I'll explain the images. There was a disbelief, um, with a small papular lesion, um, you can... the stricture and measured about two and a half centimeters. So based on the picture, uh, the patient, uh, underwent a repeat cystoscopy and ureteroscopy, and with biopsy the right ureter. Was... this is where the case gets a little interesting. The bladder, there was a low grade with focal high-grade another TA lesion where you read all blacks and was negative. But at the time the, they felt that this was a benign stricture, and that the patient needed a, a reinforcement. So the patient underwent a right robotic ureterectomy with reimplant of the ureter. Um, this is where the taste gets a little weird is, uh, it showed you reader on base of high grade urothelial carcinoma, extending to the margins with extension into the deep soft tissues.

When I talked to the surgeon about this case, he... what he said, definitely, it was important to talk to him is that the tumor wasn't in the lumen of the ureter, it was around the, you know, the soft tissue, essentially what they felt was this had progressed to T3, uh, bladder cancer, you know, and they felt that this was related to the cancer. The ureter kind of throw them off a little bit, but it wasn't involving the ureter at all 'cause the lumen was totally clear. It was the soft tissue around the ureter was totally positive with cancer, kind of an unexpected finding. So basically, the patient underwent neoadjuvant chemotherapy based on it was considered a T3 lesion, muscle invasive or, or blood invasive. And they underwent four cycles of, um, um... well gemcitabine says platinum.

I'm just going to pause here for a second. We know that neoadjuvant chemotherapy has, is quickly become the standard treatment for muscle invasive bladder cancer and it goes back to the SWOG, you know, uh, Gleason 87, 10, um, basically it's, you know, the, a survival benefit for that. Chris, what are your thoughts on, you know, neoadjuvant che- chemotherapy? Um, I know you're not doing a lot of cystoprostatectomy, but you're seeing these patients. You know, are you a big proponent of this?

Dr. Chris Pieczonka: Um, absolutely. Uh, you know, I'm, I'm, I'm kind of... as you were talking kind of looking back through the earlier cases and trying to figure out whether or not I think this patient should have had a cystoprostatectomy earlier, quite honestly. But be that as it may, uh, you know, I think that there's clear and compelling evidence to suggest that if we can get neoadjuvant chemo, that you've been ontologically downstate with patients. And hypothetically, I, I assume when the imaging was done, that we did not see any nodal disease at all of those previous imaging. So this is a little bit of an unanticipated, our finding, but arguably, you could have a patient shi- shi- shifting gears a little bit who might have nodal positive disease, uh, regional nodal disease that is. Um, but you would give neoadjuvant chemo to and potentially still get a curative operation by doing an extended nodal dissection and a cystectomy.

So, um, I think if it can get done, you probably should. I think the other thing with this particular patient is that, um, you don't know... you know, that the, the surgeon's presumption was that this was T3, but God forbid there is more urethral cancer that develops down the road and the patient needs enough for your redirect into your window to get the patient full dose chemotherapy might be impaired down the road in the event the patient has renal insufficiency. So, um, that's definitely, that would be the standard of what's done in our practice here. That's not true, that's a patient. We would send a medical oncology. We don't do the in-house chemotherapy in our practice. And we get new of chemo that come back to the cert- for for my colleagues, do the procedure.

Dr. Jason Hafron: Yeah. And that's how we do in Michigan. We try to get everybody to the... to the new regimen chemotherapy. But I've had [inaudible 00:32:43] two patients, um, who, who didn't tolerate cisplatin chemotherapy. There was significant renal toxicity. And, you know, I had a, uh, uh, uh, discussion with the... with the oncologist, the oncologist do our chemo and once they weren't able to tolerate it, we just, you know, we stopped obviously the neoadjuvant and just went straight to cystectomy. You know, the, the carboplatinum is inferior. Guidelines state that, you know, if they can't tolerate the cisplatinum, um, either upfront, you should go right to cystectomy. Um, the... you know, there's no survival advantage for the carbo, so that doesn't make any sense. And out of nowhere, I've had two of those cases, which is a scheduling nightmare, tick, you know, get a cystectomy on them within a month.

That being said, Steve, I want to pick your brain and really understand my modal therapy, bladder sprain protocols. Um, and I... you know, I think it's, it's getting more and more, you know, I guess attention and it's probably been inappropriately neglected over the years within US Urology. I don't know if this is the best case for, for, for, um, trimodal therapy, but let's say you didn't have the ureter issue. Let's just start with w- who are the candidates for, for bladder sprain protocols when you're evaluating a patient with T2 muscle invasive? What, what, what... who, who, who is the ideal candidate for, for, for trimodal therapy?

Dr. Steven Finkelstein: That's a great question. So the first thing, you know, we'll get into some of the post-op issues later, but if this was a case of a person that we were trying to think about for bladder sparing, but you think about the outcomes to start with. So again, really a, a, a algorithm spearheaded by Bill Shipley over the years, and done multiple trials. In combined analysis of the radiation therapy oncology group and energy oncology patients, enrolled on concurrence as CRT trials shown a complete response rate of 69% with a five-year overall survival of 57% disease specific survival of 71%. In a propensity match retrospective analysis. Uh, the group from Princess Margaret and Toronto reported no differences in five-year disease, specific survival between trimodal therapy and re- radical cystectomy. It was 76.6% in the trimodality arm versus 73.2% in the radical cystectomy arm. A recent guideline paper from a collaborative panel of experts from the AUA, ASCO, the American Society of Clinical Oncology, Astro, and The Society of Neurologic Oncology recommended that bladder preservation is the preferred treatment.

As you asked for patients who desire bladder preservation understand the unique risks and/or those who are medically unfit for surgery. Indeed, it appears that the data suggests that this is a very reasonable approach with very similar outcomes to cystectomy. And again, like you said, it's, it's just been very underutilized, uh, in, in the general practice.

Dr. Jason Hafron: Is there anyone who's not a candidate? You know, uh, you know, is there a certain criteria that... you know, the data's always been very provocative, but the criticism of those papers is, you know, I think the patients are, are selected or, you know, they are, are cherry picked a little bit, you know? Do you agree with that, you know? Is, is trimodal therapy for everybody?

Dr. Steven Finkelstein: Yeah. You know, my, my, my thought when you were talking was the word cherry picked, right. And I think that there's a... to be on a clinical trial, you have to get the chemotherapy part, right. So, uh, you know, the radiation therapy part is I think something that can be delivered to patients. The chemotherapy, uh, depends on, uh, what your GFR is, your ability to actually get certain agents. Uh, I think, uh, we'll maybe talk about the RTG 0712 here in a second about some of the different chemotherapies a person could get, but, you know, if you don't get the chemotherapy, you're not getting trimodality. And if he can't get the chemotherapy, then you're probably not doing as well as you would do with bladder conservation.

Dr. Jason Hafron: Yeah. That essentially you're doing paliative work, you're, you're not treating for cure. Um, so let's talk about... 'cause there's a lot of cool trials going on with, you know, you, you, you hit on a few of them of, you know, tweaking the chemotherapy, adding an immunotherapeutic, you know, can you highlight some of the trials that we should be tracking and, you know, kind of the direction where trimodel therapies going with their chemo regimens.

Dr. Steven Finkelstein: Yeah. So I'm going to briefly touch on RTG 0712. This was bladder preservation with twice a day radiation plus, uh, for your sources platinum or once daily radiation plus gemcitabine for muscle invasive bladder cancer. And that was done by doctors Cohen and again, my mentor and friend, Dr. Bill Shipley is the senior author, right? The idea that those, uh, that flora you're supposed to cisplatin radiation twice daily was an established CRT regimen for bladder sparing gemcitabine. One day radiation was a well supported alternative. This trial evaluated these regiments. And in patients with clinical T2 to, for a muscle invasive bladder cancer, they were randomly assigned to either group, uh, patients underwent a transurethral resection induction to CRT to 40 gray. And those who completed a CR received consolidator of CRT to 64 gray, and the others went to a cystectomy. They administered Ashvin, um, GemCIS chemotherapy. The primary endpoint was freedom from distant metastasis at three years.

You know, this trial ran from 2008 to 2014. They were able to enroll 70 patients of which 66 were eligible for analysis. The DMF three was 78%. 84% for FCT and GD respectively. Um, post induction, CR rates were 88% and 78%, uh, sent respectively. Uh, with respect to, um, of the 33 patients in the FCT arm, 64% experience, a treatment related grade three, four toxicity with, um, uh, patients who experienced some grade three and four hematologic GI in general, your toxicity. Uh, for the GD arm, uh, the figures were 55% overall. Uh, and, um, ultimately, uh, patients did have some toxicity in that arm as well. So their conclusion in this study was both regimens dem- dem- demonstrated the MF three greater than 75%, but there were fewer toxicities of juror- observed in, in the, uh, gym side of the an arm, either jump-started once daily or a cisplatin based regimen could serve as the basis for future systemic trials.

And that leaves you to that next question. What, what is the trials that really are, are heading down the pike? And I alluded to Jason Staffie trial at SWOG, which is really looking at radiation with immunotherapy. If you believe the keynote data, there's a lot of excitement here about using a drug that would cause less side effects. And obviously, as a fellowship-trained immunotherapists as well as radiation oncologists, I have been a huge proponent of this, and we- we'd love to see what the ultimate outcomes of this trial are.

Dr. Jason Hafron: Yeah. Immunotherapy makes a lot of sense in this space, especially when you have patients with compromised, uh, renal function. Um, you know, so i-it's very exciting. And even immunotherapy in the neoadjuvant space prior to cystectomy is, is also very exciting. Um, so it's exciting to see this, you know, the anoscope- abscopal effect that, you know, could potentially occur with the radiation. So a lot of good questions, hopefully, we'll get the answers soon. So we, you know, we can better treat this lethal disease. So let's just go back to the case. That was a great summary, Steve, uh, of the current data and kind of what the future is for trimodal therapy. Reality is, you know, it's, it hasn't gotten the attention that it probably deserves over the years. Um, so pol- poll question number, you know, or hold on, I screwed up, sorry, this is jumping around. So the patient goes for cystectomy, okay.

Um, and basically, they get a rattles- ro- robotic cystoprostatectomywith robotic neobladder and they, you know, of course we always, you know, frequently find some low grade prostate cancer, but what's worrisome about this case is three out of the five, right, pelvic lymph nodes were positive. One out of the five left pelvic nodes were positive, the right distal ureter, uh, showed invasive urothelial carcinoma, small nested variant. Uh, the final path on the right ureter was negative. Interestingly, the, the chemotherapy led to a T0, no residual tumor in the bladder, but the guy was N2. I know we don't have a hem-onc on, on the line today, but I'll throw it back to you, you know, Steve, what would, you know... wha- how would you manage this case?

Dr. Steven Finkelstein: So, you know, I, I, I think, obviously, uh, agiment chemotherapy in adjuvant immunotherapy are potential options, uh, with clinical trials have been done in that space. Uh, again, I don't do that as part of my work. Uh, if we want to talk about agiment post-op radiation therapy, uh, you know, radical cystectomy with, or without chemotherapy cures about 60% of patients with, with pathologic T2 disease confined to the bladder, but only about 40% of those with pat T3 disease. When the disease is extending the extra vesicular tissues. The pelvic failure rates after radical cystectomy are known to be quite common, especially for path T3 or higher urothelial would the acumen of incidence of local regional failure of approximately 32% of five years in the SWOG, 87, 10 cohort. Adjuvant radiation therapy can reduce local regional failure and may even improve overall survival, but currently has no defined role in part because the toxicity reported and the older series using 1980s radiation techniques, right, uh, was not the greatest.

And that's not really what we do in 2021, right? So a risk stratification to identify patients at highest risk for local failure were likely to benefit from radiation from an adjuvant radiation therapy was developed. It was externally validated international cohort specifically in Europe and Asia. Uh, recently in the States has been growing interest in adjuvant radiation therapy. And several clinical trial organizations, including the Energy Oncology and groups in the United States and Europe and India have been studying the role of adjuvant radiation for bladder cancer patients. I have the pleasure of being one of the, uh, investigators on Energy 001, helped to build the contrary Atlas. So what we aimed at, in, you know, in, in today's world, it didn't exist.

And so led by, uh, John, uh, [Krista Ducasse 00:43:59]. This is his work. Um, you know, we were able to perspectively put together, um, with a group of experts, the, the actual targets to what to go after in the post-op space. Indeed, energy G001 was a prospective trial agiment radiation versus observation for patients at the highest risk for local regional failure falling radical prostatectomy. And at that trial required IMRT, radiation therapy, which is to reduce the toxicity to organs at risk and minimize the significant GI toxicity reported in the past. Uh, with the adoptions of highly conformal radiation technology. Um, you know, you actually have to aim at once your... what you want to treat.

And so, um, this trial sort of had that. The aim of what you're, what you want to treat. And so, um, this trial sort of had some issues re- regarding, uh, cruel as, as many trials that you can in the bladder space have, have had. Um, but you know, it's... for radiation oncologist, uh, I think it's a very interesting thing. So the better we know where, where to aim, the better we can cover the targets and prof- potentially provide some, some benefit in those patients.

Dr. Jason Hafron: That's a great point. So I'm just going to skip to the poll question, you know, and send it to the audience. You know, you brought up radiation therapy as a next line of therapy. You know, Chris, what would you, would you consider observation, chemo, immunotherapy, or radiation? What would you, what... where would your thought process be with this patient?

Dr. Chris Pieczonka: I would ask the pathologist for a little bit more information before I made a choice. So, uh, as I'm reading this, I have some suspicion that maybe there's metastatic prostate cancer too, but apart from that, it would be important to assess the PD1 status on this, uh, and potentially, with the FGFR status on the, on the tumor biopsy. So, um, you know, we're, we're getting into more of a world of what the next options are, you know, from a precision standpoint. Um, there are some agents that we can use for... that are FGFR inhibitors, not right away, that that wasn't part of the polling question, but it'd nice to know that upfront. But I definitely think we would need to find out, 'cause I think we're going to probably, you know, one of the choices is immunotherapy and, um, you know, the indication for immunotherapy for this particular patient cohort is either patients who, you know, could not have received chemotherapy, which is obviously not the case in this patient, or they have to have a certain status in terms of their expression of, uh, immune markers for them to be considered off label.

So I, I, I, I think I wouldn't, I wouldn't... I would like to get more information before I answered that.

Dr. Jason Hafron: No, that's a fair question and a good point, you know, because essentially, that's where we're headed towards precision-based care, you know, sequencing these tumors and, and, and, and, um, you know, precision care. But I think we gotta be clear with the audience. Um, current guidelines recommend observation. There's no prospective data proven advantage for adjuvant chemotherapy. It's mostly retrospective and it's flawed, it's retrospective, but I think what's exciting is there's a lot of cool trials going on. Um, looking at agiment therapy, um, you know, specifically immunotherapy, the guy's already faced chemotherapy and has progressed through that, you know. Can we add, you know, immunotherapy to improve outcomes in these patients and kind of what Steve brought up, and we know that their GFR is going to be compromised, especially after a cystectomy.

This is a ripe area for, or for chemotherapy. With that being said that, you know, 50% of our audience polled said that they, they would go with chemotherapy, um, you know. Obviously, maybe consider a different regimen with your oncologist, but he already got, you know, four cycles of GemCis and still was positive, uh, in the lymph nodes. 25% would observe, which is current recommendations, probably what we kind of don't agree with now, but that's what our current standards are. And 25% of the audience, um, said, um, they would consider immunotherapy. Probably, they would have to do it on a clinical trial, um, or, you know, potentially would qualify because they're in... you know, they progressed on GemCis.

Dr. Steven Finkelstein: I would say one more thing, you know, despite the... my little spiel there. And, uh, the fact that, uh, for March, 2021 in the NCCN guidelines for patients with pad T3, pap T4, zero to two urothelium bladder cancer following radical cystectomy, right. Uh, consider postop aspirin pelvic radiation is category 2B, right. I went, oh, over the, uh, over the respondents who were on the call, right. So, so essentially, what we're, we're seeing is why the energy 001 has such a hard time with a cruel, um, people think that that maybe other things are better. And I, I would encourage, you know, um, it really depends on what you're doing. Just like surgery is very dependent on, on what you operate on, in radiation oncology, if your radiation oncologist can target the disease when you tell them as a urologist. You know, working within a look, the model, I think you're going to get potentially better outcomes.

Dr. Jason Hafron: And, uh, I'll just keep going with the case. The guy was actually treated with 28 fractions of adjuvant radiation therapy to the pelvis, so that, you know... I know Steve that you're going to treat this guy, but, um, you were in agreement with the local ra- radiation oncologist for this patient. He got treated, um, he had somatic testing, kind of what Chris alluded to. Uh, PDL1 status was 20%. And based on following radiation therapy, he was started on, uh, pembrolizumab. So it's kind of, um, you know, not what the audience, uh, considered, but, uh, you know, kind of what the panelists today felt was something that they would consider. Um, so would that being said, let me just do some rapid fire questions. I think that we got some great questions from the audience. And the first question, is if we thought this was T3 disease, who would have performed the neobladder.

Dr. Chris Pieczonka: That'sa good question. I don't think that that would be where I would go, particularly in hindsight, if the patient was found to have prostate cancer. It'd be curious, you didn't w- this wasn't included in the case is what the patient, at least in our practice, uh, you know, we, we, we would, as a standard thing, get a PSA, a patient is going for cystectomy to make sure that the best that you can, that there's not a cold prostate carcinoma, so-

Dr. Jason Hafron: Yeah, it was a Gleason six, though. It was like a small volume Gleason six, but you know, it's a great, you know. Should we be doing neobladders on T3, suspected, T3 disease? I think it's a fair question. Um, hindsight is always 2020, and you know, the guy had to get adjuvant radiation with a neobladder in place, you know. Um, that's always a little worrisome, but, uh, it's a fair question ... um, to consider. Um, Chris, you alluded to this, but we've got a question from the audience. What is the role of molecular subtyping in bladder cancer?

Dr. Chris Pieczonka: Um, so I think for this particular case, the PDL-1 status needs to be greater than equal to 10% in order to be considered on label for pembro. Um, now, to give you full disclosure, this patient is probably somebody that, although we could give Kaytruda within our practice, he probably would have been on a well-trodden path with the medical oncologist and probably be in their world. Um, but about the administration of Kaytruda and all these other checkpoint inhibitors, I think urologists are gonna need to be prepared to do, because there will be adjuvant, uh, immunotherapy for cystectomies. And there's going to be adjuvant immunotherapy for renal cell at some point soon-ish. So that having been said, I think you've got to get the PDL-1 status, and you really need to get an FGFR testing on this patient.

So there is FDA-approved, uh, uh, medicine, uh, for, uh, that are FGFR inhibitors for patients that, uh, are on second and third line therapy, uh, who are failing chemotherapy. And, um, that's precision-guided because if they don't have the FGFR mutation effectively, you can't get the medicine and their companion diagnostics that can be done. This type of testing that could be done is usually how it's sourced by the local pathology hospital, uh, to something like one of the, you know, commercially available labs. And you get a really nice report and we'll get, uh, essentially a companion diagnostic report in that that says you could use X, or you could potentially use Y, subject to the clinician's discretion of whether or not the patient meets the criteria. So you kind of get the result back. And if it's a positive for what's called the companion diagnostic test, and usually that's pretty smooth sailing in terms of whether or not, uh, that the patient could get that approved by the insurance company if you saw fit.

Dr. Jason Hafron: No, I think that's an important point. I think we're, we're gett- we're doing a better job in prostate and, you know, you know, getting, uh, somatic testing. I think we, we obviously have a lot of room, uh, to grow in blad- in bladder cancer. And as we know, this will continue to evolve, um, as the technology develops. Any closing thoughts, Steve, on this case or anything that you wanted to add? No.

Dr. Steven Finkelstein: Sorry, I just wanted to say it's, it's, you know, it's exciting time, uh, to be in the [inaudible 00:53:12] field, I think is a radiation oncologist. One who was a surgeon who became a radiation oncologist. It's great to work with my neurology colleagues. And I think the closer we work together, the better outcomes we get, especially in a difficult problem like bladder cancer.

Dr. Jason Hafron: Thank you. No, that's very important. You know, it w- you have... the close relationship is key to getting these patients to the appropriate care. Chris, any closing thoughts you have any of the cases presented?

Dr. Steven Finkelstein: Uh, LUGPA groups need to develop advanced product or cancer clinics that needs to happen, uh, because this is a very breadth of knowledge, and it's just impossible for each provider in the practice to do this. I think the days of kind of just the average urologist, understanding all this are, uh, got to be over with. And I think to do the right thing on our patients, we, you know need to have these types of sessions, have to have educational guidance at the AUA and, and LUGPA, uh, to really develop that. And we're thinking about that. We do not have to basketball or cancer clinic in our practice.

Dr. Jason Hafron: Yeah. I, I can't agree with you more, Chris. You know, that's something we're working towards. And I know a few groups have already started that, uh, process. But you know, it's at its infancy. It's a good time to other LUGOPA groups to identify your champions, you know, get, you know, figure out navigation and getting these patients the appropriate care, you know, bladder cancer is, we know, a lethal disease. And, uh, if, if it's mismanaged, it will literally affect patient's lives. So it's critical that we get the experts that the doctors are passionate about it, um, so that these patients can get the care that they so deserve.