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Brian: Great question. Again, no clear right answers here. In general, the approach that we were taking at WashU when I was there was for patients where we felt like the risk was greater for distant relapse. So the patients had positive nodes; the priority would be systemic therapy. For patients who were, say, T4 node-negative, and especially if they were positive margin patients, we would usually start the radiation first, and then be giving the immunotherapy concurrently or start the radiation and give the immunotherapy afterwards. Parminder's presented some very encouraging preliminary data on the SWOG/NRG bladder trial, that concurrent chemo RT plus atezo, again in a slightly different disease setting, tack bladder setting, is very well tolerated.

And our limited experience doing combined Nivo and radiation or combined pembro and radiation in some cases has been also quite good. With IMRT, I think it really helps. I think that arguably the immunotherapy for most patients probably should be started first, and that you can see how well they're tolerating that from a GI perspective before adding in another potentially GI-toxic treatment. But I think these are questions that need to be answered. We don't really know adjuvant radiation in combination with adjuvant immunotherapy. It's a great trial concept.

Leslie: I just want to second the point that Brian brought up about the toxicity data from SWOG/NRG 1806. What's been presented thus far is that there's no additional toxicity when you combine the two treatments to the immunotherapy alone, and it is very well tolerated and so I've been willing to overlap the treatments, especially since in the adjuvant setting you're commonly going to a lower dose anyway if you're respecting bowel tolerance. So I haven't avoided an overlap.

Scott: Who else has a question? I'll bring you the mic that way we don't have to repeat. It's a small group.

Ali Khaki: Hi everyone. Thanks. Excellent talks. I'm Ali Khaki from Stanford University. Parminder, question for you. You were talking about building on 1806 and intensifying systemic therapy and I think in the concept, you presented thinking about it after doing the chemo RT, what about doing it before? Using CTD data to select for people who have systemic ctDNA positivity just with MIBC and then intensifying those people with systemic therapy prior to doing chemoradiation? Any thoughts on that idea?

Parminder Singh: You can have a seat. So Ali, thanks. Great question. And I am going to come back to Ken's question again because I have a question on top of that. So to answer Ali's question, Ali's asking why not do a neoadjuvant strategy in the after 1806 concept? So again, that concept is in build and we are doing brainstormings and there will be a session for brainstorming here also on that. And all options are on the table. Now what we thought of as the experiences we are gaining from 1806 will be incorporated into the next trial, and one of the experiences, which Scott has contributed a lot of patients, over 60 patients on that trial, is that one, patients want to get started with their treatment right away. And then only if we tell them that they are very, very high risk is when they would opt for subsequent therapies.

Otherwise they want to just finish off and leave because they're coming from far off places, coming to these centers. And so thinking of those designs is that, okay, so the definitive therapy is chemo RT and we have done that, and now if we can identify patients who truly need intensification, maybe those who have some residual disease in the bladder, maybe those who had high risk features, which we will identify on 1806 because we have stratified those risk factors, T3, T4 versus T2 chemotherapy regimen node radiation, not radiation. So we will get all that data from 1806 and we can very finely predict events. Are they happening locally regionally or they're happening distantly? And then we are collecting blood samples on 1806 to do ctDNA testing. So the next trial will be built on 1806 and our hope is that we'll be able to build a high risk trial.

But if it turns out to be that that is a hurdle because we want to keep eligibility open, we could then design a trial where we'll allow all comers who want to opt for the trial and then do a predefined subgroup analysis in a high risk patient population later on. So I agree with that, but I think some of the experience from 1806 is guiding us towards a design where patients who are post therapy and we feel that they're still high risk, that we would encourage them to go on to that trial. So Scott.

Scott: And one of the other potential options in your design is if you're agnostic to what happens prior to TMT, it will allow docs who say, "Look, I've got a really bad one. I want to give neoadjuvant chemo because it's a healthy 65-year-old patient." They're going to look at that data and say, "I'm going to give neoadjuvant chemo, then I'm going to give TMT." They still can go into your trial as long as we don't exclude them because of prior neoadjuvant chemo.

Leslie: Ali, I think another point to make about using CTCs to decide on therapy upfront is, and we'll be waiting for the data from 1806 to understand how CTCs exist and work in a TMT population. Remember these patients have had maximal TUR before they're deciding on therapy, so they might not have many circulating tumor cells and so we don't even know in the patients who are choosing radiation, what is a threshold, how important is that in that population that's already had TURBT and no evidence of metastatic disease. So I think that there's a lot to be learned yet, but that intensifying systemic therapy is really important and figuring out the exact timing is key.

Parminder Singh: I need to go back to Ken's question. So a question to you Brian. When you plan adjuvant radiation in a case like this, wouldn't you offer them concurrent radiation? And then we are saying then they are getting concurrent chemoradiation and plus Nivolumab for a year. Is that how you would propose that design?

Brian: So I haven't done a lot of adjuvant concurrent chemo and radiation just because the prospective data was doing the chemo sequentially with the radiation from the Egyptian trial. I think it's reasonable. Anecdotally, we did it once or twice on young very healthy patients where we wanted to be maximally aggressive. I think it's certainly reasonable, and with the IMRT toxicities being so low, it's certainly reasonable. I think that there just isn't data for the value of adjuvant chemo RT given concurrently. But look, we can extrapolate from the concurrent chemo RT data from BC 2001. Biologically it makes sense that there could be a good sensitization. I think it depends some on just the performance status and baseline GI toxicity of patients we're encountering. 

Leslie: And I think also it's really important to distinguish adjuvant versus salvage. If you've got a salvage patient with a local recurrence, chemoradiation makes sense. We at USC did a small retrospective study of our experience with that, and the combination of chemoradiation in a salvage setting is beneficial because you're getting the radiosensitization. In an adjuvant setting where you're treating just microscopic disease, I think we don't obviously have data, as Brian's saying, but possibly in that setting, just the IO plus radiation is enough. Anne.

Anne: [inaudible].

Leslie: So the question is a two-part question, Brian, which is for I think mostly you and I, which is one, what is a maximal TURBT in the setting of T4 disease? Maybe Scott as well. And then also use of fiducials plus/minus. What are they helping with? What are they doing? I can answer the second question first and then Brian, obviously, jump in, or Scott or anyone or Kent as well. So many people use fiducials to delineate the tumor bed because on SWOG/NRG 1806, there is the option for what's called a tumor bed boost. Instead of treating the whole bladder to the whole dose, you treat the whole bladder to a little less dose and then you complete the radiation dose to just the tumor bed.

And so in that setting, fiducials make a great bit of difference because you can very easily see obviously what is hard to see on cross-sectional imaging with a CT. There's not great data as of yet to say that a tumor bed boost actually is beneficial over whole bladder therapy. And when they've looked at subset analysis from BC 2001, they showed that that bladder tumor boost didn't really make a difference and it also didn't really decrease toxicity. And so then you really do have to say, "Well, then why would you do it?"

And so I think there's at least two schools of thought on that. You could point to in that BC 2001 study, they didn't use IMRT and so they had larger fields. As a radiation oncologist, we could sit and pick it apart. But regardless, I think that is the role of fiducials. I don't love them personally, but I know a lot of people who like them. I think there's an interesting question of whether or not you should actually be giving more dose, like an integrated boost, a little extra dose to the tumor bed. That's not been looked at, that's something that certainly is a question to look at, but that's not the way that-

Anne: [inaudible].

Leslie: Right, that's exactly it, because it's not really a tumor. Because when most people hear tumor boost, they think the tumor's getting more dosed. It's actually really deescalation to the rest of the bladder is the way that it's currently done. I don't know if others... I don't want to monopolize. Brian, Scott, do you guys want to talk about the TURBT in T4 disease?

Scott: All of our TURBTs are maximal. Down to fat, transmural, I call it a transmural radical resection, which many would say that would be a perforation, but it's not. It's a transmural resection. In the T4 setting, I think I've only put maybe two or three patients that have T4 disease, really elderly patients. And you're just resecting down and you go all the way through the bladder and you see fat in a normal area and then you still see tumor? I don't keep resecting beyond that. You could, but not a great idea. You'll be leaving the Foley in for a month and they won't like you. So I think it is an interesting question. I've got other slides. Is the fact that you can achieve a gross complete TUR, whatever that means, is that prognostic or is it predictive?

We don't know. The British are trying to figure that out. They may, but we don't know the answer. But it definitely gives me a sense in consultation with the patient, number one, what was the total volume? Because I've found in my experience, if I'm resecting half this patient's bladder, even if they had good function beforehand, they're not going to have great function after. So I made the mistake of being ultra aggressive early on and I've resected some people's transmurally 50% of their bladder. Look, it took me forever to try to get them to get their bladders out for a functional reason and they got reflux and they had noncompliant bladders, but it was rare. And I've learned, look, if you very, very high volume, probably go down a surgical pathway way. And it gives me a little bit of an idea of prognostication for the patient.

Brian: Yeah, I'm happy to weigh in on the fiducial. I'm of similar mind to Leslie on that we were using Trace It when it was commercially available. It's no longer available, so the urologists that I've worked with, we typically haven't placed fiducials. I do tend to do more of a tumor boost, but again, as Leslie defined it, not higher dose, but really just deescalating. But only in very select patients where I think I can get away with it, and I'm often defining the volume, getting the full dose, very generously. So in a sense I'm almost just looking for, especially at the dome of the bladder, are there areas more in the dome close to bowel that I'm quite confident don't have gross disease? And then I'll cheat with some of my contours there.

So I'm not asking my dosimetrist to treat the entire bladder to full dose without prioritization on where they could cheat a little bit in the interest of reducing toxicity and then focusing dose where I want it, which is the areas more likely to have tumor. I think that the T4 into the prostate is a unique situation. My feeling there is if the surgeons aren't able to do a big resection of the prostate, that's fine. I'll sometimes dose escalate the prostate. We can take the prostate to a very high dose if we need to, so I've even gone above our usual bladder doses for T4 of the prostate knowing that radiation can control gross disease in the prostate very well.

Speaker 7: I also wanted to just add on that note that some of these patients that we have treated, a lot of them are very older too. And in our smaller study for DUART, we didn't actually see the outcome difference between patients who had maximal TURBT versus those who didn't, so more to come from Parminder's study is whether that shows a difference. But there is a feasibility issue in these older patients, and a lot of times I've seen even the urologists don't want to do maximal TURBT because they're worried about the tolerance of future treatments if they go. So while it's desirable, I think with the era of immunotherapy, we still need to see how the responses would differ.

Scot Niglio: Hi, Scot Niglio from NYU. So one, thank you for all of your work you're doing to help patients preserve their bladders. I'm wondering, while we still have to wait for SWOG to finish readout and this durva trial to finish and readout, what are your thoughts of PD-1 versus PD-L1 at this point? Because we had in the metastatic setting some PD-L1 inhibitors that have lost their FDA approval, with durva and atezo, with negative trials with atezo 130 and 010. Just general thoughts and what do we do if these trials are negative? Do we look forward to a PD-1 trial? How does that impact new trials we design?

Parminder Singh: Yeah, thank you so much for that question. That's something we have learned over the years as these molecules were approved in 2015/16 and then these subsequent trials came out. In the early times, there was a sense that maybe they were not different in their activities across the board for bladder cancer. And so at that time when these trials were being designed, they were agnostic to this idea that there was a difference. It was more an idea-based on who was ready to collaborate and wanted to move forward with the trial. So some of that played into the selection of the molecule, but as with time, the field has evolved. We are seeing that maybe some of the loss of difference was attributed to just the trial design or the selection of the patient and how patients responded in the standard of care arms.

And maybe we lost the benefit because the true benefit was very limited, 10, 15% benefit with IO alone in metastatic disease. But yes, now where we are is that PD-L1s have lost the ground to PD-1s. And so that's why at this point, the next trial we put pembro in the treatment arm thinking that maybe when this trial comes out, pembro will be one of the approved agents and will be part of the combination. And then we also know there is a contemporary trial to S1806, which is run by Merck, looking at pembro in the chemo RT space. And so it will lay the field out, so we will not lose time in the sense that that trial is also running and S1806 is running at the same time. And as data comes out from both these trials, we'll have a sense of where the activity is.

Now the question is, that has not been investigated previously, is the combination of PD-L1 in conjunction with radiation. And so we can still say there is hope that because this is a novel strategy which has not been tested in the previous trials, which have shown less activity of PD-L1, is this combination of PD-L1 with radiation may play out in their favor and may turn out to be positive. And so that's why the EPIC trial, which is the next trial, will have the standard-of-care treatment, as Scott alluded to, going into that adjuvant phase.

Whatever the standard of care would be at that time, if patients have received chemoradiation with a definitive intent with whatever combination, they can then get this additional therapy based on maybe their high risk features and get this intensification of combining 80 CCs with pembro and then move forward with the next design. And so yes, we are considering what you're saying, the now lack of efficacy of PD-L1 in advanced settings. But at the same time, these radiation trials will read out in the next times and we'll find out how atezo with radiation lines up with atezo with chemo or atezo alone in advanced disease settings. So thanks for that question.

Leslie: I actually have one question for the surgeons in the room. So to engage all of you... Oh, did you want to make a comment?

Speaker 7: Yeah, can I just add something? I think the comparison of PD-1 versus PD-L1, I think it's still very premature to say. It's a million-dollar question, and we all know avelumab worked in advanced settings, so I think we shouldn't forget that the PD-L1s have an advantage. So more to come on that, but I don't think so we are in a position to say which one is better, but of course some of the reads for PD-1s are coming out better. But again, avelumab is approved.

Leslie: Okay. So I think everyone in this room probably agrees that chemoradiation TMT is equivalent to cystectomy in the properly selected patient, says a radiation oncologist. But what I want to know is Scott presented data on RTOG 0926, a trial looking at chemoradiotherapy in the non-muscle invasive space in patients who were intended for their next step to be cystectomy. That was a very important enrollment or eligibility criterion. It wasn't just that they had BCG unresponsive disease, it had to be that their next step was to go to cystectomy. How far are we away from that being something that is widely accepted? Where in non-muscle invasive disease, you have a patient who is BCG unresponsive, has gone through other lines of therapies, and the next step is cystectomy. "No, we're going to give them chemoradiation." Scott, do you want to start? Anne? Other surgeons, these are just who I know.

Scott: I personally think that in the T1 setting, there's a role in a trial. So T1, T1 with LVI, or just T1 recommending them for cystectomy, I'm happy to offer that patient a trial. I think outside of the T1 space, it becomes a little more problematic, and there are challenges in accruing patients in this space. The ADAPT-BLADDER trial, an amazing trial, if anybody in here is on that trial, but the list of authors was longer than the number of patients in the trial. It was a phase one, it came out of a CTPM from the NCI, a lot of effort went into that trial, but there were more authors than there were patients. It is an extraordinarily difficult space and we'd have to get buy-in across the board. I think the buy-in would have to be on that T1 population. Any other surgeons in the room want to comment?

Speaker 7: While they're commenting, can I add something to the surgeons? So once they do get focal radiation, is it really hard to resect the bladder? Can you share that as well? Because can patients go through that and then undergo radical cystectomy, or is it an absolute no?

Scott: No, no. There's data out of Boston on salvage cystectomy. Thankfully, we've put a lot of patients on chemorads, I've only had to do a couple of salvage cystectomies. But for the potential loss in functional ability to have a continent orthotopic neobladder, which is not always there, but typically these patients are, at least in my world, out of the age range for that anyway. I'm sort of community doc with an academic title.

Leslie: [inaudible].

Scott: I know you do. I know you do, I know it's there. But the majority of these patients in my practice, are going to get a conduit regardless because of their age range. I don't find that the salvage cystectomies have been that much different. They're all done open or robotic, however you do them. Complication rates are high regardless of how you do them. It's a nasty surgery. It's a nasty recovery for the patient. It's a fun surgery for the surgeons.

Leslie: Does anyone else want to comment on the T1 issue?

Scott: Oh, I'm sorry.

Anne: No, no, that's okay. Actually, I just wanted to hear from the patients actually, if we have any, about this question. In my experience, and I'm not a surgeon or a radiation oncologist, but when I've talked to patients about this issue, what it always comes down to is, "Will I have a chance to remove my bladder later or if I go down the chemo RT route, have I sentenced myself to having this bladder and potential distant metastases associated with it?" And so for... Yeah, great. Well, I'd love to hear from the patients about thinking through that idea of having maybe an increased risk of a surgical option after radiation, especially in the T1 space. 

Scott: Now I do want to address it real quick. I just want to say one thing. Unlike prostate, if you're a prostate cancer patient and you walk into any of the tertiary centers in the US, you most likely are going to get great quality care because you're going to see a radiation oncologist and a surgeon, and maybe a medical oncologist. If you're a bladder cancer patient, you don't have multidisciplinary care at 95% of the places, even the tertiary or quaternary care centers that are on the billboards. And I think that's something that needs to change because we all bring our own inherent biases.

How many times does a prostate cancer patient show up to me who's 68, he's got Gleason 7 disease and somebody's told him, "Well, if I have radiation, I can't have a prostatectomy." I'm like, that's not true. I do salvage prostates all the time, or we can do ablation. There are other options, but just because your urologist doesn't do it or he's got that preconceived bias, we have to eliminate those things and really present this data to the patients fairly. And I don't think the urologic community has done a good job of doing this in the US and we have to... Now on the other side, radiation oncologists love to radiate. Okay? So there's a balance and maybe the medical oncologist is the arbitrator here.

Speaker 9: So this is something when I talk to patients, I always tell them they need to ask the question. I think there is relevance to the, what is my current status, my age, my physical condition. I think those are factors, and I think it's going to be a very individual decision. I think for many people, the risk of recurrence is high on the list, if you remember the slide that Parminder presented. So I think that we always have to keep this in mind front and center.

Armine Smith: Armine Smith, a surgeon. So I think I can address... I have a question and I think we can address some things too. I think this is such an exciting space, the bladder preservation, and I think we have more questions than answers right now, and it's just really exciting that everybody's moving in this direction and there's enthusiasm about it. So starting with the MDC question, we've tried, and we have a lot of these MDC discussions at Hopkins among us, but it's hard to bring patients in a time-sensitive manner to MDC for bladder. And I think that's been the stop gap for a lot of it because for the prostate MDCs, there's never an emergency to get a patient in to get everything done, or occasionally there is. But for bladder, we try to get them in as soon as possible.

And I think bringing things in a timely fashion is usually the constraint. But I agree, I think if you have multiple people in place, the discussion is much better and the options are wider for the patient. When I offer patients chemo or TMT, I always start by telling them, "There are studies that show that the results are just as good. We don't know who's the best candidate for it. And unfortunately, I think you might be limited in the urinary diversion options afterwards." And that's the conversation that happens, and a lot of people pick based on their preferences. So I think more urologists should be offering it, I agree, and I think as this data becomes more mainstream, that will happen eventually. As far as the T1 disease, I think it's going to be hard to accrue in this setting because it's hard to put a patient who does not have a worsening of disease, so it's a TA or CIS patient, to offer them chemo radiation because I don't think we know if this is going to work for CIS patients, right?

The thinking is we won't. Yeah. So for T1 and I think variant histologies, we might have a better success recruiting patients for that. Now, the question I had for the group is... And what caught my attention is when you said the maximum TURBT may not be offering as much of a benefit as we think, now do you think our treatments are becoming as good that we don't need to eradicate the disease? So when we put patients on bladder preservation, before our goal was to eradicate as much as possible a visible disease and get them through. Now, do we have our treatments to the point that we can just get a sample, just maybe debulk the tumor and send the patient? And if not, then we should be utilizing more maybe partial cystectomy than maximum TURBT for smaller tumors. So just some thoughts more than anything else.

Speaker 7: I think that's a good point. I think it's a very big may right now. So we will need to know if maximum TURBT does, but the initial appearance maybe that perhaps there are more cancer cells and maybe they are improving the immune response. Just a thought, I think it has been floated and there is some literature around it. Don't know if that would be, but you're right, as we improve our systemic therapies, maybe that may not be the crucial barrier.

Brian: Yeah, my personal bias is that yes, a maximal debulking TURBT adds value. There's a lot of US data suggesting that. I think some folks on the panel brought up, "Well, is it predictive? Is it prognostic?" I don't know the answer, but if we just extrapolate from other diseases as well as from the bulk of the bladder cancer literature, and there's very strong data in breast cancer, which bladder preservation is essentially just mimicking what happened with the breast conservation studies of the 1980s. We're just decades behind breast cancer. But there, the high quality lumpectomy was hugely important for the success of that approach, and I firmly believe that the TURBT is at least as important, maybe more so than anything I'm doing with the radiation. The same way that breast cancer lumpectomy and radiation is still a surgically treated disease, this is a surgically treated disease. And good surgery by skilled urologists is absolutely critical.

Adam Gadzinski: To also comment on the high grade T1 question, Adam Gadzinski, I'm a urologist at Beaumont Hospital, work at a group like Dr. Delacroix out in the community, but getting a lot of interesting things that come through our doors. What I found is I remember explaining to a patient once had high grade T1 recurrence. I go, "Well, I think we should take your bladder out at this point." And they're like, "Well, I just want to keep it." I was like, "Well, if it was in the muscle, then I'd be telling you we could do chemo and rads." And realizing that this just is an odd explanation, "Oh, if only your cancer was worse, then you could keep your bladder."

And so I think there is that space for a high grade T1, just explaining that to someone or trying to rationalize my recommendation against guidelines and realizing that from actually a rational person standpoint it sounds crazy. But I think that that is a place that if you're probably going to start somewhere with chemorads for primary non-muscle invasive, maybe even in the recurrent setting. But I know that's what that original trial was for. And they accrued what? 37 patients over a decade? Pretty small place.

Brian: We're hoping with the follow-up trial, and again, it's really going to be dependent on urologists like those in the room and medical oncologists as well, that because of that data and because of important data that Leslie and the folks at MGH have published, there's a newspaper that's coming out, The Red Journal, that there's more and more data now that chemo RT can achieve outcomes comparable to cystectomy. And now that we're doing it more on this SWOG trial, why not try it in recurrent high grade T1? So we're excited to try to bring this trial forward and hopefully we can get it approved and look forward to your support. To those of you interested in opening it is that this comes to fruition.

Suzanne Cole: So the way the discussion has turned really gets to my question. So I'm Suzanne Cole, I work at UT Southwestern, which is a dominant urology-centric place. And so at the beginning when Parminder was talking about how he shopped his idea around to all of the cooperative groups, I'm really curious, and Monika, you can talk to this too, about how did you guys get buy-in? Because I've been in SWOG with you where everybody just tears everything apart, especially the surgeons who dominate everything and are super against radiation, which was not done at our institution, not done. I don't think anybody had had chemoradiation ever until your trial came out and we opened your trial and then people started doing it. And so I'm curious, how did you get buy-in? Because the task force, there's so many opinions.

Parminder Singh: Again, very important question, Suzanne, and that's where this... Seth always taught me this, that it always takes a village. And so from the very beginning, I started working on putting this group together and we knew from the beginning... And it was not only surgeons but also medical oncologists, which balked at the idea, "Oh, this trial will not accrue." This was in the GU 2016 when I was presenting, and senior folks, even Med Oncs were saying, "This is not going to accrue." And so there were many things which are here. One was to reach out to each cooperative group, engage with NCORP, figured out which centers are accruing well on 1605 because that's, again, a bladder preservation idea, even though it is a non-muscle invasive space, reach out to patient advocates. To put this from patients' perspective, we need to push this idea that patients are asking. And you can see all those things.

So we did surveys, we reached out to all surgeons in SWOG committee, "If we open this trial, what do you think? How many patients? Can you put one patient a month? Can you put two patients a month?" And we added those data in, and my estimate even before the trial was open was that we could accrue eight patients a month if at least these folks can pitch in their patients. So I have a sense, "Okay, eight patients." So we proposed our design based on that and we are now hitting close to nine.

And so each peg in this wheel contributed to move forward. It was not just the surgeons, it was everybody. And as Scott said, patient starts asking for it. That, "Oh, there's a bladder preservation idea, so we want to do it." Even if Scott would say there is a maybe slightly higher or slightly less in the beginning that the outcomes could be compromised, but still patients wanted it. And so I think it is a multi-prong approach. You reach out to everyone, you slowly buy in. Patients are asking, cooperative groups, NCORP sites. So all that put together is able to move this thing forward, it was not just one.

Scott: The ship is turning. Look, who would've thought 1806 would've accrued this many patients in this timeframe? It's changing. But the urologists in the room, I'm the oldest one in here probably. Okay. Yeah, I'm the oldest one in here. So I think it's the next generation of urologists too who are very engaged. And this bias held strong. I remember being a couple years out as a faculty, I sent the patient to a psychiatrist who wanted chemo rads. I'm serious. I'm serious. And it's not a joke, it's serious. That's how ingrained it is at many places in this country.

Leslie: And then that's why for the purpose of this panel, you notice that Brian and I are the only radiation oncologists. We intentionally wanted to make this a discussion that's multi-specialty because it really is a multi-specialty discussion, and you need engagement from everyone to make this happen. And I also feel your pain, having been a radiation oncologist at USC for nine years before switching to Cedar-Sinai, I tried to get bladder preservation on so many patients and it just took perseverance.

Speaker 7: Just to add to Suzanne's question and everybody on the panel, I think this is so correct. All hands need to be on the deck for the bladder preservation. We all like it or not, I think the gatekeepers of the bladder cancer is our urologist, and that's their first contact. So I think if they're not hearing this, they're probably not going to hear anything you say after that. And I've seen it personally. It's true in some, but I think we are making some changes, and speaking to the cooperative groups is very important. I know EA8185 is not doing so well as 1806, but also hit in the time of Covid where people didn't want to open rare tumor because they wanted to preserve their resources for the most common cancer types of the trials. So I think little rationing also didn't do very well, but I think having a multidisciplinary meeting is so important. And either somebody in the room mentioned it that it's different than the prostate, it is so true. When these patients come, I think we need to channel them as fast as we can.

Speaker 13: Just a quick comment. I agree with Scott, I think that the tide has shifted so much. I haven't seen a bladder cancer patient in the last two months who's doing any research at all who doesn't say, "I read I can keep my bladder now." And so it's a totally different conversation, which is obviously just going to continue to push the field forward. And I do think it's going to still be a pretty tough cell in the non-muscle invasive space. I think particularly with some of the...

There's so many novel intravesical and salvage intravesical treatments and pretzels and blah, blah, blah, that I think that there's perceived, we don't know yet, less toxicity with those treatments than with radiation in a non-muscle invasive space. And despite being part of the papers showing that urinary diversion is not affected by radiation, I think that that's pretty selected. And I also think that there are really probably a lot of gender differences in that that we certainly have not looked at. And I think in female patients, to me, no question, doing a neobladder after radiation is still something I would not offer personally in terms-

Speaker 9: So we have made so much progress, but we are changing a culture. So one of the things, and I want to go back to Suzanne's comment, one of the things that I think needs to be really considered is how we frame things in the guidelines. If you frame the question, does the patient qualify for radical cystectomy, that's the wrong framing because that means radical cystectomy is king. And as we change going forward, the guidelines have got to come along with us, and they've got to talk about whether or not bladder preservation makes sense. Not whether radical cystectomy is the first choice.