Patrick Hensley: Welcome to the UroToday coverage of the International Bladder Cancer Group, bladder cancer forum, at the AUA 2022 in New Orleans. I'm Pat Hensley. I'm a fellow at the University of Texas MD Anderson Cancer Center. And I'd like to welcome our guests today, Dr. Gary Steinberg professor at NYU and Dr. John Taylor professor at the University of Kansas. Gentlemen, thank you very much for joining us.

Gary Steinberg: Thank you.

John Taylor: Pleasure. Thank you.

Patrick Hensley: Today, we'll be discussing the role of bladder preservation and after a complete clinical response in muscle invasive bladder cancer patients after they undergo neoadjuvant chemotherapy. And I'd like to start with you, Dr. Steinberg, if you will talk to us a little bit about the role of radical cystectomy as the standard of care in a patient who achieves a complete clinical response after appropriate neoadjuvant chemotherapy.

Gary Steinberg: Well, that's an excellent question and it's a little bit loaded because everyone wonders. If you've had a complete clinical response, why do you need to remove the bladder? And again, I think that is our ultimate goal, that we will not need to remove the bladder. However, how we define complete clinical response is not anywhere near as vigorous as we need. We're still in an era where we're giving patients one size fits all chemotherapy. It's kind of an empiric base and everybody gets the same chemotherapy. And I really do believe that until we get into the era of personalized therapy and targeted therapy, we have to be very careful when we tell patients that there's a complete clinical response and there's no benefit to removing your bladder

Patrick Hensley: And Dr. Taylor I'll ask you the same question and have you defend perhaps the bladder preservation arm of this? So you have a patient with clinical T2 disease. Who's undergone cisplatin-based neoadjuvant chemotherapy achieved a complete clinical response. How would you counsel this patient on the oncologic safety of bladder preservation?

John Taylor: I don't think that Dr. Steinberg and I are far off in our opinions of this think that there are ways to approach the patient that might be slightly different. I agree that today our standard is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy as standard and the best way to preserve long term survival. But I frame my side of the argument around a challenge and a question to all of us in the field and to people coming into the field. Why are we still doing this radical cystectomy was introduced over 70 years ago.

If we look at other cancers that are body disfiguring, breast cancer, for example, breast cancer has gone from advanced stage presentation to a radical mastectomy, to genetic screening, preemptive surgery in people who are high risk for developing disease. And outside of that organ preservation based on genetic factors and screening of the genome, we haven't changed since cystectomy was introduced the way disease presents and the way we handle it has, has been essentially unchanged. And I think that as Dr Steinberg said, we are not ready for prime time, but there is data out there that is very compelling. If you look in the literature in the past, and one of my old professors used to say, you want to do something new, go back 20 years and do it again. So let's go back 20 years, 1998, the Memorial group published a paper on 111 patients that refused cystectomy after achieving what was deemed clinical response, not pathologic response, clinical. And there's a fine difference between the two. And they had a 10 year survival rate of 75% with a bladder preservation rate of around 70%.

Now we've introduced this platinum based chemotherapy to the mix, and there's further data, very compelling at five years, showing very similar numbers from single and multi institutions reviewing the same type of thing. We've got to do a better job. We've got the tools in place. We've got the ways to evaluate this, and we've got to figure it out like breast cancer, where we can tell this patient, you are at high risk for failing cisplatin-based chemotherapy, you need to have your bladder out. There is definitely going to be a cohort of patients that will be able to preserve their bladders and have reasonable oncologic outcomes. And I think that should be our goal. That should be what we're discussing with our patients. And I think today it's a little bit premature, but we could have those discussions with patients as to what's going on in the trial based error space and what we know and what we don't know.

Patrick Hensley: I think one of the biggest hesitancy for bladder preservation protocols is our inability to accurately clinically stage patients, both at the index tumor resection and imaging at the diagnosis of muscle invasive disease, but also after neoadjuvant chemotherapy prior to surgery, when you're restaging a patient to monitor therapeutic response, how would you in your practice, if you were to put a patient on a bladder preserving protocol, how would you restage a patient accurately after neoadjuvant chemotherapy? I'll start with Dr. Steinburg.

Gary Steinberg: Yeah. And that's where there's a tremendous need for improvement. I think that the prostate cancer field with, with the MR and now they're even talking about PET MR and so forth to try to identify prostate cancer clearly identifying treated bladder cancer patients have been treated may be even more complicated than an untreated bladder cancer or an untreated prostate cancer in terms of using better imaging to detect prevalence of additional or recurrent or residual disease, whether immediately after therapy or down the road. And so the question becomes, how often do you screen, I will tell you that in the patients who have been treated with bladder preservation in terms of chemotherapy and radiation therapy, and a lot of these patients are getting post treatment, CT scans and MR and cytoscopy.

I find it very difficult to know what I'm looking at when I look at those patients, the MR though may be a residual mass and you try to biopsy those patients, but you're not sure how deeply you're going. And I worry that with our present management, that there are patients who are relieving bladder cancer behind in invasive bladder cancer. And we know that if you leave invasive bladder cancer, untreated, ultimately it will cause mortality from the disease. So I don't really feel very confident about that. And I have seen patients that were following with bladder preservation that developed metastatic disease right in front of our face because of our shortcomings in our follow up surveillance regimens and our imaging.

Patrick Hensley: Dr. Taylor, how would you endoscopically evaluate a patient after neoadjuvant chemotherapy? There's some, if you look at the retrospective series, there're some protocols that just did a cysto biopsy, maybe cytology others did a radical, deep resection at the resection band to get into perivesical fat to adequately fully stage the transmural bladder wall. How would you in your practice handle a patient endoscopically after neoadjuvant chemotherapy? Would you do a formal resection of the previous site or just biopsy?

John Taylor: Yeah, I think that we're obligated to look for cancer. As Dr. Steinberg said, we leave a lot of cancer behind in our imaging studies, whether it's MRI or CT scan, or are woefully unsuccessful at predicting the presence or absence of disease. I think that we under stage as many people as we over stage to the point where, what is the value of a post neoadjuvant chemotherapy, CAT scan, or MRI of the pelvis? We just don't know. I think if we're going to go this route, we're obligated to prove down staging or no cancer. I think down staging to non muscle invasive disease can be considered. If you look at the trials that are being run, now, that's part of the inclusion criteria. But I think that we need to go back to some old school.

I think we need to deeply resect the prior scar. And I think we need to do bladder mapping. We've kind of moved away from bladder mapping in urology. And I think that if we really want to be predictive about what we're doing, we need to know what's there. So I think we need to look under every stone so that we at least have a sense of where we are going into the potential act of surveillance protocols.

Gary Steinberg: And to make that easier, we should remove the bladder. Then the bladder mapping will be much easier and much more accurate. So again, I think that we need to, we can't over extrapolate the data. And so we have to recognize that this is not going to be for all patients. We have to make sure that patients understand that there are going to be nuances and that some patients clearly will benefit from having their bladder removed. I think that as John said, we're doing cystectomy. We started doing them 70 years ago. We certainly need to improve our technique, continue to improve our technique. We need to improve our options of urinary tract reconstruction. But, quite honestly, there are a number of patients. Again, bladder cancers, most commonly affects men in their seventies. A lot of these patients are not physically fit. They're not what you would call athletes, and that believe it or not a good quality radical cystectomy urinary diversion, especially in ileal conduit in that cohort of patients is actually an improvement in their quality of life.

Patrick Hensley: Absolutely.

John Taylor: Yeah.

Patrick Hensley: And Dr. Taylor, you mentioned that some of the ongoing trials are preserving bladders in patients who don't have a complete clinical response, but have residual non muscle invasive disease. How do y'all feel about preserving a bladder in someone who is downstage maybe from muscle invasive disease to high grade T1 does that make you a little uneasy about preserving that bladder?

John Taylor: Yeah, I think certainly a high grade T1 would. I think if you look at the trials that are ongoing now, the only patients that are really offered active surveillance, or if they're downstage to CIS and I believe that's the Alliance Trial is allowing CIS in there just to go back to one of Gary's points about, about cystectomy. I think that we become complacent sometimes as surgeons with our success rates. And it takes one patient that dies from a non cystectomy or non-surgical related C. diff toxic megacolon, it's a morbid procedure. And the people that we're operating on are at high risk for perioperative morbidity and mortality, not from the surgery itself, per se, but from having undergone a general anesthetic and a surgery, there are other problems that they can face afterwards. And you just need one of those patients to remind you how big an operation this is.

Patrick Hensley: Absolutely.

Gary Steinberg: Yeah. If there, there's no question that a real surgical innovation will be when we can no longer when we no longer have to use the gastrointestinal tract to divert the urine. And I've actually had some elderly patients recently where I've done cutaneous ostomies avoiding a bowel anastomosis. And I must say that they do much better when we were trying to create Neo-Urinary conduits. This is a company named Tengion which is no longer in existence. We did about 10 cases at the University of Chicago. And at John Hopkins, those patients postoperatively three weeks postop, it looked like they did not have a major operation. The problem was, is we couldn't regenerate urothelium, and we ultimately had to bring them back and then create a ileal conduit later. But I think that's really where we need to focus our energy. Is can we regenerate urothelium to avoid using the gastrointestinal tract?

Patrick Hensley: No doubt that decrease in the morbidity of cystectomy would be the logical next step in this paradigm, a couple of the ongoing trials that are looking at bladder preservation, prospectively are using DNA damage response, gene alterations, to triage patients for cisplatin sensitivity and bladder preservation. Talk to me a little bit about how you feel adding a genomic biomarker into, into the mix, improves our clinical staging, these patients, and understanding their disease biology, rather than just relying on the CT, MRI, biopsies, Dr. Taylor.

John Taylor: I mean, that's the future. I mean, that really is the future. I go back to breast cancer. It's molecular staging at this point, cystectomy is not going to go away. So I think that as Gary said, we need to refine our operation. We need to make it a better operation. So there's less perioperative morbidity and or mortality, but we need to come up with a genomic signature, whether it's at the RNA level, whether it's at the gene sequencing level, we need to explore that more deeply.

We have the tools and the tools get better and better every year. And it's just, we need to really dive deeply into that and come up with a molecular signature that is going to say, you do not need your bladder out, if you have a complete clinical response, again, we are not going to know pathologic unless we have the bladder in a bucket, but if you have a complete clinical response, whatever that is deemed to be, and you have a gene signature that predicts high likelihood of response, I think in Gupta study, they had an 89% positive predictive value in patients with DDR, deleterious gene mutations.

So the tools are out there. We just need to get smart enough to find them and put them together.

Gary Steinberg: One of the things that we have to take into consideration is that bladder cancer is a very heavily mutated cancer. And there's a tremendous amount of heterogeneity even within the tumor and within the bladder. So that just because we do an assay and there's DNA repair mutations, does that mean that there's no other clone within that bladder, that doesn't have those mutations? And so, as John said, we still need to refine our molecular staging. One of the interesting things we know is that the patients that respond to cisplatin also seem to respond to immunotherapy checkpoint inhibitors. So there's a lot of room to go. There's a lot of room to go in terms of improving our pathologic responses to neoadjuvant therapy, probably combinations of immunotherapy, maybe not seeing any benefit from chemotherapy and immunotherapy, because it seems that there, those patients that respond are the ones that would respond to either therapy alone. And there's not much synergy.

Patrick Hensley: And perhaps putting patients on a maintenance immunotherapy after a good response to chemotherapy proving that their tumor's chemo sensitive would make sense. And there's a rationale for that in the metastatic disease, maintenance immunotherapy after standard cisplatin based chemotherapy.

Gary Steinberg: Absolutely. Now looking at immunotherapy in the bladder cancer population, since we're moving it into the non muscle invasive space, I must say that there are a significant number of immune related AEs. Now those are I think we're willing to accept in the muscle invasive and beyond not so clear that we're able to accept them as readily in the non muscle invasive space. So we still need to improve our immunotherapy approaches as well.

Patrick Hensley: In, in our final moments. I'd like to just get your, your opinion on how you counsel a patient who comes to your clinic potentially off trial and asks you about bladder preservation. They've tolerated four cycles of neoadjuvant chemotherapy. Well, you do a rest staging procedure, a deep TUR it's negative, imaging is negative. And they ask you, what is your opinion on the oncologic safety of radical cystectomy versus bladder preservation? How would you counsel a patient who seeks, seeks you out individually to consider bladder preservation? I'll start with you, Dr. Taylor.

John Taylor: Yeah. I'd be very upfront with them. I've always felt that you need to be black and white with patients. I would tell them the standard of care. And if they want to see the benefit of the neoadjuvant chemotherapy, currently, they need to have their bladder removed. That is going to provide them the best chance at long term durable survival period, and in 2022, unfortunately. I would also tell them that in the trial based setting, there are alternative ways to approach this, but that while the numbers look good, it is not ready for prime time. It would not be considered standard of care. I would probably not recommend it, but I want them to know everything that's out there and what's going on.

Patrick Hensley: Sure, Dr. Steinburg.

Gary Steinberg: I think that as long as they understand the importance of careful follow up, as urologists we don't consider the discomfort of frequent cystoscopies and TURBT and all of these things but, patients don't like being instrumented. They don't like having biopsies of their bladder and so forth. So they need to understand we want to preserve your bladder, but we need to do additional evaluation and imaging. That is a nuisance, but is critically important if we're going to be successful.

Patrick Hensley: Absolutely. Well, we eagerly await the trial data on, on bladder preservation. I think there's emerging retrospective substantial series that have looked at longitudinal outcomes in these patients. And I think kind of the big thing that we need to focus on is both clinical staging and molecular staging of these tumors. I think that'll be kind of the future of this paradigm. So Dr. Steinberg, Dr. Taylor, thank you both very much for your expertise and your time, and thank you for joining us at the EroToday coverage of the international bladder cancer group, bladder cancer forum at the AUA 2022.

Gary Steinberg: Thank you.