Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And it's a distinct pleasure to welcome, once again, to UroToday forum, Professors Carmen Mir and Paolo Gontero. Welcome.

Maria Carmen Mir: Thanks, Ashish, for the invite.

Ashish Kamat: So we're going to essentially be linking the debate that we had at the EAU last month at the bottom of this discussion. And in that, you all had a debate, and of course, I had a recorded presentation, it was very well-received. But today, let's have a little bit of more deeper dive into the question of BCG unresponsive disease.

So Paolo, you presented a nice patient at the EAU debate that had non-muscle invasive bladder cancer, high-grade-- let's say it's T1 with CIS, receives BCG, becomes BCG-unresponsive, then gets gemcitabine and docetaxel, and still has persistent high-grade disease. And that's a conundrum that we face nowadays because patients are wanting to try to save their bladder. So Paolo, let me ask you first. If this patient comes to you and is in your clinic, how do you counsel this patient? What are some of the factors you consider? How do you counsel the patient on radical cystectomy, or can we try something else?

Paolo Gontero: Well, of course, this is a challenging case. The question is, do we know the outcome of this patient? Because, for instance, MD Anderson, your center, showed that, in fact, based on retrospective data, giving a conservative attempt after BCG-unresponsive, it doesn't really jeopardize the cancer specific survival over immediate cystectomy.

But what happens if we try-- if we have a failed first conservative after BCG-unresponsive and we give an additional course? I don't think we have the answer for that. We look at a large series or a retrospective series of BCG-unresponsive, and we found that the risk of progression is around-- is between 25% and 30% at five years, meaning that is not so dramatically high as compared, for instance, to the very high-risk BCG-treated in the first instance.

But of course, I tell the patient that we have to assume that being unresponsive to a second course of conservative treatment exposes the patient to a further-- a higher risk of progression. And of course, nowadays, we see that patients are not very keen on radical cystectomy. And I look at the type of the patient. Elderly, frail patients, of course, they have a high risk of cystectomy, morbidity, and also mortality.

At the same time, we know that postponing by, let's say, two or three years, the potential persistent disease exposes the patient to be even more unfit for surgery. And the other problem is that we are talking about patients that are treated in Europe. And in Europe, our treatment options are really, really restricted.

I mean, the patient that I presented received gemcitabine docetaxel, which I know is a chemotherapy combination that is also very, very much used in USA in spite of all the options that you have at the moment, but we do not have any new immunotherapies. We cannot give systemic pembro. We have no IL-15. We have no nadofaragene firadenovec approved cretostimogene.

So none of these treatments has been approved by EMA, and so we are really, really left without any effective treatment because what we can find-- when we fail in Europe, the combination of GemDoce, we cannot give gemcitabine alone, it doesn't make any sense, or docetaxel alone. We could try hypothermia, mitomycin, or electromotive drug administration. But we have very, very little data, and hardly no data as after failure of a combination of GemDoce.

And so I personally would say that, honestly, in Europe at the moment, we do not have a reliable conservative option. And so we have to strongly recommend the standard surgery, radical surgery.

Ashish Kamat: Yeah, no, I think that's an important point that you made, Paolo, because obviously, access to drugs is a critical issue. And if you don't have access, obviously clinical trials is something that we try to recommend, but you have to do with standard of care. Carmen, Paolo mentioned patient selection, and I know you are a big proponent of doing personalized therapy for these patients. So what's your approach when you see someone like that that is really adamant and wants to try to save his or her bladder? What are some of the things that you are thinking about?

Maria Carmen Mir: So that was one of my first slides. Actually, one of the main points is 96% of patients, they don't want a radical cystectomy. And for up to-- they are willing to accept up to 45% of progression rates when you discuss with them how much they want to take. How you can approach it is about for them understanding that one line of therapy-- of delay of definitive therapy that we would call radical cystectomy, it's probably safe, as we have shown similar oncologic outcomes, as Paolo mentioned. One line is safe. So one line implies generally around 12 months of treatment overall.

The other thing that I got out of preparing my slides and looking into some of the trials that we already have, is that maybe we have a difference between what we call initial responders. That means patients that initially responded, and then they had a recurrence, versus patients that never responded, and then we go into a second line. Probably there are some biological differences that we haven't really figured out because what we see in the single-arm trials that we already have, like the pembro trial or the atezo or all the ones that we have, is that patients that don't respond to initial line and they go to a second line, those lines do worse in terms of progression.

And the ones that initially respond, and then it comes back, and we would be able to do another second line, and this kind-- this type, the progressions are a little less than we see initially. So this is something that you can also discuss even though the evidence is very weak, because subsequent therapies in all these trials are poorly detailed.

I could only find, actually, detail on the pembro papillary cohort, a little bit of it, but they talk a little bit about the subsequent therapies, but they don't really mention much. But I think it's something interesting to discuss for the patient to actually decide if he wants to proceed or not with a cystectomy.

Ashish Kamat: A very important point because in our initial MD Anderson series, of course, we annotated what the subsequent therapies were. And then we did this larger BCAN/IBCG effort that was a multi-institutional effort. We also showed that patients can do fairly well, but it's important to recognize that these are all patients that are selected by the physician as being optimal.

So if someone sees you, Carmen, someone sees you, Paolo, and you're thinking at the back of your mind, "This patient is not good for bladder-sparing therapy," that patient is not counted in this series. And that's one of the problems with retrospective series. You're picking the best players. You're picking the patients that tend to do well.

With that in mind, Paolo, for some of the trainees that are listening, could you share with them your staging parameters? Like, what all do you do to stage a patient at each step that they come to you with high-risk, non-muscle invasive bladder cancer that has recurred? Let's assume they recur after just BCG, and you're thinking, is it safe or not? What all do you do to stage the patient?

Paolo Gontero: Well, certainly, the most important staging is always endoscopic staging with a deep resection and multiple biopsies because concomitant CIS in this patient population is extremely high, but also because we have to-- what we have in Europe is clinical trials, and that's a unique opportunity for this patient. Of course, I was thinking about an average scenario, but of course, clinical trials, and of course, it's a very, very important whether there is concomitant CIS or not.

We also have to think about that the combination of CIS plus T1 disease has a worse prognosis. So we have to also to think about that. But multiple biopsies, or, if available, PDD, I think is something that can be useful. And not to forget about-- that calls back the clinical case because the clinical case, the patient ended up having a tumor at the prostatic urethra. Never forget to stage the-- and to sample the prostatic urethra. At T1, high-grade disease is an 8% possibility of tumor in the prostatic urethra, which is usually poorly responding to BCG, and even more not responding to an additional conservative treatment. You have to think about that.

If the CIS in the prostatic urethra-- or T1 in the prostatic urethra is not only in the superficial layer, but is also diffuse, we have a T4 disease. And T4 disease means that the prognosis is poor. This patient would need perioperative systemic chemotherapy other than surgery.

The question would be how to position-- because CT, of course, is important for the upper tract. Is also important to provide some kind of staging, but it's not very, very, very good for local staging in the bladder. The question is, how do we position MRI in this case? MRI, unfortunately, is not widely available in my country. We have the MRI, which is overloaded for prostate cancer. MRI is in the guidelines. So it's not easy to have the availability of MRI, but definitely the staging, MRI staging, can be useful, I would say, particularly for ruling out muscle invasive disease, which you can do if you do a proper endoscopic staging.

I think that the risk of downstaging-- so missing a muscle-invasive disease, should probably not be more than 5%, I would say, if we do an accurate endoscopic staging. And the problem is that endoscopic staging is something that we have to convey to the patient during counseling because it's cumbersome for the patient. Sometimes, when you have a recurrence after, let's say, one line, two lines, you have a persistent or recurrent T1, high-grade, then what do you do? You have to do the ritual again. So it's another additional procedure for the patient.

So I think in the counseling, we have to tell to the patient that it needs to be highly motivated. That this quality of life with all this additional staging might not be ideal. I personally am not very much in favor of just doing a urine cytology and a flexible cystoscopy for this patient. We cannot do PDD flexible cystoscopy in Italy. I'm not sure whether you can do that in USA, but I am very, very cautious about the poor sensitivity of urine cytology even in patients with the CIS. So I would not recommend just urine cytology.

Ashish Kamat: Yeah, no, again, excellent points because our duty to the patient at each point is to make sure we're not missing the window of opportunity to cure the patient. The patient should not die of their non-muscle invasive bladder cancer. And just doing cytology is clearly not sufficient. I mean, you have to actually do a nice biopsy sample, the prostatic urethra, everything that you said.

We could chat about this forever, but in closing, let me ask you both-- and let me start with you, Carmen, and then you, Paolo, in this current stage and era that we have so many different drugs and agents being looked at and evaluated, what is your sense of whether we are reaching, finally, a stage where we might be able to essentially get rid of radical cystectomy?

In other words, are we getting to a point where even high-risk non-muscle invasive bladder cancer is going to become a chronic disease that we're just going to keep treating? Assume you have all the drugs available, do you think we're going to get to a point where the patient is going to have multiple therapies year after year after year? Or do you think that we're should not get too excited about that possibility? So Carmen, you first, and then Paolo.

Maria Carmen Mir: I personally think we are moving into the era of the biomarkers and the targeted therapies. We see it with TAR-210, these FGFR mutation. We have a drug for that, we treat it. And that might allow us to get rid of the problem somehow. We don't know how long yet or how is it going to happen, but I see targeted therapy as something that it's coming, we need to learn about it.

And in terms of staging that we were mentioning, I think we are moving into the era of the combination of different things. Like, we are not only going to have MRI, the fourth staging, probably it is going to be the combination of biomarkers like ctDNA plus the MRI plus other things that will help us determine, oh, this is non-aggressive high-grade, or this is something we should worry about and we need to look further instead of not being a problem.

Ashish Kamat: Great. And Paolo, last words from you?

Paolo Gontero: This is indeed an excellent, the key question, actually. I think, yes, as Carmen anticipated, that's the path that we are heading to. And all these new treatment opportunities are effective, I would say, even if they're being assessed in the single-arm prospective trial, most of them. GemDoce, by the way, is mainly tested in retrospective, but it doesn't really make a huge difference.

What is really, really making me thinking that probably we are heading towards making this a chronic disease without removing the bladder is the five-years' follow-up results with nadofaragene, for instance, where I was really, really impressed to see that the risk of progression is so low in spite of many patients actually failing the treatment in the short-term.

Meaning that probably, this disease-- and I'm saying something that is against what I was saying at the beginning, is probably not so bad. I mean, we are not dealing with a 70% risk of muscle-invasive progression at five years, but probably is something much lower. And with all this sequencing of treatment, which, at the moment, we don't know actually how to sequence-- well, we cannot even use in Europe, but probably in USA where you can probably use the whole spectrum of possibilities, but probably you don't still know what is the best sequencing.

But definitely, yes, I think there is room for making this chronic disease for a few years. And of course, for the young patient, for instance, five years of keeping your bladder without, let's say, a dramatic risk of losing the window of opportunity, it makes sense because it's five years with rectal function without having probably a stoma or the side effects of neobladder.

So I think it is important for the point of view of the quality of life. If you are 80-something, probably these five years, you just spend the natural course of your life and you don't die of disease. You die for something else, for an unrelated cause. So I think that's the reason why this is really a breakthrough, and there's a fascinating field that we are facing in treating this disease, which is-- which used to be considered as a deadly disease, but maybe no longer.

Ashish Kamat: Great points, both of you. Just for the audience, I want to emphasize, this disease still can be deadly, but in expert hands, as you heard from Professor Gontero and Professor Mir, if you stage the patients correctly, if you make sure there's no deeper disease, then we might be able to make it chronic. But it's very important to do that staging and patient selection and personalized recommendation at each phase. Paolo, Carmen, really, thank you for taking the time. It's always a pleasure. See you soon.

Maria Carmen Mir: Thanks.

Paolo Gontero: Our pleasure. Thank you.