Clinical presentation and initial evaluation of non-muscle-invasive urothelial bladder cancer (NMIBC)

DR LOVE: Welcome to Oncology Today: The Management of Nonmetastatic Urothelial Bladder Cancer. This is medical oncologist, Dr Neil Love. For this program, I met with Dr Sia Daneshmand from the University of Southern California. In addition to this interview, there is also a corresponding video program featuring Dr Daneshmand’s slide presentation. To begin, I asked him to overview the initial workup for patients presenting with non-muscle-invasive UBC.

Let’s start out talking about non-muscle-invasive. What’s sort of the typical clinical presentation that you see with non-muscle-invasive bladder cancer? And what’s usually the initial evaluation?

PROF DANESHMAND: So, typically the patients are coming in with gross hematuria or sometimes microhematuria. And the first step is cystoscopy, usually in the office, flexible cystoscopy, just to look and see what we have. And, of course, as part of that workup we get a CT urogram just to make sure the upper tracts are okay and see if we have any extravesical disease or any other source of these problems like stones and other sources.

So the first step is that flexible cystoscopy. And typically we’re not taking biopsies in the clinic — we then book the patient for transurethral resection, which is done in the operating room with a resectoscope. So with these scopes working, we can remove the tumors.

That is a very important step of the evaluation. That initial step. You need to do a good TURBT. This means, for the medical oncologist, all they see is our report and the patient certainly has a stage. That stage is very, very important. We make decisions based on that stage. So that stage is dependent on whether you went deep and got muscle in the specimen. We need to make sure we did a good resection here. So we really put emphasis on the initial TURBT.

The data shows that in papillary disease, mostly low grade, but even in some high-grade disease, that after resection, if we don’t suspect it’s muscle-invasive, we should be giving a one-time dose of intravesical chemotherapy. In the past we used to mitomycin, but it has a lot of side effects. But now we use a single dose of intravesical gemcitabine immediately after resection to reduce the recurrence rates within the bladder by about 10%.

So that initial TUR is done. We get the path report. And then have the patient come back and start making decisions about what the next step is.

Now if you have CIS-only or high-grade Ta disease, have muscle in the specimen, we’re done. We move onto therapy. The initial therapy would be intravesical BCG. And we can talk a little bit about the BCG shortage and what the alternatives are a bit later, perhaps.

If the patient has high-grade T1, whether or not you have muscle-invasive disease, it’s really imperative that the patient go back to the OR for a re-resection about 4 to 6 weeks later. The reason is, the high-grade T1 tumors that are in the lamina propria, that first layer of the bladder, they can have roots that go deeper into the muscular layer of the bladder. And so you may have missed that in the beginning. And it’s not that you didn’t go deep. It’s not that you didn’t get it. But you don’t know where those roots are.

So in about 10- or 15% of patients, initial high-grade T1 tumors is actually a T2. So the recommendation overall, generally, is to re-resect patients with high-grade T1 so that we make sure that is their stage before we move on to therapy. Because lots of times these patients are getting intravesical therapy and it would be very inappropriate for them to get intravesical therapy if they have muscle-invasive disease.

DR LOVE: But from sort of a surgical perspective, in general you have R0 resections though when you do TURBT?

PROF DANESHMAND: Yeah, great question. That’s the goal. So if it’s manageable, yeah, we can sit there for 3 hours and chip away at these tumors, try to get that sort of R0. We don’t talk about R0 because we can’t really tell of the margins. But we try to go as deep as possible and get muscle and clear the disease. Two reasons. One is A) we want to get the diagnosis and make sure we have muscle in the specimen and that patient has muscle-invasive disease or not. And the second reason would be to completely clear them so that if they’re candidates for chemoradiation, or that’s what they want to do, we’ve already done that complete TUR before moving on to bladder-sparing protocols.

Alternative induction regimens when BCG is not available

DR LOVE: Could you comment on what we know about the outcomes when you use BCG? And what’s happening in terms of access to BCG right now and how it’s affecting the way you take care of patients?

PROF DANESHMAND: Yeah, big problem. So BCG is highly effective. Has been so for over 40 years and it’s still the number one drug used all around the world for non-muscle-invasive bladder cancer. The response rates are spectacular, in the 80% range, for patients. The problem right now is we have a national and international shortage of BCG. Merck is the only company that makes the drug. There are approximately 800,000 vials made in the US. And the demand is about 1.2 million vials.

So we have a shortage. It’s an issue. Patients are waiting. More importantly, they’re not receiving maintenance BCG, which has shown in multiple studies to reduce, not only recurrence rates, but also progression rates. So patients are getting their induction therapy at some point. They get put on a wait list and then we’re not using maintenance therapy. That also has implications on patients entering clinical trials. If you don’t have that 6+3, that induction 6-wk, plus a minimum of 3-wk of maintenance therapy before you are deemed BCG-unresponsive, you can’t enter into a clinical trial. It has to be done within a year.

So what’s happening is, patients are sort of getting their 6 weeks and they’re responding. And then maybe at a year and a half they’re getting another recurrence, getting some more BCG, but now they’ve already gone past that one year. They can’t enter into most clinical trials. So it’s a double-edge sword.

We have two problems. No company has thus far, been brave enough to come head-to-head against BCG, but I tell you, there are some that are coming on and some exciting new Phase II and III trials they’re going to be going up against BCG as first-line therapy.

So that’s exciting because that’s what we need right now. We have a big void in this space because there’s not a whole lot of hope that this shortage problem is going to be resolved in the next five years.

DR LOVE: And are there patients who literally are not able to get access to any BCG? And what do you do in that situation?

PROF DANESHMAND: So there are patients who wait an uncomfortably long time. So we put patients on a list and that uncomfortable, to me, is about 3 months. By 3 months, you’re due for your next surveillance. So if the patient is still on the waiting list — and by the way, this is regional. Some folks over on the East Coast don’t have as big a problem as we do in California, Southern California has a particular big problem. So we then think about alternative therapies. And we have guidelines that we’ve written for the AUA for the SUO, the Society of Urologic Society, what to do in these situations. One alternative is to use intravesical chemotherapy. We know it’s not as good. But now we have this doublet therapy that’s good in BCG-unresponsive disease, so if it’s good there, it should be in the induction phase. So we do use gemcitabine and docetaxel sometimes as induction therapy. And that one we can use maintenance therapy because it’s readily available. So we do the 6 weeks and then we do monthly maintenance therapy, up to about a year or so.

DR LOVE: This shortage, I would assume it’s economically-driven? It’s generic? Is that the issue?

PROF DANESHMAND: Yeah, it’s probably. There used to be two companies, making the drug. They had some production issues and then they decided just to get out of this business altogether. It really doesn’t make much money. But there’s a huge need.

There are lots of different strains around the world; I think there are 11 or so. So, many different countries have their own strains that they’re using with local companies. But unfortunately, as with any drug, we can’t really interchange drugs with other countries because they’re not FDA-approved here.

There was a trial, 1602, SWOG 1602, that randomized the patients between BCG versus Tokyo — the Merck, our own strain here, versus the Tokyo strain of BCG, in the hopes that in the future if they show equivalent results will actually get approval for the Tokyo strain and get that into the US market.

Treatment options for patients with BCG-refractory disease

DR LOVE: So, can you talk a little bit about the patients who don’t have responses to BCG or have progression, and then are not responding to BCG? How they’re approached outside of a trial? And then maybe talk a little bit about some of the trials and strategies that you talked about in your talk.

PROF DANESHMAND: So the first thing is, if you failed the first induction BCG, and you don’t have progression of disease, so if you have high-grade Ta, do BCG again. High-grade Ta, or CIS, then it’s very appropriate to do another course of BCG. And that could be either 3 weeks or 6 weeks. The studies don’t show any particular difference between the two. We’re on the 3 weeks because we have a shortage. And that would be given again, immediately after your second resection and then another surveillance after that.

So, if the patient still has recurrent disease, and this is all within one year, if they’re deemed BCG-refractory, that’s when they become candidates for all of these clinical trials.

Now let’s say you’re in a community practice. You don’t have access to any clinical trials. We get a phone call, what should I do with this patient? I think the next go-to would be the gemcitabine/docetaxel combination therapy, intravesical, once-a-week for 6 weeks. There’s nothing special that needs to be done.

Some offices have trouble acquiring docetaxel, or because of the doublet therapy, they prefer not to have the patient spend that much time. They refer on to other practices. But that’s the simplest thing to do.

We would not recommend a single-agent chemotherapy. We know that’s inferior to BCG. It’s inferior results to most of the combination therapies. So that would be sort of your basic standard, gem/docetaxel.

If you’re coming to us, we’re going to offer all these other clinical trials that we mentioned during the talk. One option is to send FGFR3, and if the patient is interested in some kind of oral therapy, and/or has real trouble holding onto intravesical therapy, that would be a good option. We would send the tumor tissue for FGFR3 analysis. If it’s positive, which we mention is around 40%, this is a mutational — a mutation within the tumor that is targetable. And we now have an option of doing an oral pill, erdafitinib, for these patients. So it’s randomized between the oral pill and intravesical gemcitabine. So that’s an exciting trial because for the first time we’re seeing an oral drug for non-muscle-invasive bladder cancer. Of course, erdafitinib has been approved for metastatic bladder cancer, but now moving on to the non-muscle invasive space.

If the patient doesn’t have a mutation, then, again, they’re candidates for these pretzel trials. Those are good options and that involve immuno-oncology that we mentioned.

DR LOVE: It’s interesting this idea of using systemic therapy, although it is oral, erdafitinib, for non-muscle-invasive. Because erdafitinib does have toxicity and issues. It’s not like an aspirin or whatever, the phosphorus, etc. Do you have patients on the drug? And any experience with it?

PROF DANESHMAND: Yes, absolutely. And you’re absolutely right, they do have these side effects that we, as urologists, are not used to. I have several patients on it and this seems to be quite a pattern. You’re right, you need to check the phosphate levels and occasionally use phosphate binders. We have nail issues, hair issues, dysgeusia. So, patients are complaining about things that I’m sure, as a medical oncologist, hear all day. But we’re not used to this.

So we do have the option, the use in the metastatic setting is 9 mg. We start at 6 mg and we can go down to 4 mg. There’s been a huge difference, and we’ve down-dosed patients. And we can actually do drug holidays as well. So that’s been very, very useful.

When I first started, my first exposure to the drug was a patient in metastatic disease using the 9 mg, significant nail changes. And now that I’m seeing the much lower doses being used, it’s more manageable. But you’re right, that is an issue with these drugs.

DR LOVE: It is interesting though. And the other thing is this phosphorous thing. I’ve heard people talk about diet and binders. Is that much of an issue?

PROF DANESHMAND: Not really. I’ve seen the higher phosphate levels, but again, as we lower the drug dose it doesn’t seem to be a problem. In the few patients that I’ve put on the trial, have not used any phosphate binders. But sometimes, yeah. We do have a sheet of the dietary suggestions let’s say, for them to give their phosphate levels at a reasonable level so that we don’t have to use any of those binders of have to reduce the drug doses because of that.

DR LOVE: And we were talking also about trials looking at intravesicular delivery of erdafitinib through the pretzel. And that would be really interesting.

Role of immunotherapy in treating NMIBC

DR LOVE: Of course, another issue, an approved option that you commented on in your talk, is IOs for non-muscle-invasive, specifically pembrolizumab. What’s you take on those data? and in what situations do you think this is a good option for a patient?

PROF DANESHMAND: Yeah, it would be for a patient who’s really not a good candidate for further intravesical therapy. There are patients where they have trouble, they have a large prostate. They bleed every time. Patients having horrible bladder symptoms, lots of urgency, frequency. And so, they’re not tolerating any intravesical therapy very well. I think those are ones where we tend to think, okay, what are the alternatives of not using an intravesical therapy. And if they have non-invasive disease, then pembro is certainly an option. It’s FDA-approved in this setting for BCG-refractory disease.

Our biggest concern is, of course, the systemic toxicity, but as we move on to these class of drugs, we have to learn more about it. I think the more important message here is we need to get comfortable with some of these systemic agents. But if the patient can continue to do intravesical therapy, I think we’re still, as urologists, as a community, most people are going to be comfortable doing what they know and use novel agents.

So, as these novel agents get approved, I think it’s an easy sell to say, okay, this is the new drug that you’re going to put in the bladder. But I’m very, very intrigued with TAR-210, the erdafitinib, the ErdaRIS, where erdafitinib is placed inside the bladder. As we saw with gem, there should be no real systemic toxicity to this. so it should have a very direct effect within the bladder. We’ll see. Those trials are just starting.

Role of cystectomy in treating NMIBC

DR LOVE: What are the situations where surgery/cystectomy is used for non-muscle-invasive disease?

PROF DANESHMAND: Okay, that should always be on the radar because the longer you use ineffective therapy, the higher the chance the patient has to progress and eventually die of disease. So you have to be very vigilant in not continuing moving from one ineffective therapy to another, or if the patient has developed or progressing through any of these therapies. So, even though you think, oh, it’s not muscle-invasive, the patient has no chance of death, that’s not true. In patients with high-grade T1 disease, eventually up to 20- or 30% will eventually die of bladder cancer. You have to keep that in mind. These are sobering numbers for a patient who was never muscle-invasive in the beginning.

So vigilance, A), I keep bringing this up. The surveillance cystoscopies, the CT scans. You can have lymph node involvement in high-grade T1 disease. We, and others, have shown this. it’s up to 10% of patients. So you’ve got to do your CT scans and be vigilant there.

Any patient who’s progressing from high-grade Ta to T1 disease I think is not an appropriate candidate for intravesical therapy. The biology of the disease is such that it’s progressing, those patients need to move on to cystectomy. And again, despite having all the comorbidities, we always mention cystectomy as the gold standard, as the curative therapy, even in 80-year olds. There are plenty of data that show that if you’re diagnosed with muscle-invasive bladder cancer at age 80, that the risk of death in the next two years is still from bladder cancer and not from other comorbidities. That’s the leading cause of death.

So it always should be there. I think if you’re a low cystectomy volume provider, or you’re in a hospital, you should think about referring to a higher volume provider who does this often and can take on the comorbidities of these patients.

I always say, any patient who progresses, and even the younger patients who has high-grade T1 from the outset, a 50-year-old who shows up with high-grade T1 plus CIS, we have some risk stratification within that, that we don’t need to get into necessarily, but we do have within high-grade T1, some of the clinical risk factors that we use to determine whether the patient is very high risk or lower risk within that group.

DR LOVE: You mentioned centers that have a lot of high volume. Do we have data? I imagine we have data; I’d be curious to know what it shows, in terms of how much volume you need to get into the lower morbidity and better outcomes? And any sense about what is happening in the community — in reality, for example, in the United States, in terms of who does cystectomy?

PROF DANESHMAND: Yeah, great question, and there are some data. So, the high volume center would be one that performs more than 20 cystectomies a year. And there’s data to suggest that community centers who perform less than that have three times the morbidity and mortality rate than high volume centers, despite the fact that high volume center are taking on the more complex cases. So there’s a lot of complications associated with the operation, but if you’re doing it routinely, like everything else, you identify these problems early. You bring the patients back to your hospital and identify the early infection, fluid collections and urine leaks and whatever happens, and manage them.

So we can get patients through it, and hopefully keep it in the morbidity and not in the mortality situation.

So nationally, I think one of the sad statistics is that many patients, in fact more than half the patients with a diagnosis of muscle-invasive bladder cancer don’t get any curative therapy. They are deemed to be too old, too frail, to undergo surgery. And so, there’s some limitations sometimes due to receiving chemoradiation therapy, so they just move on to another TURBT and eventually die of disease. So that’s the target population where, if you have other therapies that are not too toxic, these pretzel trials, for instance, are targeting those patients who are “unfit” for cystectomy. And this can be delivered in the community. And now most oncologists are very comfortable with IO therapy. I think we can do combination therapy, do a better job on saving these patients.

Intravesical drug delivery for patients with muscle-invasive urothelial bladder cancer (MIBC)

DR LOVE: Let’s talk a little bit more about TAR-200, the so-called pretzel. I’ve seen all these really cool diagrams and all, but I’m not sure I really understand how it works. Like, if you don’t have any visuals, how do you explain it if you’re rounds? What exactly is it?

PROF DANESHMAND: Yeah, it literally looks like a pretzel, first of all, and it’s the size of two quarters. So it’s a pretty small device. It’s very flexible. So for the urologist, inserting and removing things from the bladder is a very routine procedure. We place a catheter, an inserter catheter into the bladder first. We drain some of the urine. And then, basically it’s a hollow tube, much like a regular catheter, and this pretzel is unwound; it has a nitinol wire in it, and again, we’re very familiar with wires and how things turn because of stents — and so we unwind this and literally feed it through this inserter and the we have a pusher device that pushes into the bladder. And we can tell when it pops into the bladder because we’ve reached the end of it.

Again, it’s very easy. Very simple, straightforward. We can scope the patient afterwards to ascertain that it’s wound up. And the nicest thing is, it floats in the bladder. So it doesn’t sit there like a stent in the same place — sometimes that irritates people, patients, and it causes urgency and frequency and sometimes bleeding. But this thing is floating in urine, literally. So it’s not sitting in one place. It doesn’t irritate the bladder as much. And it slowly is dissolving these gemcitabine pellets.

And then when you take it out, you can tell — again, very easy to take out; it’s just like removing a stent. It’s done in the clinic. We go there with a flexible cystoscope. We have a wire grasper and we literally grab one end of it and pull out the whole thing. It unwinds and comes out the urethra. So pretty easy. It’s done within a few minutes. And I think it’s a really exciting novel sort of delivery mechanism. And we have to figure out in combination, what’s going to work best.

DR LOVE: It sounds so interesting. But I mean it almost sounds like computerized drug delivery, but obviously you’re not putting a computer into somebody’s bladder. It’s just the material itself, when you embed it with drug, it goes out slowly I guess.

PROF DANESHMAND: It’s really fascinating, Neil. There’s so much science behind this actually, because the gemcitabine pellets are different than the ErdaRIS pellets, right, so you can’t have the same drug. The permeability is different, so the urine — it all is the science of the pH and the — it’s beyond what I know — but it has little pores in there and the urine gets into those pores, slowly dissolve these gemcitabine pellets. So it’s going to be different for every drug. And in the beginning, we had these 1-week formulations and now they have 3-week formulations. And they have a 6-week formulation. So it depends on how much urine is in contact with this drug and how it permeates.

So really fascinating. A lot of science that has gone into manufacturing these type of devices.

DR LOVE: The idea of combining this with an IO, is really interesting because it kind of, if you think about it, it’s really chemo plus IO, which is a very common strategy that’s being looked at, standard of care in lung cancer and a lot of other cancers. But chemo plus IO, but in a pretty different way.

PROF DANESHMAND: Yeah, that’s exactly right. And that’s the thought that we can’t just deliver something in the bladder. We need some kind of systemic — especially in muscle-invasive bladder cancer — we need some systemic therapy to take care of the lymph nodes or any cancer cells that are on their way to the lymph nodes that later lead to distant disease. So I really like that concept.

In non-muscle-invasive disease, we don’t so much worry about the circulating tumor cells, but there’s a lot of science also behind the synergy of these two types of mechanisms.

DR LOVE: I was just flashing on what other metabolic abnormalities you see in bladder cancer, and I think you can see HER2. And I don’t know how often you see HER2, and I don’t know if you see it in non-muscle-invasive. Do you?

PROF DANESHMAND: Not often, no. Unfortunately, it’s not one of our main mutations. And so, there’s not a whole lot of target for that. Most of the targets, RB1 and TERT and those things are really not targetable, we don’t have agents. The FGFR3 has really been the only novel target we have for which drugs have been developed over the past 20 years. So, nothing else. There are other people working on it, but bladder cancer is so complex. There are usually so many different mutations. But right now, FGFR3 is the only one that’s of interest.

DR LOVE: Anything new in terms of etiology of bladder cancer? Is it still primarily associated with smoking? What are some of the etiologic factors?

PROF DANESHMAND: No, there’s nothing new really. Most of it, yeah, is still smoking is the number one cause of bladder cancer. The environmental exposures, the toxins and things like that, we just don’t see as much anymore. It used to be rubber factory workers and hair dye — hairdressers that were in contact with hair dyes that were toxic. Arsenic in water that is toxic in some areas. But really, with OSHA cleaning up these types of things and occupational exposures, we’re not see that much anymore. So nothing particularly new in etiology, epidemiology, that we’re aware of. We’re constantly scanning the literature for these things.

Dispelling myths and misperceptions about cystectomy and counseling eligible patients

DR LOVE: So moving on, in terms of the issue of localized bladder cancer, I want to get into muscle-invasive in a second, but, also, I’m curious about situations where you have patients, and I hear about this, who are eligible for cystectomy, they may be young, good performance, and don’t want to have it. They refuse to have it for the reasons or concerns of morbidity. How do you approach those patients? And, for example, one of the situations, again I hear from oncologists, is that, as it relates to non-muscle-invasive, in a patient who normally would go for cystectomy and doesn’t want to have a cystectomy, and then the question of, is something like pembrolizumab worth using, or even chemoradiation?

So how do you approach, first of all, the patient who needs to have a cystectomy for nom-muscle invasive, but doesn’t want to do it?

PROF DANESHMAND: Yeah, I think it’s convincing the patient. I think there’s sort of a misconception that non-muscle-invasive bladder cancer is not aggressive enough to warrant that kind of treatment. Or that, I’m fine. Just give me another type of medication and I’ll be okay.

I’m always surprised patients are willing to undergo these multiple TURBTs because those are not fun for the patient either. We have catheters, and bleeding. And it’s really irritating.

One of the things is with patients with non-muscle-invasive bladder cancer, I try to tell them about the progression rates of disease and what happens in 5 and 10 years, not even 10 years, but in 5 years, what those progression rates are. So, I think that’s one thing to try to educate, both patient and practitioners about.

The other is making sure that you have the right diagnosis, that you’re not just giving pembro and no one’s looking at the bladder and you’re looking at CT scans. That’s not what we should be doing. We should be doing the surveillance cystoscopies every 3 months. In these patients there’s a high chance of progression.

The other thing is, I tell them the response rates. Look, we hope you have a response, but it’s really 24% at 1 year. Not very encouraging. That’s 1 year. What happens in several years? How long are you going to be on this systemic therapy, which can obviously have toxic side effects as well? So, suddenly cystectomy becomes not so undesirable if you talk about it that way.

One of the most important aspects, however, I think is that a patient who’s perhaps in their 70s, unwilling to undergo cystectomy, the first question is, how come? And the patient says, I don’t want a bag. And I said, we didn’t talk about a bag. You can have a neobladder. And I think that’s one of the things that if you go high volume center, you’re going to be offered a neobladder. Now the conversation completely changes because the patient who thought they were not a candidate for neobladder is now a candidate.

So we should disconnect this notion that cystectomy goes along with a bag. Many, many patients are candidates for orthotopic urinary diversion. And so, that’s a very important point because people will keep continuing getting ineffective therapies because they don’t want to have a bag.

DR LOVE: Can you talk specifically about the procedure that’s used in this situation? And what happens afterwards, post-op, in terms of quality of life?

PROF DANESHMAND: Yeah, that’s a long discussion. The surgery itself, the way we perform it, is about a 4-hour operation. We do an extensive lymph node dissection to make sure there’s no spread to the lymph nodes. We have lots of data that limited lymph node involvement, those patients can actually be cured with the operation without any further therapy, but we try to always give them further therapy, if possible, especially now on clinical trials. The recovery in the hospital with our new enhanced recovery protocols is approximately 4 days. What used to be 7, 8, 10 days, some places in Europe still is, is now a 4-day hospital recovery.

However, the overall recovery is actually much longer, it’s at least 6 weeks before they feel even 80% of what they were. There’s lots of potential issues that arise from intense fatigue, to urine leaks, to infection rates of 25%, readmission rates of up to 20% for various things, nausea/vomiting, bowel obstruction, things like that. Most of these are minor complications. We have a Clavien Grading System, much like the grading system for toxicities, and most of these fall into the minor complication rates. The major ones are MIs, stroke, something that requires an invasive procedure. Fortunately, those are not as common and are generally less than 15%. And most of those are just some invasive procedure to deal with the complication, for instance, placement of a drain would be a high grade complication.

So, it’s a rough go. No question. For 3 weeks, if they have a neobladder, they’re carrying a catheter. And then they come in, we take out the catheter. Teach them how to use their neobladder. A lot of incontinence in the beginning. I tell them, look, you’ve got to ride out the 3 months for recovery of this thing. By the time you get your catheter out and really recovery at home, there’s a lot of weight loss and muscle weight loss with this operation. And finally, at about 3 to 6 months, patients start to feel better. And in a year, they’ve recovered and have very good functional results and good quality of life.

So a lot of the studies show a rapid decline of quality of life and a slow rise in quality of life via validated questionnaires and validated tools, that the quality of life at 1 year is very, very similar decline — sorry — very similar to their pre-op. It’s not always exactly the same but it comes close to it. And that’s much in most cancers, right. I think we see that with treatments. In many cancers, you see that decreased quality of life with initiation of treatment.

DR LOVE: So I’m curious how you decide in an older patient or one with comorbidities whether or not they’re a candidate for cystectomy? And if they aren’t, what you usually do?

PROF DANESHMAND: So that’s sort of a moving target and it depends. I think for us, again it depends on where you’re going, but for us, a patient who’s really not a candidate for cystectomy is someone we think is going to — is not going to make it through the operation or is going to die within a 1-month period. These are patients who are coming in in a wheelchair, on home oxygen. We can’t get them through a cystectomy. I think that once you start talking about ECOG 2, 3, the chances of getting the patient through a cystectomy is very, very low. Ambulation is really key for many of these patients.

So not to say that we haven’t done it before, or that patient can’t get through it. I think it should be the last resort. But everybody else, it really depends on management. Rarely, rarely is a patient sick enough from a heart perspective, they can’t undergo a cystectomy. Honestly, those patients are probably at high risk for a cardiac event than death from bladder cancer. So we try to manage it non-surgically.

Same thing with lung disease. If the patient is on home oxygen, it depends on how much, but if they have significant emphysema, they can’t undergo a 4-, 5-, 6-hour operation deemed by their pulmonologist, I think those are the true contraindications to undergoing a radical cystectomy, which demands so much out of the body from the healing perspective, where we’re taking a few organs and then we’re reconnecting, putting urine through other organs.

Liver failure, these are really high-stake diseases where the disease itself is a risk factor. And I try to weigh the risk-benefit ratio of having a cystectomy so that they can live another 2 years versus what’s going on with their primary disease that’s going to lead to mortality even sooner.

So those are the ones we consider doing maximal TURs, chemoradiation. Sometimes they’re not even a candidate for any chemotherapy. Fortunately, with chemoradiation, we have several options. We can use gemcitabine. We can use 5-FU. We can use cisplatin. So, even if you’re not a CIS candidate, we have other options. And this is sort of “chemo-lite,” as some people like to call it, with radiation therapy. But radiation alone is an option.

The real challenging patient is really the one who has a large tumor, a large volume of tumor. Those cannot be managed I think with any kind of systemic therapy. That requires a physical removal of this tumor. Typically, we take those patients back for repeat resections until we get a reasonable outcome there.

DR LOVE: So this comes up a lot in medicine, oncology, whether in a patient who’s otherwise not much comorbidities, functioning very well, but just older. I’m curious, like what’s the oldest patient you’ve done a cystectomy on? Would you do it on a 95-year-old?

PROF DANESHMAND: I wish you said 90, because I would have said, yeah. So the oldest I did was 93. And he came to me, he was going on cruises, and he looked like he was 75 years old. And he, believe it or not, he did great. He actually ended up having a urethral recurrence. I took him for a urethrectomy. He underwent an ileal conduit. He underwent an urethrectomy a year and a half later and still is coming in. He’s alive, and well.

So it really depends on sort of your functional age rather than your chronological age. We’ve written articles on cystectomy in octogenarians. We’ve offered neobladders to octogenarians. It really depends on your functional age. And there are a number of these frailty assessment indices and tools we can use to see what their recovery might look like. You get a lot of information on a CT scan that we, as surgeons, look at, not just a disease, but how much intra-abdominal fat? What’s the muscle distribution? Are they going to end up with this massive hernia afterwards because they have a very thin sort of rectus and anterior abdominal musculature. We look at sarcopenia. We look at the paraspinal muscles and the gluteus fat to muscle ratio. Things like that. So there are a lot of tools that we have in our armamentarium to kind of try to predict the outcomes with cystectomy.

Neoadjuvant and adjuvant therapy for MIBC

DR LOVE: Let’s talk a little bit about neoadjuvant and adjuvant therapy for muscle-invasive disease. In general, is neoadjuvant chemotherapy considered standard of care? And to what extent is that actually happening?

PROF DANESHMAND: Yeah, good question. So, certainly more than before. It is considered standard of care. There’s Level I evidence from a paper more than, almost 20 years ago now, that Bart Grossman in The New England Journal of Medicine, showed that neoadjuvant chemotherapy, at the time M-VAC, was superior to cystectomy alone. So that become standard of care. It’s in the all the guidelines, that if you are cisplatin-eligible, if you’re chemotherapy-eligible, that some cisplatin-based neoadjuvant chemotherapy followed by cystectomy should be the sort of gold standard.

Now you touched upon what’s happening. All around the world, it’s probably less than 50% of patients end up getting that regimen for various reasons, whether the practitioners thinks they’re not a good candidate for chemo, or they’re in the urologist’s hand and say, well, you could get chemo, or we could just go straight to surgery. And the patient says, well, why do I need chemo? This concept of doing chemo prior to surgery is a bit confusing to some patients. They think one or the other. Let’s say it just improves outcomes. Many patients think they can get chemo, and then if their CT scan is clear they’re done. That’s a dangerous concept as well.

There are some very well thought out clinical trials right now. They’re examining and exploring those concepts of can we spare the bladder in some patients who have complete responses. There’s other clinical trials coming on looking at radiation, for instance, after a complete clinical response or near-complete response with non-muscle-invasive disease. Can we spare the bladder?

So now we can start to talk to patients about, look, there is a potential if you enroll in a clinical trial. So we still don’t know.

So everybody should get neoadjuvant chemotherapy. I always tell them, if they’re in my hands, say, look, we’re going to make an appointment in 3 months. You’re going to come back and we’re going to discuss surgery, regardless of what we have in the bladder. We actually don’t even look. We look at the CT, make sure they didn’t progress. But we don’t go looking in the bladder and looking for disease. I tell them that only 20% of patients end up having a complete response. Even those patients have the highest cure rates and if we leave the bladder behind it’s a source of other tumor.

So again, education. I think education early on. I think medical oncologists also should be telling the patients the curative part of this whole process is the cystectomy, removal of the source of disease to begin with. And the chemo is there to make outcomes better, right. Improve survival rates.

DR LOVE: So you commented in your talk about the trial looking at IO, nivolumab, in the adjuvant setting. Can you talk about right now how that is integrated into both the care of the patient who gets neoadjuvant therapy and the patient who doesn’t get neoadjuvant therapy?

PROF DANESHMAND: So for patients who are CIS-ineligible, who didn’t get neoadjuvant chemotherapy and end up having T3 disease and node-positive disease afterwards, they’re the target population. They need something. We know they’re at very high risk. What we’ve had in the past, if they’re not CIS-eligible, is adjuvant gem/carbo. We don’t like to use carbo at all in this setting, whether in the neoadjuvant or adjuvant setting. Obviously, it’s used in the metastatic setting if you’re not CIS-eligible. But in the adjuvant setting, we really need something better.

And so the first trial, the atezolizumab trial that was in the adjuvant setting, showed no difference in outcomes in recurrence-free survival for patients who were receiving atezo. Now interestingly, within that trial — I’m veering off a little bit — but within that trial, if you looked at the patients who were ctDNA-positive, they had circulating tumor DNA following cystectomy, those patients had a significant response from atezolizumab. So it’s a subset analysis. And there’s now another trial looking at specifically ctDNA-positive patients, randomizing them between atezolizumab versus not.

Okay, let’s move on to CheckMate 274, nivo. Adjuvant nivo, given the same way, somehow this trial showed a significant difference in disease-specific survival for patients who received adjuvant nivolumab. So that has become the standard of care. I see it being used very frequently in the community. I think oncologists are very well-versed in use of all IO therapy. So, as soon as they hear something’s available and are able to use nivolumab in this setting, they’re moving on to it.

So I think the uptake has been much more rapid than in the past with other neoadjuvant therapy. I think adjuvant, actually nivo, has moved much faster than neoadjuvant gem/cis.

Now you mentioned in the neoadjuvant setting, if you are part of a trial that you get neoadjuvant, for instance, gem/cis/nivo to begin with, we had that trial open and some interesting results coming on. If you have a recurrence, then the enthusiasm for using another IO in that setting is going to be much, much lower, right. These are patients who’ve progressed through neoadjuvant. So we’re going to be looking at third-line therapies like enfortumab and EV, or combination therapy, EV/pembro, perhaps. But, yeah, once you’ve seen an IO, once you progress through it, enthusiasm’s very, very low for reuse of that drug class.

DR LOVE: What about the patient who gets just neoadjuvant chemotherapy, not on study, with an IO? In what situations after surgery is nivolumab used?

PROF DANESHMAND: Same. It would be the patient who has T3 disease or higher, so T3, T4 and/or node-positive disease. Again, we’re not going to back to chemotherapy. We’re going to be looking at nivolumab. So it’s not just the CIS-ineligible patients, but certainly the CIS-eligible who receive neoadjuvant chemotherapy.

If you didn’t receive neoadjuvant chemotherapy, then the appropriate treatment still would be cisplatin. You always have to think, number one, is cisplatin. Did you receive it before? If not, give it after, if possible. And if you received it before and you progressed through it, you’re probably CIS-refractory. You really need to move on a different class.

DR LOVE: So I guess I’m wondering, and I don’t know whether you get into this, or more the oncologist does, in terms — you mentioned T3 or node-positive, and I think that relates back to the trial. But the FDA, if I read it correctly, the indication says “high risk” but doesn’t define it. So, I’m curious. Everybody’s view of high risk might be different, maybe lower than the trial entry criteria. In breast cancer, you have this concept of relative risk reduction. And some of these people who get treated with adjuvant chemotherapy have pretty low risk of recurrence. You don’t see that outside of breast too much. But I’m just kind of curious — and I don’t know what the prognosis is if you have a T2 lesion, node-negative, after neoadjuvant chemo — I’m not sure how great that prognosis is either. So, like, where’s the bar in reality?

PROF DANESHMAND: Yeah, great question. And because of the trial entry criteria, we don’t know. You’re right. A patient who has muscle-invasive bladder cancer following chemotherapy would be a candidate for it, but you’re right, it’s high risk. And high risk is defined as any patient who has muscle-invasive bladder cancer following neoadjuvant chemotherapy. In academics, obviously we’re pretty strict about our criteria. We follow whatever the trial showed. But out there, you’re right, it’s any high-risk patient. And I am seeing patients with T2 disease being placed on adjuvant nivolumab. So it’s a very good point.

I think in Europe it’s very different though. I don’t think it has the same approval because you haven’t see the overall survival data yet. Hopefully, that’s coming and hopefully we’ll see an overall survival difference for adjuvant nivo in this setting.

DR LOVE: This concludes our program. Special thanks to Dr Daneshmand and thank you for listening. This is Dr Neil Love for Oncology Today.