Transcript of May 2021 “Ask the Experts” video

Click here to view the accompanying video

Diane Z. Quale:

Welcome everyone. I am Diane Zipursky Quale, the Co-founder of BCAN, and I am thrilled to have so many of you join us this evening for our 2021 Ask the Experts Event. We had more than 500 people register, so I know this is going to be a wonderful program. We are looking forward to an engaging conversation with two experts, who’ll be discussing promising advances in bladder cancer research and answering questions submitted by so many of you.

When my late husband, John Quale, was initially diagnosed with bladder cancer 21 years ago, there was little activity in the bladder cancer space. Our research community was small, funding was almost nonexistent, and there was no patient voice demanding new and better treatments. As many of you already know, BCAN was created to address this void. When I contrast that year 2000 picture with today, I am amazed and excited. Now there are major institutions around the country that have centers dedicated to bladder cancer. There is increased funding from the National Cancer Institute as well as the Department of Defense. Many pharmaceutical and biotech companies are devoting resources to finding new treatments. Clinical trials are ongoing across the country, enrolling the necessary patients quickly and answering important questions. And we have many new treatments approved.

Since BCAN began 16 years ago, thanks to the generosity of our supporters and community, we've invested $6.7 million in bladder cancer research. The foundation of our research program is our belief that today's research fuels tomorrow's cures. Our research grant program focused on investing in people, encouraging the best and the brightest clinicians and scientists to dedicate their expertise and talent to a career focused on bladder cancer. Since 2013, BCAN has made 20 Young Investigator Awards. These awards are very effective in enabling these early career investigators to become leaders in the bladder cancer field in a variety of areas including improving our understanding of the genetic mutations that contribute to disease progressing, leading clinical trials of promising new treatments, and identifying ways to improve the quality of life for bladder cancer patients.

We are so fortunate to have two of those outstanding former young investigators with us this evening. It is an honor for me to first introduce Dr. Kent Mouw, who received the Young Investigator Award in 2016. Dr. Mouw is now Co-Director of the Bladder Cancer Center at Dana Farber Cancer Institute and Assistant Professor of Radiation Oncology at Harvard Medical School. Welcome, Kent.

Dr. Kent Mouw:

Thanks, Diane. It’s good to be here.

Diane Z. Quale:

I’m also honored to welcome Dr. Sarah Psutka, recipient of a Young Investigator Award in 2019. Dr. Psutka is a Urologic Oncologist at the Seattle Cancer Care Alliance and Assistant Professor of Urology at the University of Washington. So happy you could join us, Sarah.

Dr. Sarah Psutka:

Thank you so much for having me, Diane.

Diane Z. Quale:

Both Kent and Sarah are actively engaged in the BCAN community in so many ways, including serving on the Steering Committee for our annual Bladder Cancer Think Tank Meeting, as well as leading sessions for that meeting. We have received over 200 questions from participants this evening in advance, and we’re going to do our best to capture all the major issues and concerns raised. But I will apologize in advance if we don’t get to your particular question.

Without further ado, we are going to get started. A lot of our focus this evening is going to be on the impact of research and research advances. So, Sarah, I'm going to start with you. What new treatments or protocols are you using today to treat your bladder cancer patients that were not available five years ago?

Dr. Sarah Psutka:

Well, it’s amazing as you said, Diane. The environment that we practice in is vastly different today than it was even when I was in training about six years ago and before that. The advances over the past decade I think have really revolutionized how we think about bladder cancer. We’ve started to characterize the genetics of it in a much more granular and detailed way than we even had the ability to do before.

In terms of new techniques, I would say that one thing that has really changed how we handle the diagnosis of bladder cancer has been the uptake of enhanced cystoscopy. So many of you will be familiar with the concept of blue light cystoscopy or narrow band imaging, which are two advanced techniques that allow us to basically perform a cystoscopy during which we identify the bladder cancer tumors and to identify them with greater sensitivity. Which means we do a better job of finding smaller tumors, tumors that hopefully are earlier in their pathway. We catch them earlier, we identify them, we stage and describe the tumor more efficiently and more effectively. That allows us to develop more appropriate care plans so that we're not under treating tumors, we're identifying tumors. It's not a question of seeing an early recurrence at three months because we actually missed a small tumor three months ago. Hopefully in doing so, we're sort of changing outcomes for patients, and I think that's really been a big advance.

Diane Z. Quale:

That’s great. And Kent, how about for you? The same or something different?

Dr. Kent Mouw:

I’ll echo Sarah’s sentiment that the landscape looks different just over the course of my career to date. To build on what Sarah said, a couple of things that come to mind in the treatment space, especially for muscle invasive and advanced disease are the approval of really now multiple new systemic agents, immunotherapies being one of them. I’m sure we’ll talk about immunotherapy as well as many of the other newer therapies. Their uptake and use in the advanced disease setting I think has revolutionized the progression and the landscape of bladder cancer.

Then for the muscle invasive space, I'm a radiation oncologist, and just thinking about how I treat patients with radiation now compared to even five years ago, we're using new imaging modalities to try to increase radiation dose to the tumor and reduce dose to normal surrounding tissues to hopefully minimize side effects but maximize cures. And we're combining radiation with many of these new systemic agents, chemotherapy, immunotherapy. Most often in the context of clinical trials, I would say roughly half the patients I treat are enrolled in a clinical trial that's combining radiation with one of these newer agents. I think that's exciting and has the potential to really help patients get through their treatment and then keep their disease at bay going froward.

Diane Z. Quale:

So, following up on that then, can you give us one thing that you’re most excited about that’s in the research pipeline now that you hope to be using for your patients in the next two to five years?

Dr. Kent Mouw:

Yeah, that’s a tough question because there’s many I think. But to sort of build on what I began with, I think that it’s feasible that in two to five years for patients with muscle invasive disease we will be using genomic biomarkers to really help guide the systemic therapies that we combine with things like surgery or with radiation. Depending on a patient’s specific tumor genetic makeup, we can select the drugs that we think they’re going to be most likely to respond to and combine those with either surgery or radiation in an effort to maximize the cure rates.

Diane Z. Quale:

Great. Sarah, how about you? Putting you on the spot. One thing you’re most excited about.

Dr. Sarah Psutka:

I think just to piggyback on what Kent said, the thing I’m most excited about is personalizing bladder cancer care. 2021 is a very different time to be treating bladder cancer because of the fact that we have a lot more options. But what we’re trying to figure out is when do we use them. As we understand more about the genetics of bladder cancer, but we also understand more about these different types of bladder cancer, we are starting to really get down into characterizing cancers into their different histologies, which means what cells make up the cancer.

Then also, Diane you know this, I'm really excited about understanding more about the patient themself and understanding more about a patient's own innate vulnerabilities, so risk factors, frailty, co-morbidities, physiologic age, body composition, those sorts of things and how the patient personalized risk factors and also their strengths. So their own innate resilience, their own innate physical fitness, their nutritional parameters, how those interact with the disease. That can help up identify when it's appropriate to potentially use, for example, immunotherapy in the neoadjuvant space versus using chemotherapy in the neoadjuvant space versus using cystectomy as an upfront treatment modality.

So how do we sequence all of these tumors? When do we go with radiation? When do we go with surgery? We don't know this yet. We are still trying to figure it out, But I think we're getting closer to being able to put a much more personalized spin on how we handle each of these diagnoses. And that I think it's really exciting.

Diane Z. Quale:

That is incredibly exciting and recognizing that every bladder cancer patient is different and it’s as we like to say an N of 1. And so what works for John won’t necessarily work for Jim. And really finding what’s going to work for them. And that is really exciting. One of the questions we got, and I think you touched on it a little bit, but Kent, can you speak a little bit more about the value of tumor genotyping, about getting a genomics report and which patients should be getting that and when in the whole treatment line, should that happen?

Dr. Kent Mouw:

Yeah, I think that’s a great question. And one that I think the answer is complex. So I would say that the majority of our patients that we’re seeing at Dana Farber, who are presenting with muscle invasive or advanced bladder cancer will have tumor genomic profiling performed at some point during their treatment course, as is often the case with new therapies, often they are tested in the later stages of disease and once they’ve proven to be active in that space, they tend to move forward. And so, patients with metastatic bladder cancer now have half a dozen or more different treatment options than they had five years ago. And those same treatments now are being moved into say the muscle invasive space or even a non-muscle invasive space. And so, for many patients with advanced disease, there are sort of a standard algorithm where we continue to try to use one of a handful of regimens.

I think we'll continue to build out and personalize therapy. But especially for those patients, whose tumors don't respond fully or who need additional therapy, I think there is when the tumor genomic profile, it can really inform therapy selection. And so we had our first targeted agent approved in bladder cancer Erdafitinib [enfortumab vedotin] over a year ago now, which patients undergo genomic tests and for patients with a specific tumor mutation, they may be eligible for the specific therapy. And I think this is going to be one of the, I hope many examples to come where a tumor genomic profiling performed at some point during the treatment course has the potential to inform and guide therapy selection.

Diane Z. Quale:

And Sarah, do you see that being important also in the non-muscle invasive space?

Dr. Sarah Psutka:

I think we’re probably moving towards that. We currently have at least one trial open and we’re working on opening another one that is using a similar drug to Erdafitinib that similarly relies on a patient’s tumor expressing that specific mutation. So I think that we are moving that genomically guided, personalized approach to the systemic therapies for non-muscle invasive disease earlier in the pathway. But a lot of that is under clinical trial investigation right now. So certainly, I think that’s coming.

Diane Z. Quale:

And I know that the cost of that genomic typing has been going down over the last several years too. I mean, it’s still expensive but not as cost prohibitive as it might have been five or six years ago. When we are talking about diagnosis, another question that came up is we know that bladder cancer is most commonly diagnosed through a urine test and cystoscopy, at least in the non-muscle invasive space. Is there a blood test for bladder cancer?

Dr. Sarah Psutka:

I wish.

Diane Z. Quale:

Where are we on replacing cystoscopy with either better urine test or a blood test?

Dr. Sarah Psutka:

I can speak to that a little bit. So I think we’re ways away from that from it being ready for prime time, there are numerous active studies that are ongoing that are looking for being able to identify for example, circulating tumor cells and other … that we might be able to identify from a simple sample of someone’s blood to identify if there’s either a risk factor for harboring bladder cancer or a patient actually has the cancer, but unfortunately we’re not there quite yet. And then in terms urine tests, there are a couple of different types of tests. I saw some of the questions that raised the concept of this test called Cxbladder. It’s interesting, in the setting of COVID-19 where we could not get patients into the hospital as quickly, or because elective surgery was shut down and we were limited on who we could bring into the hospital.

There was a push to try to rely on urine tests like that to identify patients that maybe we could hold off and bring them in for a diagnostic or surveillance cystoscopy. But again, it's not something that we can use as a blanket approach at this point. At least in my practice, they are not and based on the guidelines, they're not considered standard of care able to replace cystoscopy, but we sure are working on developing those tests because obviously cystoscopy is associated with a tremendous amount of comfort bother, the number of appointments that patients have to come in for in terms of loss of work hours, loss of time with their family travel time. We're very sensitive to the fact that we do need to improve our ability to diagnose and surveil muscle-invasive bladder cancer better. But again, it's ongoing.

Diane Z. Quale:

Okay. And Kent, how accurate are imaging studies like the MRI, a CT scan or a CT urogram and also are PET scans ever used to detect bladder cancer?

Dr. Kent Mouw:

So, certainly these imaging tests are the type of studies that get ordered for many bladder cancer patients and CT, for example, is part of the standard workup for patients with newly diagnosed bladder cancer. We use sort of a variety of imaging modalities in our practice because we feel like each imaging modality has a sort of specific advantages and disadvantages. CT is great to look for things like tumor in the bladder, tumor in the lymph nodes, swelling of the kidneys hydronephrosis, MRI or something that we were getting for a lot more of our patients now, MRIs provide I would say the most sensitive look at the anatomy in the pelvis. And so we can use them to try to understand if a tumor is invaded through the entire muscle muscular wall of the bladder into the surrounding tissues or invaded lymph nodes.

And so, as part of my practice now for patients undergoing radiation, we use both information from CT and from MRI to help design our treatment fields. PET scan is interesting. I mean, unlike some tumors, for instance, lung cancer, where PET scan can be really informative. We are getting PET scans for some of our bladder cancer patients, but one obvious limitation of PET scans for bladder cancer patients is the tracer that's injected that lights up on the PET scan is actually excreted in the urine. And so the entire bladder lights up as a normal feature of it. And so you see this really bright blob, which is the bladder, and that can make it hard to differentiate, urine containing the marker from bladder wall or bladder tumor uptake adjacent to it, so it can be good for finding things like lymph nodes that may be involved, but for assessing the bladder tumor, specifically, CT, MRI, and then, cystoscopy as Sarah mentioned.

Diane Z. Quale:

Okay. And then we get this question very, very often. If my mom or dad has bladder cancer, am I at higher risk to get the disease basically? Is there a genetic component, either of you?

Dr. Kent Mouw:

That is a great question. And it’s an area of such, I’d say intense research interest. I mean, as one of our main sessions at this year’s think tank is going to be on germline or hereditary risk factors for bladder cancer. And so I think that traditionally, historically the answer would have been, no, bladder cancer is associated with certain environmental or occupational risks, but it isn’t necessarily hereditary in the same way we can think about things like breast or ovarian cancer. I think that’s actually an oversimplified view. Although I would say perhaps currently, a lower percentage of bladder tumors are obviously associated with a hereditary pattern. Then are some other tumor types like breast or ovarian cancer. I think there’s certainly a subset of bladder tumors. As we learn more about the genetic makeup of these tumors, where it’s quite clear that there was an inherited mutation or an inherited factor that increased the risk of development of bladder tumor and could have implications for the way that the tumor gets treated ultimately.

Diane Z. Quale:

Okay. So this is something we will know more about in the coming years. It’s still uncertain.

Dr. Kent Mouw:

Yeah. I would say to patients, when asked about family histories of cancer, this is certainly something you bring up with your primary care doctor. It’s not something that’s currently impacting the way that we surveil or screen patients, but important to know that as we learn more, it’s probably going to be the case that we begin to understand that, at least, a small fraction of bladder cancers are clearly due to inherited risk factors.

Dr. Sarah Psutka:

I would say, I think it is interesting because I actually see a lot of referrals for patients who have been identified with other predispositions to develop certain genetic or familial predispositions to developing certain cancers. So, for example, there’s one syndrome called Lynch syndrome that we do know does increase the risk for upper tract urothelial carcinoma bladder cancer. And so those patients actually are followed a little bit differently. It’s a very small patient population, but that’s why when we take a family history, we actually really want to know if a patient … For example, if your parents have had these cancers or if first and second degree relatives have … because it can sometimes trigger, if there have been for example, a lot of colon cancers or GYN malignancies. It can set off some warning bells that maybe we actually do need to dive into it.

And we have gotten in a lot of our ... and especially when patients present with young people with bladder cancer, we know that the median age a patient presenting with bladder cancer is 73 years. So when someone in their 30s or 40s present, that should be a trigger that we do actually probably need to dig a little bit deeper. And so I think it's one of those things, if your parents have been diagnosed, it's certainly something to bring up to your physician because there are specific situations where we'll involve genetic counselors and do some testing. Like Kent said, we were still sort of trying to figure out exactly what those different pathways look like and what those risks are.

Diane Z. Quale:

Okay. Good. So we’re going to move on a little, we know that bladder cancer is not really a single disease. There’s this very wide spectrum as it covers non-invasive papillary bladder tumors that don’t invade the bladder wall to advanced metastatic disease that involves the cancer spreading from the bladder to other organs. So we’ve got a lot to cover. We might go back and forth through these different stages, but I’m going to start with non-muscle invasive. And as we know, the standard of care has been in many cases BCG. And we all know too that there have been issues over the past too many year with the supply of BCG. So we’ve had a lot of questions about BCG treatments, as well as the alternatives. So I’m going to start first, Sarah, with just talking about BCG treatments, one of the questions we’ve got is, how long can you stay on BCG maintenance treatments? Is there a maximum number of doses?

Dr. Sarah Psutka:

It’s a good question. So the original clinical trial protocol that led to us bringing maintenance BCG into mainstream bladder cancer care suggested that patients should be treated over three years. So, the protocol is you get to three doses. So I call them booster doses at three months, six months, and then every six months for a total of three years. But we also know that patients can develop what’s called BCG relapse. So basically develop a non-muscle invasive bladder cancer after they’ve been on maintenance for some period of time. And if that’s the case, we may actually go back and give people another induction dose. And if that’s successful, go back on maintenance. So, there’s not an absolute maximum.

I saw my patients in my practice for example, who were diagnosed in say 2014 and went through the three years of maintenance and then came into my practice in 2020, six years later. And then we resumed the process when they were diagnosed with the high risk non-muscle invasive bladder cancer, where they got another round of induction and another, or we're in the middle of maintenance. So there's not an absolute maximum. 

Diane Z. Quale:

When BCG is not available, what are my alternatives? And we know that … Is gemcitabine and docetaxel as effective as BCG. Well, I guess that’s one question. Do you think that that’s an effective alternative to BCG?

Dr. Sarah Psutka:

We do. Now there’s not level one evidence at this point. There’s not a clinical trial where researchers have pit gemcitabine and docetaxel, which are two chemotherapeutic agents that are given in sequence. So a patient comes in, has their urine drained from their bladder, gets one of the chemotherapy agents for an hour, then that’s drained out and then gets the other chemotherapeutic agent. And then we do that six times in a row and then maintenance for that is usually given once a month for two years. We haven’t studied that against BCG in a clinical trial as of yet. There is retrospective data that is very supportive of the fact that at two years there about a 40% durable response. In the guidelines right now, gemcitabine and docetaxel is considered appropriate for BCG unresponsive disease.

Diane Z. Quale:

And you had mentioned, Keytruda for an immunotherapy for non-muscle invasive disease. Who’s eligible for that?

Dr. Sarah Psutka:

So that’s for patients again with BCG unresponsive disease. And we use that term to define people who have gotten BCG, they’ve gotten induction. The clinical trial definition is they got five out of the six rounds of the induction in two of three of the maintenance. It gets complicated, but they got BCG and it didn’t work. And they got BCG again and it didn’t work. So if they have non-muscle invasive disease, that’s high risk, CIS is included or Poplar disease, that has not responded to BCG pembrolizumab or Keytruda is FDA approved as a systemic therapy, that’s given through the IV usually once every three weeks in those patients.

And there's a clinical trial that's phase three randomized clinical trial that supported the use of pembrolizumab in that space. And so generally the conversation we have with patients when BCG hasn't worked twice in a row where the cancer keeps coming back, we start to talk to patients about whether or not we think it's reasonable for that patient to go on to something like additional intravesical chemotherapy like gemcitabine and docetaxel or move to a systemic therapy option like pembrolizumab.

Diane Z. Quale:

Okay. Kent is trimodal therapy, chemo-radiation, is it available for high-risk non-muscle invasive disease?

Dr. Kent Mouw:

That’s a really topical question because we’re actually expecting results of a clinical trial of just that treatment paradigm to be reported at a meeting later this year. And so the trial, which completed a couple of years ago, and we’ve been following patients since it was completed, were treated using a paradigm of chemotherapy and radiation similar to what we’ve had typically used in the muscle invasive space, but applied to patients with high risk BCG refractory T1 disease. So we expect results from that in a couple of months. Currently in my practice, I do use chemotherapy and radiation typically reserved for a very select group of patients for whom they’re not eligible for cystectomy or who choose not to avoid cystectomy.

That's really what I'm reserving trimodal therapy for in the T1 space currently. And so it is not known yet as an approved, supported algorithm, but I hope that the results of this trial, which will be approved in a couple of months will help shine some extra light on it. And may help that become sort of another arrow in the quiver for this difficult clinical situation about the disease.

Diane Z. Quale:

And Sarah, you had mentioned a new FDA approval on another drug that we’re waiting on. Can you just touch on that briefly?

Dr. Sarah Psutka:

Sure. So there are two other intravesical therapies. Nadoferegene firadenovec is the generic name. That has been FDA approved. It is basically a virus that carries something that is toxic to the cancer that’s put into the bladder. Intravesical at three-month intervals and that’s FDA approved, although we are not currently using that in practice, a lot of places it’s still being sort of brought onto hospital formularies. So it’s not quite mainstream, but it’s got the FDA approval. The other drug is something called the Vicinium or Oportuzumab.

Dr. Sarah Psutka:

Oportuzumab monatox is another intravesical agent that I believe in August, we will hear from the FDA about, that’s going to be approved. I actually looked that up just to see if they’d given us a date so yeah late August. And so that’s another intravesical agent that’s given a little bit more frequently. The medicine is given, initially twice a week in the bladder and then weekly for about a total of 12 weeks. And then at maintenance doses and the initial study demonstrates that it seems to be very successful. The two year survival is very high at 95%. And it seems like the three month complete control rate is about 40%. So 40% of patients at three months don’t have any bladder cancer in their life. So we’ll see what the FDA says about that.

Diane Z. Quale:

And just to clarify, too, for any of our listeners who don’t know, intravesical means it goes directly into the bladder as opposed to systemic into your whole body. Correct?

Dr. Sarah Psutka:

Exactly. So we think of it as topical therapy. Medicine that we put in contact with the cancer, but it’s not going through your blood.

Diane Z. Quale:

So let’s move on to focus a little bit more on muscle invasive disease. When that tumor has grown deeper into the layers of the bladder and becomes much more problematic because it can progress and spread. And as we know, the standard of care for a long time has been bladder removal and reconstruction of a new urinary system. And so we have a lot of people, who are very interested in knowing. And Kent I’ll start with you on this. What treatments are available to preserve the bladder? What are we looking at?

Dr. Kent Mouw:

Yeah. That’s a great question. Sort of the “standard” bladder sparing option today is chemotherapy plus radiation. And so it’s called the trimodal approach because it really involves, input and expertise from urology, medical oncology and radiation oncology. And so patients will undergo a maximal safe transurethral of their tumor. So a cystoscopic removal of as much tumor as is safely possible. And then, following that the patients will undergo concurrent chemotherapy with radiation. And so the most common way that it’s done at our center is it’s about a six to seven week course of daily radiation treatments given Monday through Friday, one treatment a day as an outpatient, with some chemotherapy during those weeks of radiation. And the way that chemotherapy is given depends a little bit on exactly what type of, chemotherapy regimen is chosen to be given with the radiation.

But it's typically, once to twice a week, infusion of chemotherapy during those weeks of radiation to the bladder. The goal of this combined trimodality therapy is to completely rid the bladder of tumor. And once the patients are done with treatment, they go on to a surveillance protocol that includes, relatively frequent cystoscopies. So examination for bladder tumors by a urologist as well as imaging and blood work. And so that right now I would say is our standard approved approach for a bladder sparing treatment paradigm for muscle invasive disease. That said there are numerous other bladder sparing options that are under investigation. So for patients getting chemotherapy and radiation, there's a big trial going on now, it's a randomized trial, that's comparing the standard of care, which I just sort of described the chemotherapy radiation to that standard of care. Plus the addition of atezolizumab, which is an immunotherapy agent.

The rationale being that atezolizumab is approved and has been shown to be active in patients with metastatic disease. And so we are trying to move it forward into the treatment paradigm and include it with chemo and radiation for patients with muscle invasive disease. And so that's a large trial that's ongoing currently. And then I'll just mention that we are sort of combining our discussions about tumor molecular profiling with bladder preservation. There are several interesting sort of trials underway that are using tumor genomic profiling to select patients who are hopefully most likely to respond to chemotherapy. And so the paradigm for these trials is that patients standard of care would typically be chemotherapy followed by radical cystectomy.

These patients undergo tumor genetic profiling at the beginning of chemotherapy and then they receive the new agent chemotherapy as would be the typical standard of care, but rather than going directly to radical cystectomy as would be standard, patients with specific mutations in genes involved in chemotherapy response in the tumor, at the end of the chemotherapy to have a cystoscopy performed. And if there's no evidence of tumor, they actually don't undergo cystectomy and instead follow a close surveillance protocol. And so it's a way to try to identify patients who are likely to respond to chemotherapy alone and give those patients the opportunity to keep their native bladder, if the tumor completely responds to chemotherapy, once the chemotherapy has been completed.

Diane Z. Quale:

I think for me, one of the greatest advances that I’ve seen in the 21 years I’ve been in the bladder cancer space, is this, much more attention being placed on research to find ways for patients to maintain their biological bladders and not just assume that somebody with muscle-invasive disease has to have their bladder removed. And so I’m really excited about all the different efforts that are underway to try to make that happen. I also want to give a pitch here for BCAN’s clinical trials dashboard on our website. So if any of our listeners are interested in finding out about some of these trials that we’re discussing tonight, you can go on there and find out where the trials are located and get some information to see if maybe you might be eligible now, or even if you want to consider it sometime later in your treatment. Sarah, is there any research being done into artificial bladders or some kind of transplant, so you don’t have to, once you remove the bladder, take your … because right now we used intestine to build a new system.

Dr. Sarah Psutka:

It’s a really good question. And it’s actually been an active area of research for a long time. Much of the work has actually been done in the pediatric space where for example, some of our transplant surgeons have done work looking at whether or not we could use bladders from other animals such as pig bladders, or whether they could grow a bladder in vitro, which means in an artificial system out of the body that they could create a cell structure that looked and functioned like a bladder, and then put that into a human.

We're not quite there yet with a lot of those. And one of the sort of interesting things that people are doing now is looking at using 3D printing modalities to create cellular scaffolds, which basically means create something that they could then grow bladder cells on, then that could potentially be hopefully, maybe someday transplanted into a patient so that we wouldn't have to borrow intestine to recapitulate some sort of, internal plumbing that is not nearly as good as what we're all born with.

So yes, that is definitely an active area of research. Some really, really interesting works being done there. The early trials with for example the pig bladder and the sort of artificial bladders showed that their bladders became pretty scarred pretty fast and they didn't really work. But I think that that's something that has been an active area of research for a couple of decades now. And certainly when I was in Boston, actually at Boston Children's, there was a really big lab that was working on that. So I think that, we'll see as the 3D printing modalities and also as the sort of self-culture, as our advances, we get better at basically growing normal bladder cells in culture. I think that there's potential, but we're not there yet.

Diane Z. Quale:

Okay. There were a lot more questions on this, but I want to move on to some of the other areas and move on to advanced or metastatic disease. And of course we’ve had a lot of questions related to immunotherapy. Kent should you always try chemotherapy first or for some patients, should they just start on immunotherapy?

Dr. Kent Mouw:

Yeah, it is a great question. So, it certainly is a patient dependent decision. So a patient and their provider having this discussion, currently for patients who are eligible for cisplatin based chemotherapy and cisplatin is one of the drugs that’s been shown to be most active in bladder cancer. The majority of patients who are eligible for cisplatin, by eligible, I mean, they have kidney function and they don’t have kidney function that can support getting cisplatin. They don’t have issues with things like neuropathy or hearing loss. For patients who are cisplatin eligible, most of those patients are recommended to have a cisplatin based chemotherapy as their first line treatment for advanced bladder cancer. That being said, immunotherapy still plays a big role in many patients treatment because for patients who are cisplatin ineligible, now immunotherapy agents are approved in the first-line setting.

So that would often be the first drug that would be given in a patient who wasn't eligible for cisplatin based chemotherapy. And similarly, if a patient's tumor progresses through our cisplatin, then often the second line of defense, the second line therapy in those patients is also immunotherapy. And so, I think a big percentage of our advanced bladder cancer population these days is getting an immunotherapy at some point during their treatment course. And that's where they're approved and they're being tested as we've sort of discussed throughout the spectrum including in the non-muscle space where they're approved and, in the muscle invasive space, very, very active areas of investigation.

Diane Z. Quale:

Yes. And the FDA recently approved two new drugs for advanced bladder cancer. The antibody drug conjugates, which are Padcev and Trodelvy. But tell me how do they work and who are they for? And is there any difference between these two drugs? Either of you?

Dr. Kent Mouw:

Yeah, they’re antibody drug conjugates.

Diane Z. Quale:

Which means what?

Dr. Kent Mouw:

Yeah. So it means that the antibodies, which are proteins in your body that are designed to bind specifically to another type of protein in the body. And so an antibody drug conjugates, it’s an antibody literally conjugated typically to a chemotherapy agent and the purpose of antibody drug conjugates is that the antibodies are designed to bind tightly and specifically to proteins that are highly expressed in bladder tumor cells. And so what you get then is delivery of this chemotherapy agent specifically to the bladder cancer cells at a much higher concentration than is sort of floating around anywhere else in your body.

And so, these are two different antibody drug conjugates that have been approved. The proteins that are targeted by the antibodies are slightly different than the drugs. And the chemotherapies that are attached to the antibodies are slightly different each of the two agents. But the rationale, sort of their designed features are similar in that it's an attempt to more specifically deliver bladder cancer cytotoxic agent where the bladder cells are and relatively sparing more of the normal cells in the body.

Diane Z. Quale:

Okay. But the approvals were patients can get this if chemotherapy doesn’t work and immunotherapy doesn’t work, it can’t be the first thing that anybody goes to. Correct?

Dr. Kent Mouw:

Correct. The FDA approval for both of the agents, both in enfortumab and then Sacituzumab are the names of the two drugs, that you mentioned, both of them are approved in patients who have progressed through or patients whose tumor has progressed through platinum-based chemotherapy if they were eligible and through immunity.

Diane Z. Quale:

We’re going to go to a big area but one question I want to ask about subtypes of bladder cancer, because I think it’s really important. We know that the majority of bladder cancers are your epithelial cell or transitional cell carcinoma, but we have other subtypes, such as squamous cell and small cell and micro papillary. Are there research efforts, underway or funds allocated to address the issues in these rare forms of bladder cancer? Sarah.

Dr. Sarah Psutka:

Yeah, definitely. That’s something I would say … You asked us at the beginning about big advances and one of them is us being much more specific in how we talk about bladder cancer. We don’t talk about bladder cancer now is sort of just bladder cancer in general. We know that bladder cancer gets broken down into these very specific sort of histologic types, which means what kind of cell is this cancer made of? Because a squamous bladder cancer is very different from an adenocarcinoma of the bladder, urothelium or micro papillary or plasmacytoid or any of these other types.

They behave differently. So, it's comparing apples to apples and oranges to oranges.  Some of them respond to medications. For example, certain of these tumors, like an adenocarcinoma we wouldn't give neoadjuvant cisplatin based chemotherapy. We wouldn't recommend it in that space. A patient who has an adenocarcinoma of the bladder, we know that that patient should probably go straight to surgery if they have muscle invasive disease and they're eligible to have their bladder removed.

But there's a really nice clinical trial that was published recently called the PURO One Study that had a sub-population where they were looking at using immunotherapy in patients who had a variant histology and demonstrated that there was some efficacy. And there've been some interesting studies recently that show that some of the squamous cancers actually express specific molecules that suggest that they are going to respond to immunotherapy maybe better than chemotherapy. So by being really specific about how we talk about cancers and when we get that first pathology report, where we talk about what the cystoscopy biopsy showed, like what cancer we're talking about, it can help us to start to really personalize whether we think that patients should go towards a certain cisplatin based chemotherapy therapy, other types of chemotherapy, for example the small cell you mentioned that we use a different type of chemotherapy regimen there.

So it allows us to be much more specific. And yes, there are quite a few active research studies that are going on. Ones where we're actually trying to grow these tumors in cell culture, but also in animals so that we test different drugs on them in a way that allows us to really study the efficacy of those drugs in a really targeted sense. And then the other big thing is actually just creating these … they're called tissue microarrays, which are basically laboratory tests that allow us to look at sort of how specific drugs interact with these different tumors. So that's a really hot area of research right now, and that's been an area that a lot of developments have been made in the last couple of years, particularly.

Diane Z. Quale:

Great.

Dr. Sarah Psutka:

More information on that.

Diane Z. Quale:

Great. So a big area of questions in this of course is bladder cancer has a really high recurrence rate. We all know that. And so there are a lot of questions that were raised about recurrence and the likelihood of recurrence. And we know that will depend on the stage and the grade often of the initial tumor. But one question that came up many times, is there anything I can do to help prevent recurrence? Does it depend on stage and grade? Can I do anything with nutrition, diet, exercise? Who wants to take the first shot at that one?

Dr. Sarah Psutka:

I can speak to a few things. I would say treatment-based strategies to prevent recurrence. So in the non-muscle invasive space, things like maintenance therapy in the bladder, whether it’s maintenance, ECG, or maintenance chemotherapy in the bladder, in the post cystectomy space, there are clinical trials going on right now where we are looking at whether or not giving people medicine after cystectomy. So that’s called adjuvent therapy. Whether that can help prevent cancer from coming back.

So people, for example, who are really high risk of cancer coming back who have stage T3 disease, tumor that's gone through the bladder wall, tumor in the nodes. They can enroll just a couple of clinical trials. There's one called the ambassador trial. There's another one called the Proof 302 Trial that's looking at using, a specific drug that is targeted to patients who have a mutation in their tumor to prevent that cancer coming back. A really interesting smart question is what can patients do themselves?

Diane Z. Quale:

Exactly.

Dr. Sarah Psutka:

Medicines. And so, the first thing is if you have a habit in your life that we know for example, it’s associated with bladder cancer. So the biggest thing is smoking. If you’re smoking, when you’re diagnosed with bladder cancer, the best thing you can do is quit smoking. It’s not easy, it’s not easy at all, but you can work with your doctor. And there are strategies that we can offer that can help you to stop smoking, because we know that cigarette smoking with the chemicals in tobacco and in cigarettes are concentrated in the urine and they predispose bladder cells to becoming cancerous. So that’s something that’s a major sort of step, a major moment of agency. It’s a great time to start to make a big change in one’s life.

Nutrition wise, there are things that we can do that basically improve your health. So patients who have cancer are recommended to make sure that they're eating a pretty healthy diet. One of the big recommendations is protein intake. So there's an international guideline body that says that patients with cancer should be taking in one gram of protein per kilogram of body mass, which is a lot. So if you're a 70 kilogram, that's 70 grams of protein a day, which is like bodybuilder levels.

But the importance there is that we know that cancers increase your metabolism, and they accelerate the loss of muscle mass that normally happens with aging. Our chemotherapeutics and our treatments can also increase muscle mass loss and muscle mass loss can make patients ... It has a lot of implications, but it can make people more likely to fall and have issues around sort of independence of daily living and have implications for quality of life.

But there's also some pretty good evidence that it's associated with cancer coming back and with death from cancer. So sort of fortifying your body with good nutrition and activity and maintaining your muscle mass. There's some pretty good evidence that that's likely to help. Now, those studies are also ongoing and we're working on a lot of those as we speak. So good nutrition exercise, stopping habits that are not so good, like alcohol and cigarettes, those are all positive steps that people can take in their own lives to help reduce the likelihood.

Diane Z. Quale:

We have time for one more question, and I want to have time for both of you to answer this, because again it depends on the patients and the stage and the type of disease they had. But how long do I need to follow up with my doctor? Either my urologist or my oncologist? If I haven’t had a recurrence, let’s say Kent, I’ve had … either I’ve had my bladder removed or I’ve had successful trimodal therapy. I hadn’t had a recurrence, it’s been two years, three years. How often, and how much longer do I need to come see you? No offense.

Dr. Kent Mouw:

So it’s very personalized. It really depends on exactly what therapy you got for exactly what disease types you had. But, I would say that he good news, if there is some in this space, is that, the further out you go from bladder cancer, without recurrence, we know that hopefully the less likely we are to have one. And so often much of our imaging and our cystoscopies and our surveillance is sort of front-loaded in those first couple of years. And so for patients who I’ve treated who’ve had trimodal therapy. Those folks, I see them, pretty frequently the first couple of years, but then it begins to space out. And by five years they’re often done with much of the imaging.

They continue often to have cystoscopic surveillance with their urologist. But again, sort of on a personalized basis, the further you go out, in five years is certainly not an official moment, but by that time, I'm often not ordering as many or very few, if any scans and things like that. And it becomes more just check-ins, cystoscopies for folks who still have a bladder.

Diane Z. Quale:

Got you. And Sarah, looking at people with non-muscle invasive disease, and let’s say, I haven’t … Whatever therapy I had and I haven’t had a recurrence, when can I stop getting these frequent cystoscopies?

Dr. Sarah Psutka:

Good question. And it’s a similar answer to what Kent described, which is that again, we try and be very specific and personalized. And so it’s a risk stratified approach. If your original cancer was a low risk, non-invasive TA tumor, we might see everybody sort of on the same regimen every three months for a period of time then every six months for a period of time then every year. But we know that those tumors are not likely to progress and there they have a high recurrence rate, but it’s on a different timeline than say a high grade TA or a high grade T1 or CIS. So we might see that patient with a low-grade TA at three months, and then if there’s no cancer and maybe nine months later, and then every year or so. But the high risk patients, we definitely see them in a much more front loaded fashion.

And especially if they're going through maintenance. Something like that. I think this question hinges on the key concept of survivorship. And that is something that is so important. This second, I talk to patients about the fact that the second they're diagnosed with cancer and we go through therapy, you are now a survivor. But that does mean that in some ways we sort of say, "We're going to be friends for a long time." I end up seeing patients pretty frequently for much longer than that five-year period. But even after the five-year period, I think it's important to have a handoff to the primary care doctor about key things that people should be looking for. That should prompt a quick visit back to me. And I think that especially for people who have had cystectomies, we may decrease the intensity of our cancer checkups.

So getting scans and things like that as much as five years out. But for example, if you've had a urinary diversion, I do want to check on you to make sure your kidney function is still good and your bone health is still good and your nutritional parameters are still good because that's important to you having a high quality life with this new internal plumbing. So I think that it's a lot of follow up, a lot of being a bladder cancer survivor-

Diane Z. Quale:

It’s a lifetime.

Dr. Sarah Psutka:

It’s a lifetime, it takes a lot of work. And you want to know who your people are. You want to know who your team is, and you want there to be good communication between your team, because even though you may not be seeing Kent or me anymore, you want to have our number in your back pocket, just in case something pops up. And you want to talk to your doctor about what those visits look like. I will say one other thing, an unexpected potential benefit of COVID, If we can say that there’s any silver lining has been, we’ve gotten much more comfortable with tele-health.

And being able to see our patients in ways that are more efficient for our patients and less costly, really expanded the ability of our ability to do that. And so I think we're working much harder here, for example where our patients travel really far to see us, getting scans locally and doing checkups and discussing labs and scans over telecommunication. And if we need to examine them, that's different, but we can do things to make it easier. We don't have virtual cystoscopy yet.

Diane Z. Quale:

Right. Yeah, we could get rid of cystoscopy altogether. I think that would be great. That would be great. Well, we’re coming up to the end of our hour. Stay with me for a few more minutes, Kent and Sarah. it’s been a wonderful conversation, and this could go on for hours, but unfortunately tonight we only had one hour.

Many thanks once again to our experts, Dr. Kent Mouw and Dr. Sarah Psutka, not only for sharing your time and expertise with us this evening, but for everything you do for your patients and for the BCAN community each and every day. And thanks to everyone who joined this, please visit our website regularly for additional resources. And I hope we can all be seeing each other in person very soon. Good night.