Treatment Talk | Upper Tract Urothelial Carcinoma

March 14, 2022

With Dr. Jeannie Hoffman-Censits, Dr. Nirmish Singla, and Patient Advocates: Tony K. and Christina Y.

Year: 2022

You can read the full transcript of Treatment Talks | What you need about treating upper tract urothelial carcinoma (UTUC) at the bottom of this page.

Part 1: Treating Low Grade Upper Tract Urothelial Carcinoma

Video (17 min) | Transcript (PDF)

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Part 2: Treating High Grade Upper Tract Urothelial Carcinoma

Video (17 min) | Transcript (PDF)

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Part 3: The Patient Experience with Upper Tract Urothelial Carcinoma

Video (14 min) | Transcript (PDF)

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Part 4: Question and Answer

Video (19 min) | Transcript (PDF)

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Full Transcript of Treating Upper Tract Urothelial Carcinoma

Stephanie Chisolm:

Welcome to Treatment Talk, what you need to know about treating upper tract urothelial carcinoma. It’s a presentation from the Bladder Cancer Advocacy Network. The objectives of the Treatment Talks are to increase patient understanding of existing and new treatments for the spectrum of bladder cancer diagnoses, to showcase patient questions and ask about empowering patient communication with your healthcare team. How do you talk to your healthcare team about your diagnosis? And then also to highlight current treatment advances for bladder cancer.

In today’s program we’re going to introduce Dr. Jeannie Hoffman-Censits and Dr. Nirmish Singla, both of Johns Hopkins Greenberg Bladder Cancer Institute and patient advocates, Christina and Tony, who will share their experience with low and high grade upper tract urothelial carcinoma. It’s a delight to have you here. Thank you so much. Dr. Hoffman-Censits is a medical oncologist and Dr. Nirmish Singla is a urologist, so we’re really thrilled to have you. And we know that upper tract urothelial carcinoma is a rare form of bladder cancer, so can one of you just tell me, how often do you find bladder cancer in the upper tract in your general population? Dr. Singla, do you know how what’s the percentage of upper tract patients?

Dr. Singla:

Yeah. Absolutely. We’ll talk about this a little bit more, you’ll see in the coming slides, but in general, about 5% to 10% of all patients with urothelial carcinomas are found in the upper tract, and about 2% to 4% of patients who have had a history of bladder cancer may develop upper tract urothelial carcinoma at some subsequent point.

Stephanie Chisolm:

Great. We’re going to be talking about some of the challenges of diagnosing and treating this particular rare form of bladder cancer as we go on. And we’re going to ask them to turn their screens off, and then Dr. Singla, if you want to share your screen?

Dr. Singla:

Great. Thank you so much, Stephanie. And thank you all for joining this afternoon. It’s truly our privilege and honor to be able to talk to you today about treatment options for UTUC, or upper track urothelial carcinoma. And so together, both myself and Dr. Hoffman-Censits are more than happy to initially talk a little bit about what UTUC is, and some of the background information surrounding this relatively rare entity, and then get into the weeds of some of the treatment nuances as it pertains to low risk or low grade disease, and then the higher grade and higher risk disease states.

Dr. Singla:

All right. And so just to begin, urothelial cancer on the whole is actually relatively common. It accounts for approximately 81,000 new cases annually in the United States. That being said, the overwhelming majority of urothelial cancer cases tend to be of the bladder cancer flavor, or the essentially lower urinary tract cancers, accounting for the overwhelming majority of urothelial carcinomas. On the other hand, as I said earlier, only about 5% to 10% of urothelial cancers come in the upper tract flavor, if you will, or UTUC. Now, UTUC, it’s a relatively much harder population of patients to study and to treat for a number of reasons. First and foremost, again, because of its relative rarity, it makes it rather challenging to come up with well-designed prospective clinical trials that allow for the generation of level one evidence to guide the management of this disease state.

Dr. Singla:

Furthermore, whereas for bladder cancer, we have larger instruments that we can endoscopically introduce into the bladder to get good biopsy samples and help guide management in that way, for the upper urinary tract we’re limited with our working channels through ureteroscopes, often with a very limited diameter, to allow us to get good quality biopsy tissue that would then allow us to direct the management accordingly. Furthermore, in terms of staging this disease, we currently rely on cross-sectional imaging, typically a four phase CT scan, as the gold standard approach. However, there are many inaccuracies related to staging with contemporary technology, and so this is certainly an important area of need, and one that I think would start to play a more important role as we start to better tailor individualized treatment strategies for patients. Now, I mentioned again that because of its relative rarity, it becomes a challenging state to design well-controlled clinical trials.

In bladder cancer we have lot have one evidence that supports the use of neoadjuvant chemotherapy followed by a cystectomy, for example, in patients with muscle invasive disease. In the setting of UTUC initially in large part, our management had been extrapolated from bladder cancer literature. Now we are starting to have more prospective evidence emerging, and Dr. Hoffman-Censits will talk a little bit more about this in the second half of this talk, but both for the neoadjuvant and the adjuvant, or the pre-op and postoperative use of systemic therapies surrounding a definitive surgery, the gold standard of which is called a nephroureterectomy. But there is one additional component to managing UTUC that’s also not seen so much in bladder cancer, and that’s also the fact that the gold standard treatment approach involves the removal of a renal unit. Again, a radical nephroureterectomy, which also has implications, because as you can expect, the overall kidney function may also decline after removing that kidney, and so that also has implications for the ability of a patient to receive chemotherapy following surgery.

Now, I wanted to talk a little bit about the staging of this disease, because when we approach patients with UTUC, there are two pieces of information that are important to us to come up with a treatment strategy. The first is the cancer stage, and so that essentially entails the understanding of is this entirely a localized disease or potentially a locally advanced disease that could be managed either with procedural means or some multimodal type of an approach, or is this a metastatic setting in which there are other sites that are also involved? And then the other important piece of information, particularly for localized disease, is the grade of the tumors, this low or high grade. And so just by way of example, I wanted to just show some CT scan images just to highlight the types of the spectrum that we can see when it comes to UTUC.

This is an example of a patient who had a ureteral cancer in the distal of the last part of the ureter, which is the tube again that drains the kidney to the bladder. Circled in yellow you can see that tumor. He had no other sites of disease involvement, and so he essentially classified as a localized disease and someone who actually ultimately went on to receive a multimodal approach with systemic therapy followed by a definitive surgery. On the other end of the spectrum, here’s an example of a patient who actually presented with metastatic cancer, and so this patient had multiple sites outside of the kidney and ureter that were involved with disease. And so you can see, for example, here in the liver, if you can see my cursor here, there are multiple dark spots that are shown on the CT scan, consistent with metastatic deposits from his urothelial carcinoma, and there’s also an additional one here in the spleen.

Dr. Singla:

And so this is a patient for whom surgery often will play a more limited role and upfront systemic therapy would typically be the next course of action. Again, when we talk about stage, the classic approach that we use is using this TNM staging system. And what that means is essentially we look at the primary tumor, the lymph nodes, and then the involvement of distant sites. In looking at the primary tumor, we’re most interested in assessing the degree of invasion into the lining or the urothelium, as well as into the deeper tissue layers, including the muscle, and sometimes even the fat surrounding the ureter or within the kidney itself, and so we assign something called the T grade, based on the depth of invasion. And again, this is usually based on a CT scan or an MRI that gives us this type of information.

We next look at the involvement of any lymph nodes, and so we have something called the N stage, which is based on the number of nodes involved and also the size of the nodes involved. And then finally we have an M stage, or a metastasis stage, to help us understand if there are other sites of involvement, distance sites of involvement as well. Now, I mentioned the use of grade, and the reason why this plays an important role is because again, as I had mentioned earlier, we are limited in our ability to get a lot of tissue when we do biopsies on patients with ureteroscopy. We often in particular may not get an adequate sense of how deep the tumor is going, simply because there can be sometimes risks to attempting to get particularly deep samples, especially within the ureter.

And so what our management approach has largely been predicated on is understanding what the grade of one’s tumor is, and specifically this is based on the appearance of these tumors under the microscope, and it’s a piece of information that we can often garner from these biopsies. And so in particular we either have tumors that are low grade or tumors that are high grade, and this will actually serve as the crux of our discussion today, we’re going to actually divide… I’ll talk a little bit more about the low grade UTUC flavors and the types of management approaches that we use here while Dr. Hoffman-Censits will then talk in the second half of our presentation on high grade UTUC. Specific to low grade UTUC, the good news is that in general, even though recurrences tend to be common, in other words, these tumors could certainly pop up despite attempts at treatment in other parts of the urinary tract, the fortunate aspect is that they often tend to have a low risk for progression.

The likelihood of a purely low grade tumor to invade deeply, or to spread to other parts of the body, or in some cases, even to advance to a higher grade state often tends to be limited. And so as a result, whereas in the past a radical nephroureterectomy was considered the gold standard, now we have increasing interest in managing these patients through a nephron-sparing approach, or basically an approach in which we can avoid the need to remove one’s kidney and hopefully protect their kidney function overall. And so we often will try to achieve control of the cancer using endoscopic means, or basically using your ureteroscope, often with a laser, to ablate these tumors. And that’s in large part because taking out the kidney and ureter may be considered overtreatment and subject patients to unnecessary nephrotoxicity or kidney morbidity from having to undergo that type of a surgery.

One caveat to note is that again, due to the limitations in our ability to sample these tumors endoscopically, if you look at some series, there’s actually a risk of upgrading tumors to a higher grade disease state if you were to undergo an nephroureterectomy for every single patient who was diagnosed initially with low grade disease. And so that’s why the main goals of approaching a patient in whom you suspect low grade disease would be first and foremost trying to ascertain, to the best of our ability, an accurate sense of what the true grade of the cancer is, followed by a balance between preserving kidney function on the whole, but then also making sure that we are able to attain oncologic or cancer-based control.

Dr. Singla:

And so in terms of treatment options for low grade UTUC, again, the classic approach had been to perform surgical extirpation, which would either be a radical nephroureterectomy, or in a subset of patients, even a partial ureterectomy with sparing of the kidney, depending on the location of the tumor. And then we also talked about endoscopic means, so this would be via usually a ureteroscope in either a retrograde or an antegrade fashion. A retrograde fashion being that the scope would be introduced from below through the bladder, up the ureter, up to the site of involvement, and typically with the use of some form of an ablative strategy, often with a laser fiber to ablate or essentially kill the tumor cells. Or even via an antegrade approach, which involves accessing the kidney from the back and then going down through the kidney, and plus or minus the ureter, to the destination site and treating the tumor that way.

Now, there is one strategy that recently got FDA approved that involves the use of a topical installation of a chemotherapy agent, and this is the strategy I’ll talk a little bit more about, referred to as primary chemoablation. And then there are also indeed a number of other investigational strategies that are currently being explored for this disease state as well, with the goal, again, of achieving adequate cancer control while minimizing the need to remove one’s kidney. I just wanted to briefly highlight without going too much into the details of the study, but there was essentially an open-label single-armed phase three trial referred to as the OLYMPUS trial that was published a couple years back, and led to ultimately to the FDA approval of a mitomycin containing reverse thermal gel that now is marketed by UroGen pharma as JELMYTO. And the way that this agent works is whereas for bladder cancer we have the benefit of having this gravity dependence where you can apply these topical therapies into the bladder and allow for chemotherapy to have contact with the lining of the bladder for prolonged duration.

In the upper urinary tract the main concern is that if you were to instill a fluid into the kidney, it would likely go down the ureter and into the bladder within a very short timeframe, and that would limit how much contact there would be, the duration of contact between the agent instilled and the lining of the kidney at the ureter. And so this concept of reverse thermal gelation was then combined with a chemotherapy agent commonly used for bladder cancer, mitomycin C, and they essentially developed this reverse thermal hydrogel polymer that means at colder temperatures it would be in a liquid form, but then with heated conditions, such as at body temperature, it would actually form a gel. And so this idea was found to allow for gelation of the mitomycin C for a period of about to six hours in the human body.

And so, as a result, this would actually allow for contact between the mitomycin C and the urothelium for a much longer duration of time compared to just a liquid instillation alone. And so when applied in humans in this phase three study, they actually found that for among 71 patient who are treated using this approach, 59% of patients achieved a complete response, which was actually quite remarkable. And of those patients, 41 had entered into a follow-up period, and of those patients by 12 months, 70% of patients had exhibited a durable response. And since then, there’s actually been a recent publication that has updated this experience as well. But based on the data shown here, and the fact that it was a relatively safe agent to receive with a main side effect being the development of usually transient ureteral stenosis that could often be managed conservatively, this ultimately led to the FDA approval for this agent in patients with low grade UTUC.

Dr. Singla:

And this was actually very, very exciting in our field, simply because this is a very challenging disease to study by virtue of its rarity, and to be able to conduct a phase three trial that ultimately led to the first FDA approval of an agent for its effective management to help spare kidneys, especially in those who have higher volume disease that are harder to treat using endoscopic means alone, this allowed for an extra tool in our armamentarium to treat these patients. And so on that note, I wanted to just shift gears here. I’ll hand it over to Dr. Hoffman-Censits next, who will discuss high grade UTUC.

Dr. Hoffman-Censits:

Thanks so much Dr. Singla. And I just wanted to again thank the BCAN team for allowing us to come in and talk to y’all today about upper tract urothelial cancer. We know that this is an uncommon presentation of urothelial cancer, and we’re just thrilled that BCAN is a safe place on the internet that our patients can go to get information about the disease and that you really raise awareness of the disease. I’m a medical oncologist and you’re hearing from a medical oncologist, I give intravenous and oral therapies for urothelial cancer, as well as a surgeon, a urologist, Dr. Singla today, because we really do have a partnership in how we treat this disease. And our decision about how we’re giving the presentation today is no accident. Dr. Singla is oftentimes the point person when patients present with urothelial cancer, whether or not it be in the bladder, the upper tract or both, and the main person who would treat a low grade tumor.

Tumors that are low grade under the microscope, they do not, as far as we know, respond to systemic treatments, IV or oral treatments that we would give, at least at this point in time. That may change in the future, we’ll see with research, and so really we don’t tend to see those patients with low grade upper tract disease. As you mentioned, it’s topical therapy. For high grade disease just becomes more of a multi-modality discussion with at least urology, medical oncology discussion, and then of course our other colleagues that help us take care of our patients. Pathology, radiology, nephrology, and others. Next slide.

I’m going to talk about that neoadjuvant or preoperative as well as post-operative chemotherapy. What do we know about the use of chemotherapy in upper tract disease? I know Dr. Singla had alluded to this level one evidence, or large populations of patients that have been treated in clinical trials over the course of decades with muscle-invasive bladder cancer, and the design of those trials have lead us to better understand what a current standard of care is for an invasive bladder cancer, which is to give a cisplatin-based chemotherapy prior to surgery that provides best outcomes for patients with muscle-invasive bladder cancer, because patients with upper tract urothelial cancer that’s high grade are a less common population, and because more of them are not great candidates for platinum-based chemotherapy, and that’s because of the drug is metabolized by the kidneys, also potentially toxic to the kidneys.

Dr. Hoffman-Censits:

We have very few prospective, meaning moving forward in time, clinical trials, and those designs are what best inform and help us change or alter and update standard of care. This is just a summary of some clinical trials that are out there. These are prospective studies. One that we did through what’s called a cooperative group, bringing a lot of different cancer centers together. The second one Dr. Coleman did, and this was just recently updated at a recent national meeting, looking at a regimen of cisplatin-based chemotherapy, and then two other historic ones, just providing some evidence for the use of preoperative cisplatin-based chemotherapy. Next slide.

Dr. Hoffman-Censits:

The issue is that, as Dr. Singla alluded to, the trying to stage upper tract urothelial cancer, trying to understand whether or not this is a tumor that’s invasive is really challenging, and so the rules of who may get preoperative chemotherapy, who may qualify for preoperative chemotherapy, aren’t exactly the same as those with bladder cancer. For bladder cancer, the rules are pretty clear. You have to have a specimen that has muscle in the specimen, and then tumor has to be invading into muscle. For upper tract tumor, that’s not usually possible. It’s just the way that the ureter, which is like this long straw, is designed and the way that the tumor’s going to grow off. And the equipment that’s used, you’re not often getting a ton of information, so we’re using both radiographic information, as well as the pathology to decide who is and is not an optimal candidate to get preoperative chemotherapy.

Once patients have the curative surgery and having nephroureterectomy, even our population where most… A lot of patients aren’t always good candidates to get platinum-based chemotherapy. Have to be very fit, very robust, have pretty good kidney function, pretty good cardiac function, because we give a lot of fluids. You’re going to pump those fluids through the system. No evidence of significant hearing loss, because platinum can impact that, as well as numbness tingling in the fingers and toes. As you can imagine in a population of patients with an average age in the mid-70s, there’s not a lot of optimal candidates for that treatment, so the number of candidates go down significantly in the post-op setting.

It’s a decision about whether or not to give chemotherapy with incomplete information in the pre-op setting, and someone has two kidneys and maybe a better candidate for chemotherapy, versus thinking about doing it in the post-operative setting when you have more clinical information, complete staging because the kidney and the ureter are out, and we understand what the stage of the cancer is, but maybe not an optimal time to give the treatment. We’re always living in this balance and trying to interpret all this information when we meet patients in clinic. Next slide.

This is what’s called a design of a clinical trial. This is a clinical trial that’s up and running now, actually across the country. And the design of this study is put together with teams of physicians, so medical oncologists, surgeons, other advocates and statisticians to try and influence or update the standard of care. This is just an example of what we’re doing in what’s called the cooperative group through multiple different cancer centers across the country, trying to decide whether or not standard chemotherapy with a four-drug regimen called MVAC would remain a standard that we can give pre-surgery, or should we add an immunotherapy drug called durvalumab? That’s a main part of the study. We’re looking to enroll about 220 patients. And another arm in this study, that’ll be much smaller, more what we call hypothesis-generating, is to see what are the outcomes for patients who are not great candidates for that platinum-based chemotherapy, using a non-platinum regimen with immunotherapy.

As we were talking about clinical trials and when to just present with a current example is of a large clinical trial going on in upper tract disease as we speak. What about postoperative chemotherapy? A lot of our patients have heard about the POUT trial, and kudos to our European colleagues, Dr. Alison Birtle and her colleagues that have done this trial, because it’s really the first large scale clinical trial that’s been done solely in upper tract disease. As we’ve said, because upper tract urothelial cancer is a subset of all patients with urothelial cancer, depending on the clinical trial, you can have sometimes up to 10%, 20%, even 30% of patients in a clinical trial that may have upper tract disease, depending on the study. Some are just bladder cancer, but others incorporate everybody, but this is the first really big trial that was completed in upper tract disease, and so this is important because I think this communicates to physicians, to patients, to advocates, to industry that this is a space that really is its own entity, and that clinical trials can be done, and that we’ll learn more by doing this kind of research.

Dr. Hoffman-Censits:

Essentially in this clinical trial, patients with upper tract disease, they weren’t referred for chemotherapy before surgery, they were referred only after surgery. And part of the reason that this trial worked in Europe is because that is their kind of European standard. And everyone felt comfortable with that standard, so patients with a locally advanced tumor invading into muscle or lymph node-positive were randomized. Half just were observed with surveillance, follow-up scans and cystoscopies, and the other half got chemotherapy, and that chemotherapy was predicated on their kidney function. Next slide. And what these, what’s called Kaplan-Meier plots have shown is that the three-year disease-free survival of the time where someone did not have recurrence of metastatic disease was significantly influenced by whether or not they received this postoperative chemotherapy, whether or not that was cisplatin or another drug called carboplatin.

And it was an estimated absolute difference of about 25%, which is really important. Same as metastasis-free survival. These were the curves that showed a statistical benefit in terms of getting that chemotherapy, and this was what changed standard of care, where really the push for more chemotherapy in the postoperative setting came about. The statistics didn’t work out exactly for what’s called overall survival. There may be different reasons for that. One of them that everyone hypothesizes is that there were the patients who were given carboplatin and cisplatin were looked at in the same way, and sometimes that can affect the statistics. We don’t know, but despite that I think Herculean effort and a huge congratulations to this team, because I think they really changed the face of what we understand about this disease. Next slide.

Another standard that has come about in the last year or so is using a standard of care immunotherapy drug, FDA approved for urothelial cancer, as well as many other kinds of cancers, but using it in the post-op setting. In this clinical trial, the drug called nivolumab was given to, again, a randomized design, where half the patients were just followed and half the patients were followed and given nivolumab. And in this study, patients could have gotten preoperative chemotherapy or potentially they were in that category where they really weren’t great candidates to get chemotherapy. And I’m just pointing out that about 20% of this population of all comers with urothelial cancer had upper tract disease, so a substantial amount, but again, this study wasn’t designed just to look at upper tract disease. And what this study showed, next slide, was just like in the POUT study, that there was an improvement in what’s called the intent to treat population, meaning all comers, in terms of the disease-free survival at both six months and 12 months.

It was pretty significant, so the nivolumab-treated patients were in green and the patients who were treated with placebo are in yellow, the patients alive and disease-free are on the top, and the separation of the curves is the difference between getting a treatment and not getting a treatment. This is something that we look at a lot in medicine. The biomarker called PD-L1 was also looked at on the tissue of these patients, and that may have some influence on the outcomes, but despite that, this is an option for some patients that we will talk about that have urothelial cancer, upper tract disease. Next slide. I just wanted to give a landscape of treatment in the advanced setting, just to get a sense of where maybe a treatment you may have received may be on a landscape.

Looking at where we are currently in terms of the tools available to treat advanced urothelial cancer, and whether or not that’s upper tract, urothelial cancer or bladder cancer, if someone presents with a metastatic disease, meaning tumor that’s moved outside of the organ into other areas, then we’ll treat with a frontline or first step platinum-based chemotherapy, carboplatin or cisplatnin. For patients that have what’s called a clinical benefit, meaning that they have disease control, there’s now this option to extend that disease control with immunotherapy, and we can use a drug called avalumab, FDA approved for urothelial cancer.

Dr. Hoffman-Censits:

For patients who have disease progression, or the cancer gets worse on platinum-based chemotherapy, or for patients that are not great candidates to get chemotherapy at all, we could start with one of the immunotherapy agents, and that’s noted in green. We do next generation sequencing, looking for mutations or changes in the tumor. And the reason that we do that is because we want to know, can our toolkit be expanded to include an oral-targeted drug that works on this change or mutation called the FGFR3 mutation, fibroblast growth factor three, that’s present on really a minority of high grade urothelial cancers. More commonly seen in low grade tumors, but can we use that drug? If a cancer tells us it’s dependent on that pathway, then that’s a drug that we can potentially use. If it’s not, then we, of course, would spare patient cost and toxicity and use alternate agents. That Erdafitinib drug, that oral-targeted drug is in yellow.

And then finally we have two antibody drug conjugates, so these are encapsulated chemotherapy agents that are attached to an antibody. And I think of those like a heat-seeking missile of chemotherapy, an updated version of chemotherapy, compared to platinum-based chemotherapy, which was designed decades ago. This is a more modernized kind of chemotherapy with the goal of killing the cancer and sparing patient of toxicity. Both of these antibody drug conjugates are approved. There is more drugs in pipelines, and so potentially this slide might look different and we’re invited to give a follow-up a year from now, but this is the current treatment landscape for advanced urothelial cancer, bladder and upper tract.

In terms of resources, I think one of the things that Dr. Singla and I are often doing is providing patients and families with information about their disease. It is not uncommon that patients will maybe meet me in clinic that are maybe referred from elsewhere, who hear about where their tumor is and aren’t quite clear, do they have a kidney tumor? Do they have a renal pelvis tumor? Where exactly is this? I think it is important to have resources like the Bladder Cancer Advocacy Network, as well as our own internal resources to refer back to, to have again, safe places on the internet to look up information, to read more about it, because I think it it’s challenging to find, I think, accurate information about upper tract urothelial cancer out there. And it’s one of the reasons that we felt it’s really important as a program to develop a specific medical home for upper tract urothelial cancer, where we really think about this disease a lot, we treat it and really think about accelerating the standard of care. And that’s just our Hopkins team here. Thank you so much.

Stephanie Chisolm:

This is really great, and I know that you have a really huge team of very capable people at Johns Hopkins and the Greenberg Bladder Cancer Institute, and you’re doing a lot of cutting-edge research, so this has been really a powerful explanation. I know we have a number of questions that have come in. Remember that they need to come into the Q&A box at the bottom of your screen, but I hope you are going to get a lot of good information from our two patients who have joined us on here, so Tony, if you could turn your camera on as well, that would be lovely to be able to ask you to share while we’re waiting. Good. Tony, I’m going to start with you because you had signed up first with us. And if you would give us a little history, a little bit about how were you diagnosed? Did you have any different kinds of symptoms that patients should know about, and what did you do in terms of going through your diagnoses and types of treatments that you had? Share a little bit about your experience, if you don’t mind.

Tony K.:

Sure. Sure. Sure. I’m 56 years old, and in March of 2021, I happened to notice that, while going to the bathroom, urinating, I had some irritation that got worse to where it was very painful. I do have a great primary care physician, so I went there and initially they did a urine test, a culture test to see, and put me on antibiotics and thought I had a urinary tract infection, the normal first line of defense, and probably the most probable. Anyways, unfortunately that wasn’t the case. They called me three days later and said, “Hey, we have to refer you to a urologist.” And I wasn’t in the Hopkins network. I’m maybe about an hour and a half outside, so I went to a local urologist. They did some testing and I guess it was probably April to May.

We did a cysto where they put me under, they went in and looked at the tumor, and then at the time they planned on doing whatever they needed to do, so at that point there was a carcinoma-in-situ, so there was a tumor bed inside the bladder on the right lateral wall. And he resected that tumor, and at the same time, he took samples enough to tell whether or not it was muscle invasive. So we got done that, we healed up, and the plan was that then June 21st, I think was the date, we’d go back in, he’d look at the tumor, and then we would start a course of immunotherapy, BCG treatments for six consecutive weeks. In the meantime, the bladder cancer came back and it wasn’t muscle invasive, which was great news. It was high grade urothelial carcinoma, which was the bad news part of it.

On June 21st, when we went back into the local hospital with the local urologist, he noticed how fast the cancer, the tumor grew back. And one detail I didn’t forget, there was a post-surgery where they retracted the tumor out. They did a chemo treatment right after the surgery as well. When he went back in, the tumor had grown back unfortunately pretty quickly, and he also noticed in the terminology on the right distal ureter, where it had entered the bladder, it looked as if it had some discoloration that caused concern of the tumor spreading. He obviously stopped the surgery, and once we had the follow-up, he referred me over to the Hopkins team. He said, really, at this point, that was where I needed to be, at the Bladder Cancer Institute there at Hopkins. I did obviously, with nobody there having set eyes on the tumor that I had inside me, I came and Dr. Singla did the initial intake cysto.

And he also went and made sure it was still, and he was comfortable with it, diagnosed as non-muscle invasive. Once we did that and he looked at the ureter, we then took a step back and that’s when Dr. Hoffman-Censits was brought into the conversation. And we talked about different options as far as chemotherapy and some of the benefits and pros and cons that they touched on during the presentation. We opted to do the pre-surgery chemotherapy, so I had a port put in, went through the whole process, and I can tell you that a lot of the chemotherapy, I did miss one week, but there was some really good job that Dr. Hoffman did to minimize the obvious effects of the chemotherapy with either trying to hydrate and do some other things, change up the medications that I was on to try to minimize the effects of the chemotherapy.

That brings us to the surgery, so it would’ve been somewhere July. We went in… Oh, no, I’m sorry. I already did surgery, let me get my timelines straight. We did the chemotherapy, that ended somewhere around October 15th or somewhere in around there, so they wanted to wait a period of time for obviously the inflammation, [inaudible 00:40:36] system and all those things to heal from the chemotherapy effects. On December 29th, Dr. Singla went in and he took a section of my bladder, and he also took a section of my ureter where it met that bladder farther enough up the ureter where it actually cleared the margins. And he couldn’t take all of the tumor bed out of the bladder because it would’ve been too much, and then he reattached it. And that’s what would have been referred to earlier as a bladder or kidney-sparing surgery.

Tony K.:

That was December 29th. With that out, I went home with a stent in my ureter to make sure everything stayed copacetic as far as the ureter being reattached to the bladder. At that point, about a month ago, I went and had that stent taken out. And looking forward right now, it’s going to be mid-March, we’re going to go back in, look and see how things are. One of the things when Dr. Singla took the stent out, he did another urinalysis and cultured it, and it still showed, unfortunately. And I don’t know that it wouldn’t have shown that, but still showed high grade urothelial carcinoma, so [inaudible 00:41:56] were the journey and the things that we’ve gone through. We’ve kind of neutralized it, hopefully in the ureter, and we’ll find out on March 15th, and we’re going to go back to where we thought we were in June, once he looks at that tumor in the bladder and start the BCG treatments.

Ultimately, if we don’t see what we’d like, that’s going to be a different plan. And that’s what I would say is the biggest lesson I could say with people, because I know I heard it referred to as safe space on the internet for information. You can go down many rabbit holes trying to find information, and ultimately sometimes the answers to the questions are not something that are black and white, and everything emerges or evolves over time. I know it’s difficult to have patience as you’re going through this process, but that’s the only thing I could do is encourage people to take a breath, take a step.

I mean, I’m an optimistic person, but you can easily get down and do your best. I mean, lean on the people around you, lean on your surgeon and your oncologist. Both of them have been great. If I’ve got a question I shoot them, and I am on the portal, and they get back to me right away. So that’s where I’m at. I’m optimistic that on the 15th we’re going to be kicking forward with the BCG treatments and then we’ll just start a surveillance, quarterly surveillance interval, and life will go back to normal.

Stephanie Chisolm:

Well, we’ll be sending positive thoughts your way on March the 15th. It’ll be here before you know it, so thank you for sharing, Tony. And we’ll get back to you with some questions a little bit later on. And now I’d like to talk to Christina. Christina, what about your experience?

Christina Y.:

Okay. Well, first of all, thank you for inviting me to share my experience through this journey. You can hear my voice is a little raspy. This has been happening throughout treatment, on and off, so it’s a little bit inflamed. My story started quite a while ago actually. I presented with blood in the urine in October of 2018. Testing showed nothing, that there was nothing there, and in fact, my urologist, a local urologist said it was because I had beets for dinner and he really thought it was from the beets and that it was not blood in the urine. Fast forward six months, severe left flank pain took me to the emergency department at our local hospital where they did a CT and found a stricture around my ureter. I was seen by the local urologists after that, who placed stents into my ureter and said they were absolutely positive this was not a malignancy. This was probably something completely benign.

After three stents, the last one of which was a balloon stent, nothing opened up in the ureter, so then they sent me for, I forget the name of the test. I went in and they did radio something in my kidneys, both kidneys. And one kidney, the left kidney showed that it was functioning at 25% and the other one was fine, so then I was referred to Hopkins. I saw a urologists who is no longer with Hopkins. He too did not think that I presented with any type of cancer, and he was going to place a stent as well. The stent would not go in, so then he scheduled surgery for me. Now we’re September of 2019. He said if he couldn’t fix the ureter, there was a very, very slight possibility that he would have to take my kidney and my ureter. And that’s exactly what happened.

Christina Y.:

After the surgery he told me that he wasn’t worried, we’d wait for the path report, but wasn’t concerned about what he saw. A week later I got a call that it was high grade upper tract urothelial carcinoma, and I needed to meet with Dr. Hoffman as soon as possible. So I did, and that was incredible experience. She is the absolute best physician in the entire universe, and I owe everything to her. I really mean that. We met, I have been healthy my entire life, never smoked, drank minimally, exercise, vegetarian, ate well and had no clue why I possibly could have gotten this cancer. Never heard of such a cancer, it was so rare and so aggressive. And she was very pragmatic and talked to me about what the options were, and we decided that… It was after surgery, so we were going to go on cisplatin and gemcitabine, which I did for four months.

And that was followed by another surgery, retroperitoneal lymphadenectomy, I think that’s how you pronounce it, where 52 lymph nodes were removed, and 10 of those were malignant. In August of 2020, I started on immunotherapy, and that did not work well for me. I had a bad reaction and the tumor was growing, so Dr. Hoffman took me off that and I started on enfortumab, which was pretty successful. Tumor shrunk, but what happened was my liver enzymes elevated, so the dosage had to be decreased significantly, and as a result, the tumor grew back. In the summer of 2021, I had stereotactic ablative radiotherapy, and that stabilized the tumor, the size of the tumor.

And then I was off treatment until I got my scan in September, which showed that things were growing back, so then I was on many of the drugs that were on Dr. Hoffman’s screen. I got on sacituzumab, was on that for a couple of months, that didn’t work. And right now I am fortunate enough to be participating in the clinical trial, which I started in January, and we’ll see what happens. I meet with Dr. Hoffman tomorrow, so that’s my story.

Stephanie Chisolm:

Thank you so much for sharing it. Dr. Singla, Dr. Hoffman-Censits, if you would pop back on, and Tony, jump back onto your video. I’m going to open this up. As far as Christina, did you have any particular lessons learned? You said you had flank pain. Dr. Singla, is that a common symptom for patients who have upper tract disease because of the involvement in the ureter or the kidneys? Is that common?

Dr. Singla:

Yeah. When it comes to diagnosing UTUC, most commonly it would be some form of hematuria, in other words, blood in the urine, which may be either microscopic or seen with the naked eye. One thing that is unique to a subset, but not all types of UTUC, is also the possibility of developing flank pain. That usually is in the setting of form of obstruction, so you may recall one of the example CT scans that I showed earlier in the presentation, where there was some dilation of the kidney upstream from the tumor. Sometimes when that occurs on a relatively quicker timeframe, that can actually cause flank pain, but that isn’t necessarily the case across the board. There are many cases where there could be obstruction without flank pain, or there may be tumors in the kidney that are not causing obstruction and hence not causing these symptoms.

Stephanie Chisolm:

Great. With superficial high grade upper tract disease, what are the primary methods of discovery diagnosis in the distal ureters of the renal pelvis? How do you get all the way up there to figure that out? I know you talked about it, but can you explain it a little bit better? What sort of tests do you use? Is it CT imaging? Are you just doing a wash to check cytology, see if that cancer’s still in there? What are you doing to monitor all the way up there?

Dr. Singla:

Yeah. Yeah, absolutely. For the diagnosis we still do require the use of direct visualization of the ureteroscopy, especially for CIS or carcinoma and CY2, which is a flat form of UTUC, and generally one that tends to be more superficial in nature, but not one that you often will have your classic tumor protruding into the lumen or the inside of the either kidney or the ureter collecting system. And so these are often not seen definitively on imaging because of their nature, and so oftentimes if prompted by one of these other symptoms, often microhematuria, or potentially even gross hematuria, the next step would be to… Oftentimes cytology can be a tip off for the upper urinary tract that may require the use of then a ureteroscopy for a more definitive diagnosis. But unfortunately for CIS, the sensitivity of cytology is a little bit higher sometimes compared to other forms of UTUC.

Stephanie Chisolm:

And just jump ahead to another question, and I’ll come back to the next one in the line, in the queue, but should all patients with upper tract disease be diagnosed, or should be tested genetically for Lynch syndrome? Is that something that you think should happen to all patients that have upper tract disease? Is there any implication of knowing whether or not they have the genetic mutation for Lynch syndrome in their treatment? This is a question for either of you doctors.

Dr. Singla:

Sure. I’m happy to address it. Just very quickly, Lynch syndrome, it’s also called HNPCC or hereditary nonpolyposis colorectal cancer, is a… It’s a genetic syndrome that has been shown to be associated with a number of different cancer types. Colorectal cancer is most common entity, but also there’s a unique association with UTUC as well. The truth of the matter is that more and more we’re finding that actually a lot of patients who are diagnosed with UTUC do truly have an underlying Lynch syndrome that was actually undiagnosed, and that the routine genetic testing of patients who present with UTUC may actually uncover this genetic association and may be helpful not just for that patient, but also future progeny as well. And so we’re very much in support of testing patients for characteristic mutations called DNA mismatch repair genes that are characteristic of Lynch syndrome for patients who have UTUC.

Stephanie Chisolm:

Okay, great. I’m going to ask another question in terms of staging that I’m going to ask you also to explain exactly what it is for the listeners in this group. What is the role of multiparametric MRI and VI-RADS in staging? Can you explain what those are, and then is this something that’s common?

Dr. Hoffman-Censits:

I will attempt to answer this question, and Dr. Singla may have a better answer. In terms of any kind of specialized imaging, for the most part our patients are getting either a CT with contrast or a CT urogram is the most common, and in fact, for most clinical trials we use CAT scans. Depending on the patient and the need, sometimes for renal function issues, a physician may use an MRI instead, or a different form of an MRI, and then less commonly, but often a question that’s raised by patients and families is what about PET imaging? PET imaging is tough in urothelial cancer because the tracer is metabolized by the kidneys and then excreted in the urinary system, so it’s very hard to see anything on the inside of the urinary system, so from a staging perspective, unless you’re looking for metastatic disease, it’s not helpful for looking at localized disease.

Dr. Hoffman-Censits:

I think potentially an answer to your question is that there is no, I think, kind of standard imaging, and everyone gets potentially somewhat different imaging, again, most common being a CT scan. Is it perfect? No. Could it be better? Absolutely. And in fact, Dr. Singla and I even had a meeting about this today in terms of optimizing imaging across the board for patients to help us better determine those that may have noninvasive disease, may have invasive disease, determining low grade versus high grade. There’s a lot of imaging modalities and some research being done in terms of what’s being done with multiparametric MRI and how to define that better. That’s the information I have. I don’t know if Dr. Singla, you have any additional information.

Dr. Singla:

Yeah, happy to chat a little bit more. Multiparametric MRI is essentially a special form of MRI. It was actually initially developed in the prostate cancer world, but has been extended to other cancer types as well. That involves the use of gadolinium and there’s actually multiple phases that are obtained. When it comes to, just like Dr. Hoffman-Censits said, the current sort of gold standard approach to staging, if you will, is typically the use of a multi-phase CT scan with and without IV contrast. That includes a urography or an expiratory phase to look at the ureter in particular. The problem is that not all patients can receive the IV contrast, and so a subset of patients can also reasonably be diagnosed with use of an MRI, usually an MR urography, to characterize these lesions. Now, the VI-RADS system, this is something that was actually developed for bladder cancer specifically. It’s the use of a multiparametric MRI for assessing the depth of tumors that are detectable on imaging.

And so this is… It stands for essentially Vesicle Imaging-Reporting and Data System, but essentially that is limited to those tumors that are actually detected on MRI. It hasn’t really been explored for upper tract tumors, and the biggest issue is really sensitivity of these imaging modalities. The problem actually is more whether or not we’re able to enhance our ability to detect lesions upfront using CT scans or MRIs, but then the next steps would be, are there alternative approaches such as the use of MP MRI to maybe better ascertain the depth of invasion? And so these are actually great questions that are currently under investigation.

Stephanie Chisolm:

Okay, great. I have another question that’s come in and I just want to ask sort of in general, since so many patients that have upper tract disease are at risk for losing their kidneys, and once they have had their kidneys removed, are there special dietary concerns that people should follow, that you can recommend, or questions they should be asking a nutritionist that can help keep that other kidney healthy, since now it’s doing double duty on helping? Is there anything you can suggest, Dr. Hoffman-Censits or Dr. Singla?

Dr. Hoffman-Censits:

Yeah, that’s a great question, and it’s one that a lot of our patients have. For some patients, if they do have an impairment of renal function, just like patients that have two kidneys with an impaired renal function, they may be best served to really review some of these questions with a nephrologist or an internist with a subspecialty in treating medical disease of the kidney. I think of urology as kind of the plumbing portion of that relationship, and then a nephrologist is the one that thinks about the function of the kidney and electrolytes and protecting. Oftentimes, unfortunately it’s really about protecting what you have, but a lot of nephrologists will advocate for things like great blood pressure control and avoidance of nephrotoxic agents, so sometimes depending on the kidney function, that may be IV contrast or overuse of non-steroidals.

But for the most part for our patients, we just recommend they still stay well hydrated, recognize signs and symptoms of dehydration. And again, from a dietary standpoint, it’s often not until someone has maybe a later stage what we call chronic kidney disease or CKD where dietary modifications come into play, so this isn’t really a one-size-fits-all answer, but there are specialists that think about this, and so if someone has a particular question, they may want to be referred to a nephrologist.

Stephanie Chisolm:

Would you regularly just make a referral to a nephrologist? Would they be part of the overall team if somebody did have one kidney removed? Is that something that you would normally do?

Dr. Hoffman-Censits:

I mean, honestly, if someone has one kidney, but has really good kidney function, we don’t necessarily do that. Most primary care physicians are able to appropriately manage those patients, and they don’t necessarily have a change in their morbidity, meaning like the medical problems. It may happen to them in the future, or mortality based on having one kidney. Sometimes people are born with one kidney, they don’t even know. But if someone has a significant change in their kidney function or a new diagnosis of CKD, then that’s certainly a time where we will have that conversation. And then depending on the patient and their interests, they may seek care with a nephrologist.

Stephanie Chisolm:

Okay. We have time for just a few more questions, because I know we’re at time, but we’re going to go over by just a couple of minutes. This is a good question. What is the risk of tumors arising in the bladder after nephroureterectomy for high grade upper tract disease? Is there a risk, is there a warning? Is there something that patients should be aware of if they’ve had their kidney removed, that worried about bladder cancer showing up in the bladder or in the other kidney?

Dr. Singla:

Yeah. I’m happy to feel that one. So yeah, it’s a good question. As we know, there’s absolutely an increased risk for patients with UTUC for developing bladder cancer, and likewise for patients with bladder cancer in developing UTUC, and likewise for patients who have UTUC and developing what we call contralateral recurrence, or essentially UTUC in the other kidney or ureter. Just to go over percentages, for patient who have UTUC the risk of developing bladder cancer is actually quite elevated. It’s about anywhere from 22% to about 47%. Now, there are maneuvers that we utilize intraoperatively for patients who are undergoing nephroureterectomy to help minimize that risk, both from a technical perspective and then also with the use of, for example, intravesical chemotherapy at the time of surgery.

That risk of developing… You might recall at the beginning of the talk, the question was posed for patients who have bladder cancer, what’s the risk of developing upper tract recurrence. That’s much lower. It’s about 2% to 4%, and there’s a number of hypotheses surrounding this, but one of them is the fact that for bladder cancer recurrences after UTUC, urine is kind of flowing in a top down approach rather than the down up approach. And then to just round off the discussion in terms of percentages of the risk of developing UTUC in the other kidney or ureter, if you’ve already had UTUC on the other side, is about 2% to 6%.

Stephanie Chisolm:

Okay. That also ties into the next question in there is about muscle invasive, about upstream upper tract recurrences after bladder removal. Thinking about, again, the idea that sometimes the genetic changes that could occur in some of the cells in the urothelium are really more of a field effect. Are you seeing this often, or is it a rare occurrence for patients when they’ve had their bladder removed to end up with a tumor in the upper tract?

Dr. Singla:

Yeah. And we see this again, quoted rates just across the board, again, would be on roughly the 2% to 4% scale. But in large part we don’t actually tend to treat these as metastases per se. In large part, there are similar risk factors for developing bladder cancer as there are for UTUC, and so we usually tend to treat this more of as a local recurrence and treat it as a UTUC entity rather than your typical approach to, say metastatic bladder cancer treatment.

Stephanie Chisolm:

Okay. Yeah, that’s a good point. Again, the same thing that might have triggered the cancer in the bladder itself could be present in the ureters and the renal pelvis as well, I guess, so that it’s just a matter of time if it were to flip over and cause a tumor, so thank you for sharing that. It’s really good information. We have time for one last question, and there was one that was… Hang on. I’m looking for… We answered that one. Let’s see. What are your thoughts on KEYTRUDA for treatment of upper tract disease, Dr. Hoffman-Censits?

Dr. Hoffman-Censits:

Yeah, thank you for that question. KEYTRUDA or pembrolizumab is in a class of what’s called checkpoint inhibitors, and these are kind of revolutionary drugs, FDA approved for advanced urothelial cancer, as well as a multitude of other malignancies, so we’re really fortunate to have these tools to treat our patients. For patients with metastatic upper tract urothelial cancer, they are absolutely indicated. There’s no line in the sand between bladder cancer and upper tract disease in terms of the studies that show that these drugs are helpful. For a minority of patients, they can lead to responses or shrinkage of tumor, and for a smaller minority of patients, we can sometimes see a long-term durable control. Our ability to use KEYTRUDA, as well as other agents to treat advanced urothelial cancer, is in part predicated upon how these drugs were tested and where they’re approved by the FDA.

For instance, if a drug is studied and approved by the FDA and therefore kind of like opens the door for insurance companies to then approve for me as a doctor to write it for a patient, there’s only certain circumstances that we can do that. For instance, I couldn’t take pembrolizumab or KEYTRUDA and give it to somebody with a low grade localized upper tract tumor. There’s not an indication for that. There’s not a understanding of what that might do to a tumor, and there’s no guarantee that that would be paid for it by an insurance company. But there’s two really divergent, what we call disease states.

One of the questions that we oftentimes are faced with are, well, what about for other indications? And I think that the question is important and the research is pending, I would say, so we also have these questions, and I think that utilization of immunotherapy as well as other therapies in earlier stage disease is a path that our entire discipline is working on, but probably not yet ready for prime time in terms of ability to use these medications in clinic. But I think we recognize the questions and the problems that our patients have and are working hard on solving them with that tool and others.

Stephanie Chisolm:

Well, thank you. Yeah, this is all good. There’s so much research going on. BCAN is very strongly in favor of research. We support a lot of research. We know that a lot of research is being done at the Greenberg Bladder Cancer Institute, and for that we are always grateful, because that information is getting out and helping all bladder cancer patients, so this has been wonderful. Christina, we’ll be thinking about you tomorrow and sending happy thoughts your way when you go in to see Dr. Hoffman-Censits for your next evaluation, so thank you for sharing your store.

Tony K.:

Good luck.

Christina Y.:

Thank you.

Stephanie Chisolm:

Anything else to add that you want to share with our group?

Christina Y.:

Just, I just feel very, very fortunate to be in the position I’m in, where there’ve been so many treatment options available to me as I’ve gone through the course of this disease. And I’m so thankful to talk Dr. Hoffman and Dr. Singla for taking care of me.

Stephanie Chisolm:

Great. How about you, Tony? We’ll be thinking about you on the 15th and sending positive thoughts your way.

Tony K.:

Yeah, I echo those comments. I mean, very fortunate to be in this region and have the ability to get in the schedule. You think about it, just to add the COVID layer that’s affected everybody’s life over the last two years, to switch hospitals and do all that and get it accomplished and get the treatment I’ve had, I’m very fortunate.

Stephanie Chisolm:

Yeah, definitely. Thank you so much, Dr. Hoffman-Censits and Dr. Singla for sharing your expertise. I remind everybody that you will be getting an evaluation in your email, so please be sure that you completed your thoughts about today’s program, are very important to BCAN, and the success of our Treatment Talks, and there are many other programs that you’ll be invited to participate in going from here on. Thank you all so much for joining us for today’s program, and I’m going to sign off now.