Bladder Cancer Podcast

Non–Muscle Invasive Bladder Cancer Innovations

Cheryl Lee, MD; Sima Porten, MD, MPH


November 08, 2022

This transcript has been edited for clarity.

Cheryl Lee, MD: Welcome to Medscape InDiscussion. I'm Dr Cheryl Lee. Today we'll be discussing non–muscle-invasive bladder cancer. How should we approach the diagnosis and treatment of individuals with non–muscle-invasive disease? What urinary markers should we consider in practice? What treatments exist for patients with BCG [bacille Calmette-Guérin]–unresponsive disease? For expert guidance on these questions, we've invited Dr Sima Porten. She's an associate professor in the Department of Urology at the University of California, San Francisco (UCSF). Dr Porten's research focuses primarily on urothelial carcinoma diagnostics and treatment, including genomics and personalized medicine. Welcome, Sima.

Sima Porten, MD: Thank you for that kind introduction, Cheryl. I'm really excited to be here and talk about one of the topics I'm most passionate about.

Lee: Before we jump into the main discussion, I'm sure our audience would love to learn a little bit more about you and your background, and what keeps you interested and engaged in the subspecialty of bladder cancer.

Porten: I entered this [specialty] a little bit accidentally. I set out in medical school to be an infectious disease doctor and, of course, that path is very different now. I think that my [decision] came through a series of key mentors. One of those is you, of course, as well as many, many others throughout my training. Then also from clinical experience, with patients and watching how resilient folks are as they progress through different types of treatment and different types of disease states in terms of bladder cancer. You really get a chance to have a long-term relationship with patients with this [subspecialty].

Lee: Yes, that's part of what I also love about caring for patients with bladder cancer. It's a long-term relationship with patients, especially those with non–muscle-invasive disease. I, too, really appreciate that special relationship that develops.

Let's jump right in. Given your background, your research interests, in bladder cancer, I thought it might be nice to hear about some of your general thoughts about the use of urinary markers. What do you use in your practice, and in what clinical scenario? What's new? What's coming?

Porten: We are very lucky, in that we have some very talented cytopathologists here at UCSF. I know not everybody enjoys that close relationship or that kind of expertise. We still really rely on cytology. Our cytopathologists here have aligned and report what they see on cytology using the PARIS classification, which has undergone a few revisions. A new [PARIS classification is slated to] be released in the upcoming months. There's been a real push to standardize this type of reporting practice across the United States and internationally. I think it will really help physicians, particularly urologists, in terms of making decisions by using something that is readily available to most people, as well as something we've been using for a long time.

Cytology can be great, but a lot of it depends on the information that's communicated to us. Many times, as a urologist, when you see something that says atypical or suspicious, it's a little bit of a conundrum on what you will do with this information for this particular patient. That's where more advanced diagnostics can be helpful. Right now, we are not using FISH, ImmunoCyt, UroVysion or any of those types of tests, because of the high false-positive rates. Also, we've had a real hard time getting supplies in this COVID era, so we've switched over to some home-based testing — particularly with CxBladder as our primary adjudicator for atypical or suspicious cytology after our cytopathologists report back to us. That's what we've relied on.

Lee: I think it is interesting when we think about cytopathologists, and how we communicate with them and how we really have to understand what their version of atypical or suspicious is. For most of my career, I didn't feel particularly concerned about the atypical cytology report, because I understand there are a number of confounding factors that the cytopathologists have to deal with. So, we see that frequently. But the [categorization as] suspicious is interesting. With my cytopathologist, a suspicious [cytology finding] is essentially a positive [test result]. It was interesting when you said you are using a marker to adjudicate suspicious cytology. So for you, that's not necessarily a positive. If a CxBladder [result] were to be negative, you might change your management or surveillance or your decision to biopsy a patient.

Porten: With the PARIS classification, you're correct that an atypical [presentation] — a PARIS 3 cytology — has between a 10% and 30% chance of there being a high-grade urothelial carcinoma somewhere in that urinary tract. That's fairly low, particularly when someone is undergoing intravesical treatment or has a history [denoted in the pathology report] of recent radiation, which can confound the cells [from the sample].

Interestingly enough, PARIS 4 — or suspicious for high-grade urothelial carcinoma — has between a 50% and 90% chance [of being high-grade]. With the PARIS classification as it stands right now, that ends up being a gray area and you end up having to be a really good detective: What do you think the pretest probability is for your patient to have a tumor somewhere that you're unable to see — when you're going into cystoscopy and sending cytology? [You also need to ask], what would be the risk of just taking your patient to the operating room to biopsy hidden areas, like the prostatic urethra in men? Also ask yourself if you need to examine the upper genitourinary tracts. [A PARIS 4 result as it now stands] brings up a lot of gray area. The up-and-coming next-generation urinary biomarkers are in different phases of testing, and this is where we can have a real benefit for patients. This is also where tools, such as our enhanced cystoscopy, can be useful for figuring out whether there's a recurrence, where that recurrence is, and what it might change about the management plan for a patient.

Lee: The more diagnostics we are confronted with, the more questions that seem to arise. I understand you've had some experience with Oncuria. Can you tell us a little bit about that test?

Porten: [Oncuria] is another urinary biomarker that is in current testing in clinical trials. It's different from CxBladder and some of the other biomarkers out there, which are either RNA-based or DNA-based. Oncuria is a protein-based ELISA [enzyme-linked immunosorbent assay] that looks at 10 biomarkers, along with some clinical factors such as age, gender, and race, in terms of determining whether cancer is present. There are many different disease states [in which we're] looking at urinary biomarkers. There are the patients who present with hematuria — gross or microscopic — and you're trying to figure out, Should I work this up with a cystoscopy or should I not? Then there are those patients who have a diagnosis of bladder cancer, and you're either trying to improve on your cytology, replace cytology, or adjudicate cytology that you can't interpret. There are even biomarkers [being developed that are] moving into predicting response to treatment, such as predicting response to BCG or other intravesical treatment, and Oncuria has active studies bridging these multiple disease states.

The really difficult thing with urinary biomarkers is that they're usually developed in the highest-risk patients and then taken [to patients] earlier in the setting. Your pretest probability or your suspicion of anything even being abnormal becomes smaller and smaller and smaller, and then you slowly see these different biomarkers end up in the biomarker graveyard. Over the past 50 years, we've seen many come and go. As you mentioned with our newer understanding of the biology of bladder cancer and particularly learning from past mistakes, our future looks really bright and I'm particularly excited about this protein urinary biomarker, which has great solid science behind it.

Lee: You mentioned enhanced cystoscopy. A number of opportunities have arisen for urologists to be able to think about a better resection, a better diagnostic cystoscopy. What are you using in your practice?

Porten: Currently, we have access to using blue light–enhanced cystoscopy with Cysview; that's been our primary mode of enhanced cystoscopy. Also easily available is narrowband imaging. With most of our available instruments and scopes, you can press a button and turn it on. It works by highlighting blood vessels, so you can look for redness or other [signs of pathology] between these blood vessels. So, we do use both types [white light and blue light], but we more robustly use the blue light–enhanced cystoscopy system — both in the clinic and in the operating room (OR). I do not use [blue light cystoscopy] for every single patient. It is an added cost; it's extra equipment. We do have a limited number of scopes and towers, so we need to allocate our resources properly.

I think [blue light cystoscopy] can be helpful in a couple of specific situations. For me in the OR, when I see a patient in consultation, most of the time it is after they've already had a diagnosis and they're coming to me for either guidance on treatment or a treatment has already failed them. These patients are trying to figure out if they can try something else, or if they're facing a radical cystectomy. In those situations, since many are patients who are referred, if I am going to the operating room to reassess their bladder, to reassess their disease risk and state, then I will use blue light cystoscopy to get better clearance of any hidden tumors and also identify carcinoma in situ.

Lee: We're getting better perhaps at diagnosing and detecting tumors. What about treatment? The past decade has brought a slew of new agents for non–muscle-invasive disease, particularly for patients who are unresponsive to BCG. I wonder if you might share your thoughts on some of the new agents that you are using. Do you have a preferred first-line, second-line, or even third-line treatment or therapeutic option after someone is diagnosed with BCG-unresponsive disease?

Porten: It's a really exciting time, but it's also a really confusing time for both urologists and patients. In the past, we haven't had [many treatments available] after BCG fails a patient. We had valrubicin, which was US Food and Drug Administration (FDA)–approved; however, the real-world response rate was quite poor — around 10% or 15%. So, those patients were facing the decision about whether to have a life-altering surgery; it's a really big decision to make. Right now at UCSF, we are using a combination chemotherapy regimen for most patients — with gemcitabine and docetaxel — and that's primarily because it is well tolerated; the 12-month response rate for carcinoma in situ reported was around 50%-60% for papillary disease. The [gemcitabine-plus-docetaxel regimen] is given in a pretty favorable schedule — very similar to that with BCG. I use [gemcitabine plus docetaxel] primarily for BCG-unresponsive disease, unless we have a clinical trial open. For some patients, we have been adding pembrolizumab, or systemic immunotherapy, which was recently FDA-approved primarily for patients with carcinoma in situ. The response rates are a little lower — 41% at 3 months — and then the durable response rate is about 20% overall at 1 year. But for patients who have had a lot of treatments in their bladder and have a lot of urinary symptoms, it's been a really nice strategy.

I have one patient who encompasses my treatment strategy and the decisions that patients make. He is an elderly gentleman — 70 years old. He has some comorbidities. He had a BCG-unresponsive carcinoma in situ and was having a lot of cystitis and urinary side effects. We started treating his BCG-unresponsive CIS [carcinoma in situ] with pembrolizumab, and he did well for about a year and a half. We did talk about cystectomy, but unfortunately one of his children was diagnosed with cancer and he had to go from being cared for to being a caregiver. This allowed him to do that with pretty low side effects, and he tolerated that systemic therapy well. His child unfortunately passed during that time. He was grateful to have had that time with [his child], and he ended up getting recurrent CIS again.

At each moment I do restage a patient; we've got to be careful that they haven't developed upper urinary tract disease. This happens sometimes when we continue to preserve the bladder. We have to be really great detectives in terms of making sure we're re–risk-assessing each patient and figuring out what we think is the right treatment for them — [not] losing a window for cure, particularly if that is important to that patient. He ended up deciding that he wasn't ready for [a cystectomy] yet, so he had gemcitabine and docetaxel. We treated him with that for about 2 years, and he did great. Then the CIS came back and was pretty symptomatic. Most recently, he successfully underwent a radical cystectomy and [urinary] diversion. He was ready for it at that time — mentally and emotionally and physically — and he is doing great. We see that a lot.

There're some new things on the horizon. One of them is nadofaragene firadenovec — a viral-based treatment that had great results in phase 3 trials. There's still some working with the FDA in production and trying to figure out how to deploy that, so we don't have it just yet. There were some really great data presented at our national meetings with N-803, which is a super IL-15 combination with BCG. Again, really slam-bang rates [of remission], reported a little differently than some of our previous things. So the question is, will that make it across the finish line with the FDA? There are 70% complete response rates for carcinoma in situ at any time.

So, there's a lot out there on the horizon. The hard thing is going to be how many doctor visits this will mean for patients. Are we kicking the can down the road?

Cystectomy is still a great option for many, and there's a lot of concern about how many things we can try before we lose that curative window. As you were saying, there are a lot of exciting options, but this also brings up many questions. How do we appropriately sequence this for patients? How do we help patients make a decision? I think the CISTO trial — the pragmatic clinical trial that looks at how patients make decisions in BCG-unresponsive disease — will help us shed light from a patient perspective.

Lee: I feel really excited about all of these treatment options for patients with early-stage disease, for patients with muscle-invasive disease, and for patients with metastatic disease. Obviously, we worry a lot about progression with higher-risk disease in patients in the BCG-unresponsive space. We always have cystectomy, but that is a significantly morbid treatment with real quality-of-life implications for patients. Are we making a dent in reducing progression?

Porten: I think we're making a dent for some patients, but I still think that we have a limitation in identifying which patients those are. When you look at the rates of extravesical disease, [you wonder] who had such bad progression while we were trying all these things — assuming they had non–muscle-invasive disease the whole time? The numbers are low — somewhere between 3% and 12%, depending on which trial you look at. In patients who ended up having a cystectomy, what was the final pathology? What was the truth in that setting of extravesical disease — so, greater than T2, N-positive, T3 — what we don't want to see, right? We don't want to lose our chance for a cure, right? I think that percentage is low, but I would like it to be 1% or zero — 0% would be ideal for me. So I think we have a ways to go. That's what we as a community should look at in the future. Right now, we're in our early stages; we're focused on recurrences. But I think that when we look to the future, we really should be looking at these longer-term outcomes in terms of progression, to see if we've really made a true dent in reducing both mortality and morbidity in this disease.

Lee: I couldn't agree more, Dr Porten. It's really been special being able to talk with you about some of these exciting new diagnostics and treatments for non–muscle-invasive disease, and that's a big takeaway here: We are in a time of [enormous] growth in helping us detect the disease [and] treat the disease. Hopefully, over the next few years, we'll have a better sense about treatment response with correlative biomarkers. Any last takeaway for our audience?

Porten: It is incredibly important for us not to forget the basics of making sure we do an excellent TURBT [transurethral resection of bladder tumor]. It's not as exciting as a radical cystectomy. As physicians, we've got to [care just as much about] our basics. We've got to be excellent detectives in terms of re–risk-assessing, restaging patients at each second and thinking, "What could I be missing? Is there a way to figure that out appropriately?" So, because it's gotten complex, we've got to be that much more diligent. We've got to spread the word on these exciting new treatments to try to keep everybody updated, because patients should have access to all of these advances and all of this information as quickly as possible.

Lee: Thanks again for joining, Dr Porten, and thanks to the audience for listening. I'm Dr Cheryl Lee, for Medscape InDiscussion.


Paris System for Reporting Urinary Cytopathology

Bladder Cancer Biomarkers: Optimal Utilization for Diagnosis and Recurrence

Diagnostic Performance of Oncuria™, a Urinalysis Test for Bladder Cancer

Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline

What Is a Cystoscopy?

Use of Intravesical Valrubicin in Clinical Practice for Treatment of Nonmuscle-Invasive Bladder Cancer, Including Carcinoma In Situ of the Bladder

Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer

Sequential Gemcitabine Plus Docetaxel Is the Standard Second-Line Intravesical Therapy for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Pro

FDA Approves Pembrolizumab for BCG-Unresponsive, High-Risk Non-Muscle Invasive Bladder Cancer

Pembrolizumab Monotherapy for the Treatment of High-Risk Non-Muscle-Invasive Bladder Cancer Unresponsive to BCG (KEYNOTE-057): An Open-Label, Single-Arm, Multicentre, Phase 2 Study

FerGene Announces Pivotal Phase 3 Study of Nadofaragene Firadenovec Met Its Primary Endpoint With More Than Half of Patients With High-Grade Non-Muscle Invasive Bladder Cancer (CIS ± Ta/T1) Achieving a Complete Response at Three Months

Comparing CxBladder to Urine Cytology as Adjunct to Cystoscopy in Surveillance of Non-muscle Invasive Bladder Cancer—A Pilot Study

The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology

The Paris System for Reporting Urinary Cytopathology

QUILT-3.032: A Multicenter Clinical Trial of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 (N-803) in Patients With BCG Unresponsive High Grade Non-Muscle Invasive Bladder Cancer

Final Clinical Results of Pivotal Trial of IL-15rαFc Superagonist N-803 With BCG in BCG-Unresponsive CIS and Papillary Nonmuscle-Invasive Bladder Cancer (NMIBC)

Targeted Oncology. N-803 Plus BCG Shows Encouraging Responses in NMIBC

CISTO: Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer (CISTO)

Bladder Cancer Surgery

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