Non-Muscle-Invasive Bladder Cancer: Intravesical Therapy and Beyond

Nima Almassi, MD, a Urologic Oncologist at Cleveland Clinic, joins the Cancer Advances Podcast to discuss managing non-muscle-invasive bladder cancer with variant histologies. Listen as Dr. Almassi talks about effectiveness of intravesical therapy, the importance of specialized pathology reviews, and the potential need for early cystectomy in aggressive variants.

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Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale. Shepard, a Medical Oncologist here at Cleveland Clinic, overseeing our Taussig Early Cancer Therapeutics Program and Co-Directing the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Nima Almassi, an Urologic Oncologist here at Cleveland Clinic. He's here today to discuss outcomes of intravesical therapy and the management of non-muscle-invasive bladder cancer with variant histologies. So welcome.

Nima Almassi, MD: Thanks so much for having me.

Dale Shepard, MD, PhD: So, give us a little idea of what you do here at the Cleveland Clinic.

Nima Almassi, MD: Yeah, great. So yeah, I'm a urologic oncologist. Been here since 2020. Really focusing my clinical practice and research in bladder cancer. So a lot of the patients I see are Stage 1 or Stage 2 bladder cancer. And so that's sort of the genesis of where this work started.

Dale Shepard, MD, PhD: And so just give us a little bit of an overview. A lot of different people might be listening in. When we talk about non-muscle-invasive bladder cancer, let's kind of define what that is first.

Nima Almassi, MD: Yeah. So bladder cancer staging depends on whether or not the cancer is confined to the bladder, and also the depth of invasion within the bladder wall. So these cancers originate in the lining within the bladder, the urothelium, but they can invade into deeper layers. Stage 1 cancer is cancer that's confined to either the lining or the underlying connective tissue, and that's what we call non-muscle-invasive bladder cancer. The majority of bladder cancers are localized at the time of diagnosis and non-muscle-invasive. So at the time of diagnosis, most patients are in this category and are looking for treatment.

Dale Shepard, MD, PhD: And when we think about different types of bladder cancer, we're going to talk about variant histologies. What would be considered a standard or conventional histology?

Nima Almassi, MD: Right. So over 90% of bladder cancers in the United States are urothelial carcinoma. So when we talk about bladder cancer, that's really what we're predominantly talking about. Within urothelial carcinomas, there are some variants, which is what we commonly refer to as variant histology. These are variants that are seen histologically or under the microscope that are being increasingly identified by our pathologists and have long been thought to be more aggressive and to require more aggressive treatment. And so when we look at our treatment guidelines, one thing that the guidelines still recommend is consideration of what we call early cystectomy for treatment of patients with Stage 1 bladder cancer that has variant histology.

Dale Shepard, MD, PhD: And so, you made a comment something about more commonly identifying. So is there a problem, I guess, when we think about patients coming in being identified as having a non-muscle-invasive bladder cancer, actually having someone identify these variants?

Nima Almassi, MD: That's a great question. There is evidence that pathology reviewed at tertiary high-volume centers with experienced pathologists will be more likely to identify variant histology when present. We're actually publishing a paper right now that looked at outcomes where pathology from biopsies or resection performed on the outside were re-reviewed by our urologic pathologists. And in about 20% of cases on our pathologist re-review, we identified differences in either the grade or the presence or absence of variant histology. So that now has become standard practice for us here for patients who are referred to us for us to have their pathology slides re-reviewed here so that we ensure that if variant histology is present, we identify it because that has significant impact on what treatments we recommend.

Dale Shepard, MD, PhD: And I guess we'll talk a little bit about that sort of therapy that might be given as maybe bladder-sparing or things.

Nima Almassi, MD: Yeah.

Dale Shepard, MD, PhD: I guess would you consider there might be a problem if someone's seen out in the community if they happen to identify a variant histology that they might go automatically to a cystectomy when maybe that might not necessarily be the necessary step?

Nima Almassi, MD: Absolutely. There's limited evidence thus far to help guide treatment decisions, and that's the genesis of this study, which I think helps inform the literature beyond what we already knew. But certainly, guidelines currently do recommend early cystectomy to at least be considered for patients with Stage 1 bladder cancer with variant histology. Here we sort of counsel patients and make decisions on a case-by-case basis. But for patients who are good candidates for bladder-sparing treatment, we do try to prioritize that because that does have better quality of life outcomes compared to cystectomy.

Dale Shepard, MD, PhD: And so we'll talk about the sort of bladder-sparing therapies and kind of what your studies have shown here in a second. Just one more background. How common is it still that you might have people coming in without really knowing if they have non-muscle-invasive tumors or not based on the biopsy and the depth of the biopsy? Is that still continued to be somewhat of an issue?

Nima Almassi, MD: Certainly, because it depends in part based on how extensive or thorough the initial resection was. We see some cases where clearly simple biopsy was performed without fully resecting the tumor. In that case, there's a very high risk of undergrading or understaging, and that puts the patient at risk of receiving inappropriate treatment. Whereas other patients who are referred in did undergo a complete resection. Even in those cases, we may have to repeat a resection to confirm a Stage 1 diagnosis to offer appropriate treatment, but that's highly variable in the patients we see who are referred to us.

Dale Shepard, MD, PhD: Yeah, I think I'm a little biased. I just saw one recently where it's non-muscle-invasive, but no muscle in the biopsy, so can't really know that.

Nima Almassi, MD: Correct. And that's one clear indication for doing what's called a restaging resection to confirm that there's no evidence of muscle invasion because the treatment for muscle-invasive bladder cancer is significantly different than non-muscle-invasive bladder cancer.

Dale Shepard, MD, PhD: Right. So if we think about non-muscle-invasive bladder cancer, what would be considered the standard approach to that? How do we treat that?

Nima Almassi, MD: Yeah. The current standard of care is complete endoscopic resection. That's called a transurethral resection of bladder tumor, abbreviated TURBT. And based on the results of the pathology, the grade, and whether or not invasion is present, that allows us to risk stratify a patient. Our guidelines currently have low, intermediate, high, and very high risk categories for these patients with non-muscle-invasive disease.

Depending on the risk category, we may or may not recommend additional treatment with what's called intravascular therapy. That's treatment that's administered into the bladder. That can either be chemotherapy delivered intravascularly or intravascular BCG. Really, for patients who would've been eligible for enrollment in this study or who we would've included in this study, these would've been patients with high-grade, non-muscle-invasive bladder cancer that would put them in the high-risk category. And so really standard of care for high-risk, non-muscle-invasive bladder cancer is transurethral resection followed by BCG.

Dale Shepard, MD, PhD: And so, BCG treatment, what does that look like just for people who are unfamiliar with an intravascular therapy?

Nima Almassi, MD: Yeah. So all these intravascular therapies are delivered in clinic in the office through a catheter. Typically, patients receive an induction course which is given once weekly for six weeks in a row. The patient will come into the office, a small catheter will be placed in the bladder, and then the BCG will be instilled through the catheter into the bladder. Patients try to hold the medication for about 90 minutes before urinating it out. They do this once a week for six weeks. Following the induction treatment, we do a reassessment, which typically involves cystoscopy and possibly biopsy as well.

Dale Shepard, MD, PhD: So we talked about standard treatment for sort of standard-risk patients. When we think about these variant histologies, tell us a little bit about what you set out to do with this particular study.

Nima Almassi, MD: Right. So we know that patients with high-grade, high-risk, non-muscle-invasive bladder cancer are at high risk of disease recurrence, namely recurrent high-grade tumors within the bladder. However, the risk of progression to muscle-invasive disease or metastatic disease is relatively low depending on the study between 5 and 8%. For patients with variant histology, we don't have much data to define outcomes with intravascular BCG.

And so in this study, we sought to evaluate outcomes for patients treated at Cleveland Clinic who had non-muscle-invasive bladder cancer, but with variant histology identified. Now, there are a number of variant histologies present. And so we actually sought to not only look at outcomes among all these patients but to see whether or not there were certain variants that behaved in a more or less aggressive manner.

Dale Shepard, MD, PhD: And I guess when we think about these patients with the variant histology, what percentage of patients have these variant histologies?

Nima Almassi, MD: For this study, we're able to identify 90 patients who were managed with endoscopic resection and intravesical therapy who had variant histology, which is certainly a subset of all non-muscle-invasive patients we see. But in terms of the incidence of variant histology among all patients with non-muscle-invasive bladder cancer, it's less than 20%.

Dale Shepard, MD, PhD: Looking at these variant histologies, looking at the sort of traditional therapy, what did you guys find?

Nima Almassi, MD: So we certainly saw that there was a spectrum of response to intravesical therapy among these patients. We saw certain variants, namely plasmacytoid and sarcomatoid variant as behaving in an extremely aggressive manner. And recurrence-free survival was extremely poor for these patients. Risk of progression and death from bladder cancer was extremely high. A larger subset of variants actually demonstrated outcomes that were similar to what we would expect to see with non-variant urothelial carcinoma with recurrence-free survival in the range of 50 to 60% and progression-free survival over 90%, which is quite good. And then micro-papillary variant, which has been studied in the literature as well, but not in this context, showed a sort of intermediate behavior with recurrence-free survival, again on the order of about 50%, but a higher progression-free survival than what we would normally expect with non-variant urothelial carcinoma.

Dale Shepard, MD, PhD: When you look at this particular study, these were patients that were getting BCG or chemo or some combination of those.

Nima Almassi, MD: Yeah. The majority received BCG over 80%. The remainder received intravesical chemotherapy. Some patients received multiple modes of therapy. So if they had a high-grade recurrence after BCG, they may have received chemotherapy afterwards. The incidence of progression to muscle-invasive disease was 14%. The majority of those patients were treated with radical cystectomy with or without neoadjuvant chemotherapy. The risk of metastatic progression for the entire cohort was 14%.

Dale Shepard, MD, PhD: And so when we think about the findings that sarcomatoid or histologies were more aggressive, has that changed sort of the practice in terms of maybe going to cystectomy instead of an intravesical therapy?

Nima Almassi, MD: We had very few patients with that histology that were included in this study because those patients are almost uniformly recommended cystectomy. This was a select patient population, and those patients with plasmacytoid or sarcomatoid variant were patients who were not cystectomy candidates. So we knew that they were receiving a treatment that was at a much lower likelihood of giving them long-term disease-free survival. But that was in the absence of alternative options.

Dale Shepard, MD, PhD: Tell me a little bit about, so certainly there has been some issues with this therapy, particularly the BCG. And as I recall looking through that affected this study in some way in terms of the availability of the BCG itself.

Nima Almassi, MD: Right. So at various points over the last 10 years, there have been issues with BCG supply nationally, and there are currently some centers that still are unable to access BCG that largely relates to adequate production. Currently, at Cleveland Clinic, we have adequate BCG for all patients for whom it's indicated. But when we were suffering from the BCG shortage, patients would instead receive intravascular chemotherapy. Outcomes with intravascular chemotherapy appear to be quite good. And there's currently a Phase 3 trial comparing intravascular chemotherapy with sequential gemcitabine and docetaxel against BCG for BCG-naive patients. And so the standards of care may change once the results of that trial are reported.

For patients who fail BCG, that's termed BCG unresponsive disease, radical cystectomy should be considered. However, there are alternative options, and beyond intravascular chemotherapy, there are also newer treatment options that have been approved by the FDA that have shown efficacy for BCG unresponsive disease. So we now have more and more intravascular and nonsurgical options for patients for whom cystectomy is high risk or for patients who refuse cystectomy.

Dale Shepard, MD, PhD: So tell us a little bit more about those therapies that are now available for people with BCG unresponsive disease.

Nima Almassi, MD: Right. So one is nadofaragene firadenovec, which is a adenoviral-based vector treatment that increases interferon supply to the urothelium, and that has shown response rates of 25 to 45% at one year after treatment for patients with BCG unresponsive disease. This was approved by the FDA at the end of 2022 and is now increasingly available for patients. There's also a newer intravascular treatment that improves the inflammatory response and the immune response within the bladder that when given with BCG has been shown to be effective for patients with BCG unresponsive disease. There are also clinical trials underway that are looking at combination therapies for BCG unresponsive disease as well as newer delivery options for administering chemotherapy, including with an implantable device that's placed in the bladder cystoscopically that delivers a sustained release of chemotherapy over a three-week period. So it's a very exciting time for patients with Stage 1 disease as these newer options become available.

Dale Shepard, MD, PhD: I guess this has been a recurring problem, as you said, the BCG shortage and availability and ability to treat someone who has a very treatable disease. And it's good to hear that chemotherapy is being compared, and maybe that would become the new standard and we wouldn't have to worry about the shortage. The drugs that are being studied, the approach is being studied for people who have failed BCG, are those also being studied more in a first-line setting to maybe eventually get away from BCG?

Nima Almassi, MD: I foresee that as being the case. Some of these therapies are given with BCG, some independent of BCG, but as we show efficacy in the BCG unresponsive disease state, I would anticipate us then testing those in the BCG naive state as well. Certainly, drug availability is a major issue. And I want to emphasize that whether you're looking at our study specifically or all patients with non-muscle-invasive bladder cancer, it really is a spectrum of disease with some high-risk cases and some low-risk and everything in between. And so in some patients, cystectomy truly is the best treatment option for them. But for patients who are eligible and good candidates for bladder-sparing options, we really try to promote and offer those to patients to try to optimize not only oncologic outcomes but also quality of life outcomes.

Dale Shepard, MD, PhD: And I guess because of the risk of field effect in new tumors and things like that, what does your group follow in terms of recommendations? You've gotten your therapy, how often do you monitor, how exactly do you follow patients to sort of look for recurrences?

Nima Almassi, MD: Yeah, typically it's a combination of imaging cystoscopy and urine cytology or urine biomarkers. So for patients with high-risk disease, that typically requires surveillance cystoscopy every three months for the first two years. Again, these patients are at high risk of recurrence. Most recurrences are going to be superficial recurrences within the bladder. So routine frequent cystoscopy allows us to identify and treat recurrences in a timely manner while a patient remains in the non-muscle-invasive disease state. Abdominal and upper urinary tract imaging is typically performed every one to two years, and then urine biomarkers such as urine cytology is typically conducted with each cystoscopy. As a patient develops a longer disease-free interval, we tend to increase the interval between surveillance testing.

Dale Shepard, MD, PhD: When we think about bladder cancer, a lot of this is being diagnosed and treated in the community. Who would be an ideal patient that should go to an academic center to be seen? Are there particular patients that they really more specialized evaluation?

Nima Almassi, MD: Yeah, I think cases in which the clinical behavior of the cancer is discordant with what the initial pathology showed. That definitely should, at the very least, warrant re-review of pathology by a specialized urologic pathologist and maybe referral to a tertiary care center. Patients who have BCG-unresponsive disease, I think should be seen at a center that can offer the breadth of treatment options for BCG-unresponsive bladder cancer, and for patients who have variant histology identified on their pathology. I think having an evaluation at a center that specializes in treatment of patients with these rare subtypes of bladder cancer can benefit the patient.

Dale Shepard, MD, PhD: Well, it's great to hear that there's some new things coming for all patients and specifically good attention for these variant histologies. So appreciate your insights today.

Nima Almassi, MD: Thanks very much for having me.

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