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Matthew Mossanen: So this is a case. These are real cases. These are non-airbrushed. So this is a patient that saw me in clinic. He was 46. He drove a concrete truck, the trucks that mix the concrete. He presented with hematuria. He smoked two packs per day at the time that I had seen him for the last 30 years of his life. His BMI was 46. He had diabetes and OSA. This was the workup. He had a TURBT. He had high-grade T1, but there was 90% of a small cell component and some urothelial. He had a repeat TURBT to confirm there was no muscularis propria invasion. He was also found to have CIS then. His PET CT had no distant disease when he underwent staging. A decision was made to do cisplatin with etoposide due to the high-risk nature of his histology. And then he underwent repeat evaluation with a PET CT and MRI. There's a little bit of a delay from the time he finished treatment to when he got his imaging because he wasn't quite ready to move forward with cystectomy.

He was still working on smoking cessation. And so I think this is an interesting case because it'll highlight a couple of different areas that we can talk about today. I'm going to touch a little bit on MRI, and then we're going to go through some of these other topics that are involved in the high-risk but still non-muscle invasive bladder cancer cases. So one of the things that I wanted to highlight is that for patients that present with high-grade T1 or non-muscle invasive disease, MRI can actually be quite useful. So a multiparametric MRI can help possibly with local staging. Accuracy for detecting muscle invasion depends on the radiologist and the quality of the scan, but it's around 80%. And I think soft tissue contrast of the muscle wall is better with MRI than with CT. So because it's better at detecting muscle invasion and possibly beyond the bladder wall involvement of adjacent organs, I tend to get it for almost all of my patients that are headed toward cystectomy.


Now, the reporting of the findings in an MRI are typically standardized, which is helpful. Admittedly, not every report that I read has the VI-RADS classification system, but I just wanted to put a note out there that that's the direction that MRIs are heading in. T2 is, again, good for muscle layer integrity. There's some data that even an MRI can predict future pathologic outcomes. But just as a note, it can also miss residual disease. A TURBT might impact its accuracy, but it's also good to just keep it in mind when you're managing patients.


So in the next part of the talk, I'm going to invite Dr. Yates to come up here and discuss a little bit about variant histology and some of her perspectives on managing patients that are a little bit more complicated, not just the typical urothelial cell.


Jennifer Yates: Thank you, Dr. Mossanen. We're just going to talk briefly about variant histology. And the case presented here included a small cell component within urothelial cancer, which is, as we all know, quite rare. A little more common we see squamous and glandular differentiation. How common is that? Well, unfortunately, a lot of times it's under-detected and under-quantified in the specimens. So this is on the right side a list of the ways that we can characterize bladder cancer. And on the right side of this figure are all the different variant histologies that we see typically, some more common and some less common. The clinical course of these patients is a little bit variable, and it's hard to study these patients because number one, they're under-detected. And number two, it's just less common than standard urothelial cancer without any variant histology. But generally speaking, many of the patients who present with variant histology on a TUR specimen have a much more aggressive course, and we need to keep that in mind.

Detection and quantification is critical and often falls short. And this is a study from our colleagues at Moffitt looking at a secondary evaluation. At their major tertiary care center, what is the chance of picking up variant histology if it wasn't detected on the original biopsy at an outside facility? And interestingly, none of the nested or plasmacytoid variants were detected, which are very uncommon. So that's not terribly surprising. Sarcomatoid was only identified in 53%, and we know that this often has a very aggressive progression, and micropapillary identified in only 5%. And, again, I'm going to speak about that in a moment. The clinical course often varies, and our treatment strategy may vary depending on whether these are detected in the specimen. I think this speaks to the importance of having a pathologist who is accustomed to looking at urologic pathology, take a look at the specimen and give their input as to whether there is variant histology and the degree of involvement.


So can we use BCG and variant histology? I think over the last decade there's been a lot of variation in whether we think that this is an acceptable upfront treatment or whether it is not. And I don't think we still have a really great answer, again, speaking to the challenges of studying this patient population because they're relatively rare in the whole scheme of our non-muscle invasive bladder cancer patient cohort. This is the MD Anderson experience, and it really pushed us toward believing that early aggressive treatment with cystectomy is probably the best treatment modality for patients, especially those who have micro-papillary histology in their specimens. Patients who received BCG had a worse outcome. And those patients, and this is not surprising, we know this in the other space of patients who failed BCG who don't have variant histology, but patients who had micro-papillary and received BCG then progressed to muscle invasive disease.


Their prognosis was much worse than the patients who underwent upfront cystectomy or patients who then failed one course and ultimately had undergone. So we really need to be careful in these patients who have had micro-papillary who elect to have BCG, and if there's any evidence of recurrence, push them aggressively toward cystectomy, and if they have any progression, then we know that their pathology often at the cystectomy is much worse with more lymph node disease.


Interestingly, Sloan had a little bit different findings in their evaluation of their micro-papillary patients, and they found that BCG actually does have some efficacy in these patients. And so that gives us a little bit of a question mark as to whether we should be pushing micro-papillary patients aggressively toward cystectomy versus giving them a chance of intravesical therapy. I would say that it's critically important to these patients to have a second resection if they're presenting with T1 since the under-staging of T2 disease is very, very high in this population.


And a quick mention, we could probably spend the rest of the panel discussing upfront cystectomy. There's two spaces that we're speaking to this today. Number one is in the patients with standard histology who have failed BCG. And there are those patients who have a variant histology who should be considered at initial presentation with non-muscle invasive disease to have an upfront cystectomy. Factors that we know are associated with risk of progression include tumor size, variant histology, LVI, CIS, and prostatic urethral involvement. And, of course, as we all know, this is an extraordinarily aggressive surgery with a high morbidity rate that hasn't seemed to change much over the decades, so we do need to counsel our patients accordingly about that.


Kent Mouw: Thank you. I'm a radiation oncologist. That's my disclaimer. I will talk a little bit about the limited data that exists for radiation in trimodal therapy in non-muscle invasive disease. I think the take-home point here is really that there's no standard role for definitive radiation or chemoradiation in patients with high-grade T1 non-muscle invasive bladder cancer. And really there isn't that much contemporary prospective data. We offer radiation-based treatment in highly selected patients who are guided by a few of the studies I'll talk about now, and then in one of the cases a little bit later in the session. RTOG 0926 is a single-arm phase two trial, relatively small, 37 patients accrued over a time period between 2009 and 2017. These are patients who had BCG-unresponsive high-grade T1 disease, so T1 was required for enrollment. This is a patient population for whom the next step in management would have been radical cystectomy.


A few characteristics of the trial population, the median age was 74. This was predominantly male patients enrolled, and they were treated with contemporary at the time a decade ago, what I call MIBC-style TMT, so high-dose bladder-directed radiation with concurrent radiosensitization with either 5FU, mitomycin C, or weekly cisplatin. And the primary endpoint here was a three-year freedom from radical cystectomy. This is the data that's been reported in abstract form, not yet in a peer-reviewed publication. The median follow-up was just over four years, and the three-year freedom from radical cystectomy was 88%. So met the predefined primary endpoint. The overall survival was 69% at three years and 53% at five years. You can see some of the curves from the presentation at Astro from a few years ago. Eight of these 37 patients did ultimately die from bladder cancer, and the toxicity was significant. It's what we might expect in the acute setting for TMT.


So, grade three GI and GU toxicities, two grade four toxicities, but no grade five. And then the mean AUA scores were collected for these patients. Pre-treatment was 9.8 and three years post-treatment in the patients who had their bladder was 12.0. All right, I'll turn it back.


Matthew Mossanen: So what did we do with the patient who had high-grade T1, drove a concrete truck, was a heavy smoker and had a BMI of 46? We treated him as if he had higher-risk disease, gave him neoadjuvant treatment, and I decided to do an open radical cystectomy. I gave him an ileal conduit a couple of months ago. His most recent scans are reassuring, and he's back to work. It's an interesting case. One of the things I will say the disclaimers, when I do have a patient and we are considering upfront cystectomy, even if there is no clear data, I'll still send them to medical oncology and radiation oncology so we can still have a multidisciplinary evaluation.