Challenges in plasmacytoid urothelial carcinoma underscore need for novel treatment options

In this interview, Fed Ghali, MD, provides in-depth insights into the study, “Evaluating Clinical Outcomes and the Role of Neoadjuvant Chemotherapy in Plasmacytoid Urothelial Carcinoma: Insights from a Combined National and Institutional Series,” which was presented at the Society of Urologic Oncology 25th Annual Meeting in Dallas, Texas.¹ Ghali is an assistant professor of urology in the division of urologic oncology at the Yale School of Medicine and the Yale Cancer Center in New Haven, Connecticut.

This transcript was AI generated and edited by human editors for clarity.

Fed Ghali, MD

Could you describe the background/rationale for this study?

The point of the study was to evaluate neoadjuvant chemotherapy in plasmacytoid [urothelial carcinoma.] As a way of background, plasmacytoid urothelial cancer is a rare subtype of urothelial carcinoma, mostly in the bladder. It represents less than 5% of urothelial cancers, [and] probably significantly less than that. That presents a real challenge, because it's very difficult to study. The other thing to know is that it is a very aggressive malignancy. These patients tend to have really poor outcomes. We don't do a great job of staging them before surgery, meaning getting a good sense of the extent of the disease before they undergo surgery or subsequent therapies. We just don't have the right tools. These patients face a lot of challenges. These are some of the reasons why they were of particular interest to me and to us in the community.

Historically, these patients have been studied primarily using institutional series. There are a couple of single-institution series that have reported on outcomes for these patients. The University of Washington reported their patient set. More recently, Ashish M. Kamat, MD, MBBS, and the MD Anderson group reported their patient cohort of [52] patients.²

In order to add to this, we thought it'd be interesting to look at a national data set. We used the National Cancer database (NCDB) to try to [gain] a broader understanding of how these patients do and how they're treated across the country. It was still quite small numbers, so we added our own patient cohort to this national data set, taking care not to double count patients. Of course, our patients at Yale are also included in the NCDB, so we only included our most recent patients over the last couple of years, so as not to overlap with the NCDB and thus double count patients.

This gave us a couple of different interesting [advantages]. One is it gave us a larger number. Looking at more patients gave us a more representative understanding of the disease and how this plays out. It also gave us a perspective of how this disease is taken care of outside of major academic centers like ours, like MD Anderson, like the University of Washington, and so on. You get a little bit of a picture of how these patients do from not just academic centers, but more broadly.

What were the key findings from this study?

We found a couple of key things that stand out. Most of these things add to what we anticipated ahead of time based on some of these other studies that I'd mentioned, the MD Anderson experience, which was recently reported, and other institutional series. The first thing to say is that this disease is very rare. In the National Cancer Database, we found 123 individual cases reported across the country over several years. When we add our patients, that goes up to just under 150 patients. These are not large numbers, so we're still in the position of studying quite a rare disease.

Our data reiterated the fact that this is quite an aggressive disease. The median survival across the stages of bladder cancer, including both non-muscle invasive and more advanced disease, was between 2 and 3 years, depending on the details of the cohort. In other words, these patients do face quite a challenge. It's an aggressive disease.

An additional thing that we identified—and this is has been reported, but we found this across a broad population—is that our staging of the disease tends to underestimate the extent of disease quite a bit. One way you can look at this is by looking at the clinical T stage, for example, and the clinical nodal status. Meaning, how deep do we think the tumor goes in the bladder? Do we think that there's cancer in the lymph nodes? Then [you look at] how that changes after the patient undergoes a radical cystectomy, for example, where we maybe have the closest thing to a true standard when a pathologist gets to look at the tissue under the microscope.

What you see is there's a large discrepancy. For example, around 8% or 9% of patients are thought to have cancer in their lymph nodes prior to surgery. When patients with plasmacytoid cancer undergo radical cystectomy and actually have their lymph nodes evaluated under the microscope, that number goes up to 25% to 30% depending on the cohort. What that suggests is that our clinical understanding of the extent of disease tends to underplay how extensive the disease actually is. Those of us who take care of patients with plasmacytoid urothelial cancer know this implicitly. I don't think anyone will be shocked by this, but I think it's helpful to have specific numbers to evaluate it.

Another key finding from our study was that the role of neoadjuvant chemotherapy is not well established in variant subtype bladder cancer, and specifically plasmacytoid. All of the evidence that supports early neoadjuvant chemotherapy, the really high-quality evidence from clinical trials, is in classic urothelial carcinoma. What we found is that there's a large discrepancy between how frequently neoadjuvant chemotherapy is used. In the prior reports that I mentioned, and including our experience at Yale, somewhere between 65% and 75% of patients with plasmacytoid get chemotherapy prior to surgery. We are quite active about using chemotherapy in academic centers. If you compare that to the NCDB, so looking at the experience from a broader collection of hospitals including community practice and other academic centers, the use of neoadjuvant chemotherapy drops to around 21%. So, our data suggests that the community is using chemotherapy prior to surgery much less frequently than we do at academic centers.

Then finally, I think the ultimate question is do we think chemotherapy helps? In other words, is there evidence to suggest that chemotherapy is improving survival for patients? What we find is that if you compare the patients who have received chemotherapy and those who did not receive neoadjuvant chemotherapy, we can detect a difference in how long those patients live; neoadjuvant chemotherapy was associated with a longer survival. But when we ran some statistical tests to account for differences such as the patient's age, the clinical T stage, and the primary treatment modality, what [we found] is that the benefit from neoadjuvant chemotherapy washes away. It’s not maintained. It's hard for us, based on our evidence here, to say that neoadjuvant chemotherapy is causal in any way or is resulting in prolonged survival. It's at least possible, if not likely, that there's a different type of patient—maybe a younger, healthier patient, for example—that receives chemotherapy, and that's really what's associated with survival.

Could you expand on the implications of these findings for clinical practice?

I think the first thing to say is that our study is an observational study of retrospective experiences of these patients, so we have to be careful not to overinterpret our data and not to change our practice based on retrospective evidence like this. Our findings are primarily hypothesis generating, and I don't think anyone should change how they treat patients just based on this 1 study alone. We need high quality, prospective evidence, which, as I mentioned earlier, is challenging because of how rare this disease is.

[In this study we also] looked at the patterns of spread of plasmacytoid within our patients here at Yale, inspired by the MD Anderson report that was published last year. We confirmed what they reported, which is that a large percentage—in our experience, 78% of our patients—when they had metastasis of the cancer, the metastasis was peritoneal. In other words, [it] was spread throughout the abdomen, which is pretty distinct. Urothelial carcinoma does that significantly less frequently, as do the other subtypes. It's now been reported here, with the MD Anderson experience, and others.

The implications are that this is an aggressive disease. We need to be skeptical of our clinical staging of these patients. We need to assume that they're probably experiencing more aggressive disease and more advanced disease than we can see with our clinical imaging and with our TURBTs. We should think hard about treating them as if they're more advanced than we think. In other words, bladder-sparing therapy may not be the most appropriate thing for a lot of patients with plasmacytoid cancer, even if they're clinically non-muscle invasive, for example. These are things that I think about when I see these patients, just based on some of these observations.

[Additionally,] our findings couldn't support the idea that neoadjuvant chemotherapy was likely to be causal for prolonged survival, so the jury's still out. We would all love more information and higher patient numbers. The answer to that may be that we have to combine forces. We may need multi-institutional collaborations in order to pin down this question of neoadjuvant chemotherapy and its benefit for plasmacytoid. The important thing to know is when you give chemotherapy ahead of time, that has a real cost to patients. Neoadjuvant chemotherapy can take a toll on patients, and it also delays surgery. If patients are not experiencing a clear clinical benefit for chemotherapy prior to surgery, we need to be really thoughtful about how we use it. Our data couldn't support that this was a benefit for patients. The caveat is that it's retrospective, and these are small numbers. We would love to work with the rest of the community to see if we can answer that a little bit more effectively.

One of the interesting observations they made in [the MD Anderson] report in the Journal of Urology was that the patients who received checkpoint inhibitors, immunotherapy, for plasmacytoid cancer, appeared to live longer on Kaplan Meier analysis. They seem to experience a benefit with checkpoint inhibition. We didn't look at this in our abstract, but it did raise the question of the role of novel agents like checkpoint inhibitors in plasmacytoid cancers. In our discussion, as well as in the paper reported in the Journal of Urology, [there’s] talk about if there's a way to target this peritoneal disease and whether or not novel surgical approaches or treatment within the abdomen would be appropriate for plasmacytoid patients. These are the types of things that I think we as a community will be thinking about in the future.

What are some potential next steps in research to identify effective, novel treatments options for patients with plasmacytoid urothelial carcinoma?

We are in an era where the way we treat bladder cancer is evolving rapidly. The use of immunotherapies and more targeted chemotherapies with antibody drug conjugates has reshaped how we treat bladder cancer. The role of those agents in variant subtypes like plasmacytoid is still being slowly uncovered. These agents tend to be validated in urothelial cancer, and then we apply them to these variant subtypes like plasmacytoid. I think we're going to learn a lot more about whether these agents are active and how they behave in variant subtypes of bladder cancer. There's at least some early clinical evidence from the reports I mentioned and from work we did looking at nectin-4 expression—which is one of the targets of the antibody drug conjugates—that there's at least some hope that these agents are going to be effective in plasmacytoid urothelial cancer. We'll be eagerly awaiting some real-world evidence and experiences with that.

The other thing is that we're badly in need of is strong translational models for these variant subtypes. Urothelial cancer has benefited from lab-based research in mouse models, in organoids, and in cell cultures of urothelial carcinoma, where we learned a lot about how the tumor interacts with the immune microenvironment and how tumors evolve over time with treatment. That work is in a much earlier phase in variant histologies, and that's partly because it's very difficult to develop strong translational models. We're working on that here at Yale, as are others at in other institutions. That is going to be an exciting area in the future, to see how our translational science can lead to new approaches for treating these patients.

The last thing, and I alluded to this already, is the role of treating the abdomen specifically. Plasmacytoid cancer does have this proclivity for peritoneal carcinomatosis, widespread disease within the abdomen. How that information can be used to help patients is still unclear. We don't classically treat bladder cancer by doing [hyperthermic intraperitoneal chemotherapy] HIPEC, or giving high temperature chemotherapy in the abdomen, but it's possible that that may play a role in the future in a disease like plasmacytoid. That was suggested by the MD Anderson group in their report. [We noted in our paper that] when you think about giving therapy in the abdomen, one wonders if there's a role for things like intraperitoneal immunotherapy. We have a signal that immunotherapy may be effective for plasmacytoid cancers, but this is a little bit down the road. This is definitely not ready for prime time, but these are the ways that clinical data can help inform research down the road. These are the types of things we're thinking about here.

Is there anything else that you wanted to add?

At the end of the day, we center this back to seeing these patients who have an aggressive type of bladder cancer. The bottom line is that our treatments are just not effective enough at this point. Hopefully, this work, as well as all of the other great work that this builds on, is a motivator for investigators that are studying bladder cancer to focus some efforts on a difficult disease, because these patients badly need it. It's a tough clinical problem.

References

1. Rahman S, Kong V, Jalfon M, et al. Evaluating clinical outcomes and the role of neoadjuvant chemotherapy in plasmacytoid urothelial carcinoma: Insights from a combined national and institutional series. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Abstract 106. Accessed January 9, 2025. https://suo-abstracts.secure-platform.com/a/gallery/rounds/21/details/3920

2. Zheng L, Chen H, Zhao K, et al. Plasmacytoid urothelial carcinoma of the urinary bladder-A clinicopathological and molecular analysis of 52 cases. Hum Pathol. 2024:148:1-6. doi:10.1016/j.humpath.2024.04.012