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Ashish Kamat: Hello and welcome to today's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of radiologic oncology at MD Anderson Cancer Center, and it's a pleasure to welcome to our forum Dr. Akshay Sood, who was a fellow here at MD Anderson and has now gone on to become an assistant professor at Ohio State, continuing to do the fine work that he started here in bladder cancer, and of course, urologic oncology in general.

While Akshay was here, he had an interest in looking at the non-metastatic plasmacytoid variant of bladder cancer, which as we all know is a very tricky cancer to diagnose and manage appropriately. And Akshay, you've done a great job in putting this together and published a very, what I think is a sentinel paper in the Journal of Urology.

So we'd like you to take the stage and share your knowledge with the audience.

Akshay Sood: Well, thank you very much for that introduction, Dr. Kamat, and it's good to see you virtually. And thank you again for the invitation. So today, I just want you to share a few key findings from our recently published paper looking at the treated natural history of the non-metastatic plasmacytoid subtype of bladder cancer.

So as we know, the plasmacytoid subtype of bladder cancer is a rare disease and affects only approximately 1% of patients with muscle-invasive disease. However, it's a lethal cancer, and anecdotal clinical experience suggests that these patients have poor outcomes. However, at the time we initiated this study, a thorough quantitative evaluation of the natural history of this disease was lacking.

Therefore, we undertook this investigation to better study the outcomes in these patients to identify opportunities for future interventions or trials to improve patient outcomes. So our study was a retrospective review of our prospectively maintained bladder cancer registry at MD Anderson.

We identified a total of 66 patients with non-metastatic plasmacytoid bladder cancer in this registry. Of these 66, seven were excluded due to lack of details, and three more were excluded as they were found to have metastatic disease on repeat evaluation in our clinics. So the remaining 56 patients formed the study population for this investigation.

We looked at metastasis-free survival and cancer-specific survival. We did not look at overall survival separately, as during the course of this investigation, it became clear that any patient who had passed during the course of this evaluation had actually died of their disease. So that's why we did not look at overall survival separately.

We utilized standard statistical methods such as Kaplan-Meier or Cox Regression to perform the survival analysis. So here on the right side, you can see table one looking at the baseline characteristics of these patients.

I think there are a few key things to note from this table. One, these patients are much younger with a median age of 65 years as compared to the traditional or conventional urothelial carcinoma where the median age is around 73 years. Also, these patients present with a much more advanced clinical stage, with more than 50% of patients presenting with T3 or higher stage.

And finally, I would like to give a shout-out to many investigators who have dedicated their lives to studying these rare cancers because, as you can see from table one, almost 80% of our patients included in this study were diagnosed within the last 10 years. And this is not due to an increasing incidence of this disease, but I think it is due to increasing recognition of this disease.

And I think this will really help improve outcomes as we recognize this disease more and more and separate it from conventional carcinoma. Table two on the right side depicts the perioperative outcomes in these patients.

Although all patients, all 56 patients that were included in this study were treated with curative intent. But as you can see, only 75% of patients were able to successfully undergo radical cystectomy. 20% of patients were not offered surgery as they had progressive disease on systemic therapy. And about 5% of patients were not able to complete the surgery as the disease was found to be unresectable at the time of surgery.

Almost 90% of patients received chemotherapy either in the neoadjuvant or adjuvant setting. And despite heavy reliance on neoadjuvant chemotherapy, only 7% of patients had pT0 disease at the time of final pathology. So again, this tumor definitely demonstrates a subpar response to preoperative chemotherapy. Now, with regards to the natural history of oncological outcomes, I think our study has three key findings that I would like to share today. So the first is with regards to metastasis-free survival.

As you can see from the Kaplan-Meier plotter on the left, these patients have rather poor metastasis-free survival with the median time to metastasis from the time of diagnosis of only 12 months, and from treatment only six months. And the Kaplan-Meier here depicts that the higher the clinical stage, the poorer the outcomes are, which is not very surprising.

However, I think all patients have poor outcomes with this disease. And similarly, when we look at response when stratified by pathologic response, patients who demonstrate pathologic response or complete pathologic response have slightly improved survival. But as discussed in the previous slide, these are rare patients who demonstrate that.

So again, the outcomes remain poor in this patient population. This slide here depicts the cancer-specific survival and essentially replicates the findings shown in the previous slide that these patients have poor cancer-specific survival.

This is the second major finding of our paper. And one of the really, at least for me, really striking findings, and I know I've discussed this with Dr. Kamat many times during my fellowship, is that these patients have such a striking contrast to the spread of their cancer or recurrence pattern, with almost 50% of patients showing carcinomatosis when they recur.

And if you look at the involvement of the small bowel and taken together, almost 70% of patients have some kind of intraperitoneal recurrence. And again, this is not something we see with traditional urothelial carcinoma. So this is a very striking finding that the recurrence pattern is quite distinct from what we see with conventional urothelial carcinoma.

And then finally, I think the third key finding from our study is looking at the results of salvage immunotherapy in these patients. So the patients who had a recurrence or developed metastasis after the treatment, these patients were treated, either received no treatment because they were unfit or did not want to undergo further therapy, or they were treated with chemotherapy or treated with immunotherapy after they failed chemotherapy.

So obviously, our numbers are quite low, but as you can see here, among the seven patients who received immunotherapy after failing chemotherapy, these patients had a pretty significant response. And although, again, like I said, the numbers are small, but almost 30% of patients showed clinically significant and durable response to immunotherapy. And there is good biological rationale to support this finding, which we have discussed in our paper.

But yeah, so I think those were the three key findings and they kind of lead us to discuss what may be possible in the future for these patients. One is the role of HIPEC or hyperthermic intraperitoneal therapy. And I think this, we know from literature from appendiceal tumors and mucinous GYN tumors, that this is a standard of care for patients who have relapsed intraperitoneally in those malignancies. And level one data supports improved overall survival in these patients when we utilize HIPEC.

So given the propensity for intraperitoneal spread with plasmacytoid, I think this could be a reasonable strategy at least to study. And similarly, like I mentioned briefly, when we look at the biology or when we look at the molecular makeup of these plasmacytoid tumors, and I'm sure Dr. Kamat, you'll comment on this, we shared a patient that I did during my fellowship with you that, based on the NGS and the immunohistochemical findings in that patient, the patient has done remarkably well because we, based on that finding, we utilized immunotherapy in the neoadjuvant setting and the patient has demonstrated no recurrence almost 24 months out from the procedure.

So again, I think these are two future avenues that would be worth exploring in these patients. Again, with that, I will end my talk and thank you very much.

Ashish Kamat: Thanks, Akshay, for running through the highlights and the summary of the publication. Let me ask you a few points that are based on the paper and, of course, some that are based on your general knowledge of plasmacytoid.

So what would be your take-home message for those that are not familiar with this variant or histologic subtype that encounter it for the first time in a TURBT biopsy? What are some of the pitfalls of diagnosis? What are some of the pearls that you can share with people about staging and the importance of EUA versus MRI versus CT scan?

Akshay Sood: Yeah, I think that's a very good point, Dr. Kamat. I think definitely always think about understaging these patients. And I think even in our paper, we had very few patients, only five out of 56 patients who had non-muscle invasive disease.

And when we looked at the pathologic outcomes in those patients, actually, of the five patients who had cT1 disease, two were actually found to be unresectable at the time of surgery, and they did not receive neoadjuvant chemotherapy because they were thought to be T1 disease.

The other three who did receive neoadjuvant chemotherapy and were taken to surgery, their final pathology revealed that they had pT3 disease. So definitely understaging I think is almost a rule in these patients. So I think definitely performing maybe a PET scan, CT scan, probably within a few weeks prior to operating on these patients will be a good thing to keep in mind.

And like you mentioned, I think EUA is really critical in these patients because many times you may discover that these patients have fixed disease, T4 disease could be unresectable, so you don't want to be surprised at the time of surgery. And definitely if you have any of those findings, these patients need systemic therapy for sure, and could make them resectable and then probably help with the surgery.

Ashish Kamat: Yeah, it's an important point. I wanted to highlight that if you have a diagnosis of plasmacytoid bladder cancer, consider it locally advanced until proven otherwise, and even then consider it locally advanced because it really almost always is.

There's almost no such thing as truly noninvasive plasmacytoid, even though the clinical stage, like you said, might look like it's T1, most of these patients will be non-organ confined at the time of cystectomy. The other thing I wanted to highlight is that the imaging findings are notoriously inaccurate in staging these patients.

You can have a CT scan or a PET scan that looks pristine and at EUA, the tumor has infiltrated, it's got this linitis plastica type of picture and it's completely fixed. So this is one of those situations where if the EUA is omitted, it can be a major, major disservice to the patient. And Bernie Bochner from Memorial has shown multiple examples when he does case presentations of CT scans that look pristine, and then these were fixed at the time of cystectomy.

Luckily, we do EUA for almost every patient. So it's unusual for that to happen. And luckily, we haven't had patients who have had that missed, other than the one or two that you mentioned where it was thought to be non-muscle invasive, and of course, they were fit for cystectomy. That's another important point.

Focusing now on the pattern of metastatic spread that you found in our series and your paper, what would you recommend is the counseling that should be done to patients that are considering curative cystectomy in this disease state?

Akshay Sood: Right. I think you have to counsel them that this is probably, they're in for a long haul. This is definitely a disease that requires multimodal treatment at the outset. And even with everything we have, they may recur and recur quickly after surgery.

And if that happens, I think there is kind of counseling them even before you do even the radical cystectomy to counsel them about potentially enrolling in a trial. I do think, based on our findings and some of the very limited evidence that we have generated since the publication of this surgery, that I feel maybe having a discussion with our medical oncology colleagues about trialing combination immunochemotherapy in these patients in the neoadjuvant setting might be a good idea.

At least do an NGS and IHC panel and see what that shows and if it supports using those systemic therapies. So I think that's what I would tell the patient that even with multimodal treatment, they may require multiple further treatments if we are looking to really achieve a cure in these patients.

Ashish Kamat: And again, just to caution, again, these are all hypothesis-generating questions that we have come up with from a series, but recognizing over the years that the median metastasis-free survival is really, really short in these patients, even with what seems like favorable pathology on cystectomy, unfortunately, these patients relapse and recur really quickly, and a lot of it is intraperitoneal.

I think the point that you made is good that we have to think outside the box, maybe think outside the box but inside the abdomen, think about doing HIPEC and other such things. But this all needs to be studied in a more systematic fashion and with some prospective trials being done.

This was great. Akshay, any closing thoughts you want to leave our audience as we wrap this up?

Akshay Sood: No, I think, as I've heard you talk, Dr. Kamat, given the rarity of this disease, I think one other question that you asked is what would you tell patients or physicians who don't have a lot of experience with this? I think one would be to send it to centers of excellence because they have more experience managing these patients.

And also, I think as a collaboration, then we can study these patients better, maybe within the confines of a truly prospective trial. So generate better data if these were grouped into a few institutions rather than managed in a more community setting.

Ashish Kamat: Yeah, no, I absolutely agree. And I think actually our community colleagues have caught on to that because most of them will want to send this rare subtype to an academic center, and they have been.

I think one of the problems is that sometimes it's not recognized in the community, and then the physician thinks they're doing the right thing with the cystectomy, and then unfortunately at the time of final pathology, it's picked up. So it's another one of those things where just bringing it to the forefront in the minds of pathologists, urologists, everyone concerned dealing with bladder cancer is important.

And again, a paper such as yours is very valuable from that perspective. Akshay, always great to see you. Thanks for taking the time.

Akshay Sood: Thank you, Dr. Kamat.

Ashish Kamat: Bye-bye.