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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee at Vanderbilt University Medical Center, and we are privileged to have Professor Mario de Angelis from San Rafael in Milan, Italy, joining us and looking at the impact of radiation and chemotherapy, trimodal therapy or multimodality therapy, for patients with urothelial and non-urothelial invasive bladder cancer. This is becoming increasingly important, not only in the US but throughout the world, in examining different treatment options for patients with invasive disease.

So, Professor, thanks so much for joining us from across the ocean and across multiple time zones, and we look forward to your presentation.

Mario de Angelis: Thank you, everybody. Thanks for having me. It's an honor and a pleasure to be here with you today. Today's topic is our recently published paper in BJUI entitled "Trimodal Therapy Effect on Survival in Urothelial versus Non-Urothelial Bladder Cancer: When Should We Use It?" As you know, radical cystectomy is still the gold standard treatment for a patient with muscle-invasive bladder cancer. However, in recent years, the development of various strategies, such as trimodal therapy, has gained in popularity, especially in patients who are unfit for radical cystectomy or patients willing to protect their bladder.

Current guidelines recommend trimodal therapy in the management of organ-confined urothelial carcinoma of the urinary bladder, but it's also used in non-urothelial histology sometimes in daily clinical practice. However, the problem is that the vast majority of retrospective studies and clinical trials investigating the effect of trimodal therapy all included patients with urothelial carcinoma. Therefore, it is unknown whether patients with non-urothelial carcinoma treated with trimodal therapy may equally benefit from trimodal therapy relative to the urothelial carcinoma counterparts. Moreover, it's also unknown what is the effect of organ-confined versus non-organ-confined disease on cancer-specific mortality in patients with urothelial versus non-urothelial carcinoma, because nowadays the tendency is to treat not only the patients with organ-confined but sometimes also patients with non-organ-confined disease.

So, to address all these knowledge gaps, we relied on the SEER database from 2004 and 2020 and selected above 5000 patients treated with trimodal therapy. Among them, we divided patients according to organ-confined and non-organ-confined disease and then we further divided patients according to urothelial and non-urothelial histology. As you can see, the vast majority of organ-confined patients are 95% urothelial histology, whereas only 85% of patients with non-organ-confined disease defined as CT-3, 4, and/or CN+ patients covered urothelial carcinoma.

It is important to underline that, relative to other previous retrospective analyses relying on bladder-sparing strategies, we only selected patients with trimodal therapy defined as transurethral resection of bladder cancer, chemotherapy, and radiation therapy. So, within our study, we excluded patients with radical cystectomy, partial cystectomy, metastatic disease, non-vital status, and unknown or other treatment types.

These are the temporal trends of TMT use over time according to organ-confined and non-organ-confined disease. For organ-confined disease, you can see that in urothelial carcinoma patients, TMT use has increased over time with an EAPC of 0.4%. Whereas for organ-confined and non-urothelial patients, the TMT use decreased over time with an EAPC of minus 5%. For non-organ-confined patients, the TMT use did not achieve statistical significance.

For survival analysis, also in this case, we divided according to organ-confined and non-organ-confined patients. So as far as organ-confined patients are concerned, you can see that the median survival in the urothelial carcinoma patient is five years, whereas for non-urothelial organ-confined patients the median survival is pretty half, so 37 months. Also, after multivariable adjustment for age, sites, and rate, non-urothelial carcinoma achieved independent predictive status for higher cancer-specific mortality with a hazard ratio of 1.45. On the other hand, for non-organ-confined disease, you can see that the Kaplan-Meier curves are pretty much the same, with a median survival of less than two years. Also, after multivariable Cox regression adjustment for age, size, T-stage, and N-stage, non-urothelial carcinoma did not achieve an event predictive status. So urothelial versus non-urothelial in non-organ-confined doesn't change.

So, in conclusion, we can take that in organ-confined urothelial carcinoma, TMT rates have increased over time in a guideline-consistent fashion, and also that patients with organ-confined non-urothelial carcinoma treated with trimodal therapy showed a cancer-specific mortality disadvantage relative to those with organ-confined UCUB. On the other hand, in patients with non-organ-confined stage, use of trimodal therapy resulted in a dismal effect regardless of UCUB versus non-UCUB histology.

So our analysis provided two important take-home messages. The first one is that in organ-confined stage, TMT should not be recommended to patients with non-urothelial carcinoma. The second is that in patients with non-organ-confined stage, TMT should neither be recommended to patients with urothelial nor to those with non-urothelial bladder cancer. So, stick to the guidelines, only offer trimodal therapy in patients with organ-confined urothelial carcinoma. In light of this observation, it is encouraging to notice that in our analysis, TMT use over time increased only in patients with organ-confined carcinoma but not in those with non-organ-confined disease or non-urothelial carcinoma. Thank you for your attention, and I'm happy to answer any questions you may have.

Sam Chang: Those are definitely findings that are consistent with patterns of use. If you look at your SEER data, only about 5% with the organ-confined disease actually had non-urothelial, and a little higher percentage for the non-organ-confined disease. And I know they were small numbers, but were you able to tease out if there were certain non-urothelial varieties that actually perhaps may be better treated versus other non-urothelial, or was that not granular enough in the SEER data?

Mario de Angelis: That's a very nice question. In our cohort, we didn't search for that actually. Let me explain. Among non-urothelial histology, the vast majority were squamous and small cells, approximately 90%, where the remaining 10% are all other non-urothelial histologies. But actually we didn't focus on that because there are small numbers. So basically every kind of speculation on that would be not true, probably. There is some evidence, based always on the SEER database or NCDB, that investigated different histologies, but really small numbers, because apart from squamous and small cells, they are the most prevalent non-urothelial histologies. There are really small numbers, between 15 and 35 patients basically in the cohort. So basically we didn't perform the analysis in that specific scenario.

Sam Chang: Yeah, too small, for sure.

Mario de Angelis: Too small, yeah.

Sam Chang: I mean, to me the squamous cell cohort probably is the most interesting, because if you look at other squamous cell carcinomas, squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, there are data supporting the use of sparing, avoiding surgery effective for anal cancer, penile cancer, et cetera, combination therapy. So it would be interesting in terms of prospectively carefully evaluating these patients, because you would think that they would perhaps benefit in that way, but early on, clearly the data doesn't support that.

When looking at the non-organ-confined patients, the T3, T4 patients, did these patients tend to fail locally, distant, both? What did you find in these cohorts of both urothelial or non-urothelial? Because for either one of the disease types, urothelial or non-urothelial, this combination therapy did not seem to be that effective. Were there failures locally and distant? Both? What'd you find there with that data?

Mario de Angelis: Actually, in our analysis the only outcome was cancer-specific mortality. So basically we're investigating on that also because one of the limitations of the SEER database is that we don't have the midterm endpoints, we don't have the recurrence, we don't have the progression of disease. So basically the only thing we could investigate was the cancer-specific mortality, and what we found interesting is that the cancer-specific mortality, there is a difference only for the organ-confined. So basically if you treat patients with organ-confined disease, urothelial matters, because at five years there is a difference of 9% in the cancer-specific mortality between urothelial versus non-urothelial. Whereas it seems that if you treat patients with non-organ-confined disease, the histology doesn't matter anymore because probably the disease is too advanced.

So basically the only thing that is important is the stage of disease and not the histology anymore. But also for that there are small numbers. We included T3 and T4 in combination, so like you suggested before, if probably we collect prospective data or maybe sub-analysis, we will have more numbers, probably we can see some difference in T3 as well. But for the moment we combined T3 and T4 for the same reason, because of small numbers.

Sam Chang: Yeah, no, really good point. I think, as I know you would agree, this is definitely hypothesis generating, because we already know we've selected patients upfront, a priori, those that are more healthy, maybe getting aggressive chemotherapy and then maybe surgery. Those that are less may have been put into this category of bladder-sparing, of bladder-preserving type therapy, and there's so many different reasons why. And then really knowing the true denominator, even though the results are quite poor with non-organ-confined disease, compare that to perhaps the true denominator, there may be a small benefit that we don't know, that we won't tease out.

Mario de Angelis: Exactly.

Sam Chang: Exactly. Yeah, no, good point.

Mario de Angelis: Exactly. I agree.

Sam Chang: What are you all planning on next in terms of evaluation of bladder preservation therapy? Are you going to start looking at things prospectively, other databases? What's your next research step?

Mario de Angelis: We did start planning. We are now trying to collect the data from many centers around Europe, around the world. So the next step will be to do a multi-institution database and then probably a prospective trial. We are trying to work on that. But the very next step will be a multi-institution database collecting data from different tertiary referral centers around the world to see, because also in this case, the SEER database has several limitations because we don't know the chemotherapy, we don't know the radiotherapy. And also, if we know the stage of presentation, we don't have the multifocality, for example. So the multi-institutional data setting will be ideal also to better understand, for example, if some patients better respond to certain grades of radiotherapy or certain specific regimens of chemotherapy and so on. So basically the next step will be a multi-institutional database to be able to answer some questions that was not possible with the retrospective SEER database.

Sam Chang: No, I think that'll be very important in terms of getting increased numbers, obviously, but multiple institutions. And then being a little bit more granular, just as you said: which chemotherapy, which chemotherapy regimen. Is it 5-FU and mitomycin? Is it platinum-based? Cycles? Dose of radiation? Coverage fields? All that I think would be really, really important and really will give us some insight into the disease processes.

So my only request is we're reserving some time with UroToday once that comes out so that you can share all that information with us. So thank you so much, Professor.

Mario de Angelis: Thank you. Thank you for having me.

Sam Chang: Yeah, we appreciate so much you spending some time with us, and like I said, we'll look forward to your upcoming studies.

Mario de Angelis: Thank you. Thank you very much, and it was really a pleasure and honor for me to be here with you. See you next time.