Sam Chang: Hello, my name is Sam Chang and I'm a urologist in Nashville, Tennessee at Vanderbilt University Medical Center. Today on UroToday we really have a future superstar, Dr Mattia Longoni, from actually Milan, Italy. He is at San Raffaele, and has finished a fellowship in cancer prognostics, as well as health outcomes, at the University of Montreal.

He has been the first author of a recent paper that came out in the Journal of Surgical Oncology, actually looking at cancer-specific survivals in T2 or muscle-invasive bladder cancer patients that were non-urothelial. Looked at outcomes of surgery, radical cystectomy versus trimodal therapy. This is a cohort of patients we struggle with regarding what are the best treatment options, what are the best way to treat these patients? So we're fortunate enough to have him today actually go over his manuscript. So Dr Longoni, thank you so much for spending some time with us and we look forward to your presentation.

Mattia Longoni: Thank you, Dr. Chang, for your introduction. I am pleased to be here. Thank you again, UroToday, and you of course for this opportunity to present my latest work on the trimodal therapy. So thank you again. I will introduce myself, but actually Dr. Chang presented very well my progress in my career. I am actually doing my fourth year of residency in urology, and I spent my third and half of the fourth year in Montreal, Canada, where I've been in the lab of Professor Krakowicz and researched mainly on bladder cancer, especially trimodal therapy.

So I will give you a brief introduction to what is trimodal therapy. Trimodal therapy is the combination of TURBT, chemotherapy, and radiotherapy. The rationale behind this approach is, of course, to preserve the bladder, and to achieve maximal local tumor control with the radiotherapy and bladder resection, as well as chemosensitizing the tumor and possible eradication in the lymph nodes. What is new, actually, and what is gaining traction is that the latest version of the European Association of Urology Guidelines, is that they recommend now trimodal therapy for advanced stages, such as T3, T4 disease. So now it's really an alternative for such patients.

What we know, and I presented this pivotal paper from Zlotta et al. Professor Zlotta, he's worked in Toronto and it's very keen to this type of bladder sparing strategy. The key point of this work was to demonstrate that trimodal therapy is non-inferior radical cystectomy in muscle invasive bladder patients. Although these are retrospective studies, they performed a IPTW and matching analysis and they demonstrated, actually, we don't have a disadvantage in cancer survival for trimodal treated patient as compared to the radical cystectomy counterparts. So this is what changed in the latest guidelines about trimodal therapy.

What we don't know is actually how the histological variant, which are about one out of 10 of the bladder cancer cases, what are the histological variants? Now we call them non-urothelial histological variant or non-urothelial UCB. What is the effect of having a non-urothelial bladder cancer on the trimodal therapy use on the bladder sparing strategies?

Actually, we know from retrospective data from the de Angelis et al. and Barletta et al. which are actually my other colleagues, that actually non-UCB patients have lower survival after trimodal therapy. The worst effect is observed for squamous cell carcinoma as we may expect. What we don't have, what we didn't have actually was a comparison between radical cystectomy and trimodal therapy for this type of patient.

So what I proposed was a project aiming at comparing the effects of trimodal therapy versus radical cystectomy in these type of patients actually in the localized, so T2N0M0 patient, which are actually the majority of patients to whom we propose actually trimodal therapy.

So our aim was to assess these oncological outcomes and we relied on the SEER dataset, as we did for other projects, and we retrieved all histological-confirmed, no metastatic, and organ-confined non-urothelial carcinoma of the urinary bladder patients. All patients underwent either radical cystectomy and lymph node dissection versus trimodal therapy. Trimodal therapy was actually defined as a combination of TURBT, chemotherapy, and external beam radiotherapy. We couldn't assess the sequential, which is actually a main limitation of this retrospective large population-based cohort.

As you can see, the first important information that we retrieved is that actually around three out of 10 patients with T2N0M0 non-UCB underwent trimodal therapy. This is very important to know, although the proportion of patients treated didn't significantly increase over the time, we may observe in the next years an increasing adoption of these type of bladder-sparing strategies.

As you can see, after matching, using propensity score matching, we observed a significant disadvantage in cancer-specific mortality for patients treated with trimodal therapy. We have a five-year cancer-specific mortality rate of 50% for trimodal versus 28 for radical cystectomy, which resulted also in a hazard ratio after adjustment for multiple confounders of 2.0, which was significant. We also performed sensitivity analysis according to the type of non-UCB, such as squamous cell, neuroendocrine, adenocarcinoma, and other subtypes. As you can see, the worst acting was observed for the squamous cell carcinoma group, as we may expect it. But actually, due to the small sample size, this effect was maybe masked in the adenocarcinoma and neuroendocrine subtype two. So these are very granular data, and we did our best to retrieve all the patients from SEER dataset because we know that this type of non-UCB may be lost under the radar. We don't have enough data, especially prospective data, which are actually needed to confirm our findings.

So in the conclusion, what we want to stress is that around 30, 38% of non-UCB patients with organ-confined disease are frequently treated with trimodal therapy, possibly due to age or comorbidity, that we don't know really, that TMT is associated with worse cancer-specific outcomes as compared to radical cystectomy in this population of patients. That the strongest survival disadvantage is observed for squamous cells, as we may expect it. As I was saying before, we need the inclusion in the prospective trials that are going on and then we'll enroll patients for this comparison. Also, include patients with non-UCB. My take-home message from this presentation are that now presently, whenever feasible, radical cystectomy should remain the preferred option for patients with non-UCB histology, as long as we don't have enough data, enough prospective trials.

Otherwise, trimodal therapy should be reserved for very selective patients and they should be aware of its limitation. Again, we need prospective data to confirm these and to actually know something more for the use of trimodal therapy or other bladder-sparing strategies in this subset of patients.

So my presentation is finished. Thank you very much for this opportunity again. I hope that you enjoyed this presentation from me. If you have any question, professor Chang, please ask.

Sam Chang: Dr. Mattia, That was a fantastic presentation. Very much appreciate your team's efforts to try to help better tailor treatments for these patients that have high-risk disease. Let's focus on those squamous cell carcinoma patients where you found the greatest disparity, in fact that the patients with squamous cell seem to do the worst with the combination of trimodal therapy.

That's interesting in that if we think about other squamous cell carcinomas, consider sparing of the rectum for anal cancer, use of trimodal therapy there as opposed to surgery, consider other kind of squamous cell carcinomas, there is some efficacy with radiation. Why do you think there might be a difference here? Is it selection? Is it the tumor acts differently? Perhaps the coverage isn't as good? Tell me if you all had any theories behind that difference.

Mattia Longoni: Thank you Dr. Chang for this question. Actually, we have thought about this. I think that for our experience, in our real world, of course, experience, what happened with the bladder cancer is that we don't have really a precise and controlled central pathology that is giving us the, I would say is the real histology behind... Very often, they're not only adenocarcinoma, they're mixed tumors, they're squamous, they are adenocarcinoma, they're small cells.

The other effort that I will suggest in doing is to centralize pathological reports in order to standardize the reporting. What we are doing actually in Europe with the European Association of Urology is to standardize the reporting of histological variants, what we used to call, for the bladder cancer specimen. Which is really important to start prospectively to collect this data and outcomes of these patients.

Sam Chang: Yeah, I think that is really important regarding the prospective validation of these subtypes and the therapies that are then chosen to help try to define what's better. Because as you stated and explained, these subtypes are very difficult to diagnose consistently, and we still really don't know the best treatment. At this point, I think the removal of the organ gives us the most information regarding true pathology, nodal status, etc. So understanding that right now we don't know if anything is superior or even as good as is very, very important.

Tell us, Mattia, you're back now in Italy. You've finished, got tons of information from Dr. Krakowicz, just full of ideas now. Where are you going to go next in terms of evaluating either bladder cancer patients or different types of therapy for these patients?

Mattia Longoni: Actually, now that I've been back in Italy, I wish to work at my institutional data and we're working, actually, on BCG alternatives for non-muscle invasive bladder cancer patients. I think that there will be a space also for better staging patients before indication to surgery or either trimodal therapy. I've worked on PET, FDG, PET, CT scan, for example, and we are also collecting those data for better staging before radical cystectomy. I think that next years we'll see less surgery and more neoadjuvant chemotherapy. I think that's the direction of genitourinary cancer, especially bladder cancer.

Sam Chang: No, I agree with you very much. We look forward to your future work, all the work that your university has done in Milan, really leading in urologic oncology, obviously in prostate cancer, bladder cancer, other cancers as well. So as that work comes to completion, we look forward to having you again and telling us-

Mattia Longoni: I would be honored.

Sam Chang: ... Telling us again some of the key findings that you and your colleagues have helped to unearth. So thank you very much, and stay safe, and we look forward to discussing future insights into your urologic oncology.

Mattia Longoni: Thank you, Dr. Chang. I'm really looking forward to being back with new findings.