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Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Wassim Kassouf, a professor in the Division of Urology, and Vice Chair of the Department of Surgery at McGill University. It is wonderful to have you here. 

Wassim Kassouf: Hi, Alicia. 

Alicia Morgans: Thank you. So, I think you've been talking, at least at EAU today, or yesterday it was, about some really exciting controversy that's been going on actually for a long time in bladder cancer, and you were involved in a pro-con debate. Whether you believe the side you argue for or not doesn't really matter, but I'd love to hear your thoughts on, generally, muscle-invasive bladder cancer, clinical T2 disease. What do you think about neoadjuvant chemotherapy, the accuracy of clinical staging, how we can do better? What do you think about when you're trying to put treatments together for patients with clinical T2 disease?

Wassim Kassouf: Well, for any muscle-invasive disease, I think the staging inaccuracy remains. There's still a significant risk of upstaging cystectomy. So, as in all guidelines, we'd advocate for muscle-invasive disease getting neoadjuvant chemotherapy prior to cystectomy. And the debate yesterday was more for the low risk muscle-invasive bladder cancer, the ones with the clinical T2, complete TUR, no hydro, no lymphovascular invasion in someone who is a bit older and someone in the mid-70s. Now, whether you go ahead with upfront cystectomy or give neoadjuvant chemotherapy. 

So I was asked to debate towards in favor of immediate cystectomy in that patient situation. And if you look at the data, data stemming from MD Andersen, USC, the Mayo, they've all published on low risk disease showing that despite significant upstaging, if you offer immediate cystectomy, their five-year overall survival is excellent. 84%, which is a bar quite high. It's hard to believe the neoadjuvant chemotherapy will add more and beyond this. Now, of course, in someone who is young, you want to push the envelope and even if there's any small chance, you want to offer that. But someone in the mid-70s, then you want to weigh in the pros and cons of giving a regimen that's rather toxic in exchange with survival that's excellent in patients with no high risk features.

Now, this is quite pertinent in this day and age. As you know, there have been two single-arm studies looking at immuno-oncology in the neoadjuvant setting showing high P0 rates and there is data from the adjuvant chemotherapy. So you wonder if this gets validated in a larger cohort in patients that fall in the gray zone, they're a bit older, they're worried about the toxicity of combination Cisplatin-based chemotherapy, would they actually benefit from an IO approach in the neoadjuvant setting? These preliminary results are exciting and it's just a matter of time to know if they're validated.

Alicia Morgans: Absolutely. Particularly in those older, frailer patients, patients who might not be Cisplatin candidates. I think those are really good questions. Do you think at all in these patients, the 70-year-olds, the single site of disease, no hydronephrosis, complete TUR, do you think at all about tri-modality therapy, or bladder sparing in that population?

Wassim Kassouf: Well, absolutely. In my practice, the patients who fit the low risk category, they're often recommended to have a trimodal therapy approach. Because in that highly selected patient population, the survival mirrors that of a cystectomy. So, often, someone in their 70s and 80s, they're more often treated with trimodal therapy if they are clinical T2, single focal disease, no extensive CIS, and the results are pretty comparable to cystectomy. Now, I know this varies tremendously across North America, but in Canada, we've adopted this a bit more often, mirroring or close to mirroring the practice of UK.

Alicia Morgans: Absolutely. Because when you describe that patient to me, that sounds like potentially a really good candidate for a bladder-sparing tri-modality approach.

Wassim Kassouf: And especially if a candidate will not ... if the candidate has chosen not to undergo a neobladder from the beginning. And most of them don't, particularly in their late 70s and 80s, you don't lose much from offering trimodal therapy because even if you get a salvage cystectomy in a minority of cases, those still will have picked a conduit.

Alicia Morgans: Absolutely. So what other words of wisdom do you have as we're trying to think about optimizing outcomes in muscle-invasive bladder cancer? You mentioned immunotherapy and checkpoint therapy. What is your take on some of the data looking at immunotherapy, checkpoint therapy in a neoadjuvant-type setting?

Wassim Kassouf: It's quite exciting. The high P0 rate is very encouraging. And if you look at the data today presented by Andrea Necchi, it shows that even with the new adjuvant IO therapy, the surrogate of ... the P0 surrogate, which mirrors survival, potentially may not be a great surrogate in the patients getting perioperative IO. Some patients with T3, T4 disease post-IO still has durable good outcomes in the perioperative IO setting.

Now, for patients getting trimodal therapy, it's also an exciting space to integrate IO there. The clinical trials, Canadian Clinical Trials Group has just centrally activated a randomized trial looking at trimodal therapy with adjuvant Durvalumab for a year, hoping that the combination can increase the abscopal effect and the survival in this patient. And similarly, SWOG will soon activate as well a trial, looking at trimodal therapy with concurrent and adjuvant IO. A similar concept, and hope these things can improve the cure rate of patients choosing to undergo bladder preservation therapy for muscle-invasive bladder cancer.

Alicia Morgans: Absolutely. But one thing that I want to pick up on and emphasize that you said is that the goal for treatment for these patients is going to be cure, right? For this localized disease with a bladder sparing definitive therapy. And it's really important, and I'm glad that it's been written into the protocols to have a defined duration of IO therapy. In the metastatic setting where our goal has always been really more to palliate and extend life we are asking that question now in those patients who are complete responders, when can we stop safely? And how can we discontinue? But in the curative setting, we have maybe a little more confidence in defining that upfront, which I think is really important as we consider the financial toxicity if nothing less of that approach to integration into our standard algorithms.

Wassim Kassouf: Yeah, absolutely. And it makes sense to have a defined limit, particularly if quote-unquote the disease is out, removed, or radiated. Where in the metastatic setting you still have ongoing disease there and you may postulate prolonged therapy may be better than a defined purview. But time will tell. There are trials right now currently looking at timing and duration of IO therapy even in the metastatic setting.

Alicia Morgans: Absolutely. Well, I have really enjoyed this conversation, would love to know what your closing thoughts or overarching message would be for the listeners who are not necessarily here at EAU, but who are trying to learn what they can from you?

Wassim Kassouf: I think as time goes by and more emphasis on multimodal and multidisciplinary management of this disease, not just in the muscle-invasive setting but also if you look at the BCG unresponsive setting there's more and more integrated management of the utility of IO and clinical trials. So I think from a urologist's perspective the urology should still try to be at the forefront of this, whether or not systemic therapy is being integrated early or not.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise and for taking the time to speak with me today.

Wassim Kassouf: Thank you.