Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas and it's a pleasure to welcome to the forum Saum Ghodoussipour who's joining us today to talk about a very exciting breakout session that he and John Sfakianos led at the recently concluded BCAN Think Tank in Washington, D.C. There was a lot of exciting stuff discussed, a lot of breakout sessions, very patient-centric conference as we all have recognized it has grown over the last 19, 20 years. And, Saum, thank you so much for taking the time and really love to hear what you and your group are thinking about in the tech-driven advancements in bladder cancer.

Saum Ghodoussipour: Thank you, thank you. My pleasure and it's always an honor to be able to chat with you here. So, yeah, our session was the first time at the BCAN Think Tank that they've actually covered this topic in a breakout session and our goal was to investigate the evolving intersection of technology and bladder cancer care. We had three excellent speakers or presentations that were prepared for our session and the first one was with Dr. Wiklund who's a professor of urology at Mount Sinai and the director of the robotics program there. He shared with us his perspective of the history of innovation in robotic surgery for bladder cancer care and it was great to hear his perspective as he really is a pioneer in this regard.

He shared with us that his first robotic-assisted radical cystectomy that he performed was in 2003, this was one of the first that was actually performed anywhere, maybe one of the first five, he said, worldwide. And interestingly enough, he performed an intracorporeal diversion at that time. At the time, he said that a lot of these cases had been done with the cystectomy robotically and the diversion had been done extracorporeally. And he listed off all these challenges in the development of robotic cystectomy and he explained how a lot of these challenges were actually myths that have been debunked over time. And as he showed this graph of the trends of diversion types, you can see here that the majority of diversions switched from extracorporeal to intracorporeal and I think that a lot of that credit is owed to Dr. Wiklund for popularizing and publishing on his results on this.

Now, one of the criticisms that many of us have of the shift towards robotic cystectomy is that, while it is reproducible and easy to teach, it's much easier to perform an ileal conduit which may be driving some of the disparity in receipt of orthotopic neobladders. So, I personally am trained with the Skinner principles and respect the law of Laplace and the need to make a urinary diversion that has nice compliance and Dr. Wiklund shared his technique of how he's actually able to recreate that same type of Studer pouch and do it in a way robotically that is relatively reproducible. He shared some tips and tricks and some great videos that I don't think I would be able to do justice by explaining but, if you're able to watch any of his videos, he is a master surgeon, I think a lot can be learned from watching his technique.

Aside from the oncologic outcomes which have been tested numerous times in clinical trials, it was nice to see some of the functional outcomes that he's been able to obtain. Importantly, he discussed the need for nerve sparing procedures to maintain sexual function. It was great to have patients in the room, caregivers in the room to emphasize that this is an important outcome that patients are looking at and you can see here that Dr. Wiklund in his series was able ... Patients were able to obtain continence requiring one pad or less in 86% of patients, you can see up here in the right. And then, when nerve sparing was performed, you can see here that potency was able to be maintained in a majority of the patients, some of them did require assistance with medications as well.

He also went on to talk about the evolution of robotic platforms. He told us that, when he performed his first procedure, he just had three instruments, a camera and two hands. Now we have extra ports, there's different ergonomics with the most modern version of the da Vinci 5 robot. He also showed some of the benefits of the single port approach and the Medtronic Hugo which is another platform as well as several other platforms which are in use around the world. And then he ended with some provocative videos and talks about artificial intelligence and how that's been able to advance the field of robotic surgery, specifically this robotic cholecystectomy that was performed almost exclusively with the robot itself with minimal human feedback, interaction. So, all in all, it was a great talk by Dr. Wiklund, able to celebrate some of the history of his pioneering work in innovating robotic surgery for bladder cancer.

From then we went on to hear a talk from my colleague and good friend Dr. Vignesh Packiam who I think is a young pioneer in bladder sparing technology for non-muscle invasive bladder cancer. And he started off with this statement that some of the recent improvements in outcomes that we're seeing with intravesical therapies may be independent of the intravesical therapies themselves. You can see here that the data on recurrence-free survival in patients who are being treated with BCG for high-grade treatment naive disease, historically, we were all taught that that two-year recurrence-free survival is around 60%. But as you can see, in more contemporary series, including the one from MD Anderson which I know you're well aware of, the NIMBUS trial and even the recent CREST trial, we're hitting recurrence-free survivals around 80 to 85% in the modern era and this is the same BCG that we've always been using.

Even in the BCG unresponsive setting, we have clear definitions which we'll get into in one of the later talks of what BCG unresponsive disease is, where you shouldn't give any further BCG but, again, Dr. Kamat, from your data that there actually is some benefit if you give BCG again to well-selected patients. So, what's the reason for all this? Again, the complete response rates in all of the novel clinical trials that are ongoing, we see slightly upticking numbers year by year. So, there must be something else driving these outcomes aside from the intravesical therapy and Dr. Packiam suggested that it may be due to our ability to visualize disease better and our ability to resect disease better.

So, when it comes to visualization, we talked a lot about the different technologies that allow for enhanced cystoscopy, including blue light and NBI, which allows us to more accurately risk stratify patients to get the appropriate treatments that they need and allows us to completely eradicate carcinoma in situ which may be controversial but there may be some benefit in doing that versus not. And then we talked about novel resection techniques including bipolar resection which may not be novel but there was a mix of physicians in the room who use monopolar versus bipolar energy and we even touched on the en bloc resections. Blue Light Cystoscopy, I think that many of us know what that is. Narrow band imaging as well, some nice pictures and videos that were shared in the session.

And then Dr. Packiam also shared this recent paper that he put out on almost 300 patients who were looked at retrospectively who had enhanced restaging after their intravesical therapies that included Blue Light Cystoscopy, mapping biopsies, prostatic urethral biopsies and upper tract cytologies. And you can see here in this figure that, as patients had more and more rounds of intravesical therapy, these enhanced surveillance strategies became even more sensitive at catching recurrences early. So, in this modern era of novel intravesical therapies where patients are seeing multiple lines, this enhanced surveillance is going to play an even bigger role. Like I said, we talked about bipolar TURBT, en bloc TURBT, en bloc TURBT is typically performed with a laser, there can be some technical difficulties and learning curves in doing that, there's suggestion that it does lead to a cleaner pathologic specimen. But now there's this data suggesting, or not data, some early evidence that there's augmented en bloc TURBT that can be performed with essentially a robotic resectoscope that can manipulate and pull and retract the bladder tumor in different ways.

Improved resection is important not just in bladder urothelial carcinoma but also in upper tract urothelial carcinoma. We have agents now like Jelmyto and gem/doce which can even be instilled into the upper tract that can lead to better response rates. He also highlighted a trial that is opening up that's combining gemcitabine with Jelmyto for patients with high-grade upper tract disease. And then we talked about the novel laser therapies, we had some back and forth in the session about the thulium laser and the MOSES laser. I think there was consensus that the thulium might be a little bit better because of the hemostasis that it's able to achieve. And while this navigable suction ureteral sheath has not been used in upper tract disease, it has been used in patients with stone disease to get a better stone-free rate so we had a little bit of a back and forth discussion about whether or not that would be useful in patients with upper tract disease.

Finally, we touched on the novel therapies for non-muscle invasive bladder cancer. This is a slide that was actually put together eight years ago and then, in the red here, you can see all these new agents that are actually in effect today so it's very exciting to see the progress that we've made in the field. From historical chemotherapy, we now have combination chemotherapies with gem/doce which is the most well-known, val/doce has also had some retrospective series published that show promising results. Immunotherapy has been enhanced now with Anktiva, this IL-15 super agonist is a great example of how technology can lead to greater drug development.

We looked at novel delivery mechanisms including conjugating the drugs to make a hydrogel like Jelmyto which can form these reverse thermal gels that will stick to the bladder wall and stay in the bladder much longer than aqueous chemotherapy. The TAR-200 system and TAR-210 which is Janssen's semi-permeable silicone device that slowly secretes the medications and there's even a gel now for gem/doce that's being tested overseas. The adenoviruses, nanoparticles, all of these drugs are examples of how technology is really advancing the field of non-muscle invasive bladder cancer.

So, to bring it all together, we had some slides shared by Sumeet Bhanvadia who's a urological oncologist by training but now senior medical director at Janssen on how we as academic physicians are able to partner with industry and with patients, caregivers and a multitude of different stakeholders to really bring this innovation to the bedside. Again, we summarized again all of these novel agents, you can see how many agents have been approved in the last five years. And while the science and the technology is a major driver of this innovation, a lot of this innovation actually comes from advocacy from physicians, from patients, caregivers, researchers combined with industry.

So, an example of the importance of this multi-stakeholder collaboration that Dr. Bhanvadia highlighted was the FDA definition of BCG unresponsive disease. That required multiple voices to come to the table to speak with the FDA and make it clear that we needed to think about these clinical trials in a little bit more creative way, we needed to get permission for single arm design studies, it wasn't really ethical to randomize patients to another treatment and that designation by the FDA that we could pursue single arm trials for BCG unresponsive disease is what led to the boon in clinical trials and innovation in this space. So, now, today we're faced with a wealth of riches and options for intravesical therapy and that's only a good thing to have all these options but I think that we're all excited now about moving on to multi-arm, multi-stage design studies to evaluate these. We also touched on muscle invasive bladder cancer, how similar conversations are happening now and the biggest space that they're happening in is in bladder sparing therapy, specifically patients who have a clinical complete response.

To mirror some of the conversations that happened in the main session at the BCAN meeting before the breakout, we talked about how long it takes clinical trials to come to fruition. We highlighted that it takes over a decade for these trials to complete. You have basic science research which might take two to five years before you identify a target, one to two years to test that target preclinically and then, even when you get to the clinical trial phase, that can take almost a decade on its own and then, even once these drugs are approved, bringing them to the office, to patients in the clinic, actually takes further work. So, the chance of success is low for any of these drugs to get across, the length required for registration and approval and, now that we're adding devices to drugs, the whole situation is becoming even more complex. So, it's very important moving forward that we design meaningful trials with input from all stakeholders so that we can get feasible endpoints to the table for our patients much faster.

So, we concluded by discussing how industry can support innovation. Obviously, they provide the strategy to get through all those hurdles and steps that I discussed, help with the regulatory involvement and they fund a lot of the R&D which is essential for us to identify novel therapies and novel targets. Clinical trials are able to be performed globally, not just locally as you partner with industry and industry is able to bring all these key stakeholders together, the scientists, the physicians, clinicians, experts as well as the patients. And the patients, as you said, that's the whole point of this meeting is bringing everyone together and hearing from the patients directly which is so valuable. And patients and caregivers obviously support innovation by participating in clinical trials but it's by informing that clinical trial design that everything actually happens.

Patient voices are critical in determining and communicating that unmet need and identifying any barriers to adoption so that, when we design these trials, we're doing it in a meaningful way and I think this whole era of taking 20 years for trials to read out is probably going to be a thing of the past as we design these trials better and more efficiently. So, that was our session in a quick nutshell, it was a lot of fun. As you can imagine, there's a lot of discussion that goes on with these talks as well.

Ashish Kamat: Thanks, Saum. Thanks for pretty much presenting everything you did at the workshop, I feel like I was there now.

Saum Ghodoussipour: Good.

Ashish Kamat: That was great. A few high-level comments just to augment what you said. I completely agree with the gist of the fact that, yes, the robotic cystectomy is a great tool but it's a tool. However you do it, patients need to put their quality of life, cancer cure at the forefront and just because someone is using a scalpel or a robot doesn't mean it should compromise on the principles of what we need to offer our patients which is cure from surgery but cure with good quality of life. So, I'm glad that was highlighted. I don't think, in today's day and age, anyone that truly thinks the robot is inferior is actually making much sense so that's a debate that I think we should forget about.

And then I like the way your group highlighted that, yes, the improvements in scopes, in techniques, in visualization has made non-muscle invasive bladder cancer more treatable and I think that's a very important point that you guys made, something I've been talking about for years. We need to teach people how to do TURBTs more so than we need to teach people how to do robotic cystectomies because 100% of patients with bladder cancer will need a TURBT, only 20% of patients with bladder cancer will need a cystectomy. So, I'm glad you guys highlighted that and, again, brought up some excellent points.

And then, lastly, with the talk that you had about industry partnering and the Milan meeting is the IBCG Global Society of Rare GU tumors joint meeting we had and that is in press in JCO and, yes, getting everybody to the table ... And by the way, congratulations on being a part of the IBCG now, looking forward to having you work with us.

Saum Ghodoussipour: Thank you.

Ashish Kamat: So, all that was phenomenal and I'm sure you guys have a lot of work that you're going to do in the next year. So, in brief, because I don't want you to reveal all your secrets or plans and take too much time, but where is this going next?

Saum Ghodoussipour: So, I think that we need to identify a little bit more clearly what we're doing to drive outcomes, specifically, let's talk about TURBT which was a main thing that we discussed there. I think that, if you can affect outcomes so much with the way you do this surgery, what's the best way to do this surgery? That's not something that's necessarily out there. I know that there's been checklists, which we discussed, of what constitutes the perfect TURBT or a correct TURBT but I think that that would be something that would be very excellent to define and have out there for our trainees. Another thing that we discussed is that, I don't know if there's any residents who will be listening to this, but residents often think that a TURBT is a junior level case and a cystectomy is a senior level case.

A TURBT, as you said, is arguably more important and arguably more challenging than doing a cystectomy, to do it right. So, I think that we as a field, we could come together and define what makes a quality TURBT, what's the technology, the minimum technology that needs to be used and how should we be teaching that and passing it on to all people who take care of bladder cancer. And then I think that the muscle invasive work is exciting, I think that, if patients are going to be getting a cystectomy or trimodal therapy, again, there needs to be a consensus on the best way to do each of those things and to minimize toxicity with cystectomy and with trimodal therapy. And it's not such a new concept anymore that not everyone needs to have their bladder removed so we need to ...

With the IBCG, you guys have very clearly put out some guidelines for moving forward with bladder sparing therapy in patients with a complete response, I think it's obviously a bit of a moving target still since it's not a standard of care. But I think that, probably at a BCAN meeting in the next five years, it will be a standard of care and everyone's going to be talking about the historical perspectives of when we did cystectomy for everyone. So, I think that's, in the short-term future, all of that will be defined and we'll be at a better place for our patients, all patients just like we are already with non-muscle invasive disease.

Ashish Kamat: Great points, Saum. Thank you so much for taking the time, looking forward to seeing where this goes next.

Saum Ghodoussipour: Thank you so much.