Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston, MD Anderson Cancer Center. And it's my pleasure to welcome a friend and a colleague, Bernie Bochner, who is an Attending Surgeon at Memorial Sloan Kettering Cancer Center. Dr. Bochner obviously needs no introduction in this field. He and I go a long way back as friends, but he goes even further back as a true expert in bladder cancer. And with all the craziness surrounding us in 2020, and yet with the advances that have occurred, it was only fitting that we invited Dr. Bochner to present to you, the audience, highlights in the management of muscle-invasive non-metastatic bladder cancer. Bernie, the stage is yours.

Bernard Bochner: Ashish, good morning. And thank you so much for allowing me the opportunity to chat. It's always a great opportunity to have some time with you. So as you mentioned, it's been a pretty crazy year for many, many reasons. Unfortunately, for those of us in managing this disease, the disease keeps marching on and requires us to step up and continue to help patients despite the challenges that we face in the healthcare system. So I thought I'd highlight a few of the interesting things that have come up through the year.

Obviously, it'd be impossible to discuss the year without mentioning the effects that COVID-19 has had, particularly on bladder cancer. We treat lots of different neurologic diseases, some of which can be safely put off during this time. So we can keep people safe and away from hospitals, but unfortunately, muscle-invasive bladder cancer is not one of those tumor types that just going to sit around and allow for a three-month or a longer delay in management. Early last year in the Northeast, particularly in New York, we suffered a huge surge and as a result, lost a lot of healthcare resources. And because of that, we had to really scramble to figure out how to safely take care of patients. What we did learn is that people need to continue to come in and get managed for this disease. And if surgical options need to be put off because of resources, there are other things that are available to help people with their tumors, but they simply cannot just wait until they're fully vaccinated and things are better. Get in as quickly as possible and discuss it with your healthcare partner.

Other exciting things that we have seen in the management of muscle-invasive bladder cancers... We continue now to see improvements in the surgically managed patients. So these are nonmetastatic muscle-invasive patients. We're seeing now that there have been trends over the last 20 years or so. This was sort of where we stood for localized and regional bladder cancer, not much of an improvement over time, but as we can see now from a large series that have really matured over the last several decades, this happens to be a series from Memorial, that we have seen improvements in the probability of patients with muscle-invasive disease managed with surgery, demonstrating improvements in important outcomes. Disease, recurrence risks have decreased significantly since the late nineties. And your probability of not dying of bladder cancer also has dramatically improved, a 10% improvement is what we found over this time period.

What's leading to this? Well, it's the uptake of the use of perioperative cisplatin-based chemotherapy, which we've dramatically seen improve over that time period. And as a result, we've seen improvements in the complete pathologic response to these patients at the time of radical cystectomy. We think other things that have improved the outcome as well and contributed has been the improvement in surgical technique. We see that more thorough lymph node dissections are being performed as noted by increased numbers of lymph nodes that are being reported on the past specimens. And we know that in many papers, this has independently been identified as a predictor of improved outcome. We've seen positive margins go down as well, also probably related to the use of more perioperative chemotherapy. So this has clearly become a team sport between medical oncology and surgeons. And as a result, patients are doing better.

Other improvements that we've seen is that we've now really begun to move beyond cisplatinum in the perioperative setting. And it's been very exciting to see a host of the new immuno-oncology drugs that have made their way into the management of patients with localized muscle-invasive disease. And this includes the PD-1 and PD-L1 inhibitors that are being used in the neoadjuvant setting, either alone as demonstrated from this chart that was a nice summary from what several of the studies that are available today, showing that either alone or in combination with current chemotherapy, or even in combination with other immune active agents. So, combinations such as ipilimumab and nivolumab or durvalumab and tremelimumab. So these are CTLA and PD-1, or PD-L1 inhibitors working together.

We're seeing really significant pT0 rates, which at least for chemotherapy has been a surrogate for improved outcome. We'll have to see if this holds up in the IO therapy realm as well. We're waiting for longer-term data on these studies with respect to overall survival. But we have seen in the adjuvant setting, the first IO drug, nivolumab, at least it's been reported that there's been a positive trial in the adjuvant setting. We're waiting to see that data, but again, it holds hope for us to be moving beyond cisplatin therapy.

And finally, there are just a slew of really exciting markers that appear to be coming down the road. We now know from a lot of detailed genomic studies that bladder cancer, while it may look the same under the microscope, it clearly from a genomic standpoint is a very heterogeneous tumor, and there have been lots of classification schemes now to try to help us predict who may respond to chemotherapy. And these are either based at the RNA level, in which a variety of subtypes have been identified. It may help us predict who may or may not respond. At the DNA level, we've identified as a community in urology that DNA repair genes can be very important in helping to predict who may and may not be dramatic responders to chemotherapy, cisplatin-based chemotherapy. And this is led even to some active bladder preservation strategies for patients whose tumors have these particular DNA damage repair genes knocked out and are able to get cisplatin therapy.

And as the complexity of the analyses continue to improve, we're seeing integrated genomics now, which is again, providing some interesting potential markers, all of which needed to be prospectively validated, but it's extremely exciting for this time and in the exploration of these markers for patients with bladder cancer. And I think we're going to see a lot of important changes coming up in the future.

Ashish Kamat: Thanks, Bernie. That was a very good and succinct summary of the advances that have occurred in this particular field. Let me ask you a couple of questions and let me kind of start with the last point that you raised, which is markers that are potentially going to be useful for bladder preservation. Where do you see that particular aspect of the field moving? I mean, it's been decades that we have been discussing bladder preservation with radiation and of course, with neoadjuvant chemo, and can patients avoid radical cystectomy. What's your sense based on, not just your read of the literature, but your sense, just having vast experience in the field as to how far are we from that being a reality and how should our audience be counseling their patients?

Bernard Bochner: Well, it's a great question. And Ashish, we've learned so much over the years with regards to a lot of bladder preservation strategies, and probably the most important thing we've learned is proper patient selection. We know if you pick the wrong person for a trimodal radiation-based protocol, they're going to do very poorly. However, there are some patients with very limited disease, solitary tumors, small tumors, tumors that can be maximally resected, they can do quite well. And they obviously need long-term follow-up because with the damaged mucosa, it's still present, we know that the underlying molecular defects haven't been altered by that therapy. And so their recurrence risk remains substantial.

And I think we're seeing the same thing now with the molecular markers as well. So we know for instance that it's a select group of DNA repair genes that appear to be associated with this response to platin-based chemotherapy. The mutations have to be specific. They need to be deleterious mutations, meaning they have to affect the function of the actual enzymes. And when you carefully sort of drill down, you find that it's probably less than 20% of patients with muscle-invasive disease that may actually harbor these important mutations.

They then have to receive chemotherapy that's platin-based. They have to have a complete clinical response. And it's only in that subgroup of patients that we would be willing after an exhaustive post-treatment evaluation with scanning and biopsies. And if they are deemed a complete clinical responder, that they would be reasonable then to follow with the bladder in place. And this is being studied, as you said, until we actually do the studies, we don't know how safe it is long-term. And these studies are up and running right now.

And so I think we're going to piece this together based upon the fact that we know bladder cancer is not one disease. It's a multitude of diseases at the genomic level. But, I do feel that if we do the science and we do the hard work to validate these markers and then to test them and to follow patients, a one-year bladder preservation rate is really not what we're looking for. As clinicians, as we know that these patients hopefully will be around for years and that bladder has to remain a non-threat to them during that time period. So, I'm encouraged, but I'm willing to put the work in as are you and others to make sure that, that these are validated and tested before we really put it out there for general use.

Ashish Kamat: Yeah, wise words. You know, speaking of hard work, no one can deny that Bill Shipley and of course, now Jason Efstathiou in Mass General and then Nick James and Ananya Choudhury on the other side of the pond. I mean, they've really been working hard and for a long time at trying to get radiation to be a mainstream option. Which is now, in our guidelines is something we absolutely need to discuss with the patients, which both you and I agree on, but we haven't really seen an uptick in its intake across the United States at least. What's your sense when it comes to the pros and cons of using radiation therapy in our patient population with their bladders as a potential bladder sparing therapy?

Bernard Bochner: Well, it is an absolutely viable option for a significant percentage of folks. I think that over the years, the people that you've mentioned have been tremendous at helping us identify those patients who probably are the best candidates to select for this. And again, the solitary smaller tumors with no associated hydro and the ones that we can do a really good job at maximally TURing them, not a lot of carcinoma in situ associated with it. Those are the ones that tend to do the best with radiotherapy. They also obviously tend to do the best with surgery as well from a cancer perspective, but we know that there's a subgroup of patients that are going to need treatment that maybe are not optimal surgical candidates, or they simply just don't want the bladder removed. And so everybody that treats a significant volume of patients with muscle-invasive disease at least to some degree, has to practice bladder preservation of some sort.

And so I think radiotherapy is a very good option for selected patients or for those patients who really are not good candidates for surgery, or select surgery is something they'd like to do. And so you have to work very closely. Again, it's a real team sport with the radiation oncologist and the medical oncologist to make sure that patients are properly selected, they're properly prepared. We like to put fiducial markers around the base of the primary tumor as well, to help them localize the boost to that area.

And then these patients need close follow-up because if you select the wrong patient and recurrence happens, you got to pick it up early in order to perform that salvage cystectomy. And again, if you work as a team, you'll also recognize that there simply are inappropriate patients for radiation therapy. And these are the patients that you really got to push towards surgery to be able to afford a cure if possible.

Ashish Kamat: Yeah, I'm with you there because even at our center, we consult patients and radiation therapy, and I've been actually a little bit surprised with the low percentage of patients who select radiation therapy after an open and honest discussion with them. And of course, we even send them to the radiation oncologist. So I try not to be biased, but I was worried maybe my discussion was biased, but they have a multidisciplinary discussion and they still come back. And I think it's partly because of the symptoms that they've experienced, do end up selecting radical cystectomy. So I think all the points you made are right on the money. Just two more quick questions to you.

One is the whole issue of the way that people do a radical cystectomy. And obviously, it's a complex procedure and I always tell people there's no second chance, there's no dress rehearsal with a radical cystectomy. And as you pointed out positive margins, all of those are really death sentences to our patients. And you've been very instrumental in opening the community's eyes to the equivalence, I would say, between robotic and open radical cystectomy showing that one is not clearly superior to the other. What's your sense about the way radical cystectomy is being done today and will evolve over the next decade? And what would be your advice to the young folks in the audience that are listening that might essentially find themselves being pushed towards absolutely having to do robotic cystectomies just based on their new contracts and things that they're negotiating.

Bernard Bochner: Yeah, well, I think with any cancer surgery, the first thing that all surgeons have to do is understand the disease that they're treating. They have to understand the pathways of progression of the tumor. They have to understand what the surgical tenants are in order to optimize that cancer outcome. And fortunately, we really have been standing on the shoulders of giants over the last several decades. People like Don Skinner and others who have really helped us establish how important it is to handle those perivesical tissues and to control the regional lymph nodes.

The advance of the minimally invasive tools. I mean, let's face it, the robot is probably the most amazing, sophisticated surgical tool that we've seen created in our lifetime. And for some tumor types, it has demonstrated improvement in outcome and recovery, at least we now have randomized data that shows it really isn't the big benefit that we were hoping for with respect to patient recovery. And it is advanced minimally invasive surgery, particularly for those people who are practicing intrical portal reconstructions.

So what I could say is this is that it remains a part of the arsenal that's out there. There's a learning curve that people have to recognize. And it's been well documented by Dr. Guru and lots of other people involved in the minimally invasive field. If you can accomplish the surgical tenants that have been established without cutting corners, then it probably doesn't matter what technique you use. The reality is, is that we're training a whole generation of surgeons now who are much more facile with these minimally invasive tools. They've lost a lot of their open operative skills. And so the reality is many people have to use the robot in order to do these procedures. That's okay. But just understand the disease, know the surgical tenants, don't cut corners and your patients are the ones that are going to benefit from that.

Ashish Kamat: Yeah, don't cut corners. That's the key message. I mean like I say, patient selection is absolutely critical for a lot of therapies. And when it comes to surgery, surgeon selection is very important because a radical cystectomy done right, whether that's done with a scalpel or a robot or a laparoscopically is what our patients essentially need. And it's really important as you said, that people don't try to cut corners just to adopt the latest modality, especially when all the data suggests that there is no true benefit to the patient other than maybe decreased blood loss in some hands. And with the ERAS pathway, there's equivalence in hospital stay and stuff.

Lastly, and I just want to ask you one last open-ended question since we will have to wrap this up in a minute or so, what is the key development that you are looking forward to other than of course getting rid of COVID and meeting in person in 2021?

Bernard Bochner: Well, I think probably the most exciting thing, Ashish, that we're seeing now is that there are patients who are failing local therapy, who don't respond to first-line systemic therapy who are still around now. And it's because of the introduction of some of these other amazing systemic options that we have. Whether they're targeted agents for patients with FGFR3 mutations or they're in that subgroup of patients that respond to the IO drugs.

I mean, we're now seeing patients two, three years and beyond on these drugs. And it's wonderful. It feels like a huge win because I'm sure that you, and like all surgeons when we see a recurrence, it feels like a failure on our part, and obviously we're there to help cure patients and so to see them around. To see them responding to these, even if we have to piece it together with a whole multitude of agents, it's been so gratifying and truly enjoyable to work with our medical oncology colleagues. And it really feels like as a team, we are making progress in this disease. And after 20, 30 years of working with these patients, it feels like progress, which is exciting.

Ashish Kamat: Once again, Bernie, thank you so much for taking the time to share your thoughts with me and our audience. It's always fun chatting with you. Stay safe and stay well.

Bernard Bochner: True pleasure, Ashish. Thank you so much and everybody, stay safe.