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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center. I have the honor of introducing Dr. Paul Crispen, professor of urology at the University of Florida. I've known Paul ever since he was a fellow. He has really developed quite a career in clinical trials and has actually focused on urothelial carcinoma as well.

We've asked Dr. Crispen to go over the paper that was recently published, looking at the efficacy or perhaps the lack of efficacy for patients with upper tract urothelial carcinoma that received BCG at the time/around a nephroureterectomy. Paul, it's great to see you and catch up a bit, and thanks so much for spending some time with us. We look forward to hearing you present some of the work that you all have recently published.
Paul Crispen: Well, thank you to UroToday, and thank you, Dr. Chang, for having me present our current study. We all know that urothelial carcinomas most commonly develop in the bladder. Only about five to ten percent develop in the renal pelvis and the ureter, but when they do, they seem to be genetically distinct from the tumors that primarily develop in the bladder. And when the tumors do recur following nephroureterectomy, the tumors are clonally similar in the majority of cases to the tumors that were previously in the ureter or the renal pelvis.

And so, with the established differences in the genetics and the clonality of the upper tract and bladder tumor recurrences, we sought to evaluate if the recurrence pattern following BCG therapy was different for patients with a history of upper tract urothelial carcinoma to those who developed tumors primarily in the bladder.

We compared a cohort of 25 patients developing non-muscle invasive bladder cancer following nephroureterectomy to a matched group of 50 patients with primary bladder tumors. All of these patients received induction BCG, and then our primary endpoints of interest were intravesical recurrence and the development of muscle invasive disease. Here are the results. Overall, when you looked at the recurrence rates, they were quite similar between patients with a history of upper tract disease versus primary bladder tumors following BCG.

However, the patients who had a history of upper tract disease recurred much sooner, an average of eight months, compared to almost two years in patients with primary bladder tumors. When we evaluated a history of upper tract disease and bladder tumor recurrence on multivariate analysis, it was a significant predictor of bladder tumor recurrence with a hazard ratio of 2.5. When we looked at the future development of muscle invasive disease, although it was slightly higher in the group with a history of upper tract disease, it was not significantly different than patients with primary bladder tumors.

This next figure demonstrates the bladder tumor recurrence rates following BCG of patients with and without the history of upper tract disease. The yellow line is those with the upper tract disease. Again, you see that these tumors are occurring more frequently and sooner compared to patients with primary bladder tumors.

Now, we're not the only group to evaluate this question. Two other groups have evaluated this in a similar fashion. The team from MD Anderson and a large collaborative group out of Japan. This table summarizes the recurrence rates in the bladder and progression of muscle invasive disease across all three series.

Now, what I think is pretty striking and interesting about this data collectively is the recurrence rates and the progression of muscle invasive disease are all quite similar between the three series. And so, although this is retrospective data, I do feel that it encourages us to do everything that we can to help decrease these bladder tumor recurrences with techniques at the time of nephroureterectomy. Will hopefully also support future evaluation of other adjuvant strategies to further decrease the recurrence of these bladder tumors in patients with a history of upper tract disease.

Thank you, Sam.

Sam Chang: Paul, that was fantastic. I think some take-home messages for all of us that treat bladder cancer patients, as well as those who treat patients with upper tract disease, that higher likelihood of a sooner recurrence for patients with upper tract disease, I think that there are times where we forget about the bladder in people who've had upper tract disease. It tends we're so focused on we've got everything out and that the renal fascia's okay and that the other kidney looks okay on upper tract imaging, but paying close due diligence. That timeframe you actually discussed, that within eight months was the basically median time recurrence, I think is actually really important.

Second take-home message clearly is, you know, BCG, it's still effective but may not be as effective and not to continuously give more and more BCG in hopes that it may actually be helpful in these patients. That to me were two take-home messages from this.

Tell me, what at the University of Florida do you all do at the time of nephroureterectomy, or perhaps at the time of ureteroscopy, for patients with upper tract disease? Tell me some of the strategies that you all employ then to hopefully prevent these recurrences.

Paul Crispen: Sure.

First, we'll start with the methods of prevention in nephroureterectomy, and the ones that we stick to are clearly outlined in the guidelines, right? And so early clipping of the ureter and patients where you can get distal enough on the ureter, you get into the retroperitoneum, you get the clip across the ureter as early as possible. Numerous studies have demonstrated the benefit of that.

Giving either intraoperative or post-operative intravesical chemotherapy, a single dose. Now the randomized trials that showed the benefit of that used mitomycin or epirubicin. However, we currently use gemcitabine. Again, that's either intraoperative or before the patient is discharged, before their catheter is removed.

Getting on a full bladder cuff. Not just doing a pluck, but doing a formal bladder cuff excision, sewing the bladder watertight, and that enables you to give that dose of intravesical chemotherapy.
I think at the time of surgery, those are the most important things to do that I think everyone can get behind.

Now, at the time of diagnostic ureteroscopy, that's a little different. I think there's some good series out there that show that just going up there and doing the diagnostic ureteroscopy and biopsy will increase subsequent intravesical recurrences. But with our current treatment algorithms, that's hard to get around. We need to know if it's high-grade disease up there, if it's low-grade disease so that biopsy is necessary in most patients.

Now, should we give those patients a single dose of intravesical chemotherapy at the time of ureteroscopy? I think the limited data suggests that we should, and I think those are the patients that we probably forget about the most when doing it. But whenever possible I think that is a good management strategy during the diagnostic ureteroscopy to give the dose of intravesical chemotherapy at that time as well.

Sam Chang: No, I agree with that totally.

Honestly, Paul, it was in one of these discussions it was with both Vitaly Margulis and with Surena Matin who both very similarly tout what you just say. That yes, the data is limited, but that combination of the morbidity isn't that great. It pathophysiologically makes sense, and understanding the positive benefit at the time of radical nephrou, it just... That's something that we're starting to employ as well.

It's funny you say, I just finished literally today, sure as I'm assuming, we completed a nephroureterectomy. We've gone back and forth in terms of what we do. We have switched totally to gemcitabine for years now, honestly. Basically at the time of the surgery, as soon as the catheter's put in, we drain the urine and we do it laparoscopic robotically, and as soon as we've got access, then we put the gemcitabine in. We leave it indwelling. We then actually then drain it and put it in our chemotherapy bucket and then go from there.

Jeff Holzbeierlein has described to me using a three-way catheter, where he'll instill it and plug it. But again, it just seems to make sense. We have switched to gemcitabine as well.

Tell me your thoughts about adjuvant immunotherapy, adjuvant chemotherapy, neoadjuvant chemotherapy for nephroureterectomy. Do you think that there will be benefit in terms of bladder cancer recurrences with systemic type therapies?

Paul Crispen: Hard to say. I think most of my experience with this is not with the nephroureterectomy space. It's with urothelial carcinoma in general, and usually it's patients with stage IV disease. These are the patients that I have a window into that to see maybe how their bladder tumors are responding to their systemic chemotherapy or immunotherapy. Unfortunately in my experience, this is completely anecdotal, especially with immunotherapy, they might have a great response systemically, but I continuously have to go in there and manage their bladder and reset tumors.

Now, how that translates into patients who have a nephroureterectomy, otherwise clinically localized disease to decrease future bladder recurrences? Hard to say. We do know though that with BCG refractory disease, systemic immunotherapy can have a moderate decrease in recurrences in those patients.

There's some benefit. But in my experience, it hasn't been that great.

Sam Chang: Yeah, no, I agree with you regarding the... I would say modest. You said moderate. It's not zero. It's not 50/50 for sure. There have been for sure a handful of patients that have responded and do well and tolerate it and tolerate actually the length of immunotherapy.

Yeah, I do wonder because the reason why I brought that up was because it is concerning that the progression rate to invasive disease in the nephroureterectomy series, the MD Anderson's, yours, the series from Japan, was definitely every series. Just as you said, retrospective, but every series showed that higher likelihood or propensity of progression to muscle invasive disease. Is there something that we can do to alter that actually neoplastic process from non-invasive to invasive? I don't know. I wonder, as we know with the different types of neoadjuvant regimens for muscle invasive disease, we get a benefit. Maybe we can do something to help, just as you say, prevent the cancers from occurring. But if they occur, maybe prevent them from developing into invasive disease. Questions that remain unanswered.

Tell us what's next. What else are you all going to explore with either urothelial or upper tract at Florida? What are you guys looking at now?

Paul Crispen: We had some preliminary retrospective data that suggested that the intraoperative dose of intravesical chemotherapy was better than the post-operative dose. It was 33% versus 17%. That was a retrospective series that we did several years ago.

Well, we did follow it up with a single-arm phase two trial, and it was going to enroll 55 patients. Based upon the O'Brien randomized trial, we were using intravesical mitomycin for this, so everyone got intraoperative mitomycin. Then, we followed them for recurrence. Our primary endpoint was bladder tumor recurrences at one year.

Well, we enrolled well. That at our interim analysis, we failed futility. That study ended early. In our retrospective series, the recurrence rate was around 16%. But in this prospective trial, very careful follow-up, the recurrence rate was 46% at one year. It was very high, yes.

And so, with that, I think, do we get more aggressive? And so my next step is, especially with patients with high-risk disease after nephroureterectomy, high-grade disease, do we have to be more aggressive with therapy that we offer? Is it a single dose? Some people have looked at BCG and that didn't work, but we know BCG might not be the answer. Is this a different agent with a longer dwell time? No matter what the mechanism of increasing the dwell time is for patients with high-grade tumors that we're worried about developing these more aggressive or possibly less susceptible to BCG tumors in the future.

That's the next step I think we want to go in terms of a clinical trial. Hopefully that one I mentioned earlier, we just got the secondary endpoint survival data, hopefully we'll be sharing that one soon.

Sam Chang: Oh, fantastic.

Paul, thank you so much for spending some time with this. I always enjoy, first of all, catching up with you and spending some time with you. But I always like the thoughtfulness and the care that you take for every study that you get yourself involved with and all the researchers, the University of Florida, and how much you've achieved. And so we look forward to those outcomes. I look forward to the next step that you were talking about in terms of, okay, what can we do to really actually improve those recurrence rates for those patients that get a nephroureterectomy?
Thanks again, and look forward to catching up again soon.

Paul Crispen: All right, thank you, Sam. I appreciate it. My pleasure. Have a great night.