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Sam Chang: Hi. My name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and we have the honor and privilege to have Dr. Vignesh Packiam. Dr. Packiam is, actually, an associate professor of surgery at the Rutgers Cancer Institute, but he really doesn't need any introduction to those of you who are familiar at all with anything going on with urothelial carcinoma or with urologic oncology.

We've asked Dr. Packiam, actually, to give us an update on the role of blue light cystoscopy, specifically in the setting of actually initial evaluation after induction therapy for higher risk non-muscle invasive bladder cancer. So, Vignesh, I'll turn it over to you and thanks again for I know will be a very enlightening talk.

Vignesh Packiam: Thanks so much for having me. And this is a topic that I'm really interested in and something that we've looked at for a while. So I appreciate you having me to talk about it a little bit. And a brief quick shout out, this is the lead author for this study. The first author was Ian McElree, who's one of the residents who'll be starting at Vanderbilt next year. Total superstar, and I really enjoyed working with him on this. So the title of this is the role of blue light cystoscopy and additional operative evaluations during first surveillance after induction therapy for high-risk non-muscle invasive bladder cancer.

We know that overall, thankfully, our outcomes for non-muscle invasive bladder cancer are improving. We see this both with our therapies that we've used for a long time and with the slew of new therapies that are in development. So even if you look at something as simple as BCG in patients who are BCG unresponsive, the whole reason the term BCG unresponsive was coined was because there's a low likelihood of additional BCG helping those patients and historical series have fairly consistently shown that recurrence-free survival after additional BCG is about 20% to 30%.

Now there are newer contemporary series in select populations that show that in well-selected patients giving additional BCG to BCG unresponsive patients can actually result in significantly higher recurrence-free survival. And we also see that obviously with all of the new treatments that are emerging, and we're hearing about these at our meetings and we're seeing the publications, compared to the older FDA-approved agents, the newer ones that are approved and the new emerging treatments seem to have significantly higher one-year complete response rates.

So it's very likely that we're going to be using repeated treatments in patients with non-muscle invasive bladder cancer. We're going to be able to do more effective bladder sparing over time. And that raises a question in my mind of do we need more optimized surveillance protocols? Is standard cystoscopy with white light and cytology sufficient to pick up what is going on in the bladder and importantly what's going on in the upper tracts or prostatic urethra in men, as we have patients that are living longer with non-muscle invasive bladder cancer over time?

The guidelines recommend pretty clearly the standard surveillance should be white light cystoscopy typically done in the office with cytology. They casually say to use blue light cystoscopy when available, but they don't make a strong recommendation for this. They do say you can consider FISH, UroVysion FISH testing, especially for patients who have gotten BCG. And then you can consider a variety of other biomarkers that are under development. But there really aren't strong recommendations about this. And again, the question that I asked is is this enough, especially when we have patients surviving with bladder cancer for a long time?
So we set out to address this question by looking at a cohort of patients treated at University of Iowa. And these patients actually, universally had enhanced restaging protocols after induction therapies. We had a pretty heterogeneous cohort of patients who were treated or who were evaluated after having undergone one unique induction, two unique inductions, or three or greater.

What did these enhanced restaging procedures entail? Basically, a standard cystoscopy, which is white light evaluation with cytology. But in addition, all of these patients also had blue light cystoscopy, mapping bladder biopsies, typically of five regions in the bladder, retrograde pyelograms, upper tract cytology, and prostatic urethra biopsies. So this is really a unique cohort.

So this figure illustrates what we found. Of that almost 300 patient cohort, 68% had negative standard cystoscopy with all the other additional evaluations being negative as well. So around 70% of patients, totally negative. 19% of patients had positive standard cystoscopy. This means if you were to look in their bladder in the office under white light or trying to pick something up with cytology, you're going to find cancer in those patients. And then we found that 13% of patients had a negative standard cystoscopy, but one of the additional restaging components did find occult or hidden cancer.

And when we stratified what tests were finding these positive results, the majority of positive findings were found on blue light cystoscopy. Next was mapping bladder biopsies, and then, to a lesser extent, sometimes we had upper tract cytology, prostatic urethra biopsy, and retrograde pyelograms being positive. So those are extra-vesical sites of disease.

Next question, was this the same in all patients, or did it matter how many treatments you've gotten before? And we did see a nice dose-response relationship between extent of prior treatment history and risk of finding things with these additional restaging components. So when you look at each of these, looking at blue light cystoscopy, if someone had one or two prior induction courses, the risk of finding cancer when white light cystoscopy is negative was about 6% to 7%, but you can see that if someone had three or greater unique induction treatments before, that jumps up to almost 20%.

Similar kind of trend with mapping bladder biopsies, and this illustrates beautifully that mapping bladder biopsies are not quite as rigorous as blue light cystoscopy. 2% to 4% of patients with one or two prior inductions having hidden cancer, but 8% if you've had three or greater. And then I think the most interesting thing is really these extra-vesical sites of disease. If someone's had one or two prior intravesical inductions before, very low risk of prostatic urethral biopsies or upper tract evaluation finding anything abnormal.

But if someone's had three or greater intravesical inductions before, there's a significant chance of finding something either in the prostatic urethra or in the upper tract. We did a multivariable analysis, trying to control for age, year of treatment, and presence of CIS, seeing if number of treatments would predict if any one of these additional components could find cancer. And we found clearly that patients with three or greater prior inductions did have a greater risk of finding something with these additional evaluation.

So we put together a little summary here. I wouldn't say this is ultra evidence-based, but based on our paper these are recommendations that we felt that we could make. One, I think it's reasonable to consider a risk-adapted surveillance approach, rather than a one-size-fits-all approach, as sometimes may be done. Blue light cystoscopy, we do use it fairly routinely in our practice, and in especially in patients who have had carcinoma in situ before we do recommend that those patients undergo their first initial evaluation with blue light cystoscopy.

So I'm actually taking any patient with history of CIS after their first induction to the operating room at their three-month evaluation for blue light cystoscopy, rather than just doing it in the office. Expanded use of upper tract and prostatic urethral evaluations, these are really not strongly recommended in the guidelines, and I think there's a lot of heterogeneity in practice, but I think that this data clearly shows that if you've had three or greater prior intravesical inductions, it is a good idea to look at the upper tract or look at the prostatic urethra.

And then I think these findings can and probably should be incorporated to future trial design. There has been increasing adoption of random bladder biopsies at the 12 month time point for patients with CIS when we're designing clinical trials, but I think we could go a step further especially if patients have had significant pretreatment history.

So in summary, again, we found increasing occult bladder and extravesical disease as patients had increasing pretreatment history. History of CIS, in particular, can result in finding more cancer with blue light in the future, which makes sense. And then we recommended consider using blue light when a patient has a history of CIS or a full enhanced restaging procedure if the patient has had extensive intravesical therapies in the past. Thank you.

Sam Chang: I think that was a fantastic, very, very question-provoking in terms of doing that. So I have three broad categories of questions. The first is the use of blue light cystoscopy in this cohort of population. With the blue light, and I'm going to focus on that 13%, 60% had nothing, the initial smaller percentage had found on white light, et cetera. So this 13% that really focuses on those that we would normally have missed and yet found disease. Were they all CIS? Were there actually some papillary lesions found with the blue light?

Vignesh Packiam: About 90% were CIS. That's a very good question. As you may have found, sometimes with the pathologist, sometimes we see something that totally looks like CIS but they're calling it a small papillary fronds.

Sam Chang: Sure. Sure.

Vignesh Packiam: So for the most part, it looked like CIS, and pathologically, most of it was CIS.

Sam Chang: OK, secondly when I historically have not been a big believer of retrograde pyelograms-- actually, or of renal pelvis washes because I worry about contamination, different things like that with your upper tract. So I was very intrigued. Did it makes sense over time if you're giving treatments and they continue to tend to recur, there may be something in the upper tract. And I have found that more recently. But with the upper tract cytology positive patients that you found were they all just upper tract disease positive, or were there, in fact, a combination of both bladder cancer findings as well as upper tract findings?

Vignesh Packiam: Yeah, that's a really good question. I would say probably a third of patients were positive at both sites, but 2/3 of them did have isolated disease in the upper tract. And we found that a lot of these patients had CIS or some type of changes in the distal ureter. And that could be a sign that your intravesical therapy is working in the bladder, but it's not able to access the upper tract enough.

Sam Chang: Yeah, I know. I think that cohort definitely is something that you'll want to know because ultimately I really don't know what to do with CIS of the upper tract. That's like my third bucket of questions is what do we do next? All those things. But for me the upper tract finding of CIS or positive cytology without anything endoscopically visible to me is always a tough treatment dilemma. What do you all do in terms of those patients at this point?

You don't even have to talk about these particular patients, but those without clear disease in the bladder, with positive upper tract cytology and yet nothing clear or perhaps even there's some erythema, et cetera. What are you all doing now with this small, difficult to treat cohort of patients?

Vignesh Packiam: Yeah, great question. My time at Iowa that was almost like another mini fellowship I had with Mike O'Donnell. And he was very aggressive in treating those patients. He would actually recommend a nephrostomy tube. And we had really nice results treating the upper tract with Gem/Doce for those positive cytology. We had a 90% conversion rate of the cytology from positive to negative, and that was durable out to one year.

So I think if you and the patient especially are willing to be very aggressive in treating that, you can convert that to becoming negative. What if there's a little whiff of papillary disease. That's a really tough question. Shameless plug. We're actually opening a new clinical trial looking at sequential gemcitabine followed by Jelmyto for small, low-volume, high-grade upper tract disease. That's papillary. I think that's a totally underserved population. And we're doing a lot of not for use on those patients where they need something that's better.

Sam Chang: Now, I think that's fascinating. Because there's no question, we're going to start pushing the boundaries of ablative therapies and extending them to larger lesions, to higher-grade lesions, to different locations within the upper tract, et cetera. So I love the thought process behind let's give a chemotherapeutic agent that has had some benefit and high-grade disease, and then let's combine it with something that we know sticks around longer and has shown benefit in low-grade disease. So I think that's really a fascinating study.

The last bucket of, again, study protocols. But I would love for you to tap into, and maybe we'll be able to utilize Dr. McElree's combination of you and Iowa and us at Vanderbilt, is do we know or are there studies, and you may not this, but are there differences in clinical outcomes of those patients that are found by blue light cystoscopy only versus not found with white light cystoscopy? Because my theory that we've discussed a little bit before is that there's a cohort of CIS patients clearly that progress. You know that.

Vignesh Packiam: Yeah.

Sam Chang: But I think there's really a significant cohort of CIS patients. I'm not going to give a percentage, but that will have CIS forever and will do OK and will not have any issues. And it's just it's these patients that, like you say, will have different treatments and this or that. But the hope is long-term. They never, even with CIS recurrences has never develop something progressive, metastatic, et cetera. So first of all, I don't know if you guys have looked at blue light outcomes, blue light only outcomes versus those found with conventional. And if not, maybe that's your next research project for you guys.

Vignesh Packiam: Yeah, that's a very insightful question. I think a great future research project. To my knowledge, I don't think that's been nicely teased out yet. And whatever you want to call it, selection bias, stage migration, Will Rogers effect, clearly, I think, we're picking up more focal CIS, whether it's in the recurrent setting or in the initial diagnostic setting. Perhaps that's why some of our new contemporary treatment outcomes are looking better than they used to. Maybe some of this is just stage migration. We're picking up more tiny little bits of CIS. So I think that's a really, really good question. I'd love to work on that in the future.

Sam Chang: Along that line, the next question would be the random biopsy people, those that have white light cystoscopically normal appearing mucosa that are biopsy that end up having microscopic CIS. I think those patients as a whole tend to act differently than those that have significant carpeting that you can see, et cetera. So just some research projects. But I love also the differential--

Look, if you have more therapies, you're more likely to find disease in one of these advanced metric evaluations, the upper tract, the blue light, et cetera. And I also very similar to you after that initial induction course especially with the CIS patients or those with high-volume Ta, honestly, I tend to automatically or almost by practice pattern take them to the operating room and do a blue light evaluation and biopsy. But obviously, as we evolve with other treatment options, other diagnostics, other urine markers, et cetera, perhaps we'll not have to go to the operating room, but right now that's my practice as well.

Vignesh Packiam: Yeah, absolutely.

Sam Chang: Vignesh, thanks so much for spending some time with us. And always look forward to all your research and look forward to your future projects as well.

Vignesh Packiam: Yeah, I appreciate you having me. Great to chat today.