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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston, Texas. And it is my pleasure to welcome a friend, colleague, and an expert in the field, Dr. Yair Lotan from UT Southwestern Medical Center up in Dallas. Dr. Lotan really needs no introduction to this group. He's been featured on many of our sessions, educational for the audience. And today we thought we would invite Dr. Lotan to talk to us about his experiences and some tips and pearls about blue light cystoscopy in the hospital setting. Yair, with that I'll let you take the stage.

Yair Lotan: Great. Thank you very much. So, I'm going to focus on blue light Cysview and talk about the TURBT aspect of care. I should note that I do research and consulting with Photocure, and I've also done research with STORZ, and those are the two main companies involved with this technology. The TURBT is the first-line treatment for bladder cancer, and we all recognize that improvement in the quality of TURBT could lead to reduced risk of recurrence and subsequent cost savings. We also recognize that restaging TURBT is an important component of care, especially for patients with high-grade Ta and T1 disease because of the risk of residual cancer and risk of upstaging to muscle-invasive disease.

The AUA/SUO Guidelines note that complete TURBT is critical in the management of non-muscle invasive bladder cancer for accurate tumor type, staging, grading, and optimization of patient outcomes. They specifically note that enhanced cystoscopy in patients with non-muscle invasive bladder cancer, and the clinician, should offer blue light cystoscopy at the time of TURBT if available, to increase detection and decrease recurrence. And this is a moderate recommendation with an evidence strength Grade B. They also note that in a patient with a history of non-muscle invasive bladder cancer with normal cystoscopy and positive cytology, a clinician should consider prostatic urethral biopsies and upper tract imaging, as well as enhance the cystoscopic techniques, including blue light when available. Other options are ureteroscopy and random bladder biopsies and this was an expert opinion.

So what is blue light cystoscopy with Cysview? It's a technology that is a diagnostic tool to aid in the detection of bladder cancer. It involves instilling hexaminolevulinate which is a photosensitizing agent into the bladder. It sits in the bladder for approximately an hour and is preferentially accumulated intracellularly in bladder cancer. And these protoporphyrins will appear fluorescent pink or red under blue light illumination. And this is in contrast to normal mucosa, which typically appears as blue, and images on the right show the same patient under white light and subsequent blue light. And you can see the lesion, which was difficult to see with white light, enhancing as a pink lesion with blue light. It requires specialized equipment, which is currently only available through STORZ in the U.S. whose special light source, light cable, camera unit, and then this monitor setup obviously needs to be purchased by the hospital prior to utilization. Cysview is a kit that is purchased separately and instilled like I said, one hour prior to the procedure. So why do the guidelines recommend the use of blue light?

There is strong evidence for improved detection of carcinoma in situ. There is good evidence in randomized trials in reductions in recurrence. There is some evidence for lower progression rates. The evidence currently is weak, but improving, and there is potential for improving costs, but I'm not going to focus on that. That is still somewhat controversial and depends on the population you use the blue light for. So there is an extensive body of evidence, including five multicenter phase three studies in the U.S, Canada, and Europe with over 1800 patients in these trials.  It has shown significant improvement in the detection of papillary tumors, up to 29%. It leads to improve tumor resection and leads to more appropriate treatment recommendations. Here are the various trials and all of them consistently show improved detection of patients with Ta and T1 tumors ranging from 16% to over 40%. All of these were statistically significant. This meta-analysis that was published, looked at different cancer types in different risk groupings, whether or not high-risk, intermediate-risk, or low risk, there was always better detection with blue light compared to white light alone.

This was statistically significant for all, but low-risk where the number of patients was relatively low. It also held specifically true for carcinoma in situ where there was a dramatic increase in detection rates with blue light. When looking at a patient-level analysis, you can see about a 22% improvement overall, 18% in primary, and 26% in recurrent tumors. And again, a significant risk in high and intermediate-risk patients. The numbers are too low in low-risk to find a dramatic improvement. And in patients with carcinoma in situ, there was also uniform improvement in detection. There were several studies that have looked at the effect of intravesical therapy, and prior intravesical therapy had no effect on tumor detection with blue light.

When looking at studies that looked at 12-month recurrence rates, there was a reduction in recurrence in patients who underwent blue light, an overall 34% recurrence rate compared to 45% in those who underwent white light. This was statistically significant and again, significant for both primary and recurrent tumors, as well as for high-risk patients. As far as long-term follow-up, there was a study close to four and a half years, and there was about a seven-month difference in time to recurrence between blue light patients and white light patients. And then the evaluation of progression-free analysis that you, Dr. Kamat published, you can see a trend towards a reduction in progression rates. And some of it has to do with how you define progression, but in either case, one can imagine that if you have enough patients over time, it will be shown that if you can reduce recurrence, some of those patients who recur do progress.

And so there is a high likelihood that blue light can help in this area. Even if the studies don't show it quite yet. Adverse events are quite rare, they are obviously a contraindication of people who have a reaction to protoporphyrin IX, but otherwise, the rate of adverse reactions is very low. And remember these were patients who also had a TURBT, so it's not surprising some of them had dysuria and hematuria. That concludes my presentation, and as mentioned, there is strong evidence to support the use of this technology, and it is supported by the guidelines at this time.

Ashish Kamat: Thanks so much Yair. We are also joined by Dr. Daniel Parker, who is a Urologic Oncologist at the Stephenson Cancer Center and Professor of Urology at the OU Center in Oklahoma. And while Dan is firing up his slides for us, because he is going to cover the office setting, let me ask you, Yair if you could share with the audience, essentially what are the top three indications for blue light in your practice in the hospital setting?

Yair Lotan: So generally speaking in patients with a history of carcinoma in situ, there is definitely a high rate of utilization and benefit. In patients with multifocal disease, I also like to use it.  If I hadn't used it, or if a patient gets referred in who had a prior TURBT and is going for a repeat TUR and if it hadn't been done the first time around, I do like to use it the second time around. It helps me do a better resection. And also if they have concomitant carcinoma in situ, I think it's important.

And then in patients with positive cytology in a normal white light cystoscopy, most of those cases I will do them, these procedures in the office, but if they are being done in the operating room, then I think that that is definitely useful to identify. I am a strong proponent of using it in the office. So I would argue that if you found a lesion and only in the office with blue light, you are going to have to do it in the operating room using blue light, so you could find the same lesion again.  So I cheated, I added a fourth, but those are really my main uses.

Ashish Kamat: No, that's perfect.  Yeah, that was actually a great segue for Dr. Parker to give us his presentation. And then we will have a quick little round table discussion at the end. So with that Daniel, now the stage is yours.

Daniel Parker: Hello, thank you for inviting me to speak today. I really appreciate it. I do just want to mention very quickly that I have done some consulting and advisory board work for Photocure, who is the maker of Cysview that we are talking about. And I've been sort of asked to discuss the evolution of this technology and bringing it from primarily the operating room setting to the office-based setting. And we just heard a very comprehensive talk about how blue light cystoscopy has been demonstrated to be very efficacious for non-muscle invasive bladder cancer in the hospital. And I think it's only natural now that we sort of turn our attention to the ambulatory setting where I think this technology has the capacity to make a big impact in the lives of our patients. So what a lot of people may not realize is that the data for blue light cystoscopy in the office is, is really quite robust and includes a prospective randomized control trial that was published in 2018.

In this study, our center participated in this study, I think 17 centers in total participated in the study. It enrolled more than 300 patients, and it was unique in its design in that all of the patients who were randomized to receive a blue light flexible cystoscopy exam, sort of acted as their own comparator arm in the sense that everybody underwent comprehensive white light and blue light exams. It was also unique in the sense that all patients who were determined to have suspicious lesions in the surveillance setting were then taken to the operating room where they had another blue light and white light exam, in addition to TURBT to confirm the pathologic nature of those suspicious findings. And I would say that there are really two primary takeaways from this important trial that urologists really should have in their mind, which is number one, that one out of five bladder cancer recurrences in this trial were detected only with blue light cystoscopy.

And that was the study's primary endpoint. And I think certainly we would all agree that missing one out of five potential bladder cancer recurrences is certainly eye-opening. Additionally, the study's secondary endpoint looked at the proportion of CIS lesions that were discovered only with blue light. And in this trial about a third of CIS lesions, again were identified only with blue light cystoscopy. And that also has great implications for the treatment of our patients. So in terms of level one evidence supporting the use and the transition of this technology into the office, I think certainly there is a case to be made oncologically speaking that it makes a lot of sense. Previous trials in blue light cystoscopy and the flexible trial as well have looked at the rate of false positives with the blue light cystoscopy. Certainly, the most recent trial demonstrates that in terms of false positives, flexible blue light cystoscopy is no worse than white light cystoscopy.

I would say just as an anecdote, and this is something we can discuss in the round table would be that, if this technology is coupled appropriately with office-based biopsy and fulguration, false positives really aren't too much of a clinical problem, even though 1 out of 10 may seem relatively high. I think it may be a problem for folks who have to adjudicate these types of lesions by taking their patients to the OR and putting patients under general anesthesia. But I think as the contemporary practice utilizing this in the office has evolved, these false positives really don't tend to be a huge clinical problem.

In terms of safety, as Dr. Lotan mentioned, there have been numerous low-grade adverse events that have been demonstrated repeatedly throughout the clinical trials with Cysview. There were absolutely no severe adverse events in the flexible blue light trial that were recognized, although a couple of adverse events that were not previously mentioned including erythema and some patients who developed a mild rash were noted in the flexible trial, again, none of these manifested as severe reactions. One of the other quite important assets of this flexible blue light trial was that the investigators actually thought ahead and incorporated patient-reported outcome measurement data into the design of the trial.

And they used four different validated surveys and included patients who were randomized to undergo the blue light evaluation. And so, because this was built into the trial, the response rates for these surveys were really quite high, and from that data, a couple of different publications have been released. The first was regarding something that I think all people who are looking to bring this technology into the office worry about, which is patient discomfort and patient pain. And I think what the data from the flexible blue light trial shows is that really this procedure is quite well tolerated. There certainly doesn't appear to be any major added discomfort, just using the blue light cystoscopy as compared to a normal cystoscopy. These are the mean pain levels that they reported, so some patients are going to report higher levels and some are going to report lower levels. But in general, I think the takeaway is that this is very well tolerated. The other questionnaires that were reported upon sort of deal with, what I consider to be sort of surrogates for patient satisfaction, right? So overwhelmingly, patients who undergo flexible blue light cystoscopy in the office feel that it is worthwhile, they would do it again, which is important because some of these patients will need to do it again.  For those of us who take care of a lot of patients who were in the intravesical therapy pathway, they will have multiple rounds through blue light cystoscopy and surveillance, and in general, a lot of them would recommend it to other patients who are diagnosed with bladder cancer.

I would say something that is not explicitly stated on this slide, but makes sense to me now that I've been performing it in the office for some time, is that pretty much across the board, the satisfaction scores are higher for flexible blue light cystoscopy in the office than they are for the OR and this is something that has been hypothesis-generating for us here, is that avoidance of general anesthesia, especially for small or indeterminant lesions, is something that can be a great patient satisfier and I think that may be a little bit of what we are seeing in the contrast between the satisfaction scores for the surveillance setting and the OR setting.

The Bladder Cancer Advocacy Network also did a social network or social media survey, and they looked at responses from 446 people. And the general outcome from this non-scientific study was that patients are out there looking for providers who can offer blue light cystoscopy. And I think as we go forward in our experience enhances with flexible blue light, they will be looking for providers who are providing this in the office without general anesthesia as well. Dr. Lotan and his collaborators earlier this year published what I consider to be the first sort of real-world assessment of flexible blue light cystoscopy. But there were two things about this data that I think is important to share just based on my own experience using this in the office.

And that is number one that, yes in the real world, we continue to replicate the findings of the major trials, which is that the blue light cystoscopy does what it is supposed to do. It does diagnose cancers that otherwise would be missed with just white light cystoscopy by itself. The second important thing about this first line, and you can sort of see this from Dr. Lotan's experience, is that not all blue light, positive lesions that are detected in the office have to be adjudicated in the operating room. Some of these lesions can be satisfactorily managed in the office setting, again if the blue light cystoscopy is coupled with the appropriate fulguration and biopsy equipment that is needed to do this. And so this is again, a potential avenue for improving costs and improving satisfaction associated with patients who can have these lesions dealt with satisfactorily outside of the operating room setting.

The last thing I will just mention is just that in my practice, and it appears this way with Dr. Lotan as well, more and more, I am using the blue light to adjudicate sort of indeterminate or discordant findings. So currently I'm still in the data gathering aspects of my practice and use of this technology, and so I biopsy a hundred percent of discordant findings between white light and blue light, but you can see that most of these lesions end up being benign, not all of them, but most of them end up being benign. And without the ability to adjudicate these in the office, these are all patients who may be subjected to general anesthesia and operative interventions, essentially for benign findings. And so I think that this is another area that as Dr. Lotan alluded to, that we can have impacts on cost and patient satisfaction using it in the appropriate setting.

So, the takeaways for office place blue light cystoscopy, as I see it is that, we can use this technology to help save our patients from unnecessary general anesthetics and operative interventions, because clearly, the lesions that we are identifying with blue light cystoscopy are generally small, and many of them can be eradicated satisfactorily in the office setting. I think that coupling blue light cystoscopy with office-based biopsy and fulguration is absolutely necessary in order to maximize the true value of this technology. I think in the COVID-19 era, this is certainly a path forward for urologists to start thinking about how we can help our patients avoid high-risk healthcare environments. It helps them avoid general anesthesia which I think will be borne out as a big patient satisfier.

And I think the ability to instantaneously adjudicate and eradicate suspicious or indeterminant lesions or discordant lesions actually ends up making non-muscle invasive bladder cancer a lot easier to treat for the urologist. And I'll know, anecdotally that I derive a lot of peace of mind from knowing that I spared a patient an operative intervention for a small indeterminant lesion. So I'm hopeful that as we continue to work and publish data about really how this technology impacts the office setting, that we will be able to incorporate some of our new practices into new clinical algorithms and guidelines that I'm sure will be forthcoming. So that's sort of my take on the office-based blue light cystoscopy. I really appreciate the invitation once again.

Ashish Kamat: Thank you so much, Daniel. It's funny since we started using blue light, gosh, back in 2008, there has been so much of an evolution, not just in the actual optics of the initial scope, but just overall in the flow and the process. And now obviously with the flexible scopes, we can use it in the office. So I want to thank you for kind of summarizing that data for our audience. Let me ask both of you, but maybe I'll have Dr. Lotan answer this question because he sort of alluded to this earlier in his indications for patients for the OR with blue light. So you earlier heard Daniel say that if he sees lesions with blue light in the office, he will try to take care of them in the office setting under local anesthesia itself. And your belief, I believe from times that we've chatted earlier, is that those patients should go to the OR and the blue light allows you to then kind of identify maybe even more lesions in the OR setting. Can you share with us your thoughts?

Yair Lotan: Yeah, I know, maybe it's best for me to clarify, my comment I think was that twofold, first of all, if you do see something in the clinic and you feel like you need to go to the operating room, then you obviously need to do blue light in the operating to be able to identify the same lesions. But no, I share the belief that if you can treat it in the office, then the office setting is a better one because I truly believe that for a lot of our older sicker patients, the risk of anesthesia is higher than the risk of the biopsy itself. So I do far more office-based procedures than I used to, in part because I feel patients actually tolerate it more than I initially anticipated they would.

And the fact is that many of these indeterminate or small lesions are readily managed in the office setting. Certainly, anything over a centimeter, a centimeter and a half, or a patient who has five or more lesions is more likely to need to go to the operating room. But if the patient has a lesion or two under a centimeter or a red patch, and I'm just trying to determine if they are BCG unresponsive or not, and confirm its carcinoma in situ, I do prefer to do it in the office setting.

Ashish Kamat: Okay, great. Thanks for clarifying that.  One thing that we often have to face is, how will the blue light paradigm affect the flow of our patients? And all of us are doing anywhere from 14 to 20 cystoscopies in the clinic on some busy days. With that in mind, could you share with us, and Daniel maybe I'll have you start, and then, Yair you could wrap it up. Could you share with us which patients you select amongst those coming for surveillance cystoscopy for blue light, and which patients would you use something like narrow band imaging or Stuart's enhanced imaging which is available and doesn't kind of interrupt the flow of the practice? Because that is one of the questions that folks that are trying to incorporate this into their practice face very often, which patients really truly need it, leaving aside the guidelines and what we have published and others have published, practically which patients should have blue light in the clinic?

Daniel Parker: Yeah, thanks. So, in my practice, about 75% roughly of the patients that I've done blue light on so far have been in the intermediate or high-risk AUA category. So in my mind, it's for those patients who stand to risk a change in their AUA risk category or stand to be deemed BCG unresponsive, I think that they are going to derive the greatest benefit from the addition of this technology, right? And so some of that is risk stratification that is not in the guidelines, it's knowing what the patient's bladder was like at their prior TURBT, knowing the duration of intravesical therapy for that patient. But generally, if I think that an incoming patient has a moderate to high risk of either a change in risk category or being deemed BCG unresponsive, then I think I try to offer those patients to blue light cystoscopy evaluation the most.

Clearly, for patients who are in the low-risk category, who maybe don't stand a great risk of being upgraded or having their management changed, the blue light cystoscopy, is probably overkill.  I think that to maybe go a little bit outside of the question a little bit, one question that I have sort of pondered amongst our staff and residents here at OU is, could this technology actually be opened even farther into the AUA high-risk hematuria candidates?  We know that blue light cystoscopy is FDA approved for the detection of bladder cancer, and so it stands to reason in my mind that patients who are in certain risk categories without a diagnosis of bladder cancer may benefit as well. But so in general, I think my general approach to it is that I try to think about which patients are really the highest risk for a change in management. And those are the ones that I target for use with the blue light.

Ashish Kamat: Right, thanks. Yair.

Yair Lotan: I'll echo that, so first of all, using it when there is the highest chance of having cancer is really, probably going to maximize its utility. So for me, patients primarily, intermediate and high risk, three months after TURBT is the highest risk. For me, a patient at six months after starting BCG, when we are trying to determine if they are BCG unresponsive and where it may make a difference in management, that is an important time to see if they still have persistent CIS. I mean in the academic setting, I have Merck 676 open, so at three months you might make a decision because then they would be eligible if they had persistent disease after induction BCG. But I think that the theme that you are getting is that if you think you'll change your management based on it, that's the best time to do it.

If I have a patient with low risk and I see a small bladder tumor, and I'm going to bring him back, maybe I see a couple, then I'll bring him back for a blue light cystoscopy with biopsy and fulguration. And part of the reason I bring them back is that I will give them intravesical chemotherapy at that time, just like I would in the operating room. And so then I can do a more thorough office biopsy and fulguration and instill gemcel right afterward.

So if they live very far away or they're frail, I might fulgurate a biopsy that day. But a lot of times that is more disruptive for your clinic than having them come in an hour early and get an installation of cysview, which takes my nurse five minutes or less to do. So for that reason, an office biopsy, and fulguration, I do like to bring them back to do the blue light at that time, but a patient who is a couple of years out, it's probably not going to be the best candidate for blue light, but in the first year for high risk, in the first six months for intermediate-risk, I think those are optimal patients.

Ashish Kamat: Right. Thanks again.  Obviously with you guys, I could sit and chat forever, but in the interest of time, I'm going to ask one last question and whoever wants to tackle this, please go ahead, and then we'll wrap it up. And this is a question that we often get from people about the whole reimbursement aspect as it has evolved over the years, just a short summary for the listening audience, what is the current status of reimbursement for blue light in the different settings?

Yair Lotan: Well, I can answer pretty quickly. The urologist never makes more money for doing blue light.  In the hospital-based setting, the hospital will get paid extra money for blue light TURBT beyond the reimbursement for the Cysview. The Cysview is reimbursed at all settings separately, but for the urologist, there is no additional payment for doing the technology. I think the good news is that it doesn't take very long to do it, and it is better for the patients and there are many things we do that are better for the patients that don't necessarily get reimbursed. But maybe that is one of the challenges in expanding the blue light utilization in the office because there is a capital expenditure that is not directly paid for, other than if patients come to seek you out for the technology and you do additional cystoscopies, but that's something that hopefully will lead to added reimbursement in the future but as you know, that is a complicated situation to get more money for what we are doing.

Daniel Parker: I was just saying that has been my experience as well, which is a cystoscopy in the office is billed as a cystoscopy in the office. There is a special, "A" code for insurances reimbursing the cost of the product, and we have not had issues in our clinic with the rare exception of having insurance companies be forthcoming about reimbursing the cost of the cysview kits.  So, but Dr. Lotan is absolutely right, that you won't get anything more on the physician side, just for performing the blue light cystoscopy. You might identify more lesions for fulguration and biopsy using it, which could translate into higher billing codes, but you won't get anything more for a standard blue light cystoscopy than you would with a regular white light.

Ashish Kamat: Great. Once again, thank you both for taking the time from your busy schedules. This is really, really useful and helpful to our audience and in these difficult times again, stay safe and stay well.

Yair Lotan: Great, thank you so much.

Daniel Parker: Thank you.