Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology and Cancer Research at MD Anderson Cancer Center in Houston. I'm joined today by one of my friends and colleagues, Dr. Trinity Bivalacqua, who is at Johns Hopkins School of Medicine and an expert in many things to do with bladder cancer. Today he's going to share with us his views on the role of blue light cystoscopy in bladder cancer management. Thank you so much for speaking with us today, Trinity.

Trinity Bivalacqua: Thanks, Ashish, and I will do my best to provide some insights into the role of blue light cystoscopy and management of non-muscle invasive disease. Importantly, I'd like to disclose that I am a paid consultant for Photocure and a number of the trials that I'm going to discuss, I was a participant and co-author of the manuscripts.

As it relates to surgical management of non-muscle invasive bladder cancer, the mainstay treatment is a transurethral resection of bladder tumor. This provides the urologist a number of important features that help us determine the aggressiveness of the cancer as well as the pathological assessment. We oftentimes will express and discuss the papillary appearance of the tumor, the locations of the tumor, and the size. We also, after resection of the tumor, we determine pathological assessment, which is used to guide the patient as to management, including radical cystectomy or intravesical therapy.

Non-muscle invasive bladder cancer can be risk-stratified. The AUA has a risk stratification for non-muscle invasive disease, including low-risk, intermediate-risk, and high-risk. This non-muscle invasive disease is a heterogeneous disease process, which has different recurrence rates and progression rates. You can see here in the top panel a low-grade tumor. Low-grade superficial Ta tumors have recurrence rates of upwards of 50%, but their stage progression to a higher stage, including muscle-invasive disease, is relatively low, and we often will quote less than 10%. High-grade T1 tumors, however, have a similar recurrence rate. However, the risk of progression is as high as 20% in patients that are unresponsive.

Risk stratification enables us to personalize our treatment decisions, including intravesical therapy, as well as clinical trial candidacy, as well as early cystectomy. Current predictive models are based on pathological features of the tumor, and oftentimes they underperform. Therefore, a transurethral resection bladder tumor with the ability of the urologist to determine the pathological stage, size of tumors, as well as the number of tumors is absolutely important for us to counsel our patients about therapeutic and next treatment decision-making.

As far as guidelines, the AUA and the SUO put together the non-muscle invasive bladder cancer guidelines in 2016. In this, for the first time, the utilization of enhanced cystoscopy was proposed. Enhanced cystoscopy, or blue light cystoscopy, or narrow-band imaging, was given grade recommendations on evidence strength of the data. Now, blue light cystoscopy was given an evidence strength or a Grade B recommendation, and it was stated in the guidelines that it should be offered to patients that undergo a TURBT when available. This allows you to detect and decrease recurrence rates. It was also stated that it could be utilized for patients that had positive cytology and the clinician would want to consider enhanced cystoscopy techniques in order to determine the source of the positive cytology. Now, the NCCN guidelines in 2019 also added the utilization of blue light cystoscopy as it may help identify lesions that are not seen by white light.

So, what is blue light cystoscopy? It has been FDA approved for utilization in the operating room at the time of a transurethral resection of bladder tumor. On the right side, you could see its set up. Cysview® is given in the preoperative area one hour prior to a TURBT. This is a medication that binds to both cancer cells as well as potentially inflammatory cells, and under blue light or ultraviolet light, you are able to see and detect these additional tumors more easily. This allows you to resect more tumors as well as potentially reduce the recurrence, and this has been shown in multiple randomized controlled trials. Actually, five randomized controlled trials, both in the United States and Europe, have shown this.

Recently, the FDA has approved the utilization of blue light cystoscopy in the outpatient setting for surveillance cystoscopy, and here you could see on the left side how blue light is used for surveillance. It has now been approved for a flexible cystoscopy, and it's the same type of workflow. Prior to a flexible cysto for surveillance for non-muscle invasive bladder cancer, Cysview® is given at least one hour prior to the cystoscopy, and this allows the surgeon or clinician to be able to detect any tumors. We'll go over this more in detail in a second.

So, when we think about bladder cancer, it's oftentimes, as you know, diagnosed with hematuria, pain, and then a patient undergoes a complete diagnostic workup. This includes a cystoscopy. In the current schematic, or workflow, or algorithms, we use blue light cystoscopy at the time of a transurethral resection first, and this allows us to be able to actively resect and detect additional tumors.

So, what I've done is I've put in a case of a patient of mine from a couple of years ago that had high-risk non-muscle invasive bladder cancer. He initially was stage T1, so he had invasive T1 disease, and after a BCG induction, recurred with a Ta and a CIS. He received an induction course of BCG and then a maintenance course of BCG and still had a CIS present on cystoscopy and biopsy.

He then enrolled in a Phase III clinical trial looking at Adstiladrin®, and at the nine-month cystoscopy, after receiving three installations of Adstiladrin®, the white light cystoscopy showed no mucosal abnormalities. However, he had a suspicious urine cytology.

Here we could see a video from the case where blue light cystoscopy was used. Cysview® was given prior to going to the operating room. And this is just a surveillance of the bladder. You could see that the bladder has been resected multiple times. There are a number of scars. Here at the dome, we could see some redness, a lot of hypervascularity, more tumor bases, or scars, but no papillary tumors were identified. Now, remember, his previous history was recurrent CIS. Now you could see we switch over to blue light cystoscopy and perform, once again, surveillance, and you can catch here a little bit of a fluorescence. You can notice that it is very discrete and sharp borders here above the right ureteral orifice. Now we're going to scroll up to the dome, and when we get to the dome, it becomes very apparent that there is what looks like a number of flat lesions throughout the dome. Here you can see very clearly that this is likely the source of his cytology. However, we remember there was this additional area at the trigone.

So, in my clinical practice, what I do prior to resecting or biopsying, I oftentimes will toggle between white light and blue light. We could see here, now that the bladder is less distended, you can actually see that lesion a little bit easier now with the guidance of blue light. What I do is I mark the area where I'm concerned, and there's blue light avid, for me to do the biopsy.

So here we can go back to blue light, and once again, I keep on noticing this one area here that is blue light avid. And the other thing to keep in mind is that that ureteral orifice was also raised a little, almost like there might have been something submucosal. So, then we proceeded at this point to resect the tumors at the dome as well as the tumor at the trigone, or at least the blue light avid lesions.

His final pathology demonstrated CIS at the dome, and at the trigone, there was actually evidence of T2 muscle-invasive disease. So, here's an example of how blue light cystoscopy helped identify and actually stage a patient with a positive urine cytology. The most common indications for blue light cystoscopy, I think in my clinical practice, as well as in most bladder cancer specialist clinical practice, is we utilize it at the initial TURBT. We oftentimes will utilize it at the re-staging TURBT to be able to maximally remove all papillary tumor, or even CIS, prior to intravesical therapy. It also allows us to accurately stage the cancer, and we're learning that it can be utilized after intravesical therapy to detect disease recurrence.

I think the most commonplace that people are using blue light, both in academic settings as well as in the community, is if a patient has a positive urine cytology. And for me, before I enroll any patient into a clinical trial or start them or switch them over to any form of intravesical therapy, I'm using blue light cystoscopy with my restaging exam.

Now shifting gears a little bit to talk about the utilization of blue light cystoscopy for surveillance cystoscopy in patients with non-muscle invasive disease. This was the FLEX trial. This was a Phase III comparative multicenter trial. It was randomized, prospective, and this is what gained FDA approval for the utilization of Cysview® in surveillance. I'd like to also point out that it also gained FDA approval for Cysview® to be used multiple times, so you can use multiple instillations, and it also allowed them to show that you were able to detect CIS.

Here you can see in the study D\design, patients received Cysview®. They went underwent white light cystoscopy in the surveillance setting, and then they were randomized to either toggle to blue light or they were randomized out of the study.

If the patient was randomized to blue light cystoscopy, they then marked or were able to demonstrate what additional lesions were seen on blue light. These patients then went to the operating room usually within a couple of weeks, and received Cysview® once again and underwent a TURBT both under white light and blue light cystoscopy.

The most important point I think we learned from this study is that you could have patients that had just recently received intravesical BCG or chemotherapy. In the trial, we allow patients to have it six weeks or more, and the majority of patients were getting surveillance cystoscopy at about six to eight weeks after finishing intravesical therapy. There are 304 patients. 103 patients went to the operating room for suspicious lesions. Sixty-three of these patients confirmed malignancy. And you could see here the breakdown of the pathology.

I think the most important point to point out here from this study is that at surveillance 20% of patients with recurrent tumors were only found with blue light cystoscopy. And when they went to the operating room, 35% of patients with CIS tumors were only detected with blue light cystoscopy. So, what this tells us is that about a quarter of tumors are being detected by blue light and the majority or a third of patients with CIS are being seen only with blue light cystoscopy. And this is, once again, using this in surveillance setting and then bringing it to the operating room.

Both in the surveillance setting as well as in the OR, this agent is safe with a very low side effect profile. There were no grade 3 or more toxicities.

I'd like to take a second to talk about false positivity because I do think that this is one area where there needs to be some improvement with enhanced cystoscopy. In the TURBT setting as well as in the surveillance setting, the false-positive rates in randomized controlled trials are approximately 10 to 12%. And this is, once again, in patients that are in randomized controlled trials with expert urologists that are very accustomed to using blue light cystoscopy, so this is a very select group.

But let's talk about the utilization of blue light cystoscopy just in the community setting. This is a study that we did at Johns Hopkins. One of my fellows, Filippo, put this together with our pathologist, Andres. Now, the purpose of this study was really to molecularly characterize CIS, but we also wanted to see if blue light CIS-detected lesions were different molecularly.

I'll give you the answer to that right now. They were not, and atypical biopsies that were found by blue light were also no different than that of CIS. However, what we found from this study, which was really important, is that the sensitivity of blue light in real-world practice is only about 50%. So, this is about what most urologists are seeing in the community practice, both in academic settings as well as in the community. So, it has a high sensitivity but a low specificity.

So, how will flexible blue light cystoscopy be used in clinical practice? A number of urologists from around the United States came together and came up with a position statement on this. This was published last year in Nature Reviews in Urology, and the purpose of this was to try to determine how we could use the blue light flexible cystoscopy in patients in the surveillance setting.

The majority of the panel agreed that it would be used mostly for high-risk patients. Ninety-four percent of the panel agreed upon this, that it would be used at either three months, six months, or every six months for the first two years. Fifty-three percent would use it every three months for the first years. But I think that most of the panel agreed that this might be utilized in patients with high-risk non-muscle invasive bladder cancer within the first two years, about every six months. Seventy-one percent of the panel agreed that it would be utilized in intermediate-risk, and this would be utilized typically within a six-month period. And very few people thought it would be worthwhile in low-risk patients.

When blue light cystoscopy is specifically useful, the majority of the panel thought that it would be useful after intravesical therapy in intermediate and high-risk patients within the first two years, and also utilized predominantly for people with positive cytology, where you were looking in the clinic to be able to guide what your next steps would be.

In conclusion, blue light cystoscopy detects additional tumors, which ultimately reduces recurrences. And once again, this has been shown in multiple randomized controlled trials.

The use of flexible blue light cystoscopy for non-muscle invasive bladder cancer surveillance in clinical practice remains to be determined. I do think that there may be some barriers here as it relates to obtaining the equipment and getting it into a good workflow for your surveillance patients. However, there clearly is a number of patients, specifically those patients with high-risk disease, that would benefit the most for this technology. Thank you.

Ashish Kamat: Thank you very much, Trinity. That was an excellent overview of everything that anyone might want to know about blue light cystoscopy. As you know, I'm a big proponent of enhanced cystoscopy for bladder cancer as well. We put out an editorial recently that made the point that in bladder cancer, for example, there's tons and tons of courses and videos on, for example, a robotic cystectomy, but not as much on how to do a basic cystoscopy TURBT, how to do blue light in general, so it's a huge unmet need.

But for the purpose of the next, say, five, seven minutes, let me put on a different hat and ask a few questions that some of our skeptics and cynics always ask.

The first one is we often get the question that, okay, fine, cytology did not help me find CIS, but what about all these other markers that you bladder cancer guys always talk about that seem to be very much more sensitive and even specific for CIS? Should I just use those instead of blue light?

Trinity Bivalacqua: Yeah, I think it's a great question, and I'll tell you my bias here. I am not a marker person. I don't find that they are particularly helpful for me in my clinical practice. I do think that they play a role, especially in the patients that have a suspicious or atypical cytology where you are concerned.

What I think markers do is they give you the information you need to start looking a little closer and also be able to counsel the patient that we may need to pull the trigger with potentially additional ... changing into a different intravesical therapy, or maybe even early cystectomy, but first you got to be able to find it.

So, in my opinion, markers help you tell the patient, "I'm worried. You're at risk," but ultimately a thorough TURBT, biopsy, and detecting the cancer is really ultimately what you're going to provide that patient, probably the biggest benefit to that patient. So, that's where things like enhanced cystoscopy come into play.

Ashish Kamat: Yeah, I think that's a good point because I agree with you. A marker would just tell us that we have to look carefully anyways, and then you still have to use blue light cystoscopy. So, you could actually save a step if you have the flexible system available and go straight to blue light cystoscopy.

Trinity Bivalacqua: That's right.

Ashish Kamat: The next sort of question that we often get is, "Well, why should I do it in the clinic? If I'm truly concerned about someone that's, say, T1 high grade, should I just take the patient to the OR and either do a repeat resection or blue light in the OR directly and skip the clinic flexible cystoscopy?" What are your thoughts there?

Trinity Bivalacqua: Yeah. I mean, I do believe that if you're going to be doing a restaging exam, then you could skip the blue light in the clinic and go straight to the operating room. I think the way that blue light cystoscopy, at least the way it's being used currently, at institutions that are able to provide it to their patients is honestly in the surveillance setting.

I've seen patients that have a suspicious area in the bladder, and instead of bringing them to the operating room and doing a biopsy, we bring them back the following week and do Cysview® with flexible cystoscopy. And if it does show that there is a suspicious lesion there, it's blue light avid, then we're moving them to the operating room. If there isn't and the marker doesn't show high-grade disease, then you put them back on their surveillance.

A lot of people are using it that way, and they're also using it for those high-risk patients where you're just doing it every three to six months as part of their surveillance cystoscopy. I think that's where it's mostly being utilized today.

Ashish Kamat: That's interesting, Trinity. So, you're saying that if somebody has a suspicious lesion in the clinic, you would bring them back for a clinic blue light rather than do a biopsy of that lesion in the OR for example?

Trinity Bivalacqua: If their cytology is atypical, let's say, and it's not high grade or suspicious, then yeah, that's what I would like to do. But once again, that's my comfortability. I feel very comfortable with blue light cystoscopy and in being able to say that there's something real there or not. So, I would do that in most patients, to be honest with you.

Ashish Kamat: Right. Well, I'm sure you're collecting a prospective series, and it'd be interesting to see what the outcome of these patients are because if you can show that that's a safe way to do it and save a lot of our elderly patients anesthesia, which clearly has a cognitive impact, that would be a win for our patient community.

Trinity Bivalacqua: Yeah. I mean, that's exactly the rationale for doing it because, as you know, a biopsy and bringing someone to the operating room still carries morbidity. Right? It's that quality of life that patients have after a biopsy or TUR that we're all aware of.

Ashish Kamat: The next question really refers to the elephant in the room, and this is something you and I and everybody has answered multiple times, but once again, for the benefit of our audience, cost. How would you recommend people that are trying to get this at their facility frame this to their administrator?

Trinity Bivalacqua: Yeah. As it relates to the operating room, in the OR, I do think that you have very solid grounds. We have been able to show to our administrators and, as you know, it's been shown in many clinical trials, that you're providing much better quality to the patient because you're reducing trips back to the OR subsequently over the next coming years because you're reducing recurrence. You are providing them a service where they are at less risk of potential progression, and I think there's some data that would suggest that this also potentially reduces progression. So, I think there it's been pretty easy to convince our administrators.

As it relates to its utilization in the outpatient setting, I have to admit that it is a little bit more challenging. It's actually not the capital budget to get the actual equipment. It's the disposables that you need for the surveillance, for the scope each time you utilize it, and I think that that's something that we all struggle with. It really just depends on your hospital and where you're doing flexible systems.

So, if you're doing it in an ASC, you might not be able to get that approved by your hospital because they're not going to be able to recoup the cost of it. However, if you're doing it within a hospital setting or in a freestanding, then it's something that you would be able to recoup if you're utilizing it the way that we're talking about now.

I do think it provides patients with a service. From the Phase III trial, there are actually publications that show patients prefer it. Patients like it. They think that their quality of life is actually improved with the utilization of this. It just makes them feel better about and more engaged in the treatment of their cancer.

Ashish Kamat: Yeah, great points. And, of course, there are companies that are working to develop camera heads and systems that will work with any scope, still using Photocure or Cysview® as the agent in the bladder. So, for folks that just can't get the STORZ system, I would say at least keep your eyes and ears open for the other systems that might be available, even in the US. And again, full disclosure, I am helping with some of these other companies because I really think we need to improve the penetrance of the use of the actual Cysview® Photocure agent.

Couple last questions, Trinity, before we close. People will often ask, "Well, I have narrow-band imaging," or "I have the new STORZ CHROMA CLARA system. Do I still need blue light?"

Trinity Bivalacqua: Yeah. I think as it relates to narrow-band imaging, I think using narrow-band imaging, for example, in the upper tract would make sense because you can't get Cysview® into the upper tract. So, I think that utilizing narrow-band imaging in the upper tract makes a lot of sense.

However, in the bladder, I would say the data would tell us, once again from RCTs, that blue light's just better at picking up higher grade lesions, in particular CIS, so it's my preference to use blue light cystoscopy. And if you look in the guidelines, the grade of evidence is a Grade C for narrow-band imaging in the bladder, so that's why I favor using blue light. It just allows you to detect more high-grade lesions and CIS. As far as sort of the CLARA system from STORZ, I agree, you do get some better clarity, but I don't think it replaces blue light.

Ashish Kamat: I would agree with you on both those points. So again, Trinity, this was really fun, and thank you so much for taking the time and being part of this very important educational activity. To everyone that's listening, stay safe and stay well.

Trinity Bivalacqua: Thank you.