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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia, and we're pleased to be joined today by Dr. Steve Williams, who is a professor of urology and chief at UTMB in Galveston, Texas. Steve, thanks so much for joining us.

Stephen Williams: Thank you, Zach. Nice to be here.

Zach Klaassen: It's always good chatting with you. So we're going to talk today about blue light cystoscopy, a topic that probably most of our listeners know well, in comparison with white light cystoscopy. You guys have done some great work at the population level. But before we get into the data, just tell our listeners a little bit about the pathophysiology, how this works, and why it can improve detection in non-muscle invasive bladder cancer.

Stephen Williams: Sure, and thank you and UroToday for inviting me to really share this important work. I know there's a heated debate in regards to the utility of this, but to take a big step back, conventional cystoscopy, as we all know, is performed via white light cystoscopy. But what's important is over the years we've been able to understand there are different types of cystoscopy that could be performed, one of which is narrowband imaging. And then another is blue light cystoscopy. And what blue light cystoscopy is, there are two components to this. One is the instillation of a substance traditionally known as Cysview, or hexaminolevulinate acid, and this is accumulated via rapidly dividing cells such as cancer cells within the bladder. However, there are other uses for it, but we'll focus on bladder today. After a dwell time of about an hour or so, then the patient eliminates this either naturally or you could do so even in the operating theater.

Then we insert a cystoscope. However, this cystoscope has additional blue light technology, which via the different wavelength, or unique wavelength of blue light, actually causes the cells, which preferentially are cancer cells, to essentially immunofluoresce. I always use the kind of analogy, a frame is on the wall with a white light and you're not able to see the frame or the image, but then voila, you turn on a certain light and then you're able to see the frame. So this really does allow visualization for tumors. But not only tumors, one needs to be cognizant, it could obviously have a false positive or even a false negative rate. But even in a recent case I had yesterday, which was actually in the office because I also use a flexible blue light, you're able to see lesions that potentially could have been missed, particularly if there's an area of concern outside of what you could see with a white light, the boundaries of that. So I think that does add some additional benefit diagnostically and then we'll get into the potential therapeutic applications.

Zach Klaassen: Yeah, absolutely. So just to spin off of that a little bit, so for our listeners, you can use it in the office for diagnostic purposes, you can use it at the time of TURBT, it sounds like you're using it in both, correct?


Stephen Williams: Yes.

Zach Klaassen: And if you're looking at patients, is it all comers? Is it patients that have CIS? Is it recurrent CIS? What are you sort of triaging to determine who would benefit the most in your clinic?


Stephen Williams: Sure, and that's a great point. I tend not to think of one size fits all. We have to be very selective because one thing we did as well... because this is expensive technology... and in my administrative role I'm also medical director for high value care for the health system so I have to model the way, and sometimes the sticker shock price dampens that so you can acquire additional technology. So in doing so, the population that I primarily use it for are the high risk NMIBC or suspicion thereof. I actually do initial diagnostic TURBT, resect an area for instance, it comes back as high risk NMIBC, for those patients on the restaging I would use preferentially the blue light technology to identify additional areas or margins of resection or any area that I may have missed.

I think that's where it has utility. For the flexible blue light, I like to use that for surveillance purposes. So say that same patient completes BCG induction, then a maintenance course that's adequate, BCG, then I would do or utilize a blue light cystoscopy flexible in that follow-up setting to ensure I'm not missing any areas of concern. And I think between that, the additional confidence, not from a confidence in your work but the confidence of your patient, your customer, you're able to give that additional reassurance there are no areas of concern that are in fact missing and really ensure an accurate and durable treatment response from the BCG.

Zach Klaassen: Is there a situation where you would complete induction BCG before you started maintenance? You may just do a blue light cystoscopy just to ensure that everything looks good before you go ahead and start the maintenance? Or are you doing that sort of in those select patients where you're really kind of worried about them sticking with that mostly?


Stephen Williams: That's a great question. I like to think of adequate BCG therapy, so induction followed by a maintenance. To be honest, and that's something with guidelines and I also work on the guideline panels, adequate BCG therapy is what we're shooting for, I tend not to do it after the induction of BCG, but more importantly after they receive the adequate amount. And at that point you're doing a six-week induction and then within three months you're doing a maintenance, so you're not waiting much longer. And to me, that really provides the additional confirmation because after an induction too, if on that surveillance cystoscopy, if there's a recurrence or persistence at that point you're really concerned about BCG unresponsiveness. So those would end up getting a TURBT anyway, and you could determine at that time if you wanted to use the blue light in the OR.


Zach Klaassen: Yeah, that makes sense. So let's delve into some of the data. So you guys published earlier this year in Clinical Genitourinary Cancer your initial VA data, looking at basically blue versus white light at the population level, all sorts of interesting analysis stratified by race as well. So maybe you could walk our listeners through that study and some of the key findings from that one.

Stephen Williams: Yeah, absolutely. Thank you. So really what's of interest is at the time of this study, the PHOTO trial results came out, and not to get off on a segue on that topic, but obviously those were not in support of blue light. But what was important with that study is the population itself were predominantly low risk, if not intermediate, and not high risk predominant. I'll leave that aside. So our study, what we performed was in the largest equal access care system in the United States, the VA. And of a little more than 300 patients that actually had CPT coding for blue light cystoscopy, we ended up performing a retrospective chart review of those patients to determine what was the recurrence, i.e., because all of them had to have a white light, the interval from recurrence from the white light and then also too a recurrence following a blue light.

This was really just kind of a litmus test study, if you will. Not really apples to apples per se, but we wanted to get a perspective on the population of patients that may benefit. What's important is from this study they were the majority high risk NMIBC patients with CIS, or CIS with or without papillary disease. And among those patients we noticed across all time intervals, which were a little over three years, they had a prolonged time interval to a recurrence but also had a decreased number of recurrences among those that had blue light versus white light. In addition, a majority of these patients also too received BCG, adequate BCG therapy. That's important because also too with the PHOTO trial, the majority of those patients did undergo treatment.

I think that's a key finding. And this is associations, right, so this is observational data. We cannot derive causation, but definitely as hypothesis generating for our current and future ongoing work as we're doing this investigation and really trying to describe the story in a population of patients that should derive if any benefit from the use of this blue light technology itself in regard to recurrence.

Zach Klaassen: And with regards to race, you guys found no difference with race. And as our listeners know, the VA has probably the highest volume of patients that are African American, so no difference based on race in your guys' study, right?

Stephen Williams: Correct, yes. About 10% of the population were African American, which is a substantial amount. So in an equal access care setting, when historically African Americans have a decreased incidence but an increased risk of a more aggressive bladder cancer when diagnosed, we found no difference in recurrence when we were also looking at the utility of blue light cystoscopy.

Zach Klaassen: Absolutely. So let's talk about your more recent work looking at propensity score match analysis, and this is work that you've recently presented and just tell our listeners what propensity score matching is and what the additional study tells us that we didn't know before.

Stephen Williams: Sure. So in a little over, I believe it's about 700 patients, but then we did propensity score matching, which what that means, is really an upfront... and I don't like to use the word randomization because it's not a randomization... but you're really trying to compare the number of patients that had a blue light to an exact and equal same population... roughly speaking, these are observational data... to those that undergo blue light and white light. So comparing those across known variables, which include age, sex, race, in addition pathology, BCG, so we try to match those upfront to understand moving forward what is the risk of recurrence among those populations. Then we also looked at survival benefit as well. So when we do so, we're able to follow these patients forward and we're able to find a decreased recurrence among those that have blue light, but also too the timing of recurrence is also much longer than those that underwent white light.

So once again, it shows the utility... and in these populations of patients, again I must stress, we did sensitivity analysis and it showed further support for our finding among the high risk NMIBC, but then among those that actually undergo BCG. So even furthermore it supports the utility of using blue light cystoscopy among high risk NMIBC patients. And the similar with the race theme, that we found no difference among this population. So this is quite intriguing and exciting because the initial work is hypothesis generating. This work, although not confirmatory, we're seeing a common theme even being more restrictive and more critical and really comparing two different populations of patients and still showing an increased benefit of use of blue light in this setting in an equal access care setting.

Zach Klaassen: Absolutely. It's been a great conversation. Just to leave our listeners maybe with anything we haven't touched on that you want to hit on, a couple of take home messages for the clinic tomorrow to wrap things up?

Stephen Williams: Certainly, I think the first is whenever analyzing data, and it took me to get a master in health services research, it's not about the analysis, it's about understanding your question and your data. And really when I mention that, is when you're looking at the literature and the populations, whether it's a randomized trial phase three, really robust, it's a population of patients and you have to understand what community of patients you're treating and really what you're trying to explain. And then I think there is utility and use of blue light in certain populations of patients and I think there is a decreased risk of recurrence when you use it appropriately and in the right setting.

Zach Klaassen: Yeah, absolutely. Steve, you're a great friend and contributor to UroToday. We appreciate you taking your time to talk to us today.


Stephen Williams: Thank you very much, Zach, and thank you very much UroToday.