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Ashish Kamat: Hello, I'm Ashish Kamat from MD Anderson Cancer Center. It gives me great pleasure to have one of my dear friends and an expert in the field, Dr. Sia Daneshmand joining us here. Sia is Director of Urologic Oncology at the Keck School of Medicine, USC-California. Welcome, Sia.

Sia Daneshmand: Thank you. 

Ashish Kamat: Tell me a little bit more about your involvement with blue light and how the whole trial came about and the results of the flexible blue light trial in the U.S.

Sia Daneshmand: Yeah. We got involved pretty early. First of all, thank you very much for having me on this segment. It's a pleasure to talk to you. We got involved fairly early when blue light got FDA approved for use in the U.S. It had been approved as you know in Europe for quite some time, and it was approved around 2010, 2011. We were using it for the rigid scopes for quite some time, and there was a push to move it into the clinics. There was this concept of running a Phase 3 clinical trial to get approval, and in the process also look at some prospective data. Look at cytology with the additional lesions and whether ... You know it was approved for CIS in the beginning, and really we were seeing that we were detecting more papillary tumors as well. So it was really an opportunity to look at modern data in a prospective fashion. That started a couple of years ago, and accrued really nicely at 17 centers, and then recently published just last year in the Journal of Urology.

Ashish Kamat: You mentioned that blue light was approved initially for detection of papillary tumors, right, and then not for CIS? 

Sia Daneshmand: We got involved fairly early. It got approval for use in the U.S. in about 2010 to 2011. We were one of the early adopters in our center. We were using it for the rigid scope. As you know, the indications originally were for papillary tumors and not specifically for CIS, even though that detects CIS quite well. After use for several years, there was a movement to push it into the clinics as well so that we can get the same benefits in the clinic. Flexible blue light scopes, again, had been used in some parts of Europe for quite some time.

But in the U.S. we needed a trial, so that was the beginning of the Phase 3 trial that was testing out blue light technology in the clinics. Because this was now going to be a prospective trial, there was an opportunity to look at data, look at specifically the carcinoma in situ detection rates, increased detection rates, as well as papillary tumors, look at patient-reported outcomes of the procedure, repeat use also. There was a lot of opportunities to look at modern questions and data in this trial that was run in 17 centers.

Ashish Kamat: Right. You know, of course, UroToday's done an excellent job covering that study and has reported it on the website. I encourage our viewers to go in and look at it in more detail. But just for those that are watching right now, could you summarize the findings of that study?

Sia Daneshmand: Sure. There were approximately 300 flexible blue lights that were done in the clinics. Of those 300, 100 patients were found to have lesions. 103 patients that were then taken to the operating room for further resection and/or biopsy of these lesions. Of the 100, 63 patients were found to have malignant lesions, and of those 63, approximately a third of them were detected by blue light only. It corroborated all the previous data that it increases detection rates. But these were patients that we had detected in the clinic, and many of them were white light negative. Specifically for carcinoma in situ, of the 16 or 17 patients that had CIS, nine of them were detected by blue light alone, and most of them actually had either negative cytology or just atypical cytology. So cytology turned out to not be as sensitive as we had thought prior. 

Ashish Kamat: You know recently there's been an explosion of clinical trials in a noninvasive space, which is great for us and our patients. What do you recommend to investigators and companies that are designing these trials as far as the incorporation of blue light because we don't have it everywhere in the U.S., so how would you recommend someone that's considering developing a trial in noninvasive disease and the whole blue light/white light paradigm? 

Sia Daneshmand: Right. Great question. I think this is coming up because one of the old recommendations or paradigms was to map out the bladder and do random directed biopsies. Honestly, after having done this, having used the rigid scopes blue light technology for so long, the detection of carcinoma in situ, which is really what you're trying to detect with random directed biopsies is so good the chances of you missing a lesion with white and blue light is so low that I completely abandoned doing random directed biopsies. 

But I see them in the clinical trials where they want to map out and make sure. Honestly, I think the best way to map the bladder is to do blue light. If you have a negative blue light the chances of you having occult carcinoma in situ is going to be very, very low, extremely low. I mean less than 1%, and we have data to support that. So I think in modern trials, I would say if available, just like the AUA guidelines says you should use it "if available", you should use the best technology to rule out occult disease and/or small papillary disease that we're missing. 

Ashish Kamat: Now, what about the potential for false negative and false positive blue light?

Sia Daneshmand: Sure. Let's talk about false positives first because that's on everybody's mind. You know you see these lesions. To some degree it is user dependent. We certainly saw that in the trial. There were some centers that were lower volume, and it depends on your interpretation of what you're seeing. In the trial, the false positive was the same as white light. It was 9% on both sides. We have to realize that false positives are not as important as the false negatives, right? So if we end up doing an additional biopsy and ruling out cancer, it's not as big a deal. Especially if you're in the operating room already and take an additional lesion. I don't think it necessarily leads to additional biopsies. In fact, in some ways there are lesions in white light, which I think might be suspicious, then it's negative on blue light, then I end up not biopsying those. 

So I think there's a balance there. False negative rates. It can happen. Sometimes the Cysview is not taken up very well by the tumor cells, or there are pockets I guess that are not exposed to it very well so you get false negative. But it's really the combination of white light. You never do blue light alone, right? So it's the combination of white light and blue light that that leads to a very, very small false negative rate. That's the 1% I'm talking about. Those are the random directed biopsies that we have a few of them in our prospective registry and it literally is 1%. Just one comment however. In the high-risk patients, and I think you would corroborate this, that if you have positive cytology, and you're looking in the bladder, and you find nothing with blue light, don't forget in men the prosthetic urethra is a very important area that will not light up with blue light so that's an area where I do take random biopsies. 

Ashish Kamat: Right. Very important, and of course the upper tracts as well to make sure we have imaging.

Sia Daneshmand: Yeah.

Ashish Kamat: You brought up a very important point, and I want you to elaborate a little bit on that. You said it's very operator dependent, right? So what are some of the practical tips you would advise? I mean for the benefit of our viewers. Assume that there are some residents, and fellows, or new adopters watching this right now. What are some of the tips and tricks you would recommend for people who are new into blue light?

Sia Daneshmand: Sure. Sure. Yes, it is operator dependent, but I think it more has to do with your own experience. Once you get 10 or 20 cases under your belt, you kind of get a sense of what's really positive and what's not positive. I love what I call "internal control". When you have a papillary tumor that's lighting up, anything else that doesn't light up quite as bright as that is probably negative. So I think you just need a little bit of experience. It is new, like everything else. We have videos. I think pictures and videos help a lot, and we publish a small video in Videourolgy that's part of Endourology  (Journal of Endourology) that goes through the steps to try to decrease the false positives. The tangential view is something that you need to get used to.

You need to get away from the lesion. Look at it from different angles. That's new. We haven't done that in white light. Especially in the clinic, retroflex, and look at the bladder neck, it always lights up. The trigone almost always lights up. There's a tangential view with that. There are lesions that have been recently biopsied and have that sort of heaped up look to it. Those typically have edges that are lighting up to some degree. So you're going to see these. Again, I don't think people should be afraid to biopsy anything that they think is suspicious. I think with experience you'll know what's most likely inflammatory or a false positive.

Ashish Kamat: These are great points, Sia. I want to thank you once again for spending your time with us talking about blue light technology. Thank you very much.

Sia Daneshmand: Thank you. Thank you. Appreciate it.