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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. It's a pleasure to welcome again a friend, colleague, and expert, Professor Sia Daneshmand, who is joining us today to talk about the role of blue light cystoscopy in detecting invasive bladder tumors.

Sia needs no introduction. He is a Professor of Urologic Oncology and a Clinical Scholar at USC. He directs the Urologic Oncology Fellowship, is Director of Clinical Research, and essentially is the go-to person for anything related to bladder and testes cancer. He is going to share with us his thoughts on blue cystoscopy today. So, Sia, the stage is yours.

Sia Daneshmand: Great. Thanks, Ashish, for that warm welcome. It's certainly a pleasure to talk to you again about this topic that has been near and dear to my heart. So I'll get right into it.

We've looked at many aspects of blue light cystoscopy, but this is specifically zooming in on detecting invasive bladder tumors. So let's get into a little bit of background. I am a paid consultant for Photocure. That is my relevant disclosure.

So just a few background slides here to set the stage. This is the result from a meta-analysis of nine studies in over 2,000 patients showing at least one additional Ta or T1 lesion was found in 25% of the patients. This is data from a number of years ago published in 2013. So there is a ton of data now available on the use of blue light cystoscopy. 27% of CIS patients were diagnosed with blue light alone. So I think there is this notion that blue light is great for CIS, which it is, but that we potentially could find additional TA tumors. But does it really make a difference in management?

Well, other studies have shown the rate of recurrence is reduced by approximately 10%. Another Grossman paper in 2012 showed the time to recurrence is also increased, the seven-month difference in time to recurrence. Then we do have some retrospective data that the rate of progression is reduced. These are not randomized studies, but looking back at retrospective studies, it seems that the rate of progression is reduced. Of course, you have published on this before that time to progression is also prolonged. So we do have data that it is making some impact on the overall bladder cancer management, but long-term studies are difficult to do in terms of looking at a decrease in recurrences. There are so many other factors like the use of intravesical therapy maintenance and when the trigger is pulled on going on to radical cystectomy.

Now, the use of blue light is in the guidelines, both the AUA and the NCCN. The statement is that in a patient with non-muscle invasive bladder cancer, a clinician should offer blue light cystoscopy if it's available to increase detection and decrease recurrence rates with a moderate recommendation and a Grade B evidence strength. That is the highest strength we have in the AUA guidelines, a Grade B. We do not have any Grade A recommendations because those are reserved for the randomized blinded studies. You may consider the use of NBI to increase detection and decrease recurrence, but given that there is less data there, the evidence strength is C and is a conditional recommendation.  Of course, there are similar recommendations in the NCCN guidelines that may be helpful to identify lesions that are not visible. You've seen this sort of classic picture here where there is a lesion you can't really see on white light, but it shows up very, very brightly on blue light as a fluorescent lesion.

So we'll go into this study that was looking at the role of blue light cystoscopy in detecting invasive bladder tumors. This was a retrospective look from a multi-institutional registry with lots of patients in it.  Now there are 14 study sites all around the country. The study population was patients with at least one white light(-)/ blue light(+) lesion, with invasive pathology being defined as high-grade T1 or higher as the highest stage at any time point. There were 3,500 lesions in 1,257 unique patients. 818 or about 23% were white light(-)/blue light(+). So we sort of zoomed in on this patient population.

7% of these were invasive. So it's 48 T1s and 7 T2s in 47 unique patients. I'll go into this in a little bit more detail because I think it's important. 51% of the de novo lesions were invasive. So these were not people we knew had T1 prior. These were ones that were found out by blue light cystoscopy. Looking at it the other way, if you look at all the invasive tumors, 11% of the lesions were white, light(-), and blue light(+).

Now let's go into it a little bit more detail. We have an overall population of 3,500 patients. 818 patients were white light(-)/ blue light(+) and 494, which is about 14% of them, were more than high-grade T1. Looking at those 494 patients, 55 of them had invasive tumors that were again, white light(-)/blue light(+). 48 of them were high-grade T1, seven actually high-grade T2.

Now the question comes up again, was this recurrence, did you already know the patient had a high-grade T1? 28 of these, approximately half, had de novo invasive lesions. 25, again, high-grade T1 and three high-grade T2. Again, we are talking about white light(-)/blue light(+) lesions, and then the other 27 were recurrent invasive lesions. Now, if you look at it from a patient-based analysis, a total of 1,257 patients, 27% of them were white light(-)/blue light(+), and 17% were more than high-grade T1. If you look at these white light(-)/blue light(+) patients, 47 of them were in that category with 41 being high-grade T1 and six high-grade T2.

I was really surprised to find there were several high-grade T2 lesions that were white light(-). These would have been missed completely if you had not done blue light cystoscopy. Again, 26 of these were de novo lesions, most of which again were high-grade T1, with 21 of them being recurrent lesions. So 21 with additional tumors, one concomitant CIS and T1, 20 concomitant CIS, and 8 concomitant T1. So we broke it down in as many ways as we could to show that well, this is actually making a difference, it has an impact on management.

If you look at the distribution of the white light and blue light status, the patients you see that were white light(+) and blue light(+) and had non-invasive disease, that was a majority, you see 82% of the patients here, but 18% were invasive. So that was both white and blue light together. This is white light(+) both blue light(-), so there are some patients that we are finding who have invasive tumors whose blue light is negative. Of course, we never use blue light in solidarity, it's always along with blue-light cystoscopy.

Then you can see in the last one, the white light(-)/blue light(+), you have 7% of the patients who had invasive disease. So if you look at it the other way, if you look at invasive lesions, again, the white light(+)/blue light(+), where the majority found that way, a combination of the two, there was again, 14% that were white light(+)/blue light(-) and the same percentage white light(-)/blue light(+). And you see the distribution for the T2 lesions. So again, it's really important to biopsy resect lesions that are both white light(+) and blue light(+) as well.

We didn't go too much into the false negatives here. I think that's outside the scope of this study. So how are these patients managed? I think that is one of the more important issues here. There were 32 patients that we had data for. 22 of these patients, two-thirds of them went on to radical cystectomy +/- neoadjuvant chemotherapy where seven of the patients underwent BCG induction with most undergoing maintenance, some into clinical trials and one into chemoradiation. Zooming in on the pathology of these patients who underwent radical cystectomy, the 22 patients, you can see one was T0 and one Ta and four Tis, but 23% were T1 and 50% were upstaged to T2 to T4. These again, were patients with white light(-) and blue light(+) lesions, things that would have been missed.  You can see the nodal staging with four patients actually having positive lymph nodes. Overall, 50% of the patients were actually upstaged with 22% having the same stage as going in, so high-grade T1.

So in conclusion, blue light not only improves detection of additional tumors, additional high-grade Ta tumors but also detects high-grade invasive disease and CIS in white light(-) patients. So when we use it in combination with white light, it definitely increases the detection rate of invasive bladder cancer, including T2 disease, and helps identify potential candidates for more appropriate therapy. So I'll stop there and have a discussion.

Ashish Kamat: Great. Thanks so much, Sia. Would it be fair to say then that the blue light cystoscopy is just a better cystoscopy, and we should be using it in all bladder cancer patients? Or would you make a different conclusion?

Sia Daneshmand: No, I agree. I think you're right, calling it a better way to do a cystoscopy. It's enhanced cystoscopy. It's basically helping us identify lesions that we simply can't see on white light. Also, there is another additional benefit we don't talk about very often because it's more of a qualitative and it's hard to put down in numbers, is the training aspect of it as well as the making sure that you have a complete resection. And that comes out in the time to recurrence and the progression rates. You do a great TUR and you have a five-centimeter tumor, and you've got the edges. We've learned to resect all the edges, and when you turn on the blue light and you miss one corner that you just couldn't see before, and you thought you went really, really wide. So that is where it also helps, I think, going back and forth, toggling back and forth after the resection, making sure you've gotten every corner because those are the ones that recur at three months, those are the areas that come back.

Ashish Kamat: Absolutely. The other place where it's helpful for training is in the small, tiny, low-grade lesions that you often miss. It's obvious, you look in the bladder, you resect the large one and the trainee is all happy and excited with the great resection they've done and then you turn on the blue light and you're like, "Oh, I didn't see that." Many times you have  seen that, but there are occasions where I look back and I'm like, "Oh, I would've missed that too."

Sia Daneshmand: Absolutely.

Ashish Kamat: It's certainly useful. Now, Sia, what would you say to folks that read this study and all the other literature with blue light and say, "Well, I still don't need it because I have NBI," or, "I have the Storz Clara Chroma System." How would you convince them that, "Well, yes, those are also optical enhanced technology, but blue light wins out."

Sia Daneshmand: I think we use whatever technology is available to us. So certainly NBI and Clara Chroma will help identify additional lesions and help us see things that otherwise can't be seen in white light alone. But I think the bulk of the data is with blue light. I mean, there is certainly when you see it for the first time and you see a completely white light(-) lesion that lights up with fluorescence, you're really convinced. Seeing is believing is one thing.

But really you look at the bulk of the data, we just don't have it in NBI. NBI, I think, to me at least, is highly variable in interpretation, oftentimes.  We have it too. I've used it and I continue to use it sometimes when I'm using the other scopes. But to me, it's a qualitative difference, and sometimes I'm really not quite sure ... You get this different color, it's brown, I'm not sure. Whereas with blue light, not that every blue light shows up highly fluorescent like the picture I showed you, but it's either fluorescent or not. There's no sort of in-between. We do have faint fluorescence, but I think there's more variation with the NBI.

Again, I rely on the data, and I think there is far more data available from not just multiple institutions in the US but also worldwide with blue light technology.

Ashish Kamat: Now, speaking of worldwide, I'm sure you've come across the [inaudible 00:13:59] study, the prospective randomized study of blue light versus whatever optical enhanced technology they have at their center. That did not show in their real-world setting a benefit to blue light over white light. We've seen that in a few kinds of "real world" setting studies in the US as well, especially early on. I have my thoughts as to why that might be the case, but you're the expert in the hot seat today. So what do you think are some take-home messages from these real-world studies?

Sia Daneshmand: We've seen these meta-analyses done on these studies, and I've reviewed some of these very carefully. I think part of the issue is the methodology in which these studies are being conducted. You're comparing different patient populations, you're comparing lesion-based versus patient-based. On the surface, if you don't really delve down deep into the data, it does seem like they may be similar. But the studies are done in very, very different ways. It's very hard to do actual meta-analyses on this retrospective data set that the methodology is different. So that's one.

Two, the only way to do this is sort of a randomized prospective study, which is very, very difficult to do because you'd have to have people come in and be ready to do either blue light or NBI enhanced. Until we have that kind of level of data, it's really hard to make interpretations. So you're right. I think the overall message is to use enhanced cystoscopy. I think, blue light again has more robust data. We have this very, very detailed registry that is now in 17 different institutions that have prospectively collected data. So it's very, very good, strong, robust data now. We are close to 4,000 patients in this registry. So I don't put too much emphasis on these retrospective studies until we see something prospective.

Ashish Kamat: Okay, great. Again, last, kind of question to you before I let you wrap it up. From a practical standpoint, we hear, and it's true, there are bottlenecks and sometimes having blue light incorporated into the clinical practice does slow down the day, so to speak. You've been very instrumental in several joint projects and collaborative reviews we've had in highlighting which patient population either, I hate to use the word beginner, but someone starting out or someone that has these bottlenecks should focus on. So with all the data that you presented today and all your breadth of knowledge on the field, for someone that's coming into blue light or saying, "Well, I still need to triage my patients," which are the patients you would say you absolutely should use blue light to? No questions. Obviously, you should use it in everyone, but these are my top three categories.

Sia Daneshmand: It's hard. You're right. I mean, it's hard for me to predict which patient it is going to be helpful in. I would say if you have a solitary tumor that appears to be low grade and it's a three-centimeter tumor, maybe it's not going to be as helpful. It's going to light up very nicely for you, but maybe it's not going to be as helpful. Certainly, the one that is highlighted in most articles is the patient who's got white light(-) but cytology-positive lesions. You're pretty much going in there looking for CIS, so that is very, very helpful in that setting. That's probably top on my list.

The other is multifocal tumors. So if you go in and you see several tumors and you think, "Okay, I better do a good job and find all these one-centimeter tumors," you think you have three, but you find seven. So we know that you'll respond better to intravesical therapy. Your recurrence rates are better if you do a complete resection. That's probably sort of the next category.

The next is a broader one, which is just patients with a history of high-grade disease who have any kind of recurrence of CIS or some lesion, red lesion that you might see in the clinic and you're taking the patient to the OR, certainly again, you want to be looking for additional CIS lesions. Now we know from this study and others that we are missing invasive lesions in seven to 10% of patients. So that's important. We're not just doing cold cut biopsies of these small red lesions we see on white light, but we're actually doing a resection of any blue light(+) lesions in light of this data that we just saw. So those are sort of my top categories, but I think it's probably helpful in most settings.

Ashish Kamat: Thanks, Sia, and thanks once again for taking the time today and sharing with us your paper and your insights. It's always great to see you. Hopefully, we'll see each other in person sometime this year.

Sia Daneshmand: Hopefully soon. Thank you. Thank you very much, Ashish. I really appreciate the time and the interview here. Thank you.