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Sam Chang: Hi, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and work at Vanderbilt University, and I have the honor and pleasure to again spend some time with Dr. Sia Daneshmand.

Dr. Daneshmand is actually the Director of Urologic Oncology at the USC Medical School, and works at the Norris Comprehensive Cancer Center. He's a professor of urology, as well as professor of medical oncology there. He's truly a superstar. When anyone talks about urothelial carcinoma, bladder cancer, testis cancer, I mean, you name it, larger surgeries dealing with surgical impact of oncologic care when it comes to urology, his name always comes up, and he's one of the true leaders.

We're going to spend a few minutes talking about a recent article that the group published from USC looking at the impact of Cysview blue light cystoscopy on recurrence. I know he is got a few slides, but I want to first say, thanks so much, Sia, for spending some time with us. And then, thank you also for giving us a real world perspective of the utilization of this technology.

Siamak Daneshmand: Thanks so much, Sam. It's always such a great pleasure to talk to you. Obviously, you're the father of all this, and I always learn from you. It's always great to talk to you, and I know you've been involved in this from the very beginning.

So just a few words about the registry. It's been a tremendous asset. We started way early, many, many years ago, realizing that this is fairly new technology once it got approved. And that we really need to collect prospective data from the users in a real world setting. So we now have well over 2,500 patients in the registry. It's becoming a real... Actually, I'm sorry, close to 3000 patients in the registry. Really becoming a powerful, powerful tool, to not only look at just non-muscle invasive bladder cancer, but also, start to make comparisons.

Now, this is not a trial, so it's hard to find the comparator, right? So all those trials were done earlier in the past, two decades ago actually now, and proved that blue light cystoscopy detected more tumors. But the recurrence bit has always been a bit more elusive, because it's, again, hard to do that comparison. There's always confounders, as you know.

So in this study, we tried to go back and match the patients to a known white light sort of group of patients from a previous trial. This is one of the original trials that looked at white light versus blue light for detection of tumors, Ta and T1 tumors, that Bart Grossman had published in 2012, and they were looking at the recurrences, longer term recurrences. So basically, we took that data set, and compared it to the current registry, to see whether there was a difference in recurrence rates.

Okay. So I won't go through this. So basically, again, the objective was to see what the impact of blue light was on recurrence rates. We always talk about detection. We know that it increases the chance of detection of CIS, detection of more Ta tumors, T1 tumors. But everybody wants to know downstream, does it have an impact on recurrence of these tumors? And so, we think it does. There are some retrospective studies. Kamat published one, and Chappidi has one that showed the probable recurrence rates are lower with this. So every dataset you look at it is, but now, we're taking our real world clinical care setting, so this is not a trial, and comparing it to a white light set from a trial that was done many years ago.

So this is all patients enrolled in the US Blue Light Registry. Again, we now have close to 3000 patients, but the data cutoff was 2055 patients. And then the comparison group had 261 patients, for whom data was available longer term in these 261 patients from the Grossman 2012 Journal of Urology paper.

And we matched them for age, stage, grade, clinical management, i. e., intravesical therapies. Now fortunately, honestly, not a whole lot has changed. We're doing the same white light, at least I am, that we used to do before. Yes, we have better optics, but in essence, not a whole lot has changed. And in some areas, actually, the scopes themselves haven't changed in many, many years.

So then, you are looking at KM curves and all that, log rank, some tests to perform to look at P-values on this. And here's the data. I mean, this is not subtle. There's a wide separation. We have fairly good follow-up. The mean follow-up for the Blue Light Registry is about 27 months, and 53 months for the white light control group. And you can see the recurrence rate significantly lower with the use of blue light. That's the top one.

Now, again, you may say, well, more modern management perhaps led to this, and it's true. It's really hard to separate out those subtle nuances, but I doubt the subtle nuances are making this major impact on recurrence rates.

So we think there's at least a major component of this difference has to be the detection of the tumors. Because the more you detect, the more you're taking care of it, the less the recurrence rate. So this was durable. And as you can see, we see a good nice flattening of the curve around 24 months, which is typically what we see. So the data is good quality data, we like to see this.

So basically, I think this was the first time we're reporting long-term data from the registry, looking at recurrence, comparing it to a white light registry group, showing the decreased recurrence and prolonged time to recurrence as well.

Sam Chang: Yeah. See, I think that a couple things to kind of bring up to you. As you look at this, if you look at the historical from the trials, the white light data, the 200 plus patients, those numbers are not far off at all from what you would expect from multiple large studies that have been done looking at other trials looking at non-muscle invasive bladder cancer. So to see that is not surprising.

Tell me what you think. And I've got some thoughts on clearly what blue light has done. In my opinion, you find more tumors, there's no question. But I think what is difficult to measure, but I think is really the case, is that everyone looks more carefully now with the blue light kind of capabilities. Because you now have a realization, gosh, we've missed some tumors, we are missing tumors. And I'll be honest, I spend more time, yes, with the aid of the blue light, but just understanding that I can impact kind of recurrence rates. Tell me your hypothesis or thoughts regarding, hey, there's a big differential, what's causing it? Tell me what you think.

Siamak Daneshmand: Yeah. Yeah, no question. You're right. We're just more careful. But oftentimes, no matter how careful we are in white light, there are things that are absolutely invisible. There'll be a pathway. Just today I was in a TURBT. We did a white light survey around, it was me, my fellow, and we said, "Okay, we don't see much there." And you turn on the blue light, there's a small little papillary tumor at the dome of the bladder, right in the bubble. Absolutely missed it on white light. I said, "Wow, it's showing through the bubble and we can see it." It's things like that, I think, that the next time you see the patient, it's three months later, now the tumor is bigger, possibly invasive, and that leads to higher recurrence rates, and higher progression rates perhaps. But you're right, it is really hard to tease these out.

There's definitely more emphasis on the use of perioperative chemotherapy. We try to control for that as much as possible. There's definitely that bias that patients who enter the registry are from these centers that are highly dedicated, highly expert centers that are managing bladder cancer at the highest level. But my counterargument to that is, so were the patients that went into the trial. And as you mentioned, that bottom curve, the white light doesn't look any different than most of the other trials looking at non-muscle invasive bladder cancer.

So I do think that the blue light is making probably a big impact. Whether it's 100% of that, 90% of that, 80%, whatever it is, it's a wide enough separation that I think the impact is real. And we see that in day to day where we miss things.

The other thing is, with white light, we say, okay, we resect the tumor, then you go wider. And depending on which direction you're going wider in your resection, you're like, "All right, we did a great wide resection of that tumor." Then you turn on the blue light, "Oh man, look at that edge. I missed that one corner." That's a recurrence in three months, or six months, or nine months. So those are the additional things, where you're doing, even in re-resections, where you're getting the edges of prior resection of tumor and really doing the best job possible.

Sam Chang: If I am a center considering the use of blue light cystoscopy, one of the things, what kind of advice do you give them in terms of the learning curve, getting some patience with figuring out the best way to evaluate? What's the advice do you give to someone who's just starting to use this, or considering just starting to use this?

Siamak Daneshmand: Yeah. I would say, first of all, really try to get the equipment and do with this. Seeing is believing. Once you see it a few times, it's not going to be a new first time. It's not going to be a new second time perhaps, but certainly you do 10 in a row, you go, "Okay, now I see what people are talking about." Initially, there is a flow to it. Obviously, the patients need this in the recovery room. We, and you, I'm sure, and many others who do this on a routine basis, it has become part of our routine. Even in the clinic where we are doing flex blue light in the office, I do anywhere from four to six of them in a day of flex blue light, and it can work in the clinic as well if you've got the right flow.

You want to start slow. You want to have no more than one or two scheduled the first time around, just to get the flow. There's nursing calls, there's orders, you need to place a catheter, instill the Cysview that comes from pharmacies, so on and so forth. Once that gets going, it really does become routine like anything else. We give heparin sub-q prior to major surgery. We give alvimopan, or Entereg, prior to surgery, and those things are sort of similar concepts of, they have to be given prior to the surgery starting. They come from pharmacy so on and so forth. That nurse gives it. This is not too dissimilar. You just need a catheter placed, and then this Cysview is instilled.

So when we're doing multiple cases in a row, for instance, like we did today, four in a row, once I'm in the middle of one, I'm calling and saying, "Make sure the Cysview is going in the next one." So the next patient's getting ready. It really doesn't take long. It's not a big learning curve.

What is a bigger learning curve is the evaluation itself. Because we show these great pictures, and everyone's like, "Oh, it's so obvious." And it's not oftentimes, as you know. It'll be subtle sometimes. Or, is that positive? Is that negative? I think that's a learning curve. And there are a number of sort of both false fluorescence and false negatives, true false, real false negatives that occur. And that's okay. We have lots of false negatives in white light. We have red areas that we biopsy all the time. The key is to not miss cancer, and you do one extra biopsy, it's fine. I think we need to focus less on the false positives and not miss cancer. That's the whole point.

Sam Chang: As you consider those 10 here, your points I think are excellent. The idea of, look, you don't schedule 10 on your first day, you schedule. And then the other thing that along those lines is, you set up a rhythm. Hey, look, over the next four weeks, every day there's going to be one or two of these. And you get that process down. And it's funny you say that. It does become, like you said, ritual or just, okay, sub-q heparin, just like you said, sub-q. That the nurses just write, they'll just put a little BL, right, but oh, it's a blue light. Okay. They know that catheter needs to get put in it. So the system gets set up and you build up institutional memory. It's just another part of the procedure.

So the last question that I want to end with, Sia, is, you've got this equipment that does cost more and the pharmaceutical cost does cost more. How do you decide who gets a blue light, who doesn't? Do you have a certain criteria? Is it pretty much blanket, hey, this is how we're going to evaluate you? Tell me that decision making tree of who gets blue light, who doesn't?

Siamak Daneshmand: Great question, Sam. And I think, if we can, spend a little bit of time on this, because I think it's an important question, and the one that people ask all the time and say, "I only use it in high grade. I only use it in patients with a prior history of CIS. I only use it in patients with atypical cytology.", so on and so forth. My answer to that is, not for every single patient, but for most patients, because we don't know what we're going to find in there. So if someone is going to the OR for suspicion of recurrence of tumor, then whether they had... We don't know whether we have CIS right now. So it's hard to predict and say, "I'm going to use blue light on this one, but not this one." The ones that are obvious are the patients who have obvious muscle invasive bladder cancer. They have a very large tumor, you're not looking for additional small tumors. Those are, I think, moot points to use blue light.

So I would say it's, for me, it's most patients. The vast majority I would say are blue light. In fact, they're always surprised when one of them is not blue light. I say, "No, no, no, we don't need it for this one. It's muscle invasive. We're doing a maximal resection for TMT.", for instance. And so yeah, you don't know.

The other piece that we don't talk about often enough, I think, is the training aspect. We're training residents and fellows in TURBT and techniques, and they're often surprised after they do a resection, they feel good about it. You turn on the blue light, say, "Yep, you missed that one there. But you know what? I would've missed it too." So that realization of, wow, this procedure, if you really want to do a good job in non-muscle invasive bladder cancers, clear the patient of tumor, then it's best to use the best technology you have available to you.

And then, one more point, I think the one part we haven't answered, is whether... One of the arguments is, well, so what? I already have a high grade Ta tumor. If I find additional CIS, what's the point? I'm going to give the patient BCG anyway. Well, I'm not sure we know the answer to that. I think in some patients, for instance, high grade T1 plus CIS is a different risk category, don't you think?

So finding additional CIS, or finding multifocal disease, I think, does make a difference. So if I have high grade T1 and I'm concentrating on the T1 portion section of the tumor, and I find additional CIS on the opposite side of the bladder, I do think about it differently. I think that's an additional risk factor, additional point to discuss with a patient which direction they may go. Or you might find an extensive CIS, and find out the patient is not a good candidate, for instance, for radiation now if they have muscle invasive disease.

So there are little nuances, I think, that are not born out in these types of studies, and data that are more qualitative in features of the blue light.

Sam Chang: No. I think you're exactly right. When people ask me, I say to be honest, when patients are taking however, the default is blue light.

Siamak Daneshmand: Yeah.

Sam Chang: It's actually for us, it's funny you say that. When do I not? It's specifically I know someone who has muscle invasive disease, we're considering TMT, or multimodality therapy, and even then sometimes, I'll use blue light to rule out CIS, to see if they're really a good component. I don't necessarily use it post radiation for evaluation for biopsy. Maybe I should. But it really is, I'm just thinking, why would I not? Just to the point of, you don't know what you don't know.

Siamak Daneshmand: Exactly.

Sam Chang: And the thing is, there are too many times, and as you go through the learning process with your trainees and with your fellows, it is just when they think, "I don't really need this.", that you flip it and you say, "Well, you miss this, you miss this. We can do this." So no, I really appreciate it.

One of the things that is also helpful, that I'm sure you've seen is, there are times, and this has never been published or talked about, there are times where it's difficult to find the ureteral orifice, for whatever reason. And just that you may not have, or our audience may have never seen written about is, just by being able with that blue light, you're looking for a yellow streak that under white light, you can sometimes tell what you are, but a lot of times you can't.

Siamak Daneshmand: Yeah.

Sam Chang: But that blue light can help you after resection. If you want a stat, or you can't find, or whatever, it can be very, very helpful. So I agree with you that it's almost now the default, and is very useful for the patient with non-muscle invasive disease, and even muscle invasive disease.

Siamak Daneshmand: No, I totally agree with you. I think we have a video in the Journal of Video Urology or something showing that big papular tumor, then the green hue coming out, the spewing out like a volcano, that's the urine coming out. You're right. You don't even need the Cysview for that. That's just how it looks under blue light. So very, very useful to sit there and look for the ureteral jet after, or even before the resection.

Sam Chang: Exactly.

Siamak Daneshmand: So you're absolutely right. Yeah.

Sam Chang: Great. Well, Sia, thank you so much for, first of all, all your leadership, and all that you've done in helping to kind of spearhead this registry. As we gather data, more and more data regarding, it's possible a beneficial impact of using this technology. Thanks for spending some time with us. It's always good talking to you, and look forward to seeing you in person soon.

Siamak Daneshmand: Thanks, Sam. A pleasure. Thank you so much.