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Ashish Kamat: Hello and welcome to Uro Today's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston and it's my distinct pleasure to welcome today two leaders in the field of urologic oncology and specifically bladder cancer. Professor Sia Daneshmand from USC in California and Professor Marko Babjuk from Prague in the Czech.

So today what we're going to have is essentially a discussion on optical enhanced cystoscopy with blue light for the diagnosis and surveillance of bladder cancer and we're going to have two perspectives, the US-North America perspective, and of course the European perspective from the two experts in the region, and then we'll have a short discussion. So with that, I'm going to hand the stage over to you, Sia, and take it from here.

Siamak Daneshmand:
Great, thanks Ashish and it's a pleasure to be here and talk about enhanced cystoscopy with you two. So I'll just present a few slides here and highlight some of the recent findings and old findings as well. I'm a paid consultant for Photocure, That's my relevant disclosure.

So both of you know this very well and have contributed to this for a long time, the quality control indicators for TURBT. We want to do a complete resection involved visible tumor, repeat resection of high-grade T1, adjuvant chemo after resection and having muscle node resection specimen, and obviously not perforate, and then initiating therapy within six weeks of diagnosis. These are some of the current quality control indicators and one of the most important things is doing a good job in from the outset, right? Actually removing all the tumor, so blue light has been extensively studied improving detection of bladder tumors versus white light. Historically five multicenter Phase III trials in the US, Canada and Europe with lots of patients.

Basically this is a meta analysis of all those trials showing at least one additional TA or T1 tumor in 20, almost 25% of the patients, and a quarter of the patients were diagnosed with Blue Light Cystoscopy only who had CIS. Clearly it improves the detection of tumors, both CIS and papillary tumors in a significant number of patients. Importantly, does detection lead to reduced recurrence? These are not randomized trials, but it does appear that the rate of recurrence is reduced by at least 10 or 11% and also time to recurrence is prolonged and if you look at the time to progression, this is one of the studies from Ashish actually, published a few years ago, time to progression is prolonged in patients who undergo Blue Light Cystoscopy. Again, going back to doing a complete resection. There's another study by George Askakis as well, looking at a meta analysis in the five studies supporting the assumption that that detection of tumors, non-muscle invasive bladder cancer reduces the risk of progression as well.

So this is in the guidelines, the AUA-SUO Guidelines in 2016 Enhanced Cystoscopy in a patient with non-muscle invasive bladder cancer. A clinician should offer blue light if available to increase detection and as a moderate recommendation, Grade B, there are no Grade A recommendations in the guidelines. And NBI is there as well, you may consider use of NBI to increase the detection, decreased recurrence, but that's a Grade C and it's also in the NCCN Guidelines.

Now there's a Multi-center Registry in the US and there are lots of sites. This was a publication from a few years ago, nine different sites, now I think they're 15 or 16 sites on this registry. But basically the same types of results, you see the sensitivity increases in detection of tumors. The specificity you see here overall is about 30% and the positive predictive value being 63%. We do have false positive scores with blue light and white light. So more importantly, I think that we don't want to miss any tumors.

And then recently, Flexible Blue Light cystoscopy is coming to the market in the US, it's been around in Europe for a number of years. And there was a Phase III trial, Multi-center trial done here. The 300 patients who underwent white light, they were randomized to continue with blue light, and then anyone who had suspicion of cancer went to the OR. So 103 patients had suspicion of cancer, they went to the OR, and then we had their results here. This is just one of the examples. This is you see the papillary tumor there, and you don't really see anything on white light here, but on blue light, you see these are actual papillary tumors, very small papillary tumors that are away from the center lesion, but that you see. That was with the flex blue light, by the way.

So in that study, the Phase III study, 20% of the patients with recurrent tumors were found only with blue light and in the OR, 35% of the patients with CIS were detected with blue light only. So again, these results are very, very consistent with previous Phase III studies done. In patients, I think it's worthwhile. They would have it done again, despite the inconvenience of having a catheter and having to come in an hour earlier. Angie Smith looked at the patient reported outcomes, and you can see here at 90% of patients thought it was worthwhile. I would do it again and would recommend it to others as well. So high patient sort of satisfaction as well.

Now that we've had Flexible Blue Light for a long time, I'm certainly not going to go through this in any detail, but I just want to highlight Yair Lotan and I had looked at our Flex Blue Light experience. Just look at the second line here, where we have white light negative. This is office cysto findings, white light, negative blue light, positive lesions. We had 26 patients there, and you can see the ones that were missed, three low grades, four high grades, TA6-CIS, and only two of those were benign. And many of these underwent biopsy in the clinic and others went to the OR, and again, if you have white light indeterminate lesions, but blue light positive, we had 10 of those patients, one was a [inaudible 00:06:57] 1 CIS and one benign. So, again, I think in the clinic, we're seeing very similar findings.

And then, most recently we looked at whether we're making a difference in detecting invasive bladder tumors. So we looked at the Multicenter Registry again. We looked at 494 invasive lesions to see how many would have been missed with white light alone. So there are 55 patients with white light, negative blue light, positive invasive lesions, 48 of them were pT1, 7, were actually pT2. These were completely missed with white light. It didn't represent a large percentage of the complete cohort here, but again, it is significant. We're trying to improve results and anything we can do to improve results in these patients would be helpful.

You can see that 32 patients with complete followup, a number of them underwent radical cystectomy with pathological upstaging and even four of 22 had positive lymph nodes. So again, it helps to diagnose these earlier, if we have invasive tumors that we're missing with white light, I'm almost nervous to have white light now thinking I may miss something despite our extensive experience.

So I'll just stop there. I know we'll have a discussion, but basically our early experience, at least with the Blue Light Flexible Cystoscopy is very, very similar to the Rigid Scope in the OR, it improves detection of high-grade disease in CIS and patients who are white light negative. And also, I think it helps and we can have a discussion about this, doing office biopsy and fulguration for low grade disease. Now, we don't have to take these patients to the OR if we detect these tumors earlier. We do need more data. I think we need to optimize who we use it for, and when do we stop to reduce costs. So I'll stop there, Ashish, and turn it over to you guys.

Ashish Kamat:
Great. Thanks so much, Sia. As Marko is firing up his slides, maybe I could just have you comment a little bit on your personal experience of blue light with your trainees. What's the number of cases that someone needs to be able to do in order to get proficient data?

Siamak Daneshmand: That's a great question. And I think because it's less of a... It's more cognitive than it is technical. I think it takes a good 20, 25 cases, at least for them to get a sense of what is positive and what's negative. I think especially more junior residents are very quick to call things positive and we have to point out all the little nuances of the trabeculations and the edges and the prior resection sites, the trigone, things like that and all the tangential picture. So I think in my mind, it's somewhere in the 25 to the almost 50 range before they get a good sense, but we do have the senior residents pretty well trained and they can pick out. And I think there is some subjectivity, even among experts, but there are certain things that we look for, especially, the most important is not making a decision early. If you think something is equivocal, just go away from it and come back and see. Sometimes those, what do you think once the bladder gets more distended, what you think is positive, ends up being completely negative.

Ashish Kamat: Yeah and I agree with you there. I think the false positive rate, if we would track it based on number of cases done would be the part that would actually come down, right? Because more people call things early, afraid of missing something. And then as they get more experienced, like, "No, that's just tangential," or, "No, that's just the way it looks. It's not actually positive." What's your accepted false positive rate that you would recommend to a group of urologists that might be looking to adopt this in their practice?

Siamak Daneshmand: Yeah. I think that's a great question. I think 25% is sort of a number, I'm pulling that a little bit out of a hat, but it's based on data as well. As you said, we want to make sure our sensitivity is high and we don't miss tumors. I think everyone focuses on this false positivity rate, but they'll forget that with white light, we have a lot of false positives with the erythematous lesions. A lot of it has to do with what you end up biopsying. So it's dependent on the practice patterns. If you're nervous and you end up biopsying everything, not caring about false positivity, then that number changes drastically as opposed to lesions that we ended up not biopsying. So I think somewhere around the 25% range is reasonable. If you're really 50% positive, you're biopsying too much. And if you're lower than that, you may be missing some lesions.

Ashish Kamat: Yeah, I think 25% to start is good. And then aim for the 10% that most large studies have shown. I think that's sort of a nice rough number to keep in mind. Okay, it looks like Marko has his slides up. It's my pleasure to welcome Professor Babjuk who really needs no introduction on the international stage. He is Chairman of Multiple Guidelines Committees, has done more in bladder cancer than many of us combined, and he's going to join us today and talk about his thoughts on PDD guided TURB and how this can help us achieve better outcomes. So Marko, it's all yours.

Marek Babjuk: So my task is to demonstrate our European view on the PDD guided TURB, and I think first we need to really remember what is the goal of the TURB, and this is to perform a complete resection and make correct diagnosis. So it has some diagnostic tool and all diagnostic aspect, and also the therapeutic aspect. And there are two critical points which needs to be fulfilled, which is the perfect visualization of the tumor. And second is the strategy and technique of the resection. We will talk today, mostly about the visualization of the lesion. And we certainly know that we are missing some tumors. We have a lot of studies, which demonstrate that, but just one example, this is the meta analysis of the results of Eldoret UR in T1 tumors, and you can see that the tumor was missed by in this initial TUR, in more than 50% of cases.

So apparently our standard TUR's are not perfect and we need to do our best to improve our results. One point which may be improved is the visualization of tumor lesions. And to achieve that we have today more methods available. There are some methods of so-called advanced imaging, which is fluorescent cystoscopy. We are talking about that and I will talk about the method more in detail later. There are some other method connected with some company technologies like Narrow Band Imaging, which is based on narrowing of bandwidth. This is Storz Professional Image Enhancement System, which is based on post-processing more or less. And the goal of all these methods is improve the visibility of the tumor, improve detection rate, and potentially reduce the recurrence rate after TURB, or potentially progression rates, certainly.

The goal is talk about the Fluorescence cystoscopy. Sia already mentioned many aspects. The principle is well-known. It is based on selective accumulation of Protoporphyrin IX in tumor tissue after intravesical instillation of 5-ALA, or its hexyl ester, so-called Hexvix. The typical feature of Protoporphyrin IX is that after illumination with blue light, it demonstrates the red fluorescence which may be detected by the camera. You need a special equipment. It is very important, a special light source telescopes with filters and cameras. It is very important and absolutely necessary.

We can imagine several scenarios when the system or the PDD is helpful. Here, you can see first, it's not the detection of small lesions. See, I already showed that. You can see on the video, this patient had more than 40, such a small lesions within the bladder. If you change now to the white light, you can see that you don't detect many of these lesions. So we may improve the detection of small tumors. And if you look on our data from our trial published many, many years ago, the most significant difference between standard TURB and PDD guided TURB, was between multiple tumors, which are typically such a small, multiple lesions.

Another clinical scenario is the quality control of the resection. You can prevent the tumor persistence on the range of resection area. You can see here now, some tiny tumors missed on the range of resected area. And typically we know that the most persistent tumors after TURB are at the area of original tumor.

So again, the improvement of the quality control of the resection, you can detect all these field changes, which are sometimes difficult to see as is demonstrated on these pictures. And finally, of course and most importantly, detection of carcinoma in-situ, like, is this lesion not visible on white light cystoscopy, but appear very clearly visible on PDD. This was lady with positive cytology, and we were not able to detect the tumor during white light cystoscopy.

So these are the scenarios, but of course we need to translate these clinical benefits in a better outcome of our patients. And I think Sia demonstrated a lot of studies, which confirmed the clinical benefit of the PDD guided TURB, particularly in the reduction of recurrence rate. This is the most robust data from international prospective randomized trial. You can see the benefit in reduction of recurrence rate, which was quite durable, as you can see from the curve.

And this was finally confirmed in meta analysis. This is a meta analysis, which included all trials with ALA or Hexvix, and it clearly demonstrated the reduced recurrence rate after the PDD guided TURB and some potential in reduction in the risk of tumor progression.

But, as I mentioned on the beginning, that the TUR is complex procedure, and one point, what we should do today and achieve today, is the perfect visibility of the tumor. Here you can see this papillary lesion with the satellite lesions, which we can take the biopsy. We can, of course only coagulate that. But another step is a very precise resection of the tumor. This is the unblocked resection. This is with coiling snipe, but you can of course use the loop. You can use the technique that you decide, but you can see how precisely you can resect the tumor, how with the technique, which respect to the principles of oncologic surgery. So we don't touch the tumor tissue and you can see how precisely and carefully we can finally resect the whole tumor. So I think the goal is in improvement to the visibility of tumor and also improvement in the resection technique, which should go together.

Finally, in conclusion, I believe the PDD has a lot of benefits. The PDD guided TURB, it improve visibility of the tumor during TURB, it's a reduced recurrence rate. It is safe, we know that. It has suddenly some limitations, particularly you need to use the instillation before surgery. You need a special equipment, particularly these two points can make some problems. If you, for instance, have more surgeries after another, to really make a good timing of instillations and so on. So it can make some problems. There are some costs connected to this instillation, which are quite high in Europe. So the method, this is the major limitation of this method in Europe. And this is the reason why it is not used routinely in all countries. And definitely you need also to discuss, for instance, additional benefit if you use further intravesical instillations.

But generally concerning this point, I believe that we should do the best TURB we can do, as best TURB as we can do, so we really should use this advanced method, if they are available, and if we can use that. The future, where is the future? Maybe in more sophisticated methods, maybe even in vivo pathology. Here is just example how precisely you can really examine the vision of the tumor. This was presented by Dr. Kriegmair from Germany. But of course, the question is whether some cheaper methods, which are more user-friendly without instillations based on processing of the image, whether these methods will be an advantage in the future. We will see, but generally, I must say, I believe that this advanced imaging is critically important and PDD is today, the best studied method between all of them. Thank you for attention.

Ashish Kamat: Great. That was another very good talk Marko, every time I listen to you, I learn so much. I mean, thank you for sharing all of this with us in a short and concise manner. You bring it to highlight some very important developments in newer techniques and newer modalities. And obviously with someone who's so experienced with the different techniques, could you share with us your viewpoint on how you think blue light actually compares with some of these modalities that you may have used, for example, narrow band imaging or others?

Marek Babjuk: I think the point is probably today, the selection of patients. If you have patients where you expect carcinoma in-situ, I think you should use PDD. If you have the patient with the history of high-risk lesion, high-grade lesion, and you have the positive cytology, and then probably the PDD is of a clear benefit, and it has very confirmed results. In other situations for everyday use in each TURB that you are doing during the day, for instance, if you do four or five surgeries a day, then it is very useful to have method, which you can use anywhere, anywhere. So in any minute, so which is for instance, NBI. You don't need any instillation before, you can just click on the computer and you can see this different image.

So, I think that the future is in combination of these methods, and you can definitely select some patients for PDD, because as I said, this is a very clear information, in fact, which you achieve in your eyes, it is plus minus information that is either red, or it is not red. In the all other methods NBI or in image as you always receive a more complex information, which is not so clearly translated into the results. So, I think the PDD still has some advantages, but I don't think it may be used in every patient, particularly if you do a lot of cases a day.

Ashish Kamat: That's a very good point to make Marko because for blue light, we have to plan obviously, and instill the agent into the bladder and wait, and I tend to do my practice similar to what you just mentioned, which is use NBI pretty much on everybody, because you can just flip the switch and then use PDD selectively in the clinic, at least. And in the OR of course, PDD is much more widely used, except on days when we're doing 10, 12 surgeries. And of course we don't have that much time for the equipment turnover. Sia, your experience is a little bit different at your center, right? Am I right, and I don't want to mislead the audience, and I'll let you answer this, but do you use PDD in everybody in your clinic?

Siamak Daneshmand: No, certainly not everybody in the clinic. And we had those consensus statements on appropriate use, and when to use. I agree, for the high-risk patients, I would say the answer is pretty much, yes, we do have the capability to do it. There are some logistics to be worked out. But for the high risk patients, so we look at our list of who's coming up and in high-risk patients for the first two years, we're using it after that. We're not for the low-risk patients, only the very first cysto, just to pick up any residual tumors that may have been missed in the first cysto, so that we can biopsy and fulgurate right here in the clinic and avoid a trip to the OR. And then after that, we're not using for low-risk patients.

So, that's for the flex. As far as for the OR, we use it almost on everybody. If something's obviously muscle invasive or large volume tumor, it's absolutely unnecessary to use it. But like Marko pointed out there, it does improve the quality of the resection. I never know whether I have CIS present or not. If you have a papillary lesion and you take the patient to the OR for a TURB, and then find that the patient has multi-focal CIS, well, I think that is helpful information because a high-grade T1 plus CIS is, I think, a slightly different risk category than just having T1. So it does help me to A, do a better resection in the OR. There's training aspects of it as well. And then the better diagnosis of additional lesions. So multifocality and presence or absence of CIS, that helps.

Ashish Kamat: And Marko, you saw some of the data that came out of the study here from the clinic, Flexible Blue Light, where cytology was missing CIS. And there is some talk about actually not being able to trust cytology and using blue light independent of the cytology results. Are you seeing that in Europe too? Is cytology getting to be more of a operator dependent test to a point where it's reliable and unreliable, or is it a little bit different in Europe?

Marek Babjuk: Well, I think it is very user dependent methods and it is even different within one city, between institutions, depending from the quality of pathologist doing it or phytologist. But no, it always has its limitations, but I think our approach to bladder cancer should be really much more careful than we were used to do many years ago. I think it is the TURB should be a complex procedure and you should consider all the information which is available before the surgery, not to look on the data just on the beginning of your procedure.

So I think that the approach should be individual. You should learn your residents, that they should have a look on the results of non-invasive tests like cytology and cytology is mostly available today, its still a standard in Europe. So I think definitely with daily practice, I understand that it is not available in all patients. It is also the results are probably different, even between institutions, dependent from the quality of the examiner. But, this is at least some information and if the cytology is positive, then it is for you, a very important message concerning how the TURB should be done, including the consideration of [inaudible] methods you will use as speedy difference.

Ashish Kamat: Yeah, great point, and a lot of what you just said, Marko, both you and Sia or on the white paper that we put out on best practices with TURBT recently. So everything that you were mentioning is in there. And again, I just want to thank both of you for being part of that endeavor. Thank you for taking the time to join us today and share your views with the audience. I want to give each of you, 20, 30 seconds to share your closing thoughts with our audience. So let's start with our overseas guests, Marko, your closing thoughts for the audience.

Marek Babjuk: First, I would like to thank for invitation. It's a pleasure and many greetings over the sea. And I think taking altogether what we are talking today, I think we should underline the importance of TURB, TURB is even today, the most important factor in the treatment of bladder cancer. If you make the mistake at the time of TURB, then you may lose your patients even. So, it is more important than which kind of instillation you use. So, remember the quality of your TURB and do it very carefully.

Ashish Kamat: Very good point. And Sia?

Siamak Daneshmand: Thank you, Ashish, same here. I completely agree that we should really think about that, TURBT as being the most important first step in diagnosing and going down the right path. Once you go down the wrong path, I think the patient's compromised. So whatever method it is, whether it's blue light, intravesical instillation, NBI, anything that you have in your arsenal to improve detection, surveillance, that we should be using these to improve outcomes for our patients.

Ashish Kamat: Once again, thank you both for taking the time and stay safe and stay well.

Siamak Daneshmand: Thanks so much. Thanks Ashish. Thanks Marko.

Marek Babjuk: You too. Thank you Ashish.