Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston, MD Anderson Cancer Center, and I'm joined today by two experts in the field who also happen to be good friends of mine, Dr. Sia Daneshmand from USC in California, and Dr. Trinity Bivalacqua from Johns Hopkins University in Maryland. Thank you for joining me, gentleman, today.

For the purpose of today's meeting, each of you has been assigned a side, and you will present that side during your presentation. And then we will have a discussion as to the pros and cons of the particular stance that you've taken. The topic for today essentially is a discussion of enhanced cystoscopy with blue light and in some ways contrasting that and comparing that with the benefits of perioperative chemotherapy. So with that, if you're ready, Dr. Daneshmand.

Siamak Daneshmand: Ready. Thank you, Ashish, for the invitation and it's a pleasure to be on with you guys. So I'll start with blue light cystoscopy and discuss. These are my relevant disclosures. I'm a paid consultant for Photocure®.

So blue light, there's a ton of evidence in the TURBT settings spanning back to about 15 years. It's extensively studied to investigate improvement in the detection of bladder tumors. There have been five multi-center Phase III trials in the USA and in Europe with more than 1,800 patients showing the benefits of blue light.

So here's a meta-analysis in nine studies in over 2,000 patients showing that at least one additional Ta or T1 tumor was found in about a quarter of the patients. And 26-27% of the CIS patients were diagnosed with blue light only. This was published in 2013.

We also see that blue light impacts recurrence of bladder cancer. The rate of recurrence is reduced by about 10%. And also the time to recurrence is prolonged from nine months to 16 months. So it's delaying recurrence, it's reducing recurrence rates. Pretty significant numbers here with bladder cancer standards.

How about progression? I mean that's sort of the most, what one could think the most important aspect here, and this is a study by Dr. Kamat himself showing a reduced rate of progression in bladder cancer as well. Because if you're removing a lesion, sort of at an earlier stage that there's less chance of progression. Now, this was a retrospective look, but nevertheless you can see it is significant there, with white light, 10% progression versus 6.8%.

So in conclusion, there's a significant improvement in not only the detection of patients with recurrent bladder cancer but also recurrence and progression.

I do want to bring up some recent studies. This is from a prospective registry that many of us are involved in, including Dr. Bivalacqua. These are blue light cases done at nine different centers from April 2014 to October 2016 with 533 patients. Now, this also shows pretty much the same thing, that there were a total of 1,600 separate lesions, 640 blue light procedures. We now have more than 2,000 cases in the same registry and updated results are coming, but you can see basically the same thing. The sensitivity and specificity of blue light. You see that what we really care about in bladder cancer is making sure we don't miss lesions. So sensitivity you see is 91% compared to in overall blue light picking up any bladder cancer. Now many people bring up a sort of what is a false positive with prior BCG or overall. It's somewhere in the 25 to 30% range, very similar to white light.

And so in this study, we looked at whether a patient's got prior BCG, whether we were looking at margins of prior resection. And you can see it's all in the 30% range. But again, I think the most important aspect here is not missing cancer for if we take additional biopsies, they turn out to be negative. It's not as important.

Also in this study, we looked at their AUA risk migration to see whether lesions detected by blue light actually made a difference. And you can see there the numbers. The final pathology, we went from low-grade Ta multifocal changing it to intermediate risk. So we went from low to intermediate, and in one patient with high-grade Ta we went from low to intermediate. We've had several now with invasive tumors detected. So we've gone to high-grade. So this makes a difference in management obviously when you have risk migration.

And this was the abstract we were going to present at the AUA. We will be presenting it actually I guess virtually. This is now 3,500 lesions in 1,200 patients. Eight hundred and eighteen lesions were white light negative, blue light positive. But importantly 494 of these lesions or 14% were invasive tumors. So 11% of the lesions that were completely not visible by blue light were invasive, 48 of which were T1, 7 T2. Absolutely invisible on white light.

So in conclusion, basically blue light cystoscopy increases detection, decreases recurrences, and hopefully, we'll have more or more evidence that it decreases progression rates as well. It is in the guidelines in both the European Urology guidelines as well as the AUA recommending the use of blue light cystoscopy when available at the time of TURBT. Thank you very much.

Ashish Kamat: Thank you, Sia. And now for the side of perioperative chemotherapy, we have Dr. Bivalacqua.

Trinity Bivalacqua: Thanks, Ashish. And thanks Sia for inviting me today to discuss the utilization of perioperative chemotherapy at the time of TURBT. We just heard the data to support the use of blue light cystoscopy. And I'd like to point out right now that in my talk today I will not be discussing detection, as intravesical chemotherapy's goal is not to detect additional tumors but to prevent implantation or to treat any residual cancer that's in the bladder after TURBT.

So as we are well aware, there is strong data to support the utilization of intravesical chemotherapy after TURBT. We define perioperative intravesical chemotherapy as giving shortly after the resection or within 24 hours. And there is data to show that both mitomycin C, gemcitabine, epirubicin, and pirarubicin do reduce and prevent the risk of intravesical recurrences. A single installation of intravesical chemotherapy has reduced the risk of recurrence anywhere in the order of 20 to 35% depending on the trials.

However, a single intravesical instillation does not prevent progression or death from urothelial cancer. And we'll talk more about that shortly. This is data from Sylvester, which was published in 2016 which looked at all of the randomized controlled trials looking at a single intravesical instillation of the chemotherapeutic agents that I discussed earlier, except gemcitabine. And you can see clearly that those patients that received a single instillation of chemo had a time to recurrence which was less compared to those that were not instilled. That is the blue bar compared to the orange. And importantly, there was no difference in the time to progression in these RCTs.

So who benefits the most? And that's something that we often struggle with as we're performing a TURBT for papillary tumors where we are uncertain if it is a low-grade or high-grade cancer. All of the previous randomized controlled trials demonstrated that those that benefited most were people with papillary low-grade disease or potentially high-grade disease. But intravesical chemotherapy does not seem to have much of a benefit for patients with high-grade or high-risk nonmuscle-invasive bladder cancer, particularly CIS, and really benefits those with low-grade disease.

Now this is a trial that was published from SWOG in 2018. Ed Messing was the primary author. It was published in JAMA, which showed that a single intravesical instillation of gemcitabine clearly demonstrated a reduction in the time to recurrence for low-grade cancers in the bottom panel, as well as all-comers. This trial was actually powered to look at patients with low-grade cancers, but clearly they were high-grade tumors that were also resected at the time. The thing that's so important about this study is that gemcitabine is very safe and actually showed a very good toxicity profile, which I'll demonstrate in a minute.

I'd like to point out, and Sia had this exact same slide in his presentation, that blue light also impacts recurrence after bladder cancer. And if you look at this table, it seems to have the greatest impact on patients with low-risk disease or intermediate-risk as it relates to time to recurrence. Actually pretty similar to that of intravesical chemotherapy.

So what about safety and cost? Because that is something that we oftentimes juggle in our mind when we're thinking about giving an intravesical instillation of chemo. In the past, I've actually can honestly say I've had some pretty significant side effects from mitomycin C when given intravascularly after TURBT. However, in the SWOG trial, it showed the gemcitabine had no grade 4 or 5 complications and a single intravesical instillation of gemcitabine is about $100. It's actually less in most centers in the United States, at least. However, when you compare this to Cysview®, it costs about $125,000 as capital cost just to get the OR equipment. And when you compare the recurrence rates, you can clearly see that gemcitabine from a cost-effective standpoint is actually much more cost-effective and better.

I think the question that really we should probably talk more about is the risk of progression and what happens with both of these technologies. So in summary, perioperative intravesical chemotherapy reduces recurrences but does not prevent progression. It is cost-effective and safe. And in real-world practice, the utilization of blue light cystoscopy and perioperative intravesical chemotherapy should be standard of care as dictated by the guidelines both from the EAU and AUA. Thank you.

Ashish Kamat: That was excellent. Both of you. Thank you so much for taking the time to put together such a succinct presentation on the topic. Let me address some practical questions that we often get from viewers and audience members in this situation. Focusing entirely on the operative side of things, if you have a patient with suspected low-grade bladder cancer, which one of the two, if you only have the choice to choose one, would you select and why? And let me start with you, Trinity.

Trinity Bivalacqua: Yeah, I actually think that if you pinned me down and said which one would I utilize, I think there are advantages to both. I will say that patients that you perform blue light cystoscopy on with low-grade papillary tumors, we're all aware of those satellite lesions, those small tumors that you really can't see and blue light really gives you a clear advantage in resecting and removing those. What intravesical chemotherapy does is it allows you to prevent that sort of tumor seeding and actually may potentially treat some of those smaller tumors. So if you had to pin me down, I'd say for detection and resection I'd use blue light, but overall I think gemcitabine, which is what I use in clinical practice, I think would be equally effective in that sort of small volume, low-grade papillary disease state.

Ashish Kamat: And if you had the choice of only having one of these available to you, what would be the ideal patient in whom you would use perioperative chemotherapy and the ideal patient in whom you would use blue light over perioperative chemotherapy?

Trinity Bivalacqua: Yeah, I think for perioperative chemotherapy it's that patient in my practice, honestly with both high-grade and low-grade disease that has papillary disease, low volume. Where I think I can do a good TURBT, and we're all aware of sort of the importance of a TUR, and then I can give intravesical chemo, prevent that tumor seeding, and more importantly also potentially treat with the cytotoxic effects of chemo, and with gemcitabine, potentially an immunological effect on those smaller lesions. The patients that I'm going to be using blue light cystoscopy on are those with CIS and high-grade disease whereas Sia pointed out, where we're really looking to do a better detection rate and potentially detect that invasive disease that we may have missed with just white light.

Ashish Kamat: Thanks. Sia, if you had the choice of just one in a particular situation, which would you use and for which patient?

Siamak Daneshmand: Oh, interesting situation. If we had to choose just one. I totally agree with Trinity. I think in reality they're not mutually exclusive, but for the smaller tumor that you think is low-grade and a solitary tumor, I agree, I think just by cost perspective alone, and we can probably do a good job doing a TUR, I'd do the perioperative intravesical therapy specifically with gemcitabine. Oftentimes, though we don't know, right? The reality is we go in and we're not sure exactly. You may have done a cysto in clinic, and you go, "We're not exactly sure whether this is going to be low-grade or high-grade" and that's highlighted by the trial in which only low-grade patients were meant to be enrolled in this trial and you have so many high-grade patients in there.

So yeah, if you pin me down, I think I'd do perioperative intravesical therapy for the patients with the smaller tumor that I have seen that's easily resectable with no satellite lesions. But anything else that is larger, perhaps higher-grade looking and worried about satellite areas. And one thing I didn't discuss, and I think it's not borne in the literature, is the fact that we do a better TUR with blue light because you see the edges of where you missed. Of course, that reflects in the recurrence rates. But also in the training arena, once you've done your TUR or you think you're done, the blue light will highlight areas that you've missed.

Ashish Kamat: Thanks. Are either of you aware of studies that might be ongoing or data that actually looks at this question to see which one of the two falls out in a multi-variable analysis as being more important?

Siamak Daneshmand: Of any study like that I think it's very, very difficult to tease these out as individual contributors. Many of them are done simultaneously and they're both considered standard of care. I think it will be really difficult.

Trinity Bivalacqua: I mean one option is to take the Cysview® registry, which is a prospective registry and actually enroll sites that do not have blue light cystoscopy for whatever reason. It may be the cost, it may be a number of reasons and actually prospectively look at these different patient populations that we're discussing now to be able to address that. I agree with Sia. I think it's going to be hard to tease that out in a multivariate analysis. What do you control for, how do you choose that? The variables would be a challenge.

Ashish Kamat: Yeah. From a cost perspective and penetration perspective, I think it's important for the listeners and audience to remember that if they don't have blue light, then to please, please use perioperative chemotherapy because there really should be no reason why you can't use perioperative chemotherapy even if you can't have the blue light system. Another question that comes up sometimes as well. Okay, you have the blue light system in your clinic and you're using it and you see the small papillary tiny little lesion, you cauterize it in the office itself. Is that a patient you would recommend a dose of gemcitabine at that time in, Sia?

Siamak Daneshmand: That's a great question, Ashish. I think we haven't been routinely doing that, but I don't see why not. Gem is easily available in our clinics as well. So we do, I think, first of all, it's very important to biopsy those, not just full grades even in the patient who has had a history of low-grade tumors. So we do do a fair number of biopsies in the clinic and a full-grade debase. But yeah, I don't see why not. We'd have to anticipate it and sort of have it available, call the pharmacy. But that would probably lead to better outcomes even in the clinic setting, outpatient setting.

Ashish Kamat: Trinity is that something you're doing?

Trinity Bivalacqua: Yeah, I was going to say that, unfortunately, unfortunately we don't have the ability to do flex blue light and are in our ASC because that's where we do our cystos. And once again this is all because of costs, our hospital won't approve it. However, we do have the ability to do fulguration, and a number of my colleagues, Max Kates, is actually following that up with intravesical treatment, not necessarily perioperative. So in that sort of patient population where you're looking at recurrent, that intermediate-risk group where we're not sure exactly what to do with. So yeah, I think it's a great idea and I think some people are starting to do that with or without blue light.

Ashish Kamat: Thanks. Sia, just a question about the data you presented, even though it wasn't the actual topic of this discussion. But just to clarify for the viewers, you noted a 30% false-positive rate with blue light, which is higher than that reported in the studies. Did that surprise you and if not, why?

Siamak Daneshmand: No, not at all. Oh, first of all, that came from the multi-center registry and that's an overall false-positive rate. We did see there's a wide variation of false-positive. It all depends on who's biopsying what if you have something that's slightly fluorescent in the prospective. Other prospective studies in the Phase III studies, the false-positive rates have been as low as 10%. So, and again, there's wide variation. So no, not really. I think some people end up biopsying a lot more lesions just to make sure they're not missing anything. And these are per lesion, not necessarily per patient. So I don't think there's added morbidity to taking more biopsies. Particularly, there's also a learning curve. I think in the beginning anything that fluoresces even slightly some surgeons are taking additional biopsies. So that leads to the slightly higher. But it's similar to I think the red erythematous lesions that people take biopsies of and probably similar.

Trinity Bivalacqua: If I could add, if you don't mind, Ashish, I think in the registry, remember we were including a lot of patients that were post-intravesical therapy. So I think we probably had a more of a higher false-positive rate in that study because we had, I believe more of a real-world population where a lot of these patients had intravesical therapy, which we know makes it a little bit harder to detect things.

Ashish Kamat: I agree.

Siamak Daneshmand: Yeah, that's an excellent point.

Ashish Kamat: Just a follow up there then. What would you recommend in the flex cysto situation where you're recognizing a 30% false-positive rate? Would you advise people to keep that in mind when they're deciding whether to take a patient to the OR and give anesthesia in the setting of prior intravesical therapy?

Siamak Daneshmand: Yeah, I'm using a lot of flex blue and you bring up a great point because we do see these lesions that are sort of intermediate fluorescence and we're not quite sure, and really the decision is... In the prospective phase III trial, we had to take patients into the OR, we couldn't do clinic biopsies. But I think that you have two options here. One is if you're suspicious enough and it's a larger lesion and you go want to have a sampling error by taking a clinic biopsy, then you take the patient to the OR. But we again do a fair number of biopsies in a clinic, so that's an option. Another option would be to rely on biomarkers.

And one of the things that you can do, I think cytology has a very, very poor sensitivity for picking up these lesions. Even CIS in the prospective Phase III study of the flexible blue light cysto, of the 13 lesions that were detected, 13 CIS lesions that were detected by blue light cystoscopy alone, none of them had positive cytology. There were a few suspicious, but most of them were actually negative. So the sensitivity is quite poor for the small volume, CIS lesions. So another, I think biomarker that performs fairly well in this setting is Cxbladder™. So on occasion, we will have the patient, if we have equivocal findings on either white light or blue light, send a Cxbladder™ and if it comes back negative, be reassured that there's at least at 98% chance we don't have any a bladder tumor there.

Ashish Kamat: Thanks for that insight. As we're coming up on time, I'd like to give each of you a little bit of time for closing thoughts. Trinity, you first.

Trinity Bivalacqua: Great, thank you. I think I'll just summarize by saying that the data clearly demonstrates that perioperative chemotherapy, particularly with gemcitabine, reduces recurrences and also is cost-effective. And I'll also state that there is oftentimes this sort of dogma that you can't give intravesical chemo in patients that you've done potentially a large resection or a deep resection. But with gemcitabine, because it's such a safe agent I've found that at least in my clinical practice as well as talking with others that you can do that. And that is clearly shown in the SWOG trial. So perioperative chemotherapy should be utilized in my opinion and specifically in patients with low-grade papillary disease as well as those with high-grade papillary disease to help prevent recurrence.

Ashish Kamat: Thank you. Sia?

Siamak Daneshmand: I completely agree. It's routine. It's in the guidelines. The evidence is strong. Absolutely use perioperative chemotherapy, gemcitabine in particular, very safe, very effective and cheap. I think blue light if it's available, we try to do everything we can in bladder cancer to reduce recurrences, to reduce progression. This is an expensive disease and the upfront cost of the equipment may be high, but preventing recurrences and progression down the line may have untold cost savings there as well, but more importantly, effect on the longevity of the patient. And so if available use both, do everything you can.

Ashish Kamat: Great points both, of you. And as far as the cost of blue light systems are concerned, there are new equipment manufacturers coming in to look at potentially scopes and lenses that work independently of the actual manufacturer of the TUR equipment that you use. So that might drive the cost down, which would really help get this in the hands of people that need to use it. And they'll use the same drug, Cysview®, Photocure®'s drug, but just the end equipment will be hopefully cheaper. So that's a little ray of light at the end of the tunnel for those that can't navigate the cost issue.

Thank you both so much for taking the time to be part of this important educational activity. Stay safe. Stay well.

Trinity Bivalacqua: Thank you very much.

Siamak Daneshmand: Great, thanks, Ashish. Bye-bye.