Is There an Optimal TURBT Technique and the Color War? - Ashish Kamat

November 15, 2018

Ashish Kamat discusses the importance of TURBT and its value for diagnosis, therapeutic and prognostic purposes as an essential part of multidisciplinary care with specific regards to clinical trials.  Ashish also compares different agents for the detection of bladder cancer and how these agents are reflected in the AUA/SUO Guidelines.


Ashish Kamat, MD, MBBS, President, International Bladder Cancer Group (IBCG), Professor of Urology & Cancer Research, MD Anderson Cancer Center, Houston, Texas

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Ashish Kamat: When I was asked to talk about Optimal TURBT Technique here, one of the things I was thinking about, well it's kind of a basic topic, right? But, why is it important? Well, some of my disclosures here. The only two that are relevant to this talk are Photocure® and Imagin. The rest are research but not related to this.

So why is TURBT important? Well, we all know. It clearly is the first step in the management of a very complex disease. It's important for diagnosis, it's important for therapeutic purposes and prognostic purposes. But it's also very important today in the world of multidisciplinary care, especially when we're enrolling patients on so many clinical trials with immuno-oncology, with novel therapies, with chemotherapy and laser, et cetera. And it's because you probably have seen a lot of reports coming out. The FDA allows single-arm studies. And a lot of these studies report P0 rates. Now with an optimal TUR, we can render a patient P0 just by TURBT and as high as 30 to 40%. And some of the newer reports that come out and look at drug X for example, look at maybe an I-O agent, report PR rates after the drug, after TURBT, of 20, 25%. And everybody gets really excited about it when you with a good resection could get a P0 rate of 30%. So a TURBT's important for many reasons but especially today with the multimodal investigational agents that we're looking at in bladder cancer.

Now clearly it's an important thing. We have a course at the AUA and some of my slides are from the course that I participate in with Cheryl Lee, and Fred Witjes, and Mike O'Donnell. And also in the new bladder cancer update, the ICUD EAU update that we put forth, some of the slides that I will show you are from that book as well. So if you want more details, those are the two references for it.

Back to basics. So we've always thought about, you know, what kind of anesthesia to use for our patient. Should we paralyze, should we use succinylcholine. We use that sometimes to decrease the obturator reflex. We've talked about it a little bit. And your patients end up with spasms. We don't have to worry about it anymore. Clearly general paralysis, paralytics, is the way to go for an optimal TURBT. Now we don't have to worry about it because those anesthesiologists have suga. As they call it, sugammadex, which is a reversing agent that works fairly quickly. And you can give your patients rocuronium, have them paralyzed, perform a nice deep resection on the lateral wall tumors. And within ten minutes, the patient's awake and the paralysis is reversed.

Creating a checklist is the next way that we can clearly improve the results of a TURBT. That's a busy slide, it's from the reference down there. But I wanna highlight these few points that are very important. So in our EMR that we adopted at MD Anderson and one of the things that our task force created was create a checklist like this that everybody doing a TURBT has to answer. You may not do something, you may not give intravesical perioperative chemotherapy, you may not do a EUA. But at least you have to mention yes, no, did I do it, did I not do it. And there've been several studies that show if you incorporate this checklist in your practice, it improves the recurrence rates of these patients because you are just thinking about these things or resecting better. So clearly this is an important part of a well-performed TURBT.

This may seem very basic to many of you in the room, but it's really important. Do not blindly place the sheet into the bladder and use all the lenses that you have, the 30, 70, 120. The reason for this and the reason we made a big deal of this in the book is because it's not uncommon that we're referred patients, patients are sent to me either for cystectomy or to enroll in a clinical trial for BCG unresponsive disease, and you happen to look in the bladder and lo and behold there's this big tumor hanging right behind the bladder neck, which was clearly there when my referring urologist performed this cystoscopy. But it was missed because he or she did not use the appropriate lenses or did not use a flexible cystoscope. So clearly, we need to look at the corners that are not visible just with the 12- or 30-degree lens.

Assessing the grade and stage is something that we are very good at doing. And it's important to do when you're performing the TURBT because that helps us decide if we're gonna use preoperative gemcitabine or mitomycin in everybody, or are we gonna subject these patients to a deep resection if we think they're high grade. Or can we just resect the tumor and cauterize the base if we think it's Ta low-grade tumor, which is very acceptable. You don't have to go deep in Ta low-grade tumors. And we're really good at this. In one study that Harry Herr published, 99% of the time the urologist was able to classify a tumor as Ta low-grade if this patient had no prior history of a high-grade tumor and the cytology was negative. 99% is a pretty good number. And only 7% of tumors that were high grade are misclassified as low-grade in the presence of positive urinary cytology. So we're really good at assessing this and this is something that you should do as soon as you enter the bladder. Make an assessment as to whether it's a low-grade or high-grade tumor so you can plan the extent of your resection per se.

Now if it's a high-grade tumor, especially if it's a T1 tumor, be kind to your pathologist. You know, oftentimes we get a report back from the pathologist, we can't really tell if they mean that the muscle is involved, if it's present, et cetera. That's because we give them a big chunk of the tumor and they can't really tell us what the base is. So if it's a big tumor, or it's a T1 high-grade tumor, be kind to your pathologist. Get a separate biopsy from the base and send it off so they can actually assess for the depth of invasion.

Another option which not many of us in the U.S. follow is an en bloc resection. So this is a technique that was popularized in the Asian countries. And that's partly because of the fact that their loops were built a certain way and they couldn't really get the finer loops and they had to come up with ways to do en bloc resection. And it's trickled over into Europe and I've used it here in a few cases as well. The technique is really simple. For those of you that are used to using the needlepoint during your TURBT or VIU's, it's the same needle essentially.

So the first step is to mark the borders of the tumor with the needle. Then you actually take this needle and insert it into the areas that you've marked, which you've used cautery on. Once you insert it in there, then you perform a blunt dissection. So that's where the beauty of this comes in. Where you're not using heat at the base of the tumor, you're not distorting the architecture to where the pathologist has to say, "Well it's cauterized fragments. I can't see what's going on." So this is blunt dissection where the tumor is pulled away from the bladder wall and essentially moved out and then at the last point, if you need to do a little bit of point cautery to detach the final fibers, that's appropriate.

This has been shown in several studies to improve the reporting that you get from our pathologist as far as depth of invasion's concerned. And it does make it easier for them to actually report on this finding. It also, in theory, decreases the tumor cells that are shed and are scattered about the bladder. We all know when we resect a bladder tumor, you do see cells floating around and those have to be irrigated out. And there's some concern that those are the cells that implant into the other areas in the bladder and are responsible for at least some of the early recurrences that we see.

Speaking of cautery, bipolar has been shown in multiple studies to clearly be superior to monopolar. A shorter operative time, less blood loss, shorter hospital stay. But in general, the complications from a TURBT are so low in most people's hands, that that difference is really minute. So whether you use a bipolar or a monopolar, it doesn't make that much of a difference in absolute terms. But between the two, a bipolar is better and that is a recommendation that we have in the book and in the course.

Talking about complications of TURBT, I just wanna highlight that the complication percentages are low. The overall percentage is 5% or so with bleeding and perforation being the two most common complications. And if you look to see which patients actually develop complications, it's your classic, thin, female, with a BMI of less than 25. In multiple studies that have been performed, this is just one example of close to 1300 patients; if you look at the factors that cause bladder perforation, it's not, believe it or not, related to the experience of the surgeon, the type of anesthesia, the number of tumors, the size of a tumor. It is the thin, female bladder in a woman that doesn't have much adipose tissue and has a low BMI. And those are the patients that we just need to be a little bit careful of.

Now that was TURBT and I touch upon a few points, not wanting to belabor the issue amongst experienced urologists such as yourself in the room. Moving forward to the colorful part of the thing. You know, this has been what we've had standard for many years. Clearly, we wanna look to the future and not hang around in the past. And that's what brings us to the first of the different technologies that I'll talk about. And this is Cysview®, which all of you know is a hexyl derivative of ALA. It's approved in the United States by the FDA. This is initial approval to be used as an adjunct to standard white light cystoscopy for the detection of bladder cancer especially papillary tumors.

This is the KARL STORZ PDD System that many of you are familiar with. You have the tower, you have the camera, the fibers, the scope, all of that, et cetera. The trials have been performed many years ago. So these are trials that were reported back in 2004, 5, and all the way up to 2010. And in summary, this agent has been extensively studied. There have been five multicenter Phase III trials in Canada and Europe with close to 2000 patients. And all these trials use central pathology. So that confounder was taken away and other than one single trial, all of these trials use central pathology.

The bottom line is from the Pivotal study, which is a study performed in the United States that got Cysview® approved here by the FDA. In this study of 286 patients, Ta or T1 bladder cancer was detected on biopsy. The bottom line is in this graph. 16.4% of patients had a tumor that was only seen with blue light technology. And when you look at the breakup between Ta and T1 at 16% and 13% which averages out to 16.4%. But when you look at the CIS patients, 46% of patients overall had an additional tumor which was CIS detected with blue light technology.

Importantly, if you look at the additional tumors that were detected with the blue light technology, they were high-grade or T1. So clearly the types of tumors that make a difference in our management in as many as 43% of patients. There was no difference in the false positives. You'll often hear people talk about blue light and say well, "I'm biopsying things that don't really look like a tumor to me. They're shining pink and I don't know what to do with these." In the instance of false positive with the white light cystoscopy biopsy, whey you biopsy something that looks suspicious, or blue light positive biopsy is the same. It's in the range of 9, 10, 11% depending on which study you look at.

This was just a pictorial example. You can clearly see the big tumor there with white light. You can sorta see what's there, the little satellite tumor under white light as well. With the blue light, it just makes it easier to see. This is more of an example where the residents and fellows working may not see the other satellite tumor that most of us in this room can see. And it helps us teach, train, and help perform better resection.

This, however, is an example of a tumor that I can't see. I'm not sure I could see this even if it was pointed out to me. There's nothing there on that particular view that looks abnormal in the white light to me. But in the blue light, you can clearly see this one patch which when biopsied was carcinoma in situ. And that clearly changes the risk stratification and management of this particular patient. Maybe not the previous patient who had one additional low-grade tumor. But the bottom line is, not every tumor that's detected on Cysview® is life-threatening. But many are and many can't be seen with regular white light.

Now the question is sure, the blue light will help me detect more tumors but does it actually affect recurrence rates? And this is a question that was brought up many a time before there was longer-term followup in the previous studies. And what the long term follow-up, and this was reported back in 2012, it was shown that yes, performing a resection with blue light will increase the time to recurrence in your patients. The time is increased from 9.4 months to 16.4 months. So clearly, you decrease the number of recurrences and prolong the time to recurrence in your patient.

The next question is, well okay fine, I can decrease recurrence rates but you're telling me it's a high-grade tumor. It's a T1 tumor. Are you actually affecting progression in these patients? And again we have to wait for longer-term followup from many of the studies. These are two publications. When Gakis looked at it in a meta-analysis, he was able to show really that blue light did decrease progression rates from 10.7 to 6.8%. And then we, with the International Bladder Cancer Group, looked at it with our definition. It kind of reached that divergence but didn't hit, it was right at P equals 0.05. So we can't say it does, but you can clearly see the separation of curves and maybe with longer-term followup, we will see that as well.

Now, many of you may have heard about the recent or renewed trial and the recent approval of Cysview® in the flexible scenario. This is where you use blue light cystoscopy in the clinic using a flexible scope. Just some summary slides. This is a Phase III multicenter study from 17 US sites, close to 300 patients, that was reported and published this year and got FDA approved for this indication. Here, if you look at the end results of the study, the bottom line is one in five. So 20% of patients had an additional tumor that was detected with blue light only. And this is in the office setting. This is not in the OR setting. This is not for a TURBT, but this is a flexible cystoscopy in the office setting. The bottom line number is one in five patients had an additional tumor detected.

And this is an important table from that publication that I wanna highlight because we've started to become a little bit more reliant on cytology than the other markers that are available to us. And rightfully so. I mean the AUA guidelines and the EAU guidelines all state that there's no role for your inner markers, just use cytology. But, the caveat is that our cytopathologists are not as good as reading out cytologies to us today as they used to be. And they admit that. They just don't train the way they did on urinary samples.

And in this study, for example, you can see here, I can't point, but if you can see here in the bar with negative cytology. So there were patients, 46% of patients who actually had a tumor in the bladder had a negative cytology. The cytopathologist read this as negative. It wasn't suspicious, it wasn't atypical. it was clearly negative. So if you rely only on cytology to decide whether or not we're gonna use blue light technology, which again I do if a patient has suspicious cytology and nothing that I see on white light, I will use blue light in that patient. But if we only rely on cytology to use blue light technology, then we will potentially miss 46% of these tumors.

And this was a press release that came out saying Photocure® announces, you know, FDA approval for the blue light in the flexible cystoscopy setting.

Now disclosure, I do help this company. But I wanna present this because this is potentially technology that's going to be available to us in the United States soon. One of the downsides of the blue light storage system, and it's not the blue light, it's not really the equipment per se, but it's the US, is that you have to switch between white and blue, white and blue, whenever you're doing the resection. You don't actually see both images at the same time. And you have to wait about 45 minutes to an hour of dwell time to be able to actually see the fluorescence.

This is a technology that is actually being tested out in Rochester by Ed Messing and that group and it was developed in California by a biotech company over there, where you can actually see fluorescence potentially as early as 15 minutes after you put the Cysview® in the bladder. And the advantage of this is that the camera head fits onto any scope. So you wouldn't potentially be tied down to just one manufacturer. You could use whatever scope you have because all the technology's in the handle and you can also then see the white light image and blue light at the same time without having to switch between the two because the software and the hardware does that for you. So that's something that should be rolling out as a clinical trial. And you know, of course, the LUGPA groups are always very high enrollers to those types of studies. But I just want to present this out there so that you can potentially enroll patients on these trials when it's enrolled.

The next technology that again, we have already, but is not as well popularized or used as it potentially could be, is narrow-band imaging. Now, what is narrow-band imaging? Essentially what it is, is it filters the white light in specific wavelengths that are absorbed by hemoglobin. That's present in the blood vessels and the tumors in the bladder per se, essentially. And that allows us to see the architecture and the depth of these tumors within the bladder per se.

So you can see here, the image on the left is a normal white light image. And when you hit the toggle button for NBI, you can see the image changes to what's on the right. So essentially what it helps us do is see things a little bit more clearly. I think of NBI more as adjusting the contrast on your television set. You can see things a little bit better. But it's not necessarily gonna show you things that are not visible with white light in the first place. Again, it's a useful training tool. It's present on many scopes. You just press the button. There are no added costs. So if you have it, by all means, use it.

And there have been multiple studies that have been performed using NBI. Most of these in Europe, but one large study here from the United States. Again, that was from New York from Memorial Sloan Kettering, Harry Herr's data. And you can see that on average, that one in five number kind of still hangs in there. So it's 17%, 12%, 27% in one study, additional tumors that are detected with narrow-band imaging.

Two studies that I wanna highlight. One is the CROES study that was published in 2016, where they tried to see whether narrow-band imaging would decrease recurrence rates. The bottom line is it didn't reach its primary endpoint and that's why many people don't talk about this study. But it's important to recognize that it did reduce recurrence rates in a subgroup of patients. Those are the solitary Ta, small, low-grade patients. And those are the patients that we actually don't do anything else to. So we don't treat them with chemo, we don't treat them with BCG. So it does have an effect on that group of patients. So if you have it and you're using it, you're definitely helping that group of patients per se, so keep using it.

And this is another study from Denmark that looked at close to a thousand patients and found that narrow-band imaging actually did change management in a small percentage of patients. But it was actually effective in increasing the number of tumors you detect and changing management in a statistically significant percentage of patients, albeit a small percentage of patients which they said was 1.9 which is small.

Putting this together, it's not really trying to compare the two but just to kind of highlight a few pros and cons. So NBI does not need installation of any agent. You can perform a TURBT using narrow-band imaging. It is cost-effective and it does increase the detection of tumors. The cons are that there's no cancer outcome data that has actually been published. There's no large randomized study that has actually been published on narrow-band imaging that's convincing. And there is high inter-observer variation.

With blue light, it's clearly been studied extensively as I showed you. It has been shown to decrease recurrences and progression. You can perform TURBT under blue light of course. There's less inter-observer variability because if something's pink, it's pink. You can biopsy it. Your false positive rate might be a little higher when you're first starting out doing blue light cystoscopies, but it quickly drops to that 9, 10% range. And it does detect CIS which is harder to detect with narrow-band imaging.

The cons with blue light that it requires the installation of a drug, an agent, into the bladder of the patient about an hour before you perform your cystoscopy. It is cost-involved. There have been some changes to the reimbursement paradigm, but in general, it is a cost to the system, the catheter, the nursing time, et cetera. And in the US, as of now at least, we can only use it with the KARL STORZ system. It's not like in Europe where you can use it with multiple systems and the technology that I showed you where you can use it with different scopes isn't available in the US yet.

So the AUA and SUO guidelines that came out essentially reflect everything that I've talked about. They say for blue light with Cysview® in a patient with non-muscle-invasive bladder cancer, a clinician "should offer" blue light cystoscopy. Evidence strength is Grade B. For NBI, it's pretty much the same jargon but rather than saying "should offer" because it's evidence strength Grade C, the guidelines say, "may consider." The bottom line is if you have NBI, use it. If you have blue light, you should use it. If you don't have it you should consider getting it. And I, in my practice, actually use both interchangeably depending on the particular situation and the venue that I am at. Thank you very much.