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Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston. And it's my pleasure to welcome two colleagues today who will join us and talk to us about a very important topic, which is the transurethral resection of bladder cancer, and give us their perspective on the TURBT process, and also highlight some of the studies that they've done and are undertaking over across the pond.

First off we have Dr. Param Mariappan, who is Consultant Neurologic surgeon at the Edinburgh Bladder Cancer Surgery Center, Western General Hospital at the University of Edinburgh. And following that we have Prash Patel who is Consultant Neurologic Surgeon at the University of Birmingham in UK.  And both of these are, of course, experts in their field. Today they're going to focus their expertise on TURBT and bladder cancer. So with that, Param, take it away.

Param Mariappan: Thank you for the kind invitation, Ashish and UroToday. I will focus on the first part of the brief, exploring quality indicators for TURBT. I really don't have any conflicts of interest, but do apologize in advance to your viewers for having to highlight some of the work that we've done in this area later on. Let me firstly emphasize, especially to our trainee colleagues in the audience, that the TURBT is not to be trivialized, and we should all take pride in doing this operation really well.

Therefore, the premise of this QI work is essentially that the TURBT is a cancer operation, and it's no less important than the major surgery we carry out. Secondly, despite best efforts, it's just not practical for it to just be in the hands of a select few surgeons. And it is for this reason that benchmarks and quality control are required to standardize and obtain meaningful outcomes.

So if we now look at the mind map and focus our thoughts, quality is going to be a measure of how effectively we have achieved the endpoints, which in turn, are driven by the objectives.  And in this case, I'd like to look at them as the CIS of TURBT, or clearance, information, and safety. In other words, when performing a TURBT, the relevant questions that should be asked are; have I cleared all tumors effectively? Have I reliably determined the biological potential of the cancer? And have I done these safely?

First, the R0 for clearance of cancer can be represented by early recurrence, residual disease, and to some extent, understaging in the case of high-grade cancer.  While being able to effectively risk-stratify patients, and recommend the appropriate treatment, and also measuring complications. But these endpoints often take time, especially those measuring clearance of cancer. Therefore there's a real need for surrogates or QIs, which feature further upstream in the thought process.

For example, emphasizing the importance of the pathologist in all of this, I would place having a pathology standard checklist as QI #1. Secondly, the single-shot chemotherapy installation in a select group of patients as a QI is really a given, considering the known level of evidence.

So let's now explore where the urologist features in the QI process. First and foremost, there are some essentials that encourage effectiveness and efficiency in a service for TURBT. I'd like to call this the AI, not artificial intelligence, but attention to detail and willingness to audit. Secondly, having the infrastructure that is conducive to aligning all of the ducks in a row that will allow and facilitate future optimum results.

However, essential as it may be the A and I are not actually easy to measure. This, therefore, highlights that pragmatic QIs and surrogates need to be specific, measurable, achievable, relevant, and trainable, and to some extent, timely.

So let's now explore some pragmatic QIs here. We know that the resection quality is highly variable, as seen from the results of this very important study. Maurizio Brausi and colleagues went back to one of the trials and performed a quality control check. They explored the association between a comprehensive list of variables, as seen here, and the development of early recurrence. What they found was that the recurrence at the first check cystoscopy was lower when the clinician carrying out the operation used a bladder diagram, and when the surgeon was a member of staff, as opposed to a trainee. But experience, as we all know, is quite hard to measure. So seeking a useful measurement yardstick, if you may, in 2005, having just introduced a bladder cancer performer into our service, I went to my URO pathology colleague and asked Ken, can you tell me how often we get detrusor muscle in the first resection specimen?

That question resulted in this study. What we found was that the absence of the detrusor muscle was associated with relative inexperience on the part of the surgeon and a higher risk of early recurrence and residual disease, as well as under-staging in pT1 cancer.

We went on to validate these findings both in time and place, and actually, as we were embarking on PDD shortly thereafter, we recommended the benchmark pentafecta, if you may, for good quality white light resection, which was to form the control for future comparison.

As you know, since then there have been several studies gauging the association, and perhaps the lack of association between detrusor muscle, experience, and early recurrence. Most important of these, the LA SEER database  has demonstrated a poorer survival in all grades of non-muscle-invasive bladder cancer, and particularly those with high-grade disease when the detrusor muscle was absent.

And secondly, this European collaborative suggests a specific benefit for selectively performing re-resection only in patients with no detrusor muscle in the resection specimen for high-grade disease.

Having a comprehensive checklist ensures we'll remember the important things and potentially bring together the quality elements into the equation, as well. As you know, the Sloan Kettering Group have suggested a possible positive relationship between a 10-item checklist and obtaining detrusor muscle in the specimen.

So now, this is what our mind map looks like once we've added in the quality indicators mentioned previously. It is nonetheless important to once again mention that experience, supervision, and training cannot be overemphasized as far as TURBT is concerned, given its critical place in patient management.

And so the ideal service set up should comprise a dedicated list with all of the bells and whistles where possible, populated through a process of triage, supported by a multidisciplinary team, whilst ensuring good communication with the patient. And then contributing to a national audit and quality control process.

The question, therefore, is can this be emulated in a larger potentially national populace? It's been fortuitous for us that we have the Scottish QPI Program, which essentially incorporates QIs for cancer within a framework of governance and prospective audit. All of this is designed to improve outcomes and smooth invariance across the country.

We've introduced in 2014, 12 quality indicators, as seen here, of which half are related to non-muscle-invasive bladder cancer and TURBT. So as part of a large real-world study on bladder cancer, we've recently published the early outcomes following the first three years of implementation. As can be seen here, there's been gradual, but steady, improvement in the documentation around the TURBT process. Detrusor muscle was obtained in 80% of all resections, and two-thirds of non-muscle-invasive bladder cancer patients received a single shot of mitomycin C, and this is data from the whole of Scotland.

We've also made some interesting post-hoc observations in relation to the association seen between hospital volume, surgeons, detrusor muscle, and early recurrence, which I'm sure we can discuss later. But the key findings here, Ashish, were that we had low levels of early recurrence. A third of high-grade disease patients had residual disease at re-resection and here, I've shared with you and your viewers a table, which actually isn't in the paper, but highlights the breakdown of those with residual disease.

Understaging was very low in high-grade cancer. And we have emphasized, possibly for the first time in a real-world setting, the value of a single shot chemotherapy installation, specifically in the low-grade noninvasive bladder cancer patients in reducing early recurrence.

And finally, Ashish, I am pleased to share with you the apparent fall in early recurrence and residual disease over a 40-year period in our public-funded hospital. This seems to tie in with the little quality interventions mentioned previously and numbered here along the way. Now I fully recognize, given the differing grading systems and definitions and so on, I may be comparing different apples and that these findings may not necessarily be unique to us, an intriguing observation, nonetheless, which we could certainly explore later, time permitting.

Regardless, I hope you agree that quality control is here to stay and that it is no longer a tenuous proposition in bladder cancer. I thank you once again for this opportunity, Ashish and UroToday. Thank you very much.

Ashish Kamat: That was great, Param. That was very interesting. Prash, you're up next?

Prashant Patel: Hello. I'm Prash Patel, Consultant Urologist in Birmingham, UK. I will show you the English perspective of TURBT series and the challenges we pose.

The NHS was founded about 72 years ago, and in present times, 140 hospitals in England provide urology care. In this health service, it is completely free at the point of entry.

TURBT is a vital part for diagnosis, staging, and treatment of bladder cancers. And most importantly, 90% of the patients meet the target from hematuria to the first assessment by flexible cystoscopy, within 14 days in the UK. But only 75% of the patients will meet the 62-day target, i.e., to undergo a TURBT from the time of referral to secondary care. I think there is room here to improve.

Furthermore, it takes 144 days for time to cystectomy, allowing the times for neoadjuvant chemotherapy in patients with muscle-invasive bladder cancers. And there's also time to improve in this area.

Quality indicators already discussed in detailed by Mr. Mariappan, but there are no doubts that they're extremely important. I'd like to emphasize that TURBT can be done routinely as a day case. And reassuringly, there has been emerging guidance, especially from the GIRFT Report led by Professor Simon Harrison, a report being published in July 2018.

The length of stay in England has a ninefold variation ranging from 0.3 to 2.6 days, averaging 1.2 days, mainly due to different care pathways. The British Association of Day Case Surgery advises that 60% of the TURBTs should be done as a day case. And if that was the case, then only one hospital would have achieved this particular target. Only 8 out of 140 hospitals achieve 30% of their TURBTs at day case. And overall only 10% of the TURBTs in England are done as a day case.

These can be achieved by having clear policies, by patient selection, as in ASA scores, age, comorbidities, and so on and so forth, but more importantly, by educating the team as well as the patients using checklists, harmonizing pathways nationwide.

The workload in the NHS is expanding year on year. And hence there is a need to innovate. And innovation or change is possible, as demonstrated by Dominic Hodgson's group, where they have done a relatively small, but effective, retrospective studies evaluating day-case TURBTs. And they're shown successfully without compromising the care, as evaluated by non-quality indicators.

The biggest challenge we will need to deal in the coming times is tackling the COVID crisis and how do we restructure all our services within the NHS, and even globally for other countries.

Improvement in quality of TURBT is currently being evaluated by the RESECT study, but the need for TURBT, particularly in muscle-invasive bladder cancers, will be best evaluated after the publication of the results of the BladderPath trial. These are highly welcome for the future. Thank you very much for listening.

Ashish Kamat: So thank you both so much for that very, very informative discussion. That was very concise and presented a lot of data in a very short time. Thank you for doing that. Prash, since you presented second, let me ask you the first question. When it comes to the global practice of TURBTs, and not just in the UK or in the US, but globally, what would you say are some of the top three challenges facing people taking care of patients with bladder cancer?

Prashant Patel: I think the first challenge is to get the TURBT done in time. As demonstrated, I mean, Mike Wallace had presented a large series on, again, UK population. And he found that even a 14-day delay from the presentation of hematuria to assessment can cause a significant impact on overall survival downstream if you follow these patients long enough. And this was statistically proven.

So firstly it is the timing from presentation of hematuria to getting the TURBT done. Secondly, emphasizing the importance of hematuria in the primary care, as well as with the patients. I mean, it cannot be taken lightly. Men, in particular, will ignore hematuria, and I'm afraid clinicians in particular, will ignore non-visible hematuria, particularly in female patients. And the younger they are, they're more likely to be ignored. So I think that level of education is important. And once they have hematuria, to turn them around very quickly is of prime importance.

The second challenge is from the point of doing a flexible cystoscopy to doing a TURBT. Now globally, the healthcare services are very different in the UK because we have a single point of entry, which is from primary care to secondary care we have to harmonize the way these patients are referred. So having robust pathways for these patients is terribly vital.

And the third thing is the biggest question which we're currently trying, is TURBT really necessary? Particularly for those patients where on flexible cystoscopy you find that these patients have got solid-looking muscle-invasive lesions. And on visual impressions, we are pretty good at actually identifying those with the likelihood of them to have muscle invasion. So I think these are the three main areas where I would focus.

Ashish Kamat: So these are excellent points. And of course, you bring up the timing of the referral and the delays that occur. And it's an important point that I want to emphasize that you made, is that oftentimes men will delay self-referral to their physician, but the physicians will delay the referral of our female patients to the appropriate evaluation. So it's important for everyone, the public, as well as the MDs, to recognize the importance of hematuria and the appropriate referral. We clearly don't want to overload the system, but the appropriate management.

A question to you, Param, when it comes to the TURBT data and the day case surgery data that Prash presented, what do you think some of the barriers are for the ability of a particular physician, center, or patient to be managed as an outpatient?

Param Mariappan: It's a really good question actually, Ashish. I've had very little experience in trying to perform day case TURBTs. It's probably just because of the setup we have. So we've not really pushed for day-case TURBTs to be done. It's probably a bit different in England, in Prashant's set up.

I suppose, to some extent, it is the ability to give the installation of the mitomycin or any chemotherapy installation post-op. We've had challenges in trying to do it in theater. So it often happens within the first 24 hours albeit on the ward area after the operation, and often the next day. Many of these patients are obviously elderly. The average age is about 70 or 72, and it's quite difficult to try and boot them out of the hospital just so that we can save a bed. I think these are probably the two main challenges.

The third one probably has something to do with the actual clinicians doing the operation itself. And going back to actually trying to link that with your first question. There seems to be still a lack of interest in actually performing TURBTs well. Often in many places, it's still left to the junior-most person in the service to probably try and do a TURBT in the end of the list just after someone's tired after a cystectomy or a nephrectomy. That shouldn't really happen. So if we try to move on to a mindset where we have dedicated lists, carrying out TURBTs and endoscopic bladder cancer operations, I think in that way, lots of things can happen, including day case surgery.

Ashish Kamat: You raise very good points and that was going to be my next set of questions or comments. But it's very, very important for everybody listening in our audience, and we can't emphasize enough that a TURBT, the resection of the bladder tumor, is an oncologic procedure. It's probably one of the most important steps in the management of our patients with bladder cancer. It can pretty much make the difference between a person saving their bladder, having intact bladder, responding to BCG, or needing a cystectomy, leaving alone the complications.

So it's very, very important that A, the people that do the procedure are supervised. It's fine to train trainees on how to do it, because clearly we need to train people so they can go and do it in the community. But we need to supervise them hands-on. It's not a procedure where we should be telling people, well, take the tumor out and then call me when you're done. It's a much more critical procedure than that.

And I think you're right in some ways that the reason in many places and this is just discussions that I've had with folks all over the world, that oftentimes the patients are not able to be managed as day surgeries is because there's a high incidence of readmission with hematuria that occurs when you try to send the patient home the same day, and that essentially sours the whole experience. And then people go, I'm just going to keep the patient overnight.

At our center, most patients resist staying in the hospital. 90% of my resections are day. If it's a large tumor involving 80, 90% of the bladder, then I'll keep the patient overnight. But they are often, oh, do we have to stay? It's a different mentality as such. I suspect some of that falls into play as well.

But along those lines, let me ask you, Prash, at your center, what is the training protocol for your trainees that are learning how to do TURBT? How are they trained? Who do you select to do a particular TURBT? Share with us some of your part.

Prashant Patel: Ashish, that's a very, very good question. We, in England, have got trainees, which come through a national selection process, a bit like your National Resident Matching Program after the MD [inaudible], although, in the UK, we don't have to do an exam. But they go through a formal interview process and then they are matched and then they are sent to different training centers. Now, all these trainees have been given or assigned by the college indicative numbers across all different types of surgeries within the neurology program to achieve by the end of their training. And not just the numbers, but also the level of competence, so there are different levels of competence. One, i.e., they can barely hold a telescope and four, as in they are fully competent as a consultant surgeon. So we've got variation of the trainees who come across through our hospitals.

And one of the first things we do with our trainees is to look into their logbook, see what their competence profiles are, and then accordingly allocate these doctors to the resectionists. And I, once again, bring up, Param, what you just said, and as echoed by Ashish, that this is a cancer operation. So I do impress on them, on all the trainees.

I always supervise the trainees when they do a TURBT. However small the particular lesion might be, I always supervise their documentation. And the documentation, we've got a performer that all these fields have to be filled in. And I classically use this statement around the act of omission and act of commission, particularly when it comes to giving postoperative mitomycin. So if it's not written, then it is not done. But if you have written why you are not giving mitomycin, then it is done. And I impress on all our trainees that this is how it should be done.

And finally, I also use my executive privilege of being the head of the department, that I will be signing off your feedbacks and your training competencies. So a little bit of taking control on the cancer, taking control on the operation from the clinicians is absolutely vital.

Ashish Kamat: Excellent points there. I think once you incorporate the checklist, and whatever checklist it is, but once you incorporate checklist into the actual performance of a procedure, whether it be TURBT or anything else, it forces the person, however junior or senior it might be, to actually remember those things. And we're all humans, surgeon included, even though a lot of surgeons think that we are above being human, and we tend to sometimes forget things. So having a checklist, like you mentioned, is absolutely critical. Param, in the data that you presented, if you had to have one or two key takeaways for the audience, what would they be?

Param Mariappan: So in relation to the QPI experience we've had, Ashish, I think it goes without saying that most of us have been quite proud of this introduction and development within Scotland. It's really been a game-changer. I think just merely having this process has changed the landscape for a lot of bladder cancer patient's treatment. Not only bladder cancer but actually a lot of other cancers as well. We wish this can be rolled out, as you say, whether it be England or globally, because many places may not necessarily have the infrastructure, as you might have in MD Anderson Center, where you can make sure you look after patients as best as you can.

The second thing is obviously what was a stark observation was the fact that the single mitomycin installation following surgery made such a big difference, especially to the low-grade non-invasive bladder cancer patients. And we know we're aware of data that's come up from lots of places where there's this poor compliance in putting in this chemical into the... It's a simple step, but it's not easily done and most people are not compliant.
So I think those are the two main things, is having a process that's probably driven by government, in a sense mandated, but within a framework of governance, and prospectively auditing your data. And every time you actually look at your own results, I think you're bound to get better when you start watching where you've been a year, two years ago. And of course, being able to instill the chemotherapy installation.

Ashish Kamat: So let me ask you, as far as the installation of the chemotherapy is concerned, is mitomycin still the main agent that is used?

Param Mariappan: Yes, it is. So I think we had probably about three months when I believe it's the production in Japan, I think that, I may be wrong, that caused us to halt the supply, but it's now come back. So during the period when we had the shortage, we explored things like epirubicin. There was once when we use gemcitabine as well. In fact, I got in touch with one of my friends in the States to find out how you give gemcitabine to get the regime. In the past, and obviously my center being one of the places where the initial installation studies came about, the randomized control trials, so we've got experience with epirubicin in the past, other drugs like doxorubicin and thiotepa. So these are all drugs that were used in the past and now available with oncologists. So yes, mitomycin is still the mainstay installation.

Ashish Kamat: Okay, great. In the US pretty much most of us have gone away from mitomycin and more towards gemcitabine, for many reasons, in our production, availability, cost, and also we have Level 1 evidence from the SWOG study showing that gemcitabine was effective. And also, in salvage therapy, gemcitabine and docetaxel combinations tend to work better, so people are getting more familiar with non-mitomycin based regimens. Prash, closing thoughts from your end. Maybe what would be the two highlights you want the audience to take away from your talk?

Prashant Patel: I think take the operation seriously. And always question whether the operation is really necessary and that the operation we are referring to is TURBT.

Ashish Kamat: Excellent. Well said. This has been wonderful, a great discussion. Clearly, we could go on forever talking about this important topic, but we do have to close. I do want to thank both of you for taking time off from your busy schedules. Stay safe and stay well.

Param Mariappan: Thank you very much, Ashish.

Prashant Patel: Thank you.