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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. And we're joined today for a UroToday discussion with Dr. Kevin Gallagher, who's coming to us from Edinburgh, Scotland. He is a specialist trainee in urological surgery in Edinburgh, as well as an honorary lecturer at University of College London. We are delighted to have you, Dr. Gallagher.

Kevin Gallagher: Thanks a million, Zach, delighted to be here.

Zach Klaassen: So we're going to touch on some really interesting data that was presented recently at ASCO, basically surrounding the RESECT study, and this is a huge undertaking so maybe just walk our viewers and our listeners through the study design for RESECT before we get into some of the data.

Kevin Gallagher: Sure, absolutely. RESECT is a great endeavor that's bringing together over 200 hospitals across the world in all five continents. It's a retrospective and a prospective observational study, but embedded within it there is a cluster randomized controlled trial of audit and feedback and education with the aim of improving the quality of TURBT surgery and reducing early recurrence rates. It's ran by a trainee research collaborative in the UK called British Urology Researchers in Surgical Training or BURST, and we've got hospitals from all over the world, including about 20 in North America, taking part.

Zach Klaassen: That's incredible. I mean, just from a design and logistical standpoint to get multiple continents involved, just walk us through how long that took and what the process included.

Kevin Gallagher: I'd say study conception 2017, funding 2020, launch late 2020, early '21, coming to completion just now. So yeah, about six year total timeline but the study itself took three, four years. What's crucial, I think, is the network that BURST has and how we harness social media sort of marketing campaigns. I think the unique thing about it is that we do this on extremely low budgets. Most of our study team is dedicating their time for free just through love of research and through passion for the topic, as are all of our investigators across the world, and we must give a huge thank you for that. We've a small budget for a study administrator and a software developer and our statisticians and methodologists who we want to invest in to have high quality on that side of things. But otherwise, we do this on a very low budget through the goodwill of our investigators.

Zach Klaassen: That's incredible, and I think too you have a built-in collaboration now with all these places too, right? So the next 10, 15, 20 years could spin off additional research just because of the network that's already set up across these continents.

Kevin Gallagher: Absolutely. That network is so important, isn't it, those relationships? And you start thinking, as soon as you conceive a study, you start thinking internationally now instead of nationally.

Zach Klaassen: Absolutely.

Kevin Gallagher: That's what we want to do.

Zach Klaassen: That's incredible. So walk us through some of the data that was presented at ASCO 2023. I mean, anything that comes out of this study, I think, is just incredible because of that global nature of the study. So just walk us through some of those results.

Kevin Gallagher: Absolutely. So we analyzed the observational retrospective part of the study. And for that data in ASCO it included data from 186 hospitals. We were just looking at the first resection, the index tumor resection, and they had about on average 25 cases each from the hospitals and we wanted to find out if there was true variation in the early recurrence rate that could not be explained by tumor factors; by tumor size, by tumor number, by tumor grid and tumor stage. That old adage that you always get in comparison between sites, it's the case mix, right? We have bigger tumors, we have higher grade tumors, that's why our results are different. And look, it is the case sometimes, but we had the power to assess that through the number of cases we had. So we ran a mixed effect regression analysis controlled for those tumor factors at the patient level, put site in as a random effect, and when we do that we find that the variation between the sites is highly significant and it's independent of the tumor factors.

Zach Klaassen: Yep, excellent. I've heard Ashish Kamat talk about this, I've heard Alex Zlotta, who was one of my mentors when I was a fellow in Toronto, the quality of the TURBT is so important. And it oftentimes becomes, if we're looking at the cases for the week, you've got the cystectomies, the RPLNDs, that the senior residents are going to do those with the attending. The TURBT often gets turfed to the junior resident. But it's really an important, and I stress this with them too, it's the most important staging aspect of the disease process. So just for our listeners, just to refresh everybody's memory, just talk about how important that quality of a TURBT really is.

Kevin Gallagher: So I mean, why is it important? I mean, I think you could say two very high level things about it. The quality of the TURBT can save the patient's life. This is a cancer operation, but a potentially curative cancer operation. And everything that happens afterwards is so dependent on the quality of that operation for clearance of the disease at the first sitting and secondly the importance of the accuracy of the grading and staging that we get from that first operation. If you're delaying that, if you're not getting the accurate grading and staging until further down the line when you're resecting the recurrences, suddenly your treatment timelines for the really aggressive disease get longer and longer and outcomes are going to be worse. So that is where you really make the difference, particularly in the high grade cases, and the pathological staging being so important.

We're not getting into the T1 sub-staging being mentioned in the WHO 2022 guidelines. The quality of resection specimen is everything for your pathologist to be able to do that. That's for the high grade stuff. Then why is the quality important for low grade tumors? Well, the second thing I say then is that you can save the patient's life and you can make the patient's life better, by meaning that they don't have to come into hospital every six months to have small recurrences sorted out. Your first resection can reduce the recurrence rate going forward. And all the models that predict progression have prior recurrence rate as one of the strong predictive factors for progression in the future as well. That's why it's so important, you make a difference to mortality rate and to patient quality of life and healthcare resource usage.

Zach Klaassen: That's a great answer. I think that's excellent. Two just sort of little more pointed questions about RESECT. Are you guys looking at, and there's been some data coming out of Europe primarily, a little bit out of the US, but looking at en bloc versus not en bloc in this study?

Kevin Gallagher: It wasn't one of the primary objectives of the study, however, it is a planned analysis. So just before the meeting today, I thought you might ask about that so I had a quick look at how many en bloc cases do we have in this study? So there's 18,000 cases in the study in total, about 15,000 of them are first tumors. And of that 15,000, about 2000 are en bloc resections. So we've got a nice observational cohort that we can say, look, in real life practice just observing we can match those en blocs to similar piecemeal resections and see what was different. But of course, there's a randomized study published in abstract form now from Dr. Teoh in Hong Kong showing real benefits from en bloc resection.

Zach Klaassen: That's great. I mean, 2000, you can easily match those with the other 13,000. That's going to be great data as well. You may not be able to answer this, but is there any plans or is there any discussions with some of the guidelines, whether it be the EAU or otherwise, in terms impacting the guidelines with this study? Or have they reached out to you guys to sort of say can we look at this because we really want to tweak the guidelines a little bit?

Kevin Gallagher: We have some connections with the EAU guidelines committee through the University of Aberdeen where the staff there are very closely related to that and as well as one of our key steering committee, Professor Mariappan, and also sitting on the non-muscle invasive bladder cancer guidelines committee. So although there's nothing specific planned I'm sure that we will be having discussions.

Zach Klaassen: Great. Last question for me is, you kind of touched on it a little bit in terms of additional analysis, is there anything else planned coming up in terms of what you guys are looking at? You mentioned the en bloc versus not en bloc.

Kevin Gallagher: I mean, the planned analyses mainly fit inside the main objective of determining high quality effects and the early recurrence rates. But even within that data that we presented at ASCO, we've shown that it's in independent of the tumor factors, but what are those factors that are dictating the variation exactly? We're saying it might be operative quality, but what do we mean? What exactly do we mean by operative quality? Is it surgeon experience? Was it all down to giving single shot chemotherapy or not? Was it the type of hospital, the type of list, dedicated TURBT lists rather than general lists? Was it surgeons with specialist interest in bladder cancer?

We learned recently at our national conference that there's a new movement in the UK to have specialist non-muscle invasive bladder cancer surgeons, surgeons that almost just deal with non-muscle invasive bladder cancer. Are these kind of things making a difference? In addition to that, other analyses that will be possible, we collected a huge, really granular dataset for these 18,000 cases, and I want to give a huge thank you to our investigators who spent the time diligently collecting that data. But we have things like what's the diagnostic yield of random biopsies? Some people are doing that.

Zach Klaassen: That's great.

Kevin Gallagher: I mean, there's no clear answer whether that's a good thing to do or not. Is it picking up more CIS? And there's some data on that in the literature. We've actually got about 200 laser resections in the cohort, which is obviously not very common, but it would be interesting to have a bit of a look at that.

Zach Klaassen: A decent number too.

Kevin Gallagher: And 600 cases in the dataset use PDD, photodynamic diagnosis, that's also there. And then we have good data about diagnostic practice and timelines. So about 1500 or 10% of all the cases and the inclusion criteria is presumed no muscle invasive bladder cancer, about 10% turned out to have T2, muscle invasive disease, 1500 cases. What were the diagnostic timelines and practices the brought us up to diagnosing the muscle invasive bladder cancer in those patients and how did that affect their treatment and outcomes? Because they're the ones you really need to get through and pick up as soon as you can.

Zach Klaassen: No, we'll definitely be looking out for that on the UroToday side as more data comes out for sure. So thank you so much for the discussion. If you can just leave our listeners with maybe two or three take home points from RESECT, either in general or from the ASCO data, that would be tremendous.

Kevin Gallagher: I mean, I think the key message is that this procedure has been termed the neglected procedure in the literature before. I think we should be proud to do this potentially curative cancer operation and give it the attention to detail that it deserves. And one of the sort of acronyms that Professor Mariappan, my mentor, and consultants always use is, think CIS. So he says clearance, and you absolutely have to clear the disease, and S for safety, do it safely, and do it in the right patients and it's got to be quite patient specific, and information, that's the I, which is the really crucial thing is that you've got to give your pathologist an excellent specimen so that they can give you all of the information that you need.

And within that information component, I think that we should really be thinking about data. I think data and surgery is going to become more and more important. I'm not a consultant yet, but when I am a consultant, I would really like real time feedback on how I'm doing, not two years down the line in a static report so I can't even remember what the case was. I want to see month to month how were my resections, how were my outcomes, and tweak month by month how my practice is. So that's clearance, information, and safety.

Zach Klaassen: That's great, I love that take-home message. That's fantastic. Dr. Gallagher, thank you so much for your time and we'll do this again when more data comes out. I appreciate your time today.

Kevin Gallagher: Delighted to be here. Thanks, Zach. That was great.

Zach Klaassen: Thanks so much.