Kevin McVary: I was asked to talk about this particular topic. I was happy to get the invitation from Neal and I appreciate the invitation to speak today. So the question is do we really need all this MIST stuff? And disclosures, and I'd say the way to get there I think is to start with this, The Urologic Disease in America Project, whether you probably saw a recent paper from this project, and it has some implications for LUTS/BPH and I think implications for MISTs.

So the percentage of men getting some type of treatment for the LUTS/BPH is growing in the cohorts and the cohorts are enlarging. This is medicine and there's a pretty steady climb regardless of decade of life. At the same time, the percentage of men choosing a surgical intervention is decreasing, and I would say in some ways decreasing pretty dramatically. The ones which have flat lines are those men that have the very lowest risk of choosing the surgical procedure, but the message is that there is pressure on the system.

Now you're probably saying this is not what I'm experiencing in my practice, and the reason is because the demographic, the pool is much bigger. So there's a lot of pressure here. Note that from The Urologic Disease in America Project, this particular data set stops at 2013, the exact year when we might begin to see the two new MISTs coming on board, that would be Lift® and then Rezūm™ slightly thereafter. And it doesn't matter, at least in the previous data set that stopped in 2013, it doesn't matter which type of procedure you look at, they're all dropping.

What's going on? Well, it's this dilemma. I like to say that urologists that treat LUTS/BPH are on this fulcrum. We have defined procedures which we would say are good outcomes, and known entities on impact, on LUTS, flow rate, and durability. But there is risk and American men, I think all men, but I know American men will choose a more modest outcome if they can have less risk. Paternalistically, urologists may not be happy with it, but that's the behavior of American men, and I suspect Western men, and I suspect all men, but I don't really know the latter two groups. So this is the fulcrum we're dealing with.

So what's driving this? Well, when I say risk, what I really mean, it's not incontinence, it's sexual dysfunction. And men only voice concerns about it when you ask, and if you don't ask you'll say they're not concerned, but if you do bring it up, they're going to jump on that bus like, right now. So again, like I mentioned, urologists might choose a more invasive, more definitive procedure. The patients aren't into that. They are very interested in choosing something different.

There is movement away from the medical therapies. Alpha-blockers, there's data, I don't know how great it is, frankly, I don't think it's good at all about its risk to dementia, anticholinergics are a little bit more reliable in that regard, and 5-ARIs we know have some baggage. And it's this type of thing which I think is motivating for patients, I don't think urologists, it's that particular motivating. And then when you look over the entire medical field, compliance is really bad. Greater than 60% of men not being compliant with their medications, and at least 30% stopping in a few months, and probably 50% stopping in 12 months. So it's a big opportunity for MIST.

If MIST is going to succeed, what does it have to do? Well patients got to know about it and want to choose it. From my perspective, I think it has to avoid progression of BPH. Affecting the symptoms is important, but will it change the things we care about longterm: retention, stone, dysfunctional bladders, stuff like that. Is it generalizable, I mean, does it go from the trial to the general community practices of urology and perform in the same way, and I'd say keep an eye on that. Are we impacting obstruction? The obstruction, which we hope this is why we're doing this, the guess is probably, although that data is not there, and durability. Durability is not uniformly defined and therefore I think we are manipulated passively or proactively by these definitions of how durable these technologies are.

I'd say things that we would like, that patients would like, that urologists maybe would like, would be able to do it in the office, have a rapid recovery, no catheter or a minimal catheter and then back to golf and back to your usual activity as fast as possible. So let's look at that.

Metrics that we should use that I would propose that we use, the usual patient-reported outcomes, these adverse events reported as event rates, not adverse profiles, and this idea of what's ED. Again, patient-reported outcomes would help us with that. And then I think the real bugaboo is what about the catheter? What is a catheter time, how frequently are patients on the catheter? And that is pretty loosey-goosey if you look at the data.

So just one look, one technology here, the Lift®, I think probably everyone in this group is familiar with exactly how it works. The idea is to change the prostate looking from this to something like that by using compression rather than ablation. Its impact is pretty good. It has a nice change from SHIM and then importantly does not impact sexual function, depending on how good the man's function is going in, there's a preservation. If his sexual function is not so good going in, it actually improves, but that's actually probably regression to the mean, it's not really a treatment for ED.

What about vapor? I'm sure most of you know about this injection in the prostate itself with steam, the idea is to ablate tissue in a serial fashion, in some ways akin to the way you delivered TUNA for those of you that may have had part of that. Outcomes, pretty decent outcomes. I don't show the SHIMs here, for reasons of brevity, the control groups, but it's a significant difference in both flow rate and IPSS. And importantly when you look at patient-reported outcomes of erection and ejaculation, they are straight lines across. Any way you measure it, there's no impact with Rezūm™ on this.

I think importantly is how do these things compare with medicine? It's an important question because when you look at where these patients come from in the urologist practice when he just starts the therapy, he substitutes the MIST for the TURP. And once he or she gets comfortable with it, suddenly he stops doing that and he pulls all these patients out of this medication pool. In a sense, PVPs and TURPs don't drop in a high-frequency misuser, but all those new patients coming in for MIST are out of the medicine pool.

So what's the impact? It's a really hard question to understand because no randomized controlled trial has been done and the ones that have been done with MIST versus medicine, have failed. There was an NIH trial, I was, unfortunately, part of it, that was called on futility because men don't randomize. Long story short, MIST compares very favorably in preventing progression in LUTS/BPH, if you do one of those propensity weighted studies, which is what were reported here.

It's a favorable comparison, I'll say that for sure. WhereRezūm™ really doesn't even register on retention and incontinence, modest worsening and IPSS compared to the different arms of the MTOPS trial. So a favorable comparison, and a favorable comparison in symptoms, and a favorable comparison in the sexual adverse events in all categories. So it's a pretty good competitor for medical therapy. Whether or not we ever get to a randomized trial, I wouldn't hold your breath, but anyway, we'll see. And in terms of generalizability, in the few trials where it's reported, those lines are right on top of each other, suggesting that it is, in fact, generalizable, but we need a second randomized cohort to really answer that.

We have an experience looking with this therapy on men and urinary retention. It's a different cohort, it's a sicker cohort, a larger prostate cohort, ASA threes and fours, men that could not get cleared for surgery, bottom line is 70 some percent of men can become catheter-free. I wouldn't advocate this for men who can take it, I wouldn't necessarily advocate it for men, because this is a longer period of time for successful de-catheterization in this relatively ill cohort. It's hard to understand what this will mean for your more standard patients.

One of the metrics I propose in terms of MIST is, are you doing it in the office? And I know in the Lift® trial which I was a part of, obviously those were all done in the office, but those have really moved out of the office in most practices, probably more for other reasons than the fact that they couldn't get it done. When you look at steam, that is some almost 90% of these cases are being done in the office, so it's a more likely procedure be done in office, and there are again financial reasons to promote that to caregivers.

The real issue in my own view is this, what is a failure, what is a procedure which is not durable? And this was defined a little oddly in the Lift® trial and I'm going to just show the data here. This is looking at four- and five-year data, on these last two lines, and you can see the so-called reoperation rate is relatively stable, 13 some percent. But there's a percentage of men that go back on medications, some men that go and have some of those pledgets removed, and so when you start to add those into a retreatment rate, you really see a much higher retreatment rate, 30%, 33%, in my own view that's kind of high. And is this failure or not? In my own view, I think it is. Maybe the government will help us decide if that is.

What about how does steam compare with this in terms of durability? And I would say, well, if we define it in the same way, the same categories, at least at four years in terms of reoperating, you're looking at 4% that seems pretty steady, maybe it's hit new plateau. And in terms of men going onto medications perhaps, and we may still see that climb, but anyway, at four years you're looking at someplace around nine to 10%.

Is this a fair comparison? Well, this slide is to tell me that maybe it is a fair comparison because these two cohorts look pretty close. And if you take a look at retreatment rates graphically, you see something like this, and these graphs to me look substantially different.

So summarizing what is the report card on MIST. And I kind of went over this quickly, but as we look at those attributes that maybe a MIST ought to have, black is good, red is, well I'm not sure. And I'd say that the jury is still out on many of these aspects about versatility, durability I've mentioned, we really don't know some of the ideas of generalizability and change in urine dynamics, and whether or not we're really going to see this in the office. A distinct advantage of Lift® over steam is this ability to avoid the catheter, which in patients' minds is huge, and we're going to have to come to terms with that. Patients are going to have to obviously come to terms with that.

So just by way of the retrospectoscope is this slide, I call it the prosthetic gizmos. And this was the list of things that I could think of that we have done to the prostate. Notice, don't really have a TURP on here because you all know that, and I'm sure this is a partial list, so we got to stay like this kid here. So who is this kid? Well, it's picture day in the Chicago public schools and he wore a Green Bay jersey. So you just got to be ready to be unpopular and say that maybe our prosthetic gizmos haven't really lived up to what we've expected. Thank you for your time.

Tom Jayram: Thanks so much Dr. McVary for providing such a great overview of a busy topic. Maybe just in the sake of time, Dr. Sellinger and Dr. Sussman, can you make a comment on challenges, obstacles, on incorporating or trying to bring all of this into community practice and what have you guys observed in your busy practices?

David Sussman: Yeah, I think it was a great talk. Good talk, Kevin. I appreciate it. I think that we can all agree that getting away from medical therapy probably is beneficial. I think a lot of us in this audience went through that day when all of a sudden I'm doing TURPs on everybody, we did Flomax® and Hytrin® and such, and I think we're in a better course now.

I do think the patient experience is a big part of it. I think, we mentioned the issue with catheters. I guess the question is going to be what triggers now for these minimally invasive therapies. We knew that a patient came to see us with outlet symptoms, we had no problem giving them a script for Flomax® or alfuzosin. Do we have the same triggers now that we did with medical therapy? Should we think differently about that? I think that's an interesting comment because we all write scripts for medical therapy all the time. Probably not the best therapy.

Kevin McVary: Well it's a great question. One we probably spin through our mind very fast every time we see a new patient and you're trying to say, okay, now where are we going to go here? I would say many urologists and myself included in this, let's try meds, we'll bring you back and see how you do. That is not wrong if that patient's fulcrum is torqued that way.

The BPH guidelines support skipping medicine, going right to an intervention provided the patients are informed. It's the only standard in all the BPH guidelines is informing the patient of the options. So I have guys that come in and say, hey, I'm not a pill taker, philosophically I don't want it. I don't force them into it. I may go say, "Fine, let's start working on an intervention, which might be a better idea for you longterm".

So I mean we have to change our mindset, and I've fallen. It's certainly easier to give them a script and say onto the next one. That's certainly easier. When I do it now, I try to do it with this idea that hey, we got these other things, they're a lot better than they were. I suspect they do have some negatives, like a catheter.

Scott Sellinger: So once you make that decision to do one of the minimally invasive surgical therapies on the patient, what's your typical algorithm for following those patients? And when and at what point do you decide to pull that trigger to move to a different therapy once you've reassessed them?

Kevin McVary: Well, in terms of medicine onto a MIST or to an intervention it's, is it doing the trick for you. And I look at their score and if they're in moderate or severe, saying, "Hey, are you really happy with this?" And if they say, "yeah I don't mind," fine, I don't mind you getting up five times a night, I can live with you living with it. But if that conversation is such that that's not such a good thing, then I introduce these. And I don't introduce the MIST, I introduce the idea of intervention. And I say intervention is really based on volume. And volume really steers me in terms of what we're going to do, what are we going to choose. I mean if he's 120 grams, I'm not going to recommend a MIST for him, because he's going to lose that fast recovery advantage of the MIST. If he's in the cherry spot, I'll mention it. If he's outside the cherry spot in terms of volume, I'll say, well we're in a little bit uncharted territory here, MIST may or may not be a right answer, if you were my brother, I might just instead want to greenlight you, do the last operation first.

I've had very little experience of having to redo a patient of mine who underwent MIST. I just haven't had that. Perhaps I'm a little bit more conservative with its application. I've seen plenty of patients elsewhere that I have done something after a MIST, and that runs a spectrum.

David Sussman:  For the patient who may have the appropriate anatomy for a MIST, when do you decide to go with an ablative therapy, whether it's laser or TUR, what are the kind of the triggers for you in your mind that that patient, even though they have the appropriate anatomy for MIST, really needs something more aggressive done?

Kevin McVary: Yeah. So a typical one would be if the guy is unwilling to accept the lack of durability information. If you can handle a second procedure in a few years, then that's okay, but if you want one and done, then you might need to look beyond the MIST therapy. They can't understand that risk of ... It's a lack of knowledge of durability that's really the problem.