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Zach Klaassen: Hello, my name is Zach Klaassen. We're live in Chicago at AUA 2023. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And with me today is Dr. Neil Mariados, who is a radiation oncologist. And we're really happy to talk to you today as you are the lead author on both the SpaceOAR pivotal trial as well as the Barrigel^® pivotal trial. So welcome Dr. Mariados.

Neil Mariados: Thank you for having me here. It's a pleasure to speak about the spacing.

Zach Klaassen: We're excited to hear about it. So from a high level, what is rectal spacing? Why do we do it? What are the indications? And if you can just sort of expand for our urology audience.

Neil Mariados: Some of the challenges that we have in radiation is to target the prostate to a very high dose, but the rectum is right against the prostate and it's hard to keep the dose off the anterior rectal wall. And now, we used to have conventional fractionation before 44, 45 days, and now with hypo fractionation to 28 days, we've noticed that there's an increase in rectal toxicity. Now we are going to ultra hypo fractionation at five days. And so that increase can be as high from anywhere from quoted in the literature from anywhere from 10 to 18%.

Zach Klaassen: How does one put a rectal spacer in? If you just take us through the logistics of it.

Neil Mariados: So there are two different types of spacing agents that have been on randomized trials that are FDA approved and one is SpaceOAR and the other is Barrigel. There is some differences in how the technique is, but overall, you insert the gel between the rectum and the prostate and obviously, if you can get nice, symmetrical spacing from the base to midline, midline to apex, right, that'll be fantastic from the... It's a radiation oncologist's dream.

Zach Klaassen: Right.

Neil Mariados: One of other things is that when you have that space, the further away you have the rectum from the prostate the less dose you get, and the less to less toxicity to the rectum.

Zach Klaassen: And as a urologist, these are the side effects that we worry about from a patient's standpoint is obviously the bladder toxicity, but the rectal toxic toxicity and having a rectal spacer then decreases its toxicity.

Neil Mariados: Yes.

Zach Klaassen: We're going to talk a little bit about the comparison between the two products, but we recently had, you're the lead author on the JAMA Oncology article that came out in February looking at Barrigel. If you could tell us a little bit about Barrigel, the product itself and then we can walk through some of the data.

Neil Mariados: Barrigel is a different type of product compared to the SpaceOAR. In SpaceOAR you have polymerization and you have to put that in very quickly, otherwise it polymerizes, could polymerize right in the needle, but with Barrigel, so it is a non-animal stabilized hyaluronic acid. So what it really means is that there's no polymerization. So you can take your time to sculpt the product from the base of the apex, from left lobe to right lobe and really get good symmetrical spacing. There has been a safety profile that has been associated with that as far as toxicity and things, but in general that's how you create the space.

Zach Klaassen: That's great. So looking at the trial, so this was a randomized trial, two to one to basically Barrigel plus fiducials to fiducials alone. So if you can walk us through what patients these were, what some of the key primary and secondary endpoints were.

Neil Mariados: In the trial We had about 201 patients who were randomized two to one with spacing agent versus the control. And what we had is that there had to be a greater than 75% reduction in the V50 for the high dose region. And what we had in the trial that we saw very quickly was 98.5% grade reduction.

Zach Klaassen: Yeah. And then also among those patients that had the reduction, there was also additional benefit that 85% reduction, if I'm not mistaken.

Neil Mariados: Exactly.

Zach Klaassen: In that V50.

Neil Mariados: Exactly.

Zach Klaassen: Talk to us about some of the patient-reported outcomes. Because I know these are the folks that are going to come to our clinic. What was the outcome from a patient standpoint?

Neil Mariados: The outcomes? What we found is that as far as toxicity that patients had, there was a grade two toxicity was reduced remarkably in the first three months in the Barrigel trial. But in the SpaceOAR trial, it was not recent until about 18 months.

Zach Klaassen: I see.

Neil Mariados: So that was a big find for the Barrigel trial.

Zach Klaassen: Yeah, absolutely. So you have extensive experience in doing both. Both from a SpaceOAR standpoint as well as a Barrigel. Tell us in your opinion why Barrigel may be maybe safer, may be better. What aspects of the procedure and the product lead to better outcomes?

Neil Mariados: I think that most operators that use Barrigel realize right away that they have time to create the space, and that space can be created symmetrically. And obviously, when you have that symmetry and that time, there's increased safety as well.

Zach Klaassen: Yes.

Neil Mariados: Because you don't have this thing called rectal wall in invasion where you put the agent into the rectal wall. And in when you compare the two trials, there's a big difference between the two. In the SpaceOAR trial, there was nine patients that had that rectal wall invasion and the Barrigel trial, there was one. And rectal wall invasions are pretty significant because you can have this ulceration, which can lead right up to fistula and really affect the patient's quality of life.

Zach Klaassen: Absolutely. And I think too for maybe some of our urology colleagues out there that are listening that may have heard about spacing, and that certainly that's probably the one thing that people worry about is we don't want to hurt the patient with the procedure that's supposed to help their quality of life.

Neil Mariados: Correct.

Zach Klaassen: And I think to your point, if you look at the real world database that's out there, there's been zero reported Barrigel outcomes or adverse events. Am I right?

Neil Mariados: Yes. You're talking about the MAUDE database.

Zach Klaassen: Correct.

Neil Mariados: Which is a voluntary reporting of problems. So we know that rectal wall invasions is really under reported, especially with complications like rectal wall invasion.

Zach Klaassen: Yes.

Neil Mariados: But yeah, you're right. There's nothing that's been reported in, but it's still at the early stages. Right?

Zach Klaassen: Sure.

Neil Mariados: But there's really just minimal toxicity that's reported by using Barrigel.

Zach Klaassen: So when you see these patients post-operatively, do they feel like they're sitting on anything? Do they know that anything's been done? When you see these patients in follow up, what is their experience with the procedure?

Neil Mariados: What I found in the SpaceOAR patients, that they were probably about 10% of them that felt like they were sitting on a hockey puck or a golf ball. And it was kind of an uncomfortable type of feeling, which they would come back through radiation, they would be complaining about that. But in the Barrigel, when you feel it in your hand, it's kind of squishy. And none of our patients with the Barrigel reported that. So that was quite amazing.

Zach Klaassen: It's almost like it's sculpting to their perineum in their prostate when they're sitting down essentially.

Neil Mariados: Exactly. Yeah, exactly.

Zach Klaassen: When we think about the procedure and how we're teaching it, how could you see this as a benefit for resident or fellow training? Obviously part of it has comes down to probably the time constraint with spacer injection versus the no time constraint for Barrigel. If we're teaching fellows and residents, how could Barrigel be easier to teach?

Neil Mariados: So I think the hit, this is a really important point here because with SpaceOAR, once you get a needle in place, you have to push the whole thing within 10 seconds and it goes where it goes.

Zach Klaassen: Yes.

Neil Mariados: So the material controls the operator. With Barrigel, the operator controls the material. So you can inject this and sculpt it to and see it on ultrasound. Whereas in Barrigel, you really can't see it on ultrasound. So there's instant feedback that you're getting from the ultrasound. And it is, it's very comfortable because the resident or new operator can see that and they can judge for themselves. Obviously-

Zach Klaassen: Immediate gratification. Right.

Neil Mariados: Yeah, it's right. But also what we find is that we have, when teaching some of my colleagues how to do this, they seem to get it almost right away. So the learning curve is very short.

Zach Klaassen: Yes.

Neil Mariados: There's a report from a person called Pinkawa that showed that they took about 64 patients that were in the SpaceOAR trial and they found that it took about 32 patients to kind of-

Zach Klaassen: That's a lot.

Neil Mariados: -get it comfortable. And I have a good friend and a colleague, Dr. [inaudible 00:09:08], he had did seven cases in an afternoon. And from the first case to the seventh case, the spacing was just beautiful. And one thing that usually you cannot control with the SpaceOAR is to get good apical separation.

Zach Klaassen: Yeah.

Neil Mariados: And with Barrigel you can sculpt it and you get great apical separation. And I think that that's where most of the toxicities and the urinary complaints and all come from men.

Zach Klaassen: No, I think you're absolutely that third vial, basically for our listeners, it's a syringe in three vials. There's really no setup or prep. And that third vial really is key for getting that touch up, whether it be laterally or the apex. And we're wherever you may want to get a little bit more lift. I think that's an important point too.

As a radiation oncologist, you're used to looking at these either on CT or MRI after they're placed as part of the treatment planning. Can you walk through how, maybe people that are listening to have used SpaceOAR, which has the iodinated contrast, which makes it light up on MRI. But how do you look at these? What's your technique for actually looking at it with the Barrigel after the procedure?

Neil Mariados: Yeah. We know as radiation oncologists that if we just use a CT for planning that we overestimate the prostate. Yes. That means more bladder's being treated, more rectum is being treated. And we cannot really see, I mean as urologists you know, that you can't really see where the apex is on a CT. So you need for precise treatment planning, you need the MRI.

Zach Klaassen: Yeah.

Neil Mariados: And we have gold fiducial markers to locate and localize the prostate. And when you window level and you do it the right way, you can delineate the prostate and you can delineate the Barrigel quite easily.

Zach Klaassen: Yes.

Neil Mariados: And on MRI, Barrigel just lights right up.

Zach Klaassen: Yes.

Neil Mariados: So when you do this thing called registration of CT to the MRI, it is very easy to know where the Barrigel is, where your fiducials are, where the prostate is, and where your treatment volume is.

Zach Klaassen: And you mentioned something earlier I think I want to hit on too. Is part of the coverage and decreasing toxicity is that symmetry? Can you talk about symmetry between the two products?

Neil Mariados: Yeah. So symmetry, when you have time, and you have sculptability, and you have control, control giving you sculptability, you can have this even spacing called symmetry. From base apex left to right. And but in SpaceOAR, we did not find that we... Things would go off wherever the material found the least path of resistance. So about 50% of the time it was asymmetrical.

Zach Klaassen: Coin flip chance.

Neil Mariados: Yeah.

Zach Klaassen: Wow.

Neil Mariados: Yes. And not only that, they found that in this paper by Fisher Valek, that 68% of the time there was hardly any spacing agent in the apex in this SpaceOAR.

Zach Klaassen: Wow. Wow.

Neil Mariados: So this is with Barrigel, you get this even symmetrical space. Now why do you need that? Because yes, you can really work our planners and our dosimetrists and our physicists to try to curve that area off it. But you're still not getting the best plan where if you had good symmetry, you can almost get the high dose areas nowhere near the rectum.

Zach Klaassen: Yeah.

Neil Mariados: And that means for outcomes, you have great results as far as rectal toxicity.

Zach Klaassen: Absolutely. And more than 95% of patients in the trial had symmetry in the Barrigel trial. Correct?

Neil Mariados: Correct, correct.

Zach Klaassen: So I think if we look at that from a patient being comfortable, and the surgeon's not rushing, and you're able to get a great outcome basically every single time, that's a huge advantage compared to the SpaceOAR.

Neil Mariados: Absolutely. Yeah. That's excellent.

Zach Klaassen: Just give our listeners a couple of two or three take home messages. Anything we didn't touch on that you want highlight, as well as some take home messages?

Neil Mariados: One of the things is that the take home messages would be you have control.

Zach Klaassen: Yeah.

Neil Mariados: You have sculptability and you have safety. I think that is the key. And also what you have is reproducible results all the way through.

Zach Klaassen: Yeah.

Neil Mariados: And I think that's the... And it's easy to learn.

Zach Klaassen: Absolutely. Listen, we enjoyed your time. You're the expert in the field with this and we appreciate you sharing your insight with our listeners.

Neil Mariados: Thank you for having me here. It was nice talking to you.