Michael Chao: I really appreciate the opportunity to talk to you, Zach.
Zachary Klaassen: Oh, it's-
Michael Chao: I follow your UroToday. I've listened intently. I saw Dr. Martin's ESTRO presentation to yourself a couple of weeks ago. That was phenomenal to be able to relive it, because unfortunately I wasn't able to get to Milan, so that was phenomenal.
Zachary Klaassen: No, thanks so much. It's good for those conference highlights, and certainly we discussing the three-year Barrigel™ safety data with Martin was awesome. So just today, we want to level set for our listeners. Why do we do rectal spacing? Why is it important before prostate radiotherapy?
Michael Chao: Well, Zach, the fundamental issue is anatomy. The prostate unfortunately sits right in front of the rectum. And when we deliver radiotherapy to the prostate, particularly with the high, high doses that we use today, some of that radiation will unfortunately impact on the rectal wall. The rectal spacer thankfully changes that anatomy in our favor.
By physically separating the prostate from the anterior rectal wall, even by a relatively short distance, we can produce a significant reduction in the radiation dose received by the rectum. And it's certainly far greater than even the most expensive machines produced in the world today. For example, protons. In fact, I understand the proton operators are some of the biggest users of rectal spacers. And that is important because in radiation oncology, dose actually matters. Reducing the dose to the normal tissue translates into lower risk of toxicity. And when we are talking about the rectum, that reduces rectal urgency, frequency, bleeding, and perhaps even avoid an ulcer.
We now have very good randomized evidence for this. As you've spoken to Dr. Martin not long ago, the Barrigel™ randomized trial of hyperfractionated radiation therapy, we saw a dramatic 98.5% of patients receiving the spacer achieve at least a 25% reduction in high doses received by the anterior rectal wall, which we call the RV54, with an average reduction of about 85%. And in fact, 20% of these patients had a 100% reduction in high doses to the anterior rectal wall.
And more importantly, this translated to a reduction in grade two or greater acute GI toxicity from almost 14% in the control group down to about 2.9% in patients who had the Barrigel™ rectal spacer. This is important because the PACE-B sub-analysis has actually shown that if you do get acute grade two plus toxicity, this predicts for not only late grade two plus GI toxicity, but also persistent late grade two plus GI toxicity. So it's an important parameter toxicity that we need to reduce.
In addition, as Martin had reported to you, the three-year Barrigel™ trial showed a 9.5% late grade two or greater GI toxicity in the control arm, dropping down to 0% in the Barrigel™ spacer arm. In addition, we also saw a reduction in late grade one plus GU toxicity, halving from about 25% down to 12%. And you know what, Zach? I know some may dismiss grade two toxicities as not being important, but from my point of view, I think it has an important impact on the patient's quality of life. Grade two diarrhea can mean going to the toilet up to six times a day. Grade two fecal incontinence can actually mean urgency severe enough for someone to actually wear a pad. So I don't think it's conducive to normality.
So in addition, we also saw in the study, if we achieve adequate rectal spacing at the apex, which is defined as 10 millimeters or more, bowel quality of life was actually improved as well. So for me, rectal spacing is not simply about producing a better looking treatment plan. It is about physically moving that vulnerable normal organ, the rectum, away from the high dose region and creating an additional margin of safety for the patient.
And this becomes even more relevant as we move towards hyperfractionation for the majority of patients. So very few patients now get the conventional or standard fractionation. It's about 20 fractions nowadays, what we term moderate hyperfractionation. And we're also increasingly moving towards ultra hyperfractionation, i.e. stereotactic radiation, where massive doses are delivered to the prostate on a daily basis. The PACE-B and the PACE-C studies that looked at stereotactic radiotherapy showed late grade two toxicities approaching 19% at five years for PACE-B, and already 13% at two years for PACE-C. So it's something that needs to be addressed in my opinion.
Zachary Klaassen: Yeah, fantastic intro and level set for our listeners, Michael. You have vast experience with rectal spacing. We have multiple options on the market. Why have you chosen Barrigel™ for your patients? What are the reasons for that?
Michael Chao: Well, there's actually several reasons for that, Zach. Firstly, Barrigel™ as a hyaluronic acid spacer is injected as a gel. And importantly for me, that gives me control over how much I inject and also where I place it. There is no polymerization, and therefore there is absolutely no time constraints with the injection process. The ability to sculpt the spacer is one of its major practical advantages. Anatomy is not identical from patient to patient. Sometimes you have excellent separation at the mid-gland or base where the latter is probably not as important. But sometimes you need additional separation towards the apex, which we're all now finding out is the critical area where you need spacing for prostate radiotherapy.
With Barrigel™, I can assess that separation under ultrasound as I'm performing the procedure, and then place additional material where I feel it's required. So rather than simply thinking, "Have I inserted a spacer?" I'm thinking, "Have I created the best possible separation along the clinically relevant interface between the prostate and the rectum?" Secondly, there is also obviously the randomized evidence demonstrating a significant dosimetric benefit and also a reduction in GI toxicity with Barrigel™ during hyperfractionated radiotherapy.
And thirdly, hyaluronic acid is a material with a long history of medical use. So we know it's safe. It's been used in dermatology now for many years with more than 40, possibly even 50 million procedures performed worldwide. But more importantly, it's also reversible. The risk of rectal wall infiltration is very low with Barrigel™. In our Australian study of about just under 6,000 patients, we found 16 cases, and the majority of these patients also had MRI scans. So we know we've pretty accurate with our figures.
So that's a 0.3% chance. And that's consistent with the Barrigel™ trial report of about 0.6%. And this is certainly far lower than the 6% or even the 45% as reported in another study for PEG hydrogel implants. And I believe that a significant rectal wall infiltration leads to mucosal ischemia. And then that sets off a chain reaction of rectal ulceration, superinfection, pelvic abscess formation, fistula, and even Fournier's gangrene. So with Barrigel™, the risk of rectal wall infiltration is pretty low, and you have the ability to reverse significant rectal wall infiltration, which will stop that chain reaction instantly.
So we haven't seen any severe adverse events with Barrigel™. There has been no rectal ulcers, pelvic abscesses, fistulas, or Fournier's gangrene. But ultimately, I like it because of the combination of control, your ability to adapt the implant while you're performing the procedure, the evidence that's out there, and the reversibility as well. And that's very important for me.
Zachary Klaassen: Fantastic, Michael. If you look at your own practice, how does Barrigel™ work into the workflow of a daily practice? How do you set things up? Our listeners would love to hear how you've done five to 6,000 cases. What's your workflow in the practice?
Michael Chao: We've been rectal spacing now for quite a number of years. In fact, we started performing rectal spacing back in 2012, 2013. So it's actually become part of our normal prostate radiotherapy pathway, rather than treating it just as an additional or a separate procedure. It's been well and truly integrated into what we do.
I guess the first step for us is patient selection and discussion. Most of the urologists that we work with rely on us to select patients. And we implant not only patients with intermediate-risk disease, but we do also implant patients with high-risk disease. But we do look at the MRI pretty carefully. If you've got macroscopic extracapsular extension, anywhere between four o'clock to eight o'clock, we would think twice about it. But for all other patients, we're pretty happy to implant. And the urologists that I work, with that I've been working with for quite a number of years now, do know that.
So when I see a patient and we decide that prostate radiotherapy is appropriate or is certainly an option, we discuss the objectives of therapy, the potential side effects, and then also the strategies that we use to minimize the side effects. And rectal spacing forms part of that conversation. And when the patient actually does decide to have radiotherapy, the spacer procedure needs to be performed before the planning CT or MRI scan, because we obviously want the treatment planning scan to represent the anatomy that we are actually going to treat.
Plus, we also put the goal seeds in there so you get interfractional tracking. You get the best image guidance possible to minimize not only rectal toxicity, but also GU toxicity. As I've said before, I've worked quite closely with a number of urologists. I attend theater sessions with some of my urologists, and we do things a little bit differently compared to the US. While other urologists are fairly independent, in terms of the workflow, it is a little bit different from the US because we are funded to actually treat these patients or implant these patients in theater under a general anesthetic, whereas I know it's a bit different in the US.
So for us, we have the ability to plan well ahead. We can organize theater sessions with the urologist. And the other advantage that I have with the urologists is that I'm a trained brachytherapist, so I've worked closely with these group of guys and gals now for quite some time delivering low dose rate implants. And in addition, they are also pretty skilled with transperineal biopsies, having switched to that sort of procedure as standard practice many years ago. So they're very confident around the step of setup. They're very confident with the transrectal ultrasounds, and they're also pretty confident with their needle skills.
So all I need to do is actually give them a call, tell them when the indicative start date is, and then a theater time is usually organized two, maybe three weeks prior to the commencement of radiation. And one other advantage that Barrigel™ has is that it does stay in the body for a little bit longer, six months plus, so we can actually arrange the implant well ahead of the radiation time. So instead of needing to perform the procedure one to two weeks prior to the commencement of radiotherapy, you can choose to perform the implant maybe one or two months ahead of time.
The surgeon might even plan to have one session where they do all their rectal spacing procedures instead of having ad hoc procedures here and there, to just make it easier for themselves. And obviously once the spacer has been inserted and we are satisfied with the result, the patient proceeds to their simulation. We take an image for their planning, we do the contouring of the prostate and the surrounding organs, and then we generate a radiation plan. And if the implant has been, let's say, less than optimal, we do provide very friendly feedback, and it's generally very much appreciated by the surgeons.
They sort of have an idea, but it's always great to show them the pictures so that... And as I've said, the feedback is generally well taken. But the real goal is really to make rectal spacing part of that standardized pathway. Consultation, spacer placement, simulation, planning, treatment, rather than something that is frustrating, it disrupts or delays the patient's radiation treatment. We know it's part of the treatment program.
Zachary Klaassen: No, I love the collaboration between the urologist and the RadOnc. I think that's super important. And I think that's a message we've been discussing on your UroToday, as well as in my practice as well. Michael, there was a recent announcement Barrigel™ is now available as a contouring service with the Radformation's AutoContour software. Maybe just give our listeners an idea of what that is, why this could be advantageous, and maybe if you have some experience yourself.
Michael Chao: Yeah, look, I must admit I haven't played with it before, but obviously there've been other AI tools and automation tools that we use. But I totally agree. I think this is a very interesting development because it brings the rectal spacing, I guess, into the broader evolution towards automation and also AI within radiation oncology.
One of the first steps in radiation oncology is contouring. We have to identify the prostate, the seminal vesicles, the bladder, the rectum, and also all other relevant structures on the planning scan. And traditionally, many of these structures have been manually drawn slice by slice. So you can understand how boring that can be for our planners and also for us as radiation oncologists. So auto-contouring uses AI-based models to automatically identify and delineate these structures on a patient's image. And Radformation's current AutoContour platform now specifically lists Barrigel™ as a male pelvic structure that the software can identify.
And I know this may sound like a relatively small development, but it does have potential advantages. Number one, it can reduce the amount of manual contouring that's required. Number two, it may even make it easier for us to contour the Barrigel™ and may remove that need for a radiopaque spacer if an MRI scan is not readily available. I always recommend that you should fuse an MR with a CT scan when you are planning a prostate. But I do also understand that sometimes that's not readily available because of circumstances, because of insurance policies. And this may help the radiation oncologist contour the Barrigel™ without needing a radiopaque spacer.
And thirdly, there's also an interesting quality assurance opportunity here for us. If we can automatically contour the spacer, we can more easily assess its position, its symmetry, and the relationship between the spacer, the prostate and the rectum. And if we can do that, then it's easy to correlate what we achieved during implantation procedure with what we subsequently see dosimetrically on the radiation plan. So I see this as pretty exciting, and we are moving away simply from saying a spacer was inserted towards objectively evaluating the quality of that implant and then how it actually influences the treatment plan.
But just as a word of caution, with any AI contouring system or tool that we use, the physician still needs to review all the contours. So it doesn't mean it's carte blanche that we just rely on the AI and do very little. You still need to review the contours and maybe manually fix little areas. But automation should improve efficiency and consistency, but importantly, it doesn't remove the clinical responsibility on our side. So to answer your question, the second part of the question, this is something that I certainly would be very interested in incorporating into the workflow, and it'd be great to actually get that opportunity to talk to Radformation at one of the conferences.
Zachary Klaassen: Wonderful. That's great feedback as well about AI. Michael, phenomenal conversation. Any wrap up points? Anything, practical tips for people starting rectal spacing that are listening?
Michael Chao: Look, I think they just need to give it a go, but they also need to talk to their colleagues who actually incorporate rectal spacing into their workflow. They need to get properly trained and they shouldn't rush the learning curve. The injection process, as you know, Zach, is not the difficult part. As a urologist, you guys do even more difficult procedures. I still don't know how you guys remove a prostate laparoscopically, but you guys do quite successfully and effectively.
So it's easy. The key skill, I believe, is actually understanding the ultrasound anatomy and then being absolutely certain that your needle tip is in the correct tissue plane before you start injection. And good visualization is everything. Secondly, initially concentrate on straightforward anatomy. Talk to your colleagues who's done quite a number of implants. They will give you tips and tricks that you cannot learn from a video or even from learning from, let's say, a lecture theater orphan books.
Thirdly, think also about that radiation plan while you're performing the procedure. You're not simply injecting a gel, you're creating anatomy for your radiation oncologist and dosimetrists to work with. And it's that apical part of the prostate where the separation is minimal, and that's where you need to get the biggest separation with the rectal space, because that's where you get the best bang for your buck.
Another practical point, I guess, is establishing the workflow, having a good relationship with your urologist, being able to contact them, being able to tell them the start date, being able to suggest an implant date, for example. And if you guys get along well together, that's pretty easy. But also, I guess nowadays, the use of the Barrigel™ rectal spacer makes it easier as well because I think this is probably the safest and also the most forgiving implant that's out there. As I've said before, and I'll repeat it, there's no polymerization. So you can take your time with the implant and you can take as long as you need to do your first one, if not five procedures, and you learn along the way.
Zachary Klaassen: Michael, wonderful conversation. Thanks so much for your expertise and your time on UroToday. Really enjoyed this one.
Michael Chao: My pleasure. Again, thank you so much, Zach, and thank you for getting up early so that we can chat. So I really appreciate it. Thank you so much.
Zachary Klaassen: Likewise, Michael. Thanks so much.
Michael Chao: Thank you. Bye-bye.