TULSA Prostate Treatment

[Dr. Aditya Bagrodia]
Daniel and I were talking before we actually formally started. It's a little bit tricky and challenging now with the direct-to-patient advertising, medical centers advertising, and so on and so forth where I've got patients with grade group five prostate cancer coming in and say, "Hey, doc, I want to receive HIFU," or they have grade group one prostate cancer and they're like, "Can I get lutetium PSMA treatment for my grade group one prostate cancer?" You're having to explain that this is a very heterogeneous disease. Every patient's a little bit different. With that, who are your ideal patients when a new diagnosis comes in? What are the features that you're like this might be a good patient for TULSA.

[Dr. Daniel Costa]
In our case, our ideal patient is the intermediate-risk patient with a localized disease. Ideally also focally. It's certainly easier to treat lesions that are either in the lateral or anterior portion of the gland where you're less concerned about injury to either a neurovascular bundle. A medium-size prostate, because there is a maximum radius that the ultrasound beam can reach, so if the lesion is more than 3 centimeters away from the urethra, we may have trouble reaching that region.

We certainly want to also exclude large calcifications in the prostate that could act as a shield, a barrier that prevents the ultrasound beam from reaching the area to be treated. Also, a patient that we are eager to treat are patients who had radiation and have recurrent disease. Salvage post-radiation is usually a good patient for TULSA. Also, although not the core of our patient population, some patients with lower-risk disease who are extremely uncomfortable with the idea of active surveillance and that happen to have LUTS because we can tackle both BPH and the cancer at the same time.

[Dr. Aditya Bagrodia]
Fantastic. A couple of questions. You mentioned significant calcifications. Is that something that is standard reporting when you're doing an ultrasound biopsy for instance, or are you getting some type of imaging, non-contrast CT, or so forth to assess?

[Dr. Daniel Costa]
Yes, as we learned that calcifications play such an important role in patient selection, we tweaked our prostate MR protocol so that when a patient comes to get a diagnostic MRI, there is a sequence that aims specifically at identifying calcifications in patients who are referred from outside institutions and did not get an MRI with us. Some of them may require a CT of the pelvis to look for those calcifications. Ultrasound in theory can see calcifications, but because there is not a standard approach to how this is done, it's hard to retrospectively look at those images and be sure that the patient did have appropriate screening for those classifications.

[Dr. Xiaosong Meng]
I think Daniel's really led to charge there in terms of helping us work up our patients better with the issues with calcifications, because it's not only size, it's location. If it's a calcification on the other side of the prostate that you're not ablating, you really don't care about it. I think that's where the cross-sectional of imaging comes into play. The fact that we're able to get this part of every single diagnostic MRI has really helped speed up the process. Now we're not asking patients, we're going to another CT, we'll figure out if you're eligible for TULSA. It's like, here's your lesion, here's your calcifications. It's all in the same imaging sequence. I think that's really streamlined the workflow there.

[Dr. Aditya Bagrodia]
Daniel, you mentioned size of the prostate, what about size of the lesion? Is that a relative or absolute contraindication?

[Dr. Daniel Costa]
It doesn't seem to be. What you want to make sure is that the lesion is not too close to the sutures that you don't want to cause any damage to, so the external urethral sphincter, the neurovascular bundles, the bladder neck, but a large lesion in an ideal location should not be an issue just because it's large. Going back to the calcifications discussion, also an example of how we are learning about the technology as we use it.

In some men with large calcifications in a location where we do not see that as a problem, we sometimes see that large calcification as not really as much of a barrier to energy delivery as we thought it would be. In some men where we do not see any large calcification, we sometimes see a challenging penetration of that tissue. We are learning that there might be some tissue properties that interfere with the ultrasound dissipation and the heat distribution that we are not as aware of today as we'd like.

[Dr. Aditya Bagrodia]
You mentioned proximity to critical structures; the sphincter, the bladder neck, and the nerves. Generally the way I think about it for most of the ablation technology is the apex is a bit tricky. Is that true in your estimation for HIFU, or is this an area that's a little bit more amenable to HIFU?

[Dr. Daniel Costa]
That is true. We like to have at least a 5-millimeter distance from the US. It's also interesting because each man, the anatomy is slightly different from one another. The angle, the steepness of the angle that you see the apex, and the relationship between the US and the apical-most portion of the prostate. We sometimes see a US that is almost intra-prostatic. Whereas in some men there is a larger distance between those two structures. I would say these aren't set in stone, these numbers, and we really need to look at every single patient in that to see if he is a good candidate or not. That takes quite a bit of time, and it's an involved process for sure.

[Dr. Xiaosong Meng]
I do feel one thing about-- we've treated a few patients where the tumor is almost touching the external sphincter. I think you can position the device in and out. You can put where your last ablation element is, and you can put it very close to the sphincter. So far, for the few guys that we've treated where the tumors were touching the sphincter, they've not had stress urinary incontinence, which I find encouraging.

They certainly have more LUTS in the short-term, I think from swallowing other treatment, but at the moment I think for those that are very, very close, I think we're able to skirt the fine line. Because of how detailed the anatomy is, you're getting real-time MRI images to do your planning, and the ability to control the degree of heating, I think is very good. Then that certainly, I think, is one of the benefits if you're treating things close to critical structures with this technology.

[Dr. Aditya Bagrodia]
Now that's good to know. When I came to UC San Diego with recently purchased the capital equipment for HIFU, and I had in my mind as somebody that was going to be offering this treatment to patients, that I wanted them to be ideal favorable intermediate-risk posterior lesions MRI-detectable, rest of the prostate negative on systemic biopsies. Fast-forward about nine months, I'd done one HIFU and I had to slightly extend the criteria.

[Dr. Aditya Bagrodia]
Apex, again, not ideal, but case by case manageable, and then contra level grade group one, have a conversation about it. Now, one of the things that was intriguing to me, Daniel, is when you mentioned a grade group one patient with LUTS. Maybe let's talk about a little bit of patient characteristics, further anatomy, median lobe, erectile function, urinary function, previous TURP, previous euro lift where they may have some clips in their prostate. Do you want to maybe talk about some relative and absolute contraindications from your end?

Do you want to maybe talk about some relative and absolute contraindications from your end?

[Dr. Daniel Costa]
Sure. What we do know is the ultrasound beam can reach and we can measure temperature reliably within a 3-centimeter radius. That's guaranteed. Beyond that, it's uncertain. If you have a man with a prostate and a lesion that is borderline at that radius or beyond that radius, you may find yourself in a position where you can't really reach that region and therefore unable to treat that man properly. What we've done in some men is with those men on a 5-ARI regimen to shrink that prostate and repeat imaging to reassess the anatomy.

In most men, that was successful because what happens is most of those men, you were borderline 3 centimeters, 3.2 centimeters and then after three months on 5-ARI, we see a 10%, 15% volume reduction that brings that area to within the reachable area. In regards to clips, seeds, I don't think any man has been treated with a UroLift device. There have been patients not at our institution where the UroLift device was removed and then treated, but I don't have direct information about how that went. We've treated patients for salvage post-radiation with both fiducial markers and brachytherapy seeds.

The fiducial markers, I think it's a similar concept to the calcifications. These foreign bodies, they introduce noise in the images that measure real-time temperature that can affect the quality of the treatment by providing poor quality information to the system that is meant to modulate the output of energy. It may appear, for example, as if an area that has not been heated yet is extremely hot even though it isn't. Then the system will not deliver energy to that region because it assumes that that is already a hot area.

Whenever we are assessing a patient with those metallic lips, be it fiducial marker or brachytherapy seed, what we want to make sure is that those areas, how they relate to the area that we want to perform the ablation. In some men, what we can do is we can run a simulation. We bring the patient and run a thermometry map to see how much noise would be generated by those clips or those seeds.

The men that we treated after going through this vetting process, they did not seem to be an issue. We don't have long-term outcome data for those men, but the impression from the day of the treatment was extremely favorable. It does require quite a bit of care when drawing the treatment area on the day of the treatment to make sure that we do not include voxels that could misinform the system and result in undertreatment of critical regions.

[Dr. Aditya Bagrodia]
This may sound like a dumb question, and I should have probably covered a little bit about the mechanism of action for TULSA. We've got this probe in the urethra and it's able to send high-intensity ultrasound waves from the inside out. I'm thinking of a brachy patient, let's say they've got seeds throughout, and let's say they've got some brachy seeds anterior to their urethra and you want to treat something even more anterior to that, for instance. Can your ultrasounds penetrate through those brachy seeds, or is that going to be like where they stop similar to a calcification? You mentioned the impact on thermometry, but what about the effective treatment getting to the area of interest?

[Dr. Daniel Costa]
You are right in the sense that the urethral probe has elements that deliver ultrasound that results in tissue heating. The way it works is the system uses the pixels closer to the periphery of the area that we drew as the area to be treated. To reform the system, that sector has already been heated properly. It assumes that if it's hot at the periphery, that entire sector has been properly heated. That's how it knows whether or not to continue to deliver energy in a certain region or move on to another region.

In regards to whether those clips or mark or fiducial marker or brachytherapy seed could be a physical barrier to the ultrasound beam penetration, what we notice on an MRI in a patient with recurrent post-radiation cancer is that the cancer, as it grows, it moves the seeds away. It's actually when we're reviewing these patients, when we're interpreting these images, we always look for areas where we don't see that many seeds.

Because those are areas that either there is something growing that is pushing the seeds apart, or maybe there weren't seeds there to begin with and that's the area where the treatment failed. That helps us because that is the area that we want to ablate. In general, there is a posity of seeds in those regions. That may not be true for the fiducial markers but because the fiducial markers tend to be put in a structured fashion and they are so few, it's uncommon that they will be riding a critical location, but it has to be evaluated case by case.

[Dr. Aditya Bagrodia]
Fantastic. Then just going back to the lower urinary tract symptoms, are these patients, are they getting pre ablation? You mentioned the 5-ARIs which may help out with symptoms, if they've got a larger prostate, median lobes, does that impact anything at all? History of strictures, previous TURP, or if they have significant frequency urgency, are those contraindications, or how do you synthesize all of their lower urinary tract symptoms, previous BPH history when you're considering treatment?

[Dr. Xiaosong Meng]
That's a good question, because certainly these guys are a little bit more complex to treat. We've had a few guys with urethral strictures where we've basically said, look, it's not a good idea. You've already had two urethroplasties doing this, I think it's a 22-French urethra applicator and it's in there for two to three hours. Could certainly cause damage and worsening of your stricture. We've had a few patients where we said probably not the best idea to consider TULSA for you. We have treated patients who have had prior history of TURP, green light, things like that, and it seems to be okay.

We've treated some patients with median lobe. You have about a 5-centimeter reach. Not only do you have 3 centimeters from the urethra out to the periphery, the actual length, there's 10 elements, they're 5 millimeters apart, so you actually have 5-centimeter treatment length within the prostate and you can also pull back and treat more, so if you have a longer prostate. Certainly we can treat median lobe, you just basically shut off the beam because you do worry about some transmission within the urine to the bladder wall. That's one of those areas that we're very careful of if you're treating a median lobe.

These guys do have a lot of urgency, frequency. The more volume we treat, the more symptoms they have. I think, in some ways, it's probably like Rezum. You're heating up the prostate. In Rezum, you're injecting steam into the prostate, here we're heating the prostate about 55 degrees at the periphery. Certainly hotter inside when they get swelling. They have decent obstructive symptoms for the first four to six weeks, is what I usually counsel my patients.

You're going to be miserable for the first month, and things will slowly get better and better. They get put on alfuz, so they get put on Rapaflo to start before and after the procedure to help with some of the LUTS. The more we treat, the longer I'll leave the catheter in up to about two weeks for these guys with large 60, 70 cc prostates where we do near whole-gland ablation on. We're also starting to explore some of the other things, maybe giving of course of steroids to help with inflammation, NSAIDs, and things like that to really help with their symptoms afterwards.

[Dr. Aditya Bagrodia]
It's like you were reading my mind, Xiaosong, I was going to ask for your spiel/consent process for we've identified the patient, and if I may, it sounds like symptomology isn't a contraindication, they've got a AUA symptom score of 22 or so. Could this be a reasonable benefit to them from a lowering symptom perspective once they get through that initial four to six-week post-treatment inflammatory irritation episode?

As you all know, we've treated men with larger prostates or significant LUTS that are going on to receive radiation. Many times we'll do a TURP or so forth on the front end, or a median lobectomy, or whatever has been decided in conjunction with the radiation oncologist. How do you factor that in? Is that a relative or an absolute contraindication?

[Dr. Xiaosong Meng]
For LUTS alone, I don't count that as an absolute contraindication. It certainly is one of those. It's counseling, and occasionally I'll send them for urodynamics. If their symptoms are really bad or they're having urgency incontinence already, I'll send them for urodynamics to get a good baseline. When we looked at our data, looking at IPSS, looking at guys using Flomax or Rapaflo, about a third of them actually have improved IPSS scores at six months.

I think the vast majority of them are stable. We do have, I think, less than 10% of them who have worse IPSS on follow-up. It's certainly we see a change at three months, it's a better change at six months. Just like those guys that we TURP with LUTS, they will improve. It's not the immediate effect after a TURP or the slow bladder remodeling, but we do see it. Usually, I tell them it's months. It's not anything quick. It's going to be on the order of probably three to six months.