28 MRI Targeted Therapies - Tempany

Introduction to Focal Therapy

This is a talk on focal therapy.

And I have to thank Satna, who did a fabulous job introducing the concept of focal therapy already.

Much of what I say will be reinforcing the information that she gave you when we started doing the MR guided brachytherapy program, that was actually one of the first focal therapies, which was a subtotal gland treatment for prostate cancer.

And that was before we even had Multiparametric MRI.

Rationale for Focal Therapy

This nice case that Francois from Paris has kindly given me to show you demonstrates I think a great rationale for focal therapy.

You can see in all the parameters in this enormous prostate, a focal lesion at three o'clock, small, tiny little lesion here, accessible to any of the many percutaneous or transrectal focal therapies.

Instead of taking out this enormous prostate, it's sort of like the crushing of an elephant's foot just to kill a mosquito, essentially.

And I think that whole gland therapies really are becoming called into play as we, as the radiology community and using our techniques are so much better at identifying small and focal lesions and being able to exclude other lesions and not necessarily exclude completely.

Of course, as you know, and we can obviously use the MRI before, during and after focal therapies to follow these men because just like active surveillance in a focal therapy protocol follow up has to be for the remainder of the man's life unless one goes on to definitive therapy.

But even then, you're gonna follow patients.

So really it's been terms, the male lumpectomy, to try to draw again, another parallel to the breast cancer treatments.

Forms of Focal Therapy

But one of the things that Satna beautifully illustrated is what are we talking about is the important thing?

What form of focal therapy is being discussed in any given article meeting or treatment proposal?

There's single focal lesions, there's hemi gland, peripheral zone, and then individual lesions themselves.

And all of these are quite different and different ablative techniques are applied to get to this end result.

Types of Therapies

There are several types of therapy that can be used.

We've already discussed brachytherapy.

There's cryoablation, which is in trials in many places, and being used for many years.

The cryotherapy is probably the oldest and most established form of either whole gland or focal therapy in prostate cancer.

There's a so-called cold registry, which has thousands of patients that have been treated, sadly for this technique, it's good, but there's not a lot of great papers out there and documentation in the literature as to the value and the long-term follow-up and all of the important things that we need to compare these focal therapies to other standardized therapies.

So this is a, I think a little bit of a criticism of the cryotherapy world that has not been as well documented and done in as formal a way as we would've liked photodynamic therapy and vascular targeted things with laser fibers are also out there.

And then HIFU and MR Guided focused ultrasound have also we'll touch on.

Requirements for Focal Therapy

So let's just talk a little bit about what's needed to really do focal therapy and why are we discussing it more and more now?

Clearly it requires focal lesion visualization.

We know that ultrasound simply can't do this in its standard gray scale format.

But there are some techniques as mentioned earlier, such as strain wave microbubbles, other forms of ultrasound that may or may not be able to bring out more focality within a given lesion and allow us to use ultrasound in some way at some point.

But for today and for the foreseeable future, multiparametric MRI is the only technique that's really gonna help us define those index lesions.

And then the guidance modality then should really be the one that shows the lesion the best.

Again, it's somewhat akin to the biopsy story, but, and I think the registration and fusion techniques will help move the index lesion into the ultrasound framework and allow its visualization size, volume, three dimensional metrics, all very, very important.

Margin definition critical.

Where does the treatment stop and where does it end?

Really very important because this is really the margin that's going to be at risk for recurrence of disease.

How far beyond the defined tumor margin of the tumor should we be treating with any one of these focal therapies?

Five millimeters was used as an illustration of one measurement earlier in this meeting, and I think that's certainly very reasonable.

I think it depends on the ablative technique that's being applied and how good they are at this.

But this is really the critical thing is to make sure you get full and complete total volume coverage and a margin of safety around it.

Patient Selection Criteria

Some criteria have been published in the literature.

They're not universally agreed as to who are the good candidates, what is the clinical profile of the typical man who might wanna consider focal therapy.

But I think this one from Eder and others in urology now some time ago, really goes through nicely the criteria that would be used potentially to enroll patients.

In a summary, the, some people will call these the active surveillance plus group.

So there are people be on the verge of active surveillance for treatment.

That's kind of a, sort of a broad sweep, but looking at it, it's obviously low stage, early stage disease, low PSAs PSA densities less than 1.5 PSA velocities that are low.

And then they have to have a minimum number of 12 cores, 12 core biopsies is what's been defined in the past is to in assessment of these patients in the workup.

I'm not sure that's gonna maintain, given the targeted biopsies that we're talking about now with less cores.

But a typical pre focal therapy diagnostic biopsy is a 12 core.

Many people in cryotherapy have been doing those mapping trans perineal biopsies for many years.

I know Gary On and the group in Cleveland and I think it was in Cleveland, yes, they're doing the set templated five millimeter sampling all through the gland to try to get a three dimensional map of tumor volume.

That was pre our techniques.

I believe we've probably supplanted that now, and hopefully men don't have to go through that percutaneous prostatectomy just to determine where their tumor is.

So they shouldn't have any Gleason grades four or five, of course, as you'd imagine.

These are all pretty obvious. Maximum percentage core should be about should be at tops 20%.

So small volume disease and short length of disease.

And then the maximum number of percentages of total cores is 33% single lesion with a maximum size.

If it's seen on MRI, less than one or up top normal would be 1.0 0.2 millimeters.

And then little bit of capsular contact is okay, but not a lot, and of course no evidence of advanced T three disease.

And so then they get into the discussion about whether you're going to treat a patient with known unilateral disease or bilateral disease, and how do you really know that?

Because again, of course, as we know, there is occult Gleason three plus threes in a lot of these patients.

Treatment Volume and Quality of Life

We wanted to look at something, the techniques and determine which one is the maximal tumor kill method.

And we'll talk a little bit about that.

And then we've talked already about volume, but the volume, it's all a trade off here.

You're really trying to control the disease by actively doing something but preserving the quality of life.

And that's the fine line that any of these focal therapies will walk is trying to have, preserve that trifecta that we spoke about, which is cancer control.

GU and sexual function, minimal impact on that.

And 50% of, of the ablation can have about a 90% preservation of function, certainly in the GU function.

And six months recovery time, these patients will recover, A lot of them will rely on medication to maintain erectile potency.

And so there obviously problems in the long-term with these patients as well with the reliance on medication new disease, I think we have to obviously watch out for that.

Treatment Monitoring and Protection

It's critical to monitor these patients to get a really good map at the beginning.

As I've already said, an MRI really can help, as we've shown for the surgery cases, to delineate where the urethra is, where the neurovascular bundles are, obviously where the rectum is, and then to determine whether or not that's in a good place to be ablated or not.

It's stuck right in between the urethra and the neurovascular bundle is a common typical location for an early stage disease.

So these are the issues that have to be discussed.

And when you're treating this patient, regardless as to which form, be it cold therapy or hot therapy, you're gonna have to protect the urethra in some way.

So there are urethral warmers and urethral protection techniques that are used with circulating water to go through and preserve that, so that it won't get damaged because of course, sloughing and stricture and all of the complications that can come from ablation and irritation of that area are significant and well understood.

Look how close the neurovascular bundles are here.

This patient would be counseled ahead of time that unilateral nerve sparing would only be possible on this side and that this nerve would potentially be damaged.

Remember, heat and cold will damage irrevocably, the nerves and the heat particularly will cause complete dysfunction of the nerve afterwards.

So the goal is to have a hundred percent cell kill no matter which ablation technique you're using.

We know all this from all of the other ablative techniques that we use in the liver and the kidney.

Real-time treatment monitoring is really essential, be it ultrasound CT or MRI, we do this as you know, in many of the RF and laser and cryotherapy treatments elsewhere in the body.

The one that offers the only one that offers real time thermometry, which is real time thermal change imaging is MRI.

Again, of course adding unfortunately to cost and access concerns, but if you really want to see thermal changes in vivo at the time of a procedure, MRI was the only one that can show either heat or cold as it occurs, access to the tumor can be either percutaneous or transrectal or transurethral, as people are using for transurethral HIFU or focused ultrasound surgery.

And you try obviously to manage the tumor and then the minimal toxicity, the advantage of all of these is that they pretty much all have the option for re-treatment.

It's not a treatment that is left where you just only do it once.

You can go back in and repeat these therapies over and over, and I know Satna made that point.

And it is because not like surgery or radiation, it's a one shot and one chance only.

They can be used and they're used a lot, not just in primary treatments.

They're used actually probably more frequently in salvage therapy.

Algorithms at the moment for patients who failed radiation, failed surgery with local disease.

Technique Mechanisms

And so this is a, are the techniques that are out there for treating prostates or HIFU cryo and radiation.

And just explaining a little bit about the differences in the names of some of the companies that are out there making these systems for HIFU, which I'll go into in a bit more detail in a minute, probably been around almost as long, but not quite as cryotherapy.

It's a heating denaturation, coagulative necrosis of the tissue.

Cryotherapy disrupts the cellular membranes, delayed vascular occlusion.

Radiation, as we know, is a focal technique.

DNA damage, cell damage apoptosis.

And then the photodynamic therapy light activated oxygen dependent effects.

The English people are quite keen on that one.

Applications transrectal, trans perineal brachytherapy, trans perineal of course.

And then this is trans perineal delivery of light fibers and laser.

Similarly can be a trans perineal placed fiber that will cause local heating.

And you've seen examples of that, and I'll show you another one in a minute.

Companies and Systems

So companies that do make the HIFU systems, these are the transrectal ultrasound guided, Ablatherm, Sonablate, used a lot in Europe, used in Mexico.

And we've seen some examples of post HIFU treatments.

These are quite good.

You can, the results have been getting better and better.

I'll show you some of those in a minute.

They've been around for a long time.

They got off to a really bad start.

They caused trouble with all kinds of fistulas of the urethra and heating effects that were just got at a bad name unfortunately.

But it has recovered.

The MRI approaches are being introduced by InSightec.

We're involved in an early phase trial of using that in a trans rectal mode.

And I'll show some animal work.

We haven't done any patients yet.

The trial is just beginning to open.

And then cryotherapy, there's Cryocare and AccuProbe and the Gale system as well as another one that does percutaneous cryotherapy radiation.

It's a company like C-Nav, which the brachytherapy.

And then there are numerous of these photodynamic therapies, companies using different combinations of vascular targeted phototherapy.

The laser companies are Visualase and Medtronic who both have very nice systems for percutaneous and trans perineal laser therapy.

Outcome Measures in Focal Therapy

Now, one of the things that's really critical in focal therapy is to define your outcome measures.

How are you going to determine success or failure and how are you going to manage the patient and follow them up afterwards?

And again, this paper I think is probably one of the best, most comprehensive ones that sort of sets out at least a framework.

There may not be much agreement about this across the communities that treat these patients using these techniques.

But at least if we can try to standardize some of this, the reporting systems should be the same in each paper.

We'll probably never get to a randomized controlled trial of focal therapies, but it would be awfully nice if folks did report the same things.

So clearly a post-treatment biopsy mapping is usually included in all focal therapy studies at least one year after the intervention has been performed.

And so that's to watch and look to see treatment effects at the margin that I was just talking about, or to look for new foci disease elsewhere in the prostate.

So at least one post-treatment biopsy should be reported in all studies.

Imaging, of course, as we know to correlate and look at the treatment effects and they're out, their correlation with outcome.

So as Satna nicely showed, again, those necrotic black holes in the prostate, pretty much standard for cryo laser HIFU.

We wanna see where they are and then determine those in relationship to the side effects relative to the urethra, the neurovascular bundles and the rectal wall.

And of course, as we've already talked about, the quality of life reporting, I think, again, self-reported by the patient, critically important and an agreed upon metric or questionnaire format that the patients can document the morbidity rates of either urinary bowel or sexual dysfunction after any of these treatments.

And then of course, the measurement of the PSA was as again, being identified as abusing the radiation oncologists term, which is the Phoenix criteria, nadir plus two for progression and re-treatment.

Laser Therapy

Now, laser, I think Pete showed this very similarly, and this is from John Feller in the desert practice in Arizona, I believe, shows us nicely the advantage of MRI to show the laser fiber going in trans rectally here into a lesion.

But you can see the development of the heat as you do these very fast phase map images during the delivery of the laser energy.

And what's nice about that, of course, is, and this is just going in a loop cycle at the moment, but you can see how that heat generates from the center and grows outwards and it will delineate hopefully with greater and greater accuracy.

I must say it's not terribly accurate today on determining thermal map versus volume ablated.

I mean, that's not always the same thing.

So what you see is not necessarily what you always get, but it is pretty close and it is going to get better as the MRI techniques for thermometry get better.

And then afterwards, as you know, we inject the gadolinium immediately on the day, and that's important as well.

That's a baseline post-treatment image.

And then of course you get another one a year later.

But your post treatment on the day shows nicely the necrotic area centrally.

And I think you'll all agree that's a little smaller than that big thermal map was showing as it almost looked like it was going to the edge of the capsule.

So the thermal maps are overestimating in the laser, they're overestimating the thermal damage, which is good and bad, but as long as you know, you have to understand that when you don't, you don't know for exactly how to match those up.

So what's important is to really measure in the color changes, where is the really effective cell kill occurring?

Because you will get gradations of temperature change from the center to the periphery, be it in heat or cold.

So the center of the fiber is the place where it's gonna be, and the cells and the tissue around it are the ones that are gonna get the maximal cell kill.

And then as you move out with the heat sink effect and the circulating blood flow that is in all live organs, of course heat is sucked away.

Cold is sucked away. So the local thermal damage will not be as effective the further away from the fiber or the ultrasound sonication or whatever it is, the energy source.

So critically important.

So this is why the real-time images showed it bigger, but then they went back and determined what was the therapeutic dose.

And the therapeutic dose is critically important to understand.

That's when if you heat to at least 55 degrees C or higher, that you've killed all protein in all cells in that area.

And cooling similarly, you've got to get it down to below minus 20.

And you see here the correlation going across very nicely there in cryotherapy.

Cryotherapy

We've done several of these now, it's a relatively straightforward and simple trans perineal approach with mapping.

And this was done in a salvage patient after failed brachytherapy, and he had a focal lesion in the 11 o'clock, 10 o'clock location.

And you can see the urethral catheter here with a warming fluid flowing through that.

You can't see that of course, but you have to believe me.

But the water's flowing there through that.

And then you can see the ice ball here developing and the edges of the ice ball, just like the edges of that thermal map, are not as cold as the center.

And something that's really important, and something that we hope to study in a future grant proposal right now is to try to understand what's happening inside that ice ball.

This is a VIBE technique or just a standard gradient echo technique.

If this is T two, actually, sorry.

But typically for thermometry, we use this fast gradient echo technique.

That's really not good enough because it just shows this uniform black ice ball without any evidence of isotherms developing in the center.

So several authors now and Kim Butts and others have proposed using what's known as the UTE sequence, the ultra short TE sequence, which Graham Sommer and others developed for initially for cartilage imaging.

But can actually be very helpful to allow us to look inside the ice ball and look at the thermal gradients and something that Bruce Danielsen and others have worked on at Stanford.

And I think it's becoming very important, not just in the prostate, it's obviously critical for all MR Guided cryo procedures is to really understand that ice ball change.

And here we don't want to overtreat, you don't wanna ever have the treatment going beyond, but you really wanna make sure you titrate your ablation to the correct place.

Focused Ultrasound (HIFU)

So looking back at the history of MR guided focused ultrasound, or excuse me, ultrasound guided first, this is called HIFU, using ultrasound guidance to show the prostate.

And most of these were early stage studies where patients were being treated with whole gland therapy, but it goes back sometime now back to 1995, 19 years ago, the year my son was born.

So I remember that one pretty well.

But the 19 years of that data has not really panned into being a particularly well used technique in the United States, and most of it has been because of inability to identify the focal lesions.

These techniques have been tested and tried.

And recently, unfortunately, both companies, I believe it is both of these mentioned have failed to meet the bar for FDA clearance in the US.

And so none of these are FDA cleared for treatment in commercial treatment matters.

So MR Guided focused ultrasound surgery, developed by Culver by Frank Jolesz and other people at our group many years ago, combines the ability of MRI to see the heat change focally delivered by these ultrasound transducers in a phased array manner and allows for very, very tight control of the heat delivery by tightening the beam in the focal spot nicely.

And you can see on phase maps the thermal change at that exact spot.

And so it's a very, very nice technique to allow us to see that.

And then the original platform was built on a 1.5 system.

The basis of the thermal imaging is using proton resonance frequency techniques, where we can see the altered in the black and the regular images here in the short and long axis of an individual pulse of ultrasound into the tissue.

This is in an animal model here, and then this is in a uterine fibroid case down here.

You can sort of hallucinate the anterior abdominal wall here and the fibroid there, but that's not the purpose of this image is to show you only where the heat is being delivered and the volume of it.

And then this is the screen save from the device.

And you can see the temperature rising across in a focal region of interest in the red, and then in the generalized area in the green here, as you can see that all of the temperature gets to the critical number that you want to get to, which is the 55, and that's the immediate, the closed loop, the so-called closed loop feedback that you get at the time of delivering this energy.

And so it's really a very beautiful technique.

It's under trial and trials for many things.

We've, it's been FDA cleared for uterine fibroids, and we're in trials, as I just mentioned earlier, to use this.

And there are other companies, Profound and others who have a transurethral system that's being used in a pan sweep like manner to treat the prostate.

This one is transrectal, but as the technology gets better and better, the ability to put tiny transducers on small things like a Foley catheter is fantastic because you're now able to get this heating technique into really tiny spots of the body.

And this is the sort of result you can see from the delivery of the energy into the prostate with small focal area and typical black hole, as we've seen in all these ablative techniques.

The prostate, again, the motion is very important as you can see, delivering the energy here.

You've got to watch carefully again, as mentioned for the cryo, the proximity, the neurovascular bundles.

You've gotta watch this as the procedure progresses and the heat builds up.

Very important to try to freeze the motion as best as possible.

And doing motion compensation techniques is really important.

The transducer here, this is in an animal model, surrounded by a water bath to cool the rectal wall, so there's no heating of the rectal wall.

This is the same as is being used in the humans.

Again, it's circulating water here to try to protect it.

What's really nice about this technique is the really sharp histopathological boundary between the tissue that's dead and the tissue that's still normal.

You can really carve out very small focal lesions in a very nice way with minimal, if any toxicity to any of the adjacent structures as the beam goes in, and then the beam comes out.

So it's an elegant technique that I hope will eventually pan out to be useful.

We've looked at post response treatment imaging and shown this already.

But again, just to remind you, focal area of low signal intensity here, non enhancing after gadolinium in this patient who had this very tiny treatment, this comes from the European literature and then post brachytherapy recurrence there.

Conclusion

So focal therapy is in demand.

There are a lot of patients who find this as a very appealing option, and they're asking a lot of questions about it.

There are newer techniques, interstitial electroporation, is coming out as well and being used by the group at UCL, for example, for anterior lesions where you can use it there nicely.

I think it's something that deserves really good look at.

It's gotten a little bit of a bad rap, but I think at the time is changing now that the imaging has got so good and we can actually define those focal lesions.

So it's good to know about it and learn as much and watch literature as best you can.

Thank you very much for your attention.