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Arvin George: Okay, thank you Drs. Brown and Hafran for giving me the opportunity to speak. I actually started in urology at 17 years old. I did my first radical orchiectomy with one of the docs at Michigan Institute of Urology, and then shortly after that went to medical school. As a medical student, I rotated at the Cleveland Clinic where Dr. Hafran was actually Dr. Gill's fellow at the time. And then the rest is history. So I'm really glad to be here to talk a little bit about focal therapy for prostate cancer.

So one of the criticisms of focal therapy is, is focal therapy the correct management strategy? And I think that our criticisms rely on what we see in outcomes. And in my personal opinion, it's not an issue with the management strategy, but rather it is an issue with choosing the right patients for the treatment, applying the right energy source, and also applying the right treatment template for the right patients. Now, do we know all the answers to all those questions right now? We don't know that just yet, but it's being continuously studied and we are adding to our knowledge base continuously.

So today I have a lot to cover in a very short period of time. I'll try to talk about the rationale for focal therapy, not so much the index lesion theory, but why are we even considering it. Choosing the right patient? How do we pick those? How do we identify those patients? What's an appropriate pre-treatment workup? How do we follow these patients afterwards?

And really where I think that focal therapy can shine, at least for those who are considering starting a program, is really in the salvage setting and post-radiation failures. So the concept of focal therapy is a little bit different than radical treatments in the sense that while we are always aiming for a cure, I think that our strategy is very reasonable to pursue cancer control. As we understand, especially in an intermediate-risk prostate cancer, the vast majority of men who we treat are unlikely to die from their prostate cancer. Being able to control that cancer and essentially apply the same mode of treatment that we do in active surveillance where we consider a win delay of treatment for 3, 5, 7, 10 years. The goal with focal treatment would be to potentially be able to delay treatment indefinitely.

Now, if we cannot guarantee that we are going to achieve a benefit for every patient that we offer treatment to, or at least a large proportion of those patients, then we really need to make sure that what we are going to offer those patients has minimal morbidity and harm. We're starting to understand that we can offer re-treatments, and it is actually part of how I counsel patients now. I do mention that given how the technology and the treatments work, that there is a likelihood that within a fixed period of time, five years, that about 20% of men may require some sort of re-treatment either within the treated area or outside of the ablations or an out-of-field failure.

And also as I've gained more experience with focal treatments, I think that what has originally been to me is very onerous, is doing a prostatectomy on somebody post-ablation.

Prior to being at Hopkins, I was at the University of Michigan, and so I can't send that out to anybody, that's my patient to take care of. And so I've been able to do maybe about 10 to 15 patients who've had radical prostatectomy. And surprisingly it has been less socked in or less desmoplastic reaction than I would've expected. And it can be deceivingly so because your local staging information from your MRI can be unreliable. And so while you can still perform these surgeries, typically on the ipsilateral side of prior treatment or treatment failure, that is where I would do wide margins and I would not attempt to do any nerve sparing on that side.

So it's kind of easy to pick the perfect patient, MRI-visible, Grade Group 2 prostate cancer, relatively low PSA, it's target-only positive. Everything else in the gland is negative, but these are not the patients that typically show up to clinic. So we can't just apply that perfect criterion. We have to start to consider it in the context of additional things. So maybe the layering in of genomic biomarkers, I would say, "The story is still not told there," with regards to patient selection for focal treatments.

For me, how I currently use them is to identify whether or not they're a surveillance candidate or whether I would offer treatment to them, not whether I would choose focal treatment versus a different treatment, radical therapy.

When we don't have the perfect patient, we have to take into consideration way more things than I ever would've considered when I first started this journey. I think that the rubric starts to change a little bit because the treatment is different. When we look at the NCCN guidelines, typically we say a 10-year life expectancy, but if you look a little bit closer, if you have Gleason 7 prostate cancer or above and your life expectancy is five years, then in those cases we should offer radiation therapy, a definitive treatment.

So really trading off the potential harm of an invasive surgical treatment with a less invasive radiation therapy even though the life expectancy is shorter. And I think that conceptually we can understand that that goal there is not to prolong life, but there the goal is to be able to minimize progression, prevent progression, and maybe that means that we have to reconsider that as an opportunity for focal treatments as well.

I'm going to present some data a little bit later on who we can treat. And the data is, in my opinion, relatively favorable. It's not something that's unexpected. High risk are going to have poorer outcomes than intermediate risk, are going to have poorer outcomes than low risk. If I showed you survival curves in terms of treatment failure for focal treatment across risk categories, you would not be able to tell me if that's radiation surgery or focal treatments because again, higher-risk disease is going to have poorer outcomes whatever the treatment modality that you apply.

In my practice, I currently apply to Grade Group 2 and Grade Group 3 patients. I do not offer it to Gleason 6 patients. I know that there are many who consider that as a treatment strategy. And some of the early trials that were performed were done in that context, meaning that when we look at photodynamic therapy, the comparative group was active surveillance and the goal was to prevent radical prostatectomy. And while we reduced that by about 30%, ultimately when it reached the ODAC committee at the FDA, it failed to pass. And I think that when the trial was designed, what we learned about low-risk prostate cancer was very, very different.

And as a result, I would say, "That data kind of timed out." So it's a moving target to find these outcomes. The outcomes are really long-term, 10, 15, 20 years. And even in the existing studies that we have done, we have not been able to show major treatment benefits unless it's really high-risk prostate cancer. So in disease risk, can we treat higher-risk patients? Currently, I'm a little bit more conservative. If I believe that there's extracapsular disease that is not somebody that I would offer focal treatment to. But if there was no other treatment that was available to that person, I would choose a treatment in which I have confidence that I can treat outside the gland such as cryotherapy, for example.

Disease volume. So depending on the energy modality that you use, it depends on what your confidence is to be able to achieve a confluent ablation. So treatments like high-intensity focused ultrasound versus IRE versus cryotherapy, those factors based on the amount of disease and where it is, will be taken into consideration.

Again, when I first started, it was that ideal patient that I mentioned to you, but we prescribe to the index lesion theory in the active surveillance setting because we believe that what we have found is the highest-grade disease that's there. And if there's something else there, at some point we hope that it will declare itself, and we will address it at that time point. So then why is a strategy for focal therapy where we identify clinically significant disease, we destroy it and we don't have clinically significant disease elsewhere that we would otherwise observe? Why is that not an appropriate treatment strategy? I think that we are, our pattern of thinking is going to change with respect to that.

Now what we don't know is how much volume of Gleason Grade Group 1 is too much or too little. I think the real concern is the concern for occult pattern 4 in high Gleason 6 prostate cancer. Jury's still out on that. In terms of MRI-invisible disease, this is also a little bit controversial. Can you treat MRI-invisible disease? If you can't see it, how do you know where it is exactly? How do you know where the cancer starts and where the cancer stops? Ultimately, the strategy that you will apply will be an extremely large margin, which can mitigate the benefits of focal treatments in some cases. But I do think that, and we do also understand that there is a phenotype for image-visible disease. Image-visible disease tends to be, for lack of a better term, more clinically significant.

So those are kind of like the disease-related factors that I'm thinking that's running through my head when I meet that patient. But there is the question of can we treat? Then there's the question of do we need to treat? And then the final question is, should we treat? Now those last two are relatively similar, but they are slightly different. And so do we need to treat a patient, or are we going to give them a benefit if our focus is really on functional outcomes. If they are impotent already or they have poor sexual function at baseline, are you really achieving anything if you think you are going to compromise oncological outcomes? Now of course, there are many other reasons in which it can be appealing. The risk of incontinence is very low, outpatient procedure, minimal convalescence time, et cetera. But these are additional factors to consider.

Comorbid conditions of course, shared decision-making. So this is a big one to me. When we consider, we just talked about stones. Let's talk about stones. We accept that a patient has a lower treatment success rate or stone-free rate with ESWL, but we offer it to patients because if a patient tells us, "Hey, doc, I understand that I can either undergo a ureteroscopy or I can undergo a shockwave lithotripsy. You told me that my stone-free rates are going to be less, but I'm not going to require a stent. I'm going to have less side effects. I'm able to get back to work earlier. I'll accept that lower stone-free rate." We're completely fine with that.

But if we try to have a conversation with a patient for shared decision-making in terms of what would they be willing to trade off potentially from a cancer control outcome, maybe it's a financial toxicity, maybe it's something else. For them to be able to achieve the outcomes that they're looking for, of course there have to be guardrails to that. But I think that again, it's an acceptable treatment strategy. That went back, sorry, that... In terms of BPH, we're starting to see a lot of bleed. We see the ablative cancer technology starting to enter the BPH space. We start to see BPH technology starting to enter the cancer space. I'm not saying one is either right or wrong, but I do think it's an interesting concept for us to start to think about is do we uncouple or do we couple these treatments?

What we don't want to do is offer a cancer treatment in somebody who has BPH just for the sake of having cancer. I personally think that if you're really going to achieve a two-for-one, then you need to have clinically... Independently those decisions need to be made and need to be appropriate, and they need to work together in the same patient.

And then of course, the logistics for many men not having to go to radiation, even SBRT may be only five visits, but they need a simulation study. They need an additional procedure for many times, a fiducial markers or spacers, and that's at the very best. That can be seven to eight additional visits.

Now, a single outpatient procedure is very appealing and maybe it starts to compete with the brachytherapy category in which that was really where patients would identify better logistics that would maybe reconcile with their schedules or with their lifestyles or other obligations that they have caring for family members, et cetera.

And then finally, the cost. And as we know, that this is a challenge that I have pushed against for years. Recently presented to CareFirst about HIFU, and hopefully we'll get to a favorable treatment decision there. But really as we accumulate data, these things will, I do believe that we'll start to achieve coverage and reimbursement for these procedures as the data comes out. And we are starting to pay attention to real-world data.

So how do I evaluate these patients before? So I want to make sure they have really all of these things. With a fusion biopsy for me, it's really important for me to be able to track the individual cores. Now understanding that that is, it is not an easy task to do. And it is honestly, sometimes it's not even fair to ask most people to be able to do that. Now, because I live and breathe this space, I have the ability, it's very important for me to be able to, but it's very common that you'll find a lesion where you think it may overlap with the target and it actually doesn't. And you may leave disease treated or untreated based on those findings if you don't localize it exactly.

It's oftentimes the cores that we take are not where we really think they are. I tell you that because when I was a fellow at the NIH, the attendings used to do the targeted biopsies, and the fellows used to do the targeted samples, and then we'd have the residents who rotated through, they would do the systematic biopsies, but we would track all the 12 cores.

And you see that on one side, all the cores are in one sextant and it's base mid-apex, medial and lateral. They're all in the right mid medial sextant. And it was pretty consistent to be the case. So when you don't track the cores, you don't really know exactly where you are even based on the description that's given.

So which modality do you use? So honestly, I really think that you can't have, there is not ever going to be a single modality that can treat everything. There are going to be physical limitations. There are going to be physiological limitations. So for example, there is a fixed focal length for HIFU. If you have a 150-gram prostate and it is six centimeters away from your transducer, HIFU is not going to be the right treatment for that person. Similarly, if you have cancer, you can't really do a proper hemiablation with irreversible electroporation based on needle placement. And so you have to pick the right treatment for it. Where I do think that there is an opportunity is, and maybe the secret's not out yet, but it's radiotherapy. Dosimetry is a science. There are people whose entire careers are dedicated to dosing the gland and getting millimetric accuracy of precise dosing.

And really it's an opportunity for radiation oncologists, in my opinion, to be able to offer a very less invasive treatment. But again, I think that there are two concerns there. One is the lack of long-term data, and second is that there is certainly in some cases a belief that the toxicity between whole gland and focal radiotherapy may not be so significantly different that you may not be really offering benefit there.

Some newer technologies that are currently under trial is water vapor ablation, many of you know Rezum, it's essentially the same technology. There are two things that are added to that, image guidance and the ability to direct the needle to anywhere you want in the gland. That does not have physical limitations that other treatments may have like calcifications and those kinds of things. However, we don't know what the data is. So I'm not saying, "That this is the next best treatment." I'm saying, "That it has promise because it does not have physical limitations," but we will see what the data shows us.

So if we look at some of the outcomes, I'm not going to show you a meta-analysis and take too deep of a dive because I want to give a bit more of a broad overview, but I want to highlight some of the studies that I think that are important. Now, what you'll see here consistently, you'll see long years of experience with the treatment, but very short follow-up of the outcomes. And that seems to be a trend in this space. So that is a legitimate and valid criticism that we don't have long-term data and we don't have comparative data, and those are the things that we're going to work towards.

There are a number of clinical trials that are already underway. The FARP trial has already accrued 200 patients. That's randomized to radical prostatectomy versus focal ablation in Norway. There's the POT trial in the UK—the architect was Freddie Hamdy who also ran the ProtecT trial, but he has passed that on.

And also the CHRONOS trial by Hashim Ahmed at Imperial College in London, randomizing patients to focal treatment versus radiation or surgery. But if we look at that, this is one of the larger, longer-term series that are well-annotated in terms of the data for focal cryotherapy. But cryotherapy has been around for a really, really long time. We do have data from the COLD registry that's kind of voluntarily submitted, but this is prospective data accrual. So this is probably the best data that we have for cryotherapy or some of it.

So what I want to highlight here is that the vast majority of this patient population treated is clinically significant prostate cancer with almost a third being high-risk prostate cancer. Failure-free survival is different in the focal setting compared to radical prostatectomy. It's hard to compare those same outcomes because one, it's going to be very difficult to achieve those, and there's no such thing as biochemical recurrence in a focal patient.

We don't really know the context of how we should evaluate PSA. It's going to be based on two things, the volume of tissue that you ablate and the relative PSA made by the cancer versus the normal prostate gland that's left untreated. And we don't really know the answer to that, or we don't have an idea of that until after we ablate and we see the treatment response.

So failure-free survival in the studies that I'm going to show you is really going to be the need for a third ablative treatment, metastatic disease, systemic therapy, or prostate cancer-specific mortality, or transition to radical therapy. Those are going to be your definitions for failure in these studies that I show you.

So failure-free survival at 36 months was 90.5%. I would, let's see here, maybe a raise of hands from the group. Here we had 122 patients evaluable. In your radical prostatectomy practice how many of you had a 0% leakage rate, pad-free leakage rate? Great. And how many of you had 84% had erections sufficient for penetration after the prostatectomy you performed across your population? Zero.

So this is five centers showing different strategies of treatment, different patient types and intermediate and high-risk prostate cancer. Remember what you saw in this room, not a single hand was raised. Really what I'm trying to show here is the one thing that is absolutely uncontested in focal therapy is that the functional outcomes are not even close, okay. So I won't talk too much more about that.

So again, 15-year experience from the UK, but we start to see that the follow-up is only 32 months. But this is some of the best data that we have, so I'm going to share it. A very large series of longitudinal follow-up of patients from the HEAT registry from the UK. Again, vast majority of these patients have clinically significant prostate cancer, majority intermediate-risk disease, but also high-risk disease. I could take off everything from this study, just show you those curves and you tell me that looks like a great radical prostatectomy data set, stratified by disease risk and it's similar to what we see. But what do those numbers actually look like? So if we look at failure-free survival, by the definition that I mentioned to you, at five years for intermediate and high-risk, that would be 83% versus 80% for high-risk. At seven years, 68 versus 65.

How about what is the likelihood that if you treat them initially with focal treatment, that they don't require radiation and they don't require surgery in the future? So in the intermediate-risk population at five years, that is 84% for both intermediate and high-risk and about 75% of patients, 73%, their prostate remained intact after their initial treatment. To me, that's actually a very reasonable rate. Now that is going to allow some people to filter through who may still have low-volume, clinically significant disease that we decide not to treat. And so that's important to note that. It's not the purest comparison that we can make because those outcomes are going to be different.

Now in the absence of randomized control data, what can we do to show us whether or not this strategy is appropriate, significantly different from the radical treatments that we offer? We can do propensity score matching.

So here we have again a study from the UK. They have really led focal treatment. And the reason for that is that the NHS covers these focal treatments as long as these patients are placed and followed in a prospective registry. Just so you understand why all this data, why can they do all this stuff? It's because the government pays for it as long as you follow the outcomes. So in this study, almost 500 patients included both HIFU and cryo to eliminate any patient selection bias where many times there are practitioners who prefer to use cryo anteriorly and HIFU posteriorly for some of the reasons that I mentioned previously. Here you can see the definition of failure-free survival, and it was that the populations were matched for the usual suspects that modified disease risk in prostate cancer.

Now, the vast majority of this patient population was HIFU, but there was about 16% of patients who are cryo. And again, the vast majority of these patients, more than two-thirds represented clinically significant prostate cancer. So orange is going to be your focal ablative treatment, green is going to be prostatectomy. And here I want to show you at those different time points that as we go out to five years, it's 86% versus 82%, 83% versus 79% as we go out even further.

Now, the point here is not to tell you that focal treatment is better than radical therapy. You can see those confidence intervals overlapped pretty consistently. But what it does tell us is that our thinking that this may be a terrible treatment strategy and we are going to have terrible treatment outcomes for our patients is not going to be correct. So it shows promise. What do we typically see after these cases?

What I'll really focus on is the fistula rate and the series that I presented to you, the 1,379 patients, that's a primary treatment population. The fistula rate was 0.2%. The risk of a rectal injury during a robotic prostatectomy is about 0.3 to 0.4%. It is difficult to create a fistula in a primary setting if you're using all the normal safety mechanisms that you need to for a focal treatment, but it does happen.

Something that I do see commonly is epididymo-orchitis and also reduction in ejaculatory volume is something that a lot of patients mention. I think that sometimes I try my best to mention it every single time, but sometimes when you're bogged down in the cancer discussion, it doesn't always come up because you don't think it's going to be as relevant to a 75-year-old as it actually is, surprisingly.

And to kind of wrap it up in the next couple of slides, how do I follow these patients afterwards? Really everything is guided by expert consensus. We don't know the perfect strategy. This is the strategy that I use. And really there's been a loosely non-prescriptive of methods that you can use that was published in European Urology at the Kyoto Consensus, which was where this was done. There's a Delphi Consensus in Kyoto, Japan. So finally, I'll end in salvage treatment. So what do we see in salvage treatments?

So here in the guidelines, it's really after radiation therapy and it actually says, "You can use cryo or HIFU." This is where I think that it actually shines. And the reason is that the gland is already treated. So any area where prostate cancer is not has already been treated with radiation. It should also have been screened with an MRI that doesn't show you something suspicious in that area. It should also be screened by a PSMA PET, which does not show you disease in that area, and you should have biopsied that area, which shows you there's no disease in that area.

So my confidence in a focal strategy is significantly higher in the salvage space than it would be in the primary setting. So I will always restage with a PSMA PET and an MRI. You do oftentimes find discordant information. In this type of patient, you don't want to get it wrong, and you don't want to have to come back. So I throw the kitchen sink at them.

Understanding what their prior treatment is can modify what treatment strategies you use. For example, external beam versus low dose rate, brachy versus HDR. And really you are targeting now the nadir PSA. That's really the best you can achieve typically, especially if you're going to leave areas of the gland behind, so that becomes my new target. I don't routinely biopsy these men anymore if I can achieve the nadir and my imaging is negative because they've essentially received a whole gland treatment.

So in summary, patient selection is going to be absolutely critical, and that's what's going to make sure that there's longevity to this treatment strategy. Functional preservation is uncontested, and we have acceptable intermediate-term outcomes, at least not significantly worse than we can tell from radical therapies and energy selection. There's not going to be a single dominant energy source. It's really going to be identifying the right energy source for the right patient. Thank you.