Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie: Welcome to UAB MedCast. I'm Melanie Cole. And joining me in this panel today is Dr. Jeffrey Nix, he's an Associate Professor and a urologist; and Dr. Soroush Rais-Bahrami, he's a professor and a urologist, and they are both with UAB Medicine and they are here to highlight focal therapy concepts and options for prostate cancer.

Doctors, I'm so glad to have you with us. This is such an interesting topic. Dr. Nix, I'd like to start with you. It's reported that focal therapy for prostate cancer could really balance undertreatment and overtreatment of localized prostate cancer for highly selected patients. How has that field of focal therapy for localized prostate cancer evolved? Give us a little bit of the rationale for this type of therapy.

Dr. Jeffrey Nix: Well, I think you hit the nail right on the head. I mean, focal therapy for prostate cancer has been around for about 20 years in different stages of development. And really, it falls on the heels of what happened in breast cancer. You know, the Halsted mastectomy got replaced by more focal procedures like lumpectomy and radiation and different avenues based on the unique perspective of each individual patient. And so, it's an evolution of a more patient-centered approach. And it comes also on the intersection of what you mentioned. We had an overtreatment problem with prostate cancer. As we learned more about it, we realized that many of the patients that were treated were not treated with disease that needed aggressive treatments.

And so as we back down and look at the relationship between side effects and cure intent, focal therapy evolved as a natural consequence. And again, much like it did in breast cancer, as we became more understanding of the pace at which prostate cancer progresses, and it's a slow pace in most patients and then, secondly, as the effect of some of these complications or side effects of treatments became more prevalent in patient's lives, and we learned that impact. So, I think focal therapy came out of all of those things.

Melanie: Dr. Rais-Bahrami, are you going to jump in and say something after Dr. Nix?

Dr. Soroush Rais-Bahrami: Yeah, sure. And I totally agree with Jeff Nix how this has evolved in a space where overtreatment became an issue that we recognized. We obviously don't want to undertreat any individual with a new localized prostate cancer diagnosis. And this also intersects with the perfect timing as some of the ablative technologies came to fruition. And as technology advanced, we found multiple different ways to administer either heat or temperature, freezing technologies or electroporative technology directed at tissue with very good ablation, very limited side effects, and really image guidance to guide this therapy.

And one of the things both Jeff and I have worked on as well as many colleagues and collaborators throughout UAB and other institutions is the concept of seeing prostate cancer better with our advanced imaging technologies, co-localizing between those imaging technologies and our tissue sampling through diagnostic biopsies. And then when we have that detailed information and data about each person's prostate cancer diagnosis, then we can really derive the best focal therapy plans when it's appropriate.

Melanie: Thank you both. Now, Dr. Rais-Bahrami, I am going to veer off for just a second and we're going to get very technical and you're going to explain to other providers about the techniques and considerations and certainly patient selection. But I would like to ask you if focal therapy was developed as an alternative way between that active surveillance given the inherent risk of reclassification at subsequent repeat biopsies, we're talking about over versus undertreatment, there's always this cancer-related anxiety. And considering the urogenital side effects and complications of some of these treatments, can you speak just briefly about how the anxiety for the patient and their loved ones is mitigated when we decide on focal therapy because it is such a specific patient population?

Dr. Soroush Rais-Bahrami: Absolutely. And that is part and parcel of when focal therapy is appropriate. It is all the patient factors. One of which is the patient's understanding of their new diagnosis of localized prostate cancer in addition to all the different nuances that I was alluding to with imaging, co-localization, the aggressiveness of the cancer, which is defined based on the grade and the stage and all the technicalities that may make one person safe or better suited for potential focal therapy versus active surveillance or whole-gland therapies. But what you mentioned really is the key factor that we have to also consider, and that's the patient's desires, the patient's expectations, the patient's anxiety or apprehension, let's say, with any one treatment course over another, especially when they're offered different options, many of which may be safe in a particular man's situation.

One of the things I know Jeff and I have both seen in our practices is when a man has rendered a new diagnosis of prostate cancer. It really is the risk stratification. But the key of our job is to help navigate through the diagnosis, define the diagnosis for each individual man and also try to understand the man who's receiving that diagnosis, their loved ones, their priorities and, like you said, their anxiety or apprehension with what the next steps may be. And really mitigating the anxiety that comes with a new cancer diagnosis by doing the best job in educating different treatment options. And the role of focal therapy really I see as a step towards treating a dominant or index lesion, some cancer that we are aware of in their prostate gland, while minimizing the side effect profile, while still leaving doors open if future treatments are necessary at any point.

Dr. Jeffrey Nix: And I think to add or to piggyback, I think that last point you made, Soroush, is such a perfect point to sort of wrap all that up. What I would say is if men don't need treatment, so there's a moral hazard to having more stuff we could do, that we're going to lead people into this treatment that they don't need just because the side effect profile is better. So, we do have a job in terms of men who are true active surveillance candidates that, as much as possible, we leave those patients alone because they truly don't benefit from treatment.

And then, as we're looking to better define with all the tools we have who benefits from treatment or not, it would be great, which is why focal therapy has evolved, if we didn't just have one big hammer to treat the entire prostate every time. And so, it is so beneficial to patients who fit into this category to be able to say, "Hey, we have an option that minimizes the risks of some of these side effects that you've read about, that your friend had, or your neighbor had, or the thing that you've said, 'I'm not even going to go to the doctor because I don't want to know what my diagnosis is because I wouldn't tolerate that urine control issue or whatever it might be, or sexual dysfunction.'"

And so, we have an option where we can say, "Hey, look, we have treatment approaches in the right patients where we can minimize those quality of life side effects," and the thing that you sort of hit on at the end that I think is so important, "And we don't burn any bridges in terms of radical or full total prostate treatments in the future." I think those are two important parts when you're thinking as a physician of focal options. So if I do a focal therapy, whatever it is, and now the total therapy, if I ever had to go down that road, has become much more difficult and more side effects and more complications, then taking the field in an area that I don't need to. I need to be able to have a treatment that is less than in terms of side effects, but doesn't burn a bridge for me or for that patient in the future if we need to go down a different path.

Melanie: Well, I think, as we've pointed out, one of the mainstays is going to be patient selection. And Dr. Nix, what is the criteria to have focal therapy? Speak to providers that are referring their patients that are discussing this with them and discuss for us some of the emergent concepts, inpatient selection. What's different now and how is it determined for the many treatment modalities in your toolbox?

Dr. Jeffrey Nix: Yeah, that's a great question. And I think if we're talking about providers in the field of urology, even in that subset, are going to be confused. Because you read 20 papers on focal therapy, you'll see 20 different selection criteria. And so, it can get very complicated very quickly in terms of who are the best patients.

I think if we start at a 30,000-foot view, there's a couple of concepts to sort of review quickly. And one is that most prostate cancers are multifocal, is the prevailing consensus in our field. And there have been different autopsy studies and different whole-mount studies that have shown that out over the years.

So if the majority of prostate cancers aren't in a solitary focus, why are you guys talking about focal therapy? Well, Soroush already mentioned the concept of index lesion, and so that's where the concept then becomes appropriate. So, we believe there may be multiple foci of cancer in a patient's prostate, in the majority of patients, not all of them, but in the majority. But we still believe that, for most patients, the index lesion is that lesion that's dangerous. And by dangerous, I mean could spread and could go to other parts of the body and ultimately lead to a patient's death. And there are a myriad of studies that have borne that out in terms of the largest lesion with the highest Gleason grade is more likely to have extracapsular extension, is more likely to be the dominant foci of disease on final path. So, there are lots of pieces of evidence that have led us as a field to this conclusion.

And in those patients with an index lesion and other spots in the prostate, those other smaller cancers are often not clinically significant. And these satellite cancers, as we might refer to them as, typically we don't feel like are relevant clinically to the patient. Okay, so now if we've got a concept that maybe there's multifocality in prostate cancer, but we believe an index lesion is targetable and is clinically the important lesion. So, those two things are important. I've tried to establish in two seconds that it's the clinically applicable lesion.

Now, can we target it? And that's where Soroush has mentioned that these advanced imaging tools that we didn't have 20 years ago that we now have are what has really advanced this field. So, multiparametric MRI, we're going to continue to get advanced imaging in terms of PET imaging and different sorts of tracers. So as we're better able to aim our technology, then we can do a better job of treating these patients. And then, the third arm of that is, "Okay, we think it's clinically important. We can see it. And then now, can we aim a tool at it consistently with high fidelity that's reproducible?" And I think that's where the tech part of this has really helped. We only had cryotherapy and laser ablation was really investigational. And there's all these things though, over the last 10 years, that maybe Soroush wants to dive into a little bit that have allowed us to apply these technologies in a way that's reproducible.

Dr. Soroush Rais-Bahrami: Absolutely. I totally agree. And it's the multitude of different technologies that have been developed, that have been vetted, that have been tried and tested in this patient population and for treatment of this disease process that really have allowed a spectrum of different investigations to prove the values of treating localized prostate cancer in a focal or subtotal gland manner.

And Jeff alluded to cryotherapy has been the tried and tested, been around for several decades at this point for treatment of prostate cancer, originally from a whole-gland therapy, but now more localized regional therapy of a portion of the prostate gland. But following that same pattern and thought process, multiple different energy sources have been used, mostly thermal, so just taking off the concepts of cryoablation with extremely cold temperatures. Now, multiple different technologies can give increased heating and burning temperatures in a very controlled image-guided way. And these could be that focal laser ablation that Jeff mentioned; more recently, high-intensity focused ultrasound or high-intensity directed ultrasound. Additionally, multiple different radiofrequency or microwave ablative probes can be used, and these are to heat.

And then in a non-thermal way, electroporative energy can be used. So, electrical impulses to perforate the cellular membranes to allow cancer cells to die. And these are all different, again, image-guided focal or regional gland therapies that could be used to kill the prostate cancer regions. With the concept that if multifocality is present in areas of the prostate that have not been treated, we will continue to follow patients diligently to make sure that the area that was focally ablated was effective in killing prostate cancer and that prostate cancer of an impactful grade or significance never in the future appears in untreated parts. Or if it does, then we have an option of then re-ablating or addressing the entire gland through the conventional whole-gland therapies that we've known for decades and generations of care.

Dr. Jeffrey Nix: The only thing I would add to that is just to focus back on the one point, like Soroush is saying, we've got like seven or eight or nine or 10 different things, how would a patient know, "What am I supposed to do? How am I supposed to choose?" And I think there's a couple of key components there to try to limit that confusion for patients. And that is the main focus, is that can we deliver the tool, the energy, in the right space that we need to deliver it? And so, there are some technical limitations to some of these energies. So if a patient has a really big prostate and a tumor in a certain location, then I can't do HIFU. So, some of that becomes a selection based on the intrinsic properties of the tool.

But the main part that they should focus on when they're trying to decipher this world is does the provider have a lot of experience using the tool, whatever the tool is, and what are their results with the tool? And then, how are they making sure that they're directing that energy to the right location? And I think people can get a little hyperfocused on, "Ooh, I want a laser" or "I want HIFU." And what I try to tell patients, the exact energy we use is really less relevant than all of the other parts that we've kind of highlighted here, patient selection and how are we making sure that we're imaging them appropriately to direct the energy and how are we making sure we won? Did we do a good job? How are we following them afterwards? All of those things are more important in the grand scheme.

Melanie: Dr. Nix, you make a great point also when you mentioned about the physician themselves. And Dr. Rais-Bahrami, before we wrap up, and I'm going to give you each a chance for a final thought, as we're talking about what's essential for successful focal therapy, and that's based on the availability of the focal treatment modality at the treatment center, and as Dr. Nix said, the physician, patient selection, shared decision-making, tell other providers what's really exciting in the field as far as imaging. Because you've both mentioned it a few times, but there are some new exciting imaging modalities out there these days, and so I'd like you to speak about what you're doing at UAB and what you find most exciting.

Dr. Soroush Rais-Bahrami: Absolutely. So, we just mention that really a robust program that we've developed here over the past decade has been with the advancements of MRI and prostate imaging, using MRI to then guide more targeted biopsies, higher yield biopsies when significant cancer is present in the prostate gland. At times, these are patients that have had standard of care, systematic distribution biopsies that did not find cancer. But then, MRI can hone in on areas that are concerning, suspicious, and potentially had been cancer-focused in the prostate gland that was hidden or occult on standard biopsies. So, that's really shifted the needle in terms of us detecting cancers, co-localizing them when imaging is really finding them. And that has given us the roadmap to plan which patients may be suitable for focal therapies.

Additionally, as Jeff had mentioned, some of the novel PET tracers or PET imaging agents are really targeted more specifically for prostate cancer. They're not simply looking at sugar metabolism, but looking at receptors or amino acid transporters, things that are expressed on prostate cancer cells significantly more than other cells in the human body. So when we can really find prostate cancer with some of these modalities of imaging, whether within the prostate gland or immediately surrounding the prostate gland, it helps us really select patients that may be best suited for treatment, what type of treatment. And if within the prostate gland, they choose focal therapy as a potential safe option, where in the prostate gland would the energy be best implemented for focal therapy?

Dr. Jeffrey Nix: Yeah. And I think there's so much exciting about this part of the field. It feels like we've been waiting to be able to emerge into the focal field much behind our breast cancer colleagues for decades and decades. And it just needed the culmination or the crossroads of the imaging advancements, the technological advancements in terms of the tools and just the knowledge base of prostate cancer in terms of who can get these kinds of therapies and who are appropriate.

But I think that's where, even the unique location of the prostate, where you can use natural orifice treatment options. So even things like TULSA, so the laser ablation for-- I mean, most patients don't have periurethral tumors, tumors very close to the urethra. But when they do, treating them with thermal-based therapies can be very dangerous and very tricky. And so, irreversible electroporation, man, what a very, very incredibly innovative technology. But actually, the technology is pretty old, but the ability to apply that in a way that we can destroy tissue without thermal damage, that's incredible. And so, some of the ability to do these things in the prostate are just going to continue to evolve as we get more and more data.

And I think the other thing that I think is important for the providers to know is, if you're doing focal therapy and you're doing it outside the confines of a trial, we need to be collecting data on these patients. We need to be determining effectiveness because patient selection is such a huge part of this, that it's hard to put patient A and patient B and identify them exactly side by side. So, we really have to be paying very close attention. Because one of the things that are just driving us here is we're so good at curing locally confined prostate cancer, and so we're trying to do everything we can to minimize side effects now that we can't lose side of the fact that we're good at curing it. We don't want to get to technologies and approaches that make us worse at curing these patients. And so, we have to be very cautious about that. So, I think there's so much to be excited about in the field in terms of how we apply these technologies to patients.

Melanie: There is absolutely so much to be excited about. And you two gentlemen really, really hit the nail on the head for other providers. It is about patient selection. It is about shared decision-making. And the exciting advancements that you're making at UAB are really changing the face of prostate cancer. So, thank you both for joining us. This was absolutely fascinating. You're both great guests as always, and I hope you'll join us again.

And a physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST or by visiting our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.