Melanie Cole, MS (Host): Welcome to UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole and today we're highlighting focal therapy for prostate cancer with my guest, Dr. Tarik Benidir. He's a Urologic Oncologist in the Department of Urology and an Assistant Professor at the University of Florida College of Medicine.

Dr. Benidir, thank you so much for joining us. I'd like you to start by telling us a little bit about the trends in prostate cancer, what you've been seeing, the prevalence, just kind of give us a quick overview.

Tarik Benidir, MD: Great. So thanks for having me. What are the trends in prostate cancer development? Well, to really understand the trends in prostate cancer, it's kind of nice to also take a step back and say what were big advances 10 years ago? And one of the biggest advances when I was a resident was the implementation and the addition of MRI imaging to the workup of patients with an elevated PSA.

And what the MRI of the prostate did is that it not only helped improve the diagnostic accuracy of prostate cancer, but it also introduced the idea of therapy, a targeted therapy format. And so, when you think about it, if you have a patient who you do a digital rectal exam on, that gives you a very crude understanding of is the prostate normal or abnormal.

 And your finger, I mean, no matter how good you think you are at a digital rectal exam, you can't feel 360 degrees around the prostate and all the zones of the prostate. And so the MRI provided so much more information in terms of the size of the prostate and lesion location. And so that was very helpful in improving the targeting at the time of biopsy in terms of, can we improve our detection of A. Prostate cancer, B. more importantly, prostate cancer that poses a risk to someone's life, and we coin that clinically significant prostate cancer.

But also, if we're targeting an area of concern, hopefully we'll be able to reduce clinically insignificant prostate cancer. But what it also did is that by getting MRIs, we started to realize that there's these very visible lesions in the prostate that have an end to them and a start to them. And could we potentially do something called targeted therapy or focal therapy, which is therapy that's focused, treating the area of concern.

And so that's been the trend in prostate cancer over the last five to six years is can we do equal cancer control while minimizing the burden associated with radical therapy.

Host: That's so interesting. So Dr. Benidir, as we know that focal therapy could balance undertreatment and overtreatment of localized prostate cancer for highly selected patients, and we're going to talk about patient selection; but how do you see the field of focal therapy evolving? Give us a bit of some of that rationale and what has happened. How has this evolved? What's going on in the field?

Tarik Benidir, MD: First we have to kind of look at our colleagues in the breast cancer world. I mean, it took 75 years ago, someone crazy enough to say, hey, look, not every female needs a mastectomy. Maybe we can do lumpectomies in women. And the original response was met with some scrutiny because we worried that we would be leaving cancer behind, under treating women, and leading to more deaths from breast cancer.

But with this way of thinking, we learned that some women can undergo a successful lumpectomy and some women need a mastectomy. And so why is prostate cancer so delayed in its adoption of a similar pathway of thinking? And so, in the last 50 years, we've been growing so much in the breast cancer world, but we've been not questioning the same question in prostate cancer.

And, as of 10 years ago, prostate cancer was one of the few organs where, no matter where the cancer was located, the suggested treatment was at the whole prostate. And so, with that being said, the field of focal therapy has grown, and where has it grown? Well, first and foremost, we're starting to treat more clinically significant prostate cancer patients and understanding who is the sweet spot for focal therapy.

If you look at the older trials, they would include a vast proportion of patients that had low risk prostate cancer. But we know that low risk prostate cancer poses a very low risk to someone's life. And so is focal therapy even necessary in that cohort of patients? And I would argue no. Where now if you look at more recent studies, cohorts, consensus statements, they really include patients with intermediate risk and high risk prostate cancer, and so it's reflecting a more contemporary patient population.

And the outcomes of those, we now have, in certain very well conducted studies, we have 7 year and 10 year, cancer outcomes. And so we're approaching medium term oncologic outcomes for focal therapy. And so with these medium term oncologic outcome data, we're better understanding the sweet spot into whom are ideal candidates for focal therapy.

And I think that's one of the directions the field is heading is being more selective into the appropriate candidate. I think also understanding our limitations, core candidates that fail, and who are candidates that have recurrences within a year. And so it's really, the more we do, the more we learn.

Melanie Cole, MS (Host): Well, then why don't you expand on that, Dr. Benidir. Patient selection being one of the mainstays of this type of therapy, these therapies, what's the criteria to have focal therapy and how are you optimizing patient selection to make sure and to help because the side effects, erectile dysfunction, incontinence are such a concern for men going through these therapies. So speak about patient selection.

Tarik Benidir, MD: If you ask patients, 100 percent of patients think they're candidates. And they come in, and obviously if you ask most men, would you rather have a therapy that reduces incontinence and erectile dysfunction, they would say, absolutely. How would any sane man not choose that option?

And it's important for us as physicians and as urologists to not be swayed by the wish of the patient and to make a decision that's in the best interest of the patient because if there is a recurrence, guess who has to see them in a year? It's you, the urologist. And now you're dealing with a recurrence in a treated patient and the treatments for those become more limited, have higher side effects.

And if you're going to do a radical prostatectomy or radiation therapy in a prostate that's already been treated, you just have a harder job. And so you really have to be sure you're, really selecting the right patient. And with that being said, I'll dovetail to who I think is an appropriate patient for this.

So first and foremost, I think you need to have a patient that has a significant life expectancy. Because if the life expectancy is less than five years or five to ten years, you've got to ask yourself, well, am I doing the appropriate thing by treating this patient? Or is active surveillance the appropriate strategy?

The second thing is, is a lesion visible or non visible? Because if you think about it, if you have an MRI invisible cancer, where do you know when to start and stop your treatment? And so it becomes much more limited to what you can provide for the patient. So first and foremost, you need a patient who has a reasonable life expectancy and has had imaging that reflects an MRI visible area of concern.

You then have to translate that area of concern to a biopsy. Just because they have a lesion on MRI doesn't mean that their biopsies can only have co registration with a biopsy that is only positive in a lesion of interest. Oftentimes, we get guys who have an MRI that has a lesion, but their biopsy sometimes say that lesion is indolent or grade group 1 cancer.

Do you treat that? Sometimes you see a patient who has an MRI visible lesion, but that area is benign. And on the other side, there's clinically significant prostate cancer. How do you treat that one? And so just because there's a lesion on MRI does not mean they're a focal therapy candidate. It has to co-register with a clinically significant prostate cancer diagnosis at biopsy.

And then once you have that, you have the MRI, you have the co-registration with your biopsy; you then have to ask yourself, okay, what type of cancer is this? What is the stage of the cancer? And the sweet spot in most of the focal therapy consensus statements is intermediate risk prostate cancer, whether favorable or unfavorable is the ideal candidate.

So that means a patient with generally speaking, a Gleason Score 7 prostate cancer, grade group two, and on MRI, there's no concern of cancer spreading out of the prostate or starting to poke out of the prostate and to make sure that the PSA isn't rising above 20 nanograms per ml. So if you have those three things, you've at least ticked the box into hopefully achieving a better candidate for focal therapy success.

And when you look at that cohort, it's generally speaking only about one to two out of six men who come in seeking focal therapy.

Host: What's exciting in focal therapy, Dr. Benidir? What are some of the modalities that are being investigated, being used right now? What's exciting?

Tarik Benidir, MD: Focal therapy is really an umbrella term for several different types of modalities. And I tell patients focal therapy is exactly what it sounds like. It's therapy that's focused. And what are those modalities? Well, the older ones are cryotherapy and HIFU. And cryotherapy was freezing or creating ice balls at an area that was concerning. And studies have shown that it has very acceptable oncologic outcome in well selected men. HIFU does the opposite of that. It uses energy and targets ultrasound waves, kind of like a magnifying glass on a leaf. With the magnifying glass on a leaf theory, you have harmless light that then converts on a point on a leaf and becomes very hot and burns the leaf.

And so in similar fashion, you have these ultrasound waves that are harmless, but when you converge them on a, a single point, It creates a temperature that's sufficiently hot to kill tumor cells, and then you point that at an area of concern, basically the MRI visible lesion, and you can treat that area.

And those are the two forms of focal therapy that have been around for quite some time. But what are the newer ones? Well, there's irreversible electroporation. Also known as NanoKnife, which is an exciting one. And what that does, I call it acupuncture of the prostate. It uses a similar approach to cryotherapy, which is an interstitial or a needle approach, and you place your needles around the lesion of concern and you shoot electricity between the needles.

And so you end up creating an action potential that denatures the cells in between the needles, but it doesn't harm or create any current outside the needles. And so the nerves of erections, the sphincter for continence are untouched. And the benefit of that one, I think, is that you can get quite close to the urethra because it's a non-heat conducting form of therapy, and that's really exciting because most ablative therapies create heat or create a temperature that's sufficient to damage surrounding structures such as the urethra, whereas this one is a non-heat conducting form of therapy, and so you can really bring it close and even cross the urethra. So I really think that's one of the more exciting ones, and then if we have to just keep going down the list, when I was at Cleveland Clinic, there was some innovative work doing partial prostatectomies, which is surgically, removing part of the prostate.

There's laser ablation, and then there's also the thought process of can we do things not just through the perineum, such as cryo or irreversible electroporation, not just through the rectum, such as HIFU, but can we do things through the urethra, such as transurethral. It's called TULSA. It stands for transurethral ultrasound ablation.

And what it does is the actual ablation technology goes through the urethra and then aims away from the urethra at the targeted lesion. So in the last three or four years, we've seen a higher adoption of not just the approach, so transrectal, interstitial, or transurethral, and not just the format of ablation, heat conducting or non-heat conducting, but also that's enabled a wider conglomeration of patients that can be candidates for focal therapy, which is really exciting.

Host: So exciting. What an interesting time in your field, Dr. Benidir, and if focal therapy was developed as an alternative between active surveillance and more invasive treatments;

what about the anxiety, especially considering the urogenital side effects? How is that anxiety mitigated when you're talking to your patients and you're speaking to other providers on counseling their patients about the complications and the side effects from some of the treatment modalities that we've known over the years?

Now, with these focal therapies and the risk of recurrence, how is that anxiety mitigated? Are we looking at more imaging, more regular visits? Tell us about that.

Tarik Benidir, MD: Patient counseling is very important and you bring up a great point about the anxiety part because there's some studies that have come out in the Journal of Urology in 2022 showing that active surveillance causes anxiety, focal therapy causes anxiety, surgery, radiation, All those treatment options do cause anxiety.

And how do we mitigate those things? Well, first and foremost, I think painting realistic expectations. I tell patients as soon as they come to my clinic who are seeking focal therapy and are potential candidates, I tell them this is the advantage of focal therapy. And then I talk about it, and then I say this is the disadvantage of focal therapy, and I pretty much say the same thing.

Because the advantage of focal therapy is also its disadvantage. And that's the paradox of this treatment, is that we are only treating part of the prostate. And so, if we have to now talk about the advantage of only treating part of the prostate, here it is. So the advantage of only treating part of the prostate is that we mitigate the side effects of treating the whole prostate.

And so erectile dysfunction is greatly reduced with focal therapy, especially if your treatment is anterior and away from the nerves of erections. Continence. Most men after surgery, such as radical prostatectomy, will have some degree of incontinence that gets better with time; 90 percent to 94 percent of men are dry at a year.

What about with focal therapy? Well, you know, every focal therapy is different, but about 88 percent of men are dribble free and 97 percent of men are pad free as a comparator with focal therapy. And so, there's a big advantage to providing continence in men with focal therapy. But, that's the advantage.

There's more advantages such as time off work, days needing a catheter is about the same, so you have to let them know that they're not going to be without a catheter in a day or two, they need a catheter for five to seven days, just like a radical prostatectomy, but time off work, the amount of times you have to go to the hospital to get treatment, which is a downside to radiation in patients who are quite busy or live far from an academic institution.

The downside is that because we're only treating part of the prostate, what is the cancer control outcomes? And because there hasn't been level one evidence comparing radical therapy to focal therapy. And that'd be a very hard clinical trial to run. There's currently one or two that are ongoing, but because we don't have that data, we can only really extract cancer and oncologic outcomes from very well conducted multi center perspective studies on certain forms of focal therapy.

And if you look at what are the cancer control outcomes at seven years, for instance, for HIFU, it's about 68 percent are free of failure or free of needing radical surgery or radical therapy at seven years. And 68 percent is not bad. You see, 7 out of 10 men who have focal therapy won't need radical therapy in seven years.

And when you compare that to surgery, it's about 10 percent to 7 percent inferior, and so then the patient has more information and says okay, I have better side effect profile, better erections, faster or less chance of incontinence, and faster return of continence if I do fall under the minority that get incontinence.

However, I do have a slightly less cancer control rate in the intermediate risk population. The other thing is, are you willing to get surveyed indefinitely because we're leaving prostate behind? And so because we're leaving prostate behind, we have to continue with PSAs. We have to continue with MRIs. At my institution, at least, we mandate a prostate biopsy at a year.

Are you willing to get another prostate biopsy? And so it's a journey. It's part of the treatment. And part of the treatment is ongoing surveillance. And so if patients absorb all that information, that the benefit of focal therapy is in a way also its disadvantage, and that treatment doesn't end there, but treatment also includes ongoing surveillance, then maybe that'll reduce their anxiety because they'll have enough information to make a decision that's best for them.

Host: That's a really good point, Dr. Benidir, and this is such an interesting topic and I'd like you to summarize for other providers, please, what you think the key takeaways from focal therapy for prostate cancer are, the exciting things in your field and what you want them to know about referral and when they're speaking to their patients.

Tarik Benidir, MD: So I think the major, major exciting take home about this is that focal therapy is here to stay. I think this needs to be appreciated by certain naysayers, certain people who are hesitant to adopt it to their clinical practice. Patients are seeking treatments that minimize the burden of whole gland therapy.

Focal therapy is here to stay. The oncologic outcomes that have come out in seven years from either cryotherapy, HIFU, and the preserved trials coming out this year shows acceptable oncologic outcomes. And so with that being said, this is a new way of treating patients. But with that being said, just because focal therapy is here to stay, it does not mean that everybody is a candidate for focal therapy.

In fact, a minority of patients are candidates for focal therapy. And who are those candidates? I want to summarize by the sweet spot is a patient with a significant life expectancy who has clinically significant low volume prostate cancer, that's MRI visible or PET scan visible and has a biopsy that reflects a targetable beginning point and end point.

And so if you put that all together, you are then narrowing down who the candidates are. Low risk prostate cancer for the most part is managed under active surveillance. High risk prostate cancer for the most part is managed with surgery or radiation plus hormone therapy. But this intermediate risk group; that is the sweet spot for focal therapy. I think also, the way I think about prostate cancer is I think about it in three silos. You have what you see on tissue at the time of biopsy, you have what you see on imaging either before or after biopsy, and then you have the genetic composition or the biologic undertow of the prostate cancer.

So for instance, if I do a biopsy of a patient. And it's Gleason 7 prostate cancer. That's a snapshot in time of that patient's cancer. But is that patient's cancer a Ferrari moving 100 miles an hour? Or is that a slow growing prostate cancer that poses no risk to their life? And when you have a snapshot in time, you may not necessarily understand the biologic undertow.

And I think an area of future need for focal therapy is identifying biomarkers which can improve the success rate of focal therapy candidates, which basically means can we identify patients with intermediate risk prostate cancer who have an extremely fast growing prostate cancer or will have a higher chance of failure if they get focal therapy, either because their cancer is multifocal in nature or has a higher risk of metastasis than what our biopsy suggests.

And so, future work is needed in understanding biomarkers to better select patients to reduce that 20 percent recurrence rate that happens within a year of focal therapy. I also think PSA is an excellent test when you've treated the entire prostate, either through radiation or through surgery, but how good is a PSA test after focal therapy?

I mean, if you treat a quarter of the prostate with focal therapy, does the PSA drop by a quarter? Should it drop by 50%? What's a good number that suggests success? And so currently speaking, we're lacking a appropriate biomarker that helps with surveillance. And so because of that, MRIs are very important in the surveillance pathway of patients who've had focal therapy to ensure that there's no cancer that's come back in the lesion or come back in an area outside the lesion for what we call an out of field recurrence. And then finally, because we don't have a good biomarker, all patients should get a biopsy, within a year to make sure that we're not missing anything.

And so, in the future, I would really hope that we can continue working on certain biomarkers that could help us understand better patient selection, but also who has been successfully treated and who may need additional treatments.

Host: Dr. Benidir, thank you so much. That was such an informative episode. You're such a great educator and you've given us so much to think about. Thank you again for joining us. To learn more about this and other health care topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. Please always remember to subscribe, rate, and review UF Health Med EdCast on Apple Podcasts, Spotify, iHeart, and Pandora. I'm Melanie Cole. Thanks so much for joining us today.