Faculty: Mark Emberton & Peter Carroll

Panel: Laurence Klotz & Herbert Lepor

Moderators: Andre Abreu & Tom Polascik


Dr. Mark Emberton

Mark Emberton is Professor of Intervention Oncology within the Division of Surgery and Dean of the Faculty of Medical Science at University College London.  He is clinically active and holds the position of Honorary Consultant Urologist at University College London Hospitals NHS Trust where he works as a specialist in prostate cancer. 

His academic work has focused on developing novel diagnostic strategies and new therapies for men with prostate cancer.  His research has resulted in the transformation of both the diagnostic and therapeutic pathways.  These have been incorporated into international guidelines.

He has published over 400 peer review papers, holds a large grant portfolio, and lectures widely around the world and holds international honorary professorships.

He is a founding Pioneer of the charity Prostate Cancer UK. 

 

Dr. Peter Carroll

Dr. Peter Carroll is Professor of Urology and holds the Ken and Donna Derr-Chevron and Taube Family Distinguished Professorships at UCSF. He is a member of the UCSF Helen Diller Family Comprehensive Cancer Center and an expert in managing urologic cancers.

In research, Carroll’s areas of interest include innovative methods of urinary tract reconstruction, refinement of robotic prostatectomy, development of biomarkers that predict cancer aggressiveness, the use of active surveillance rather than immediate treatment for prostate cancer and how cancer detection and treatment impact quality of life. He has received many honors and awards, published more than 600 articles on cancer detection and treatment and is principal investigator or co-investigator of many peer-reviewed research grants.

Carroll graduated with honors from Georgetown University School of Medicine and came to UCSF for general surgery training and a residency in urology. He completed a fellowship in urologic oncology at Memorial Sloan Kettering Cancer Center before returning to UCSF. He received his MPH from the University of California at Berkeley

 

Dr. Herbert Lepor

Herbert Lepor, M.D. received his undergraduate degree from the University of California Los Angeles in 1975 and his doctor of medicine from The Johns Hopkins University School of Medicine in 1979.  Dr. Lepor completed his surgery and urology residency training at The Johns Hopkins Hospital. 

In 1993, Dr. Lepor was appointed Professor and Chairman of the Department of Urology, NYU Grossman School of Medicine and Professor of Pharmacology at NYU Grossman School of Medicine.  Dr Lepor is presently Chief Urologist at NYU Langone Medical Center and the “Martin Spatz Chairman of the Department of Urology” Dr. Lepor’s primary clinical and basic research interests are related to the prostate. 

Dr. Lepor  has served on the editorial boards for four major urological journals and has authored over 400 peer reviewed articles, 50 book chapters, and 12 books related to prostate cancer, benign prostatic hyperplasia, and the pharmacology of the prostate.  He is the co-founder and editor of Reviews in Urology.  Dr. Lepor has been a visiting professor at 30 institutions.  Some of Dr. Lepor’s landmark scientific contributions have focused on the identification of the autonomic intervention regulating male sexual function, development of the nerve sparing radical prostatectomy, improving outcomes following radical retro-pubic prostatectomy, outcomes following focal ablation of prostate cancer, characterization of the prostate alpha1 adrenoceptor, and the medical and surgical management of benign prostatic hyperplasia. 

In 1995, Dr. Lepor was awarded the Gold Cystoscope Award by The American Urological Association.  Dr. Lepor is a member of the American Association of Genitourinary Surgeons, Clinical Society of the American Association of Genitourinary Surgeons, the American Surgical Association, and the Johns Hopkins University Society of Scholars.

 

Dr. Andre Abreu

Assistant Professor of Clinical Urology and Radiology at the University of Southern California, Los Angeles – CA, USA.

Director of Image-guided Surgery and Focal Therapy of Prostate Cancer at USC.

He has expertise in minimally invasive and image-guided urologic surgery with focus on ablation therapy and robotic surgery for prostate cancer, and image-fusion prostate biopsy. He has published many articles in reputed peer-reviewed journals. He delivered several lectures nationally and internationally and presented numerous abstracts during the major Societies meetings, being granted with several awards.

 

Dr. Thomas J. Polascik

Thomas J. Polascik, MD FACS is Professor of Surgery, Duke University Medical Center.  He is the Director of Surgical Technology, Duke Prostate and Urological Cancer Center. He is the founder and co-director of the International Symposium on Focal Therapy and Imaging of Prostate and Kidney Cancer that began at Duke in 2008. Dr Polascik is the Editor of the text Imaging and Focal Therapy of Early Prostate Cancer. He currently is the founder and President of the Focal Therapy Society, Duke’s Director of the Society of Urologic Oncology fellowship training program and the Genitourinary Program on Focal Therapy at the Duke Cancer Institute.  He is the Medical Director of Duke Men’s Health Initiative Screening event each September and is a governing member of several medical boards and societies.  His clinical and research interests focus on prostate and kidney cancer.  He has authored over 350 peer-reviewed manuscripts and book chapters.

 

Webinar Transcript

Dr. Tom Polascik:

Hello, everybody. I'd like to welcome you today to our session sponsored by the Endourological Society and the Focal Therapy Society. This is the Masterclass in Endourology Webinar Series. Today's topic is going to be a wonderful discussion, it is sponsored and coming to you by Wasatch Medical Specialties, the exclusive national distributor for Galil Prostate Cryoablation, for their grant in support of this activity.

Dr. Tom Polascik:

A few housekeeping items; as you see here, this masterclass series listed the purpose, target audience, objectives, accreditation, designation, faculty and disclosures. I'd like to bring up the CME, please. You will receive a survey from Michele Paoli, please indicate which seminars you attend, and then you will get a CME certificate. Please fill out the evaluation questionnaire at the end of the seminar. For questions, please use the Q&A function today, we'll try to get to as many as we can. And then all upcoming webinars are listed on the Endourology Society website.

Dr. Tom Polascik:

Today we have a wonderful international panel that is going to debate a very timely topic that many urologists deal with in daily practice: Can Focal Therapy Replace Prostatectomy in Men with Localized, Clinically Significant Lesion and a Negative Standard Biopsy? The debate will be between Mark Emberton and Peter Carroll and then we'll ask Laurence Klotz and Herb Lepor to bring some balance and discussion points to the debate that you'll hear. At this time, I'd like to introduce my co-moderator, Dr. Andre Abreu. He is Assistant Professor and Director of Focal Therapy at the University of Southern California, Los Angeles. He's a Director of Image-guided Surgery, he has a broad experience with both MRI-targeted biopsy and various ablation techniques. Andre?

Dr. Andre Abreu:

Thank you for the invitation. Thank you, the Focal Therapy Society and the Endourological Society, for putting these webinars for education and discussion. I would like to move forward, so this is the topic for today. These are my disclosures, and this is the panel that Dr. Polascik already introduced for us. So, for us, we will have Dr. Peter Carroll, who is Professor at the Department of Neurology at the University of Southern California. He is distinguished professor, actually has two titles as the distinguished professor. And after we have Dr. Mark Emberton, who is Professor of Interventional Oncology, with the Division of Surgery, and Dean of the Faculty of Medical Sciences UCL, London. He is a specialist in prostate cancer.

Dr. Andre Abreu:

So, Dr. Carroll will be talking on pro radical prostatectomy and Dr. Emberton on pro focal therapy. And to start the discussion, I would like to present a case which is a common case that we see on a daily basis. He's a 63-year-old male with elevated PSA, he is asymptomatic, he had a physical and then his PSA was 5.3. On digital rectal examination there were no nodules, he has no urinary symptoms, he is functioning very well. His SHIM score is 25, he is potent, he has no clinically past medical history, no significant past medical history, and no family history of prostate cancer.

Dr. Andre Abreu:

This patient was taken to biopsy and we have a trial here that we randomize patients for MRI versus no MRI upfront. This patient was randomized for no MRI arm, and so he underwent a systematic biopsy. On the systematic biopsy that you can see, it was found to have Gleason 7, 3 + 4, on the left base lateral and with Gleason 14% and 40% or 8 mm of the entire core. Based on that then, again per trial, the patient underwent an MRI and the MRI show a 52-gram prostate with a Paris 5 lesion, 21 mm or 2.1 cm in the left anterior horn, towards to the meat of the base of the prostate. There was no suspicious for extraprostatic extension or similar vesicle invasions, no lymphadenopathy by the MRI.

Dr. Andre Abreu:

With this, there was a discussion with the patient what to do and the patient was interesting on focal therapy and based on that, as I routinely do, patients that come from outside with non-target biopsy or even in this case that biopsy was done by myself but not MRI-guided, I repeated the target biopsy and as you can see here, I targeted the center of the lesion. And I target around of the lesion, mapping the cancer as you can see at the very base, along the urethra in the very apex and some rounded the lesion to have a better idea of the cancer extension, and we biopsy the other lobe as well, so this is the second set of biopsy.

Dr. Andre Abreu:

And at this time, the targeted biopsy showed Gleason 7, 3 + 4; 4 is 40%, this cancer is 5 mm in length, that corresponds to 60% of the core. There is a cribriform pattern. In the contralateral systematic biopsy, they are all benign against the second biopsy; the contralateral lobe is all benign, the MRI is also benign there. And this patient underwent regular staging with CT abdomen pelvis, MRI and bone scan, all of them negative for metastasis. With this, we also calculated the risks of lymph node metastases for this patient using this nomogram that takes in consideration MRI-targeted biopsies. So, by this nomogram, the patient had 2.7% chance of having lymph node metastases at time of radical prostatectomy. With this, now I will invite first Professor Carroll and then Professor Mark Emberton. They will have their considerations and after them, we will go for a debate and question and answers. Please, Dr. Carroll.

Dr. Peter Carroll:

Well, I'd certainly like to thank the organizers and Dr. Polascik for the wonderful opportunity to participate in this panel discussion. It's a real honor and pleasure for me to participate in such a panel of such distinguished thought leaders and good friends. Well, clinically-significant prostate cancer, I'm going to make the case for radical prostatectomy. First, some disclosures. I believe in treatment well-matched to the patient's risk profile, age and health, and their personal preferences. I do not believe there's only one approach to manage prostate cancer. Although I'm a very high-volume surgeon, I recommend an approach only to very select patients. We have a very robust focal therapy program at UCSF with very good intermediate outcomes. However, I do believe in high-quality data and well-recorded outcomes of care.

Dr. Peter Carroll:

What about patient assessment? If you're going to select treatment for someone, you should really know a lot about their cancer. Well, like in this case, a good quality MRI, fusion biopsy, histologic subtyping augmented by gene expression profiling, and very importantly, the use of a multivariable instrument for risk assessment; not NCCN category, AUA category, not simply Gleason grade. So, an instrument we use routinely and developed at UCSF is called the UCSF-CAPRA score, a simple as 0 through 10 scale; PSA, T-stage, percent positive biopsy, age, Gleason score. This has been validated in tens of thousands of patients around the world, predicts outcomes after surgery, radiation therapy, and actually predicts long-term outcomes like prostate cancer, specific mortality, and actually overall mortality.

Dr. Peter Carroll:

Well, what about this patient if we apply a multivariable instrument? Well, this patient is a CAPRA 2, so this patient's actually a low-risk patient; low volume disease, limited secondary pattern 4, very favorable PSA density. Again, based on two rounds of biopsy. Another thing about grading, not so much in this case, but be mindful of the small volume secondary pattern 4. Commonly, tangential sectioning could give rise to what appears to be pattern 4 but it actually may be pattern 3 on deeper cuts. Something mentioned earlier was the subtype of pattern 4; this is very important, often not reported in pathology reports. In our experience, expansile cribriform histology and stromal reaction are associated with higher genomic scores and a higher risk of extracapsular extension compared to glomerulation, no stromal reaction.

Dr. Peter Carroll:

So, what would I in this case? It would be slide review, again, and slides have been reviewed and the good Quality Center confirmed diagnosis, grade and histologic subtype. Repeat biopsy, this was done. We would send this to actually genomic profiling as well. As I mentioned, it's the expansile cribriform histology which has the highest risk of adverse outcomes and actually correlates with the highest risk of a high genomic score. This patient, based on age and limited volume, it would be hard for me to argue cogently for aggressive treatment, period.

Dr. Peter Carroll:

I don't know this is going to be a fair debate based on the case chosen for discussion. This patient will be treated with focal therapy, radiation, CyberKnife alone, hypofractionation, HDR, permanent brachytherapy, radical prostatectomy, and actually I think surveillance if gene expression profiling were favorable. However, I've been tasked to talk about surgery and the results I will show you are my personal results accrued over a very long period of time. For this patient, this CAPRA score, if you would offer surgery, it would be highly likely curative, you'd have complete clarity on cancer status, pathology, fault very straightforward simply based on serum PSA, morbidity can be anticipated based on the patient age, overall health, the stint or length based on MRI. You can anticipate morbidity very well nowadays.

Dr. Peter Carroll:

There would be no need for repeated imaging, biopsy, detailed surveillance. Again, I want to point out that focal therapy, in my mind, is a variation on surveillance; you're still following that patient over time, they still undergo periodic imaging, periodic biopsy, and PSA testing. So, if this patient would have surgery based on results at UCSF in my hands, the recurrence-free survival would be 91%. I'd also want to point out that actually in this patient, contemporary patients actually have better outcomes due to improved detection and staging. Again, MRI, repeat fusion biopsy, and what I call grade or stage migration. So, even though this is 91%, I actually think this patient's outcome would be much better. Prostate cancer specific mortality, 0. Overall, survival was around 97% at seven to eight years.

Dr. Peter Carroll:

Focal therapy, let me just get out some of my concerns about it, I think this will be discussed in the panel. The vast majority of men treated with focal therapy have very low, low, and favorable intermediate risk features. Many of these patients don't even need treatment, in my mind. The published experience is still very limited; both the volume of published experience, and the follow-up. Although most patients are heavily assessed before treatment, by that I mean MRI, fusion-guided biopsy, follow-up assessment is not. Oftentimes, you'll see a for cause biopsy based on the MRI. I want to point out the negative predictive value of a normal MRI at UCSF is 79%, so we would never not do a biopsy based on MRI alone. Now, you could add PSA density to this, that brings the negative predictive value up higher.

Dr. Peter Carroll:

I think the Focal Therapy and this panel are addressing these concerns, I think we really have have to focus on, who's the best candidate for focal therapy, how to do it; interstitial laser, cryo, HIFU, now there's the so-called precision prostatectomy. And how do you follow these patients? Can we get some consensus about that? In summary, I think this patient has many options and I can't be categorical about one versus another. And I'm not sure that type of initial therapy would have an impact on prostate cancer metastases or cancer-specific mortality. However, if this patient were to choose surgery, he would likely be cured, now and forever. Thank you very much for your attention.

Dr. Andre Abreu:

Excellent. Thank you for excellent presentation. And now we will move forward with Professor Mark Emberton, please.

Dr. Mark Emberton:

Well, it's a great pleasure to be taking part in this discussion. Dr Carroll and I have been debating this for some time, and I think seasoned observers will probably realize that consensus is growing, the middle ground is getting bigger, but obviously, you will be the judges of that based on the presentations, and indeed the discussions. We can start to discuss this man with localized unifocal 8 mm cancer limited to the left anterior horn identified on one core of the biopsy, and discuss whether this is a reasonable option for this individual. The option's the critical word here. We realize and accept that men have a choice, and I'm going to argue that focal therapy, for a well-evaluated man in a good center, is a very reasonable choice for that individual.

Dr. Mark Emberton:

Focal therapy is not for everybody; if you've got bulky bilateral disease, then you need whole-gland treatment. But it is indeed very suitable, I would argue, and preferred, I think we know that, by some, possibly many. About a third of patients will be eligible for focal therapy in some way or another. This is a man who was evaluated a long time ago now, on an old scanner, but you can see he's the mirror image of the patient that we're discussing. He has Gleason 3 + 4, 8 mm disease limited to the right anterior horn with no disease elsewhere, and indeed suitable for focal therapy, just in the way that the patient that we are discussing today.

Dr. Mark Emberton:

The future of the management of localized disease will, I think, be about the management of these lesions. Men will have an MRI and there'll either be a lesion or they won't. If there is a lesion, you have two choices that you can either watch it or you can treat it, and you can treat it or you can treat the whole prostate. And here is a man with such a lesion, and when these lesions present, we don't know how long they've been there, we don't know the proliferation rates, and the only way to find that out is indeed to observe them.

Dr. Mark Emberton:

We're learning a lot about lesion management now, and in this summary of our active surveillance cohort, we've learned that the presence of lesions dominates disease progression in an active surveillance setting. And here we have the amount of time, different individuals depending on their phenotype, stay on active surveillance. So, in brown, we have non-visible Gleason 3 + 3 which is the classic microfocal prostate cancer. In blue, we have visible 3 + 3, which as you can see, is behaving like non-visible 3 + 4, so it takes you up a grade. And you can see that visible 3 + 3 and non-visible 3 + 4 are essentially the same entity. However, visible 3 + 4, which is the type of lesion that we're discussing today, behaves quite differently and men with this type of disease stay on surveillance very much, much shorter time than do the others because the chances of progression are higher. Which is hardly surprising; if you can see a lesion, it's got over 100 million cancer cells in it, they've already got to that size, it's inhabitable, virtually, that given time they will progress.

Dr. Mark Emberton:

So, men with lesions that are visible, that have 3 + 4, on surveillance don't do well, and they certainly don't spend that much time on surveillance which might suggest that we use the opportunity that when we see this to treat them early, which means we can probably treat them better with less margin, and indeed, less side effects. Here's such a man, and you can see a lesion in the left anterior horn of the prostate. The important thing here is really high-quality imaging to get location. Location is absolutely critical in this case, we use the different sequences to increase the probability that we're dealing with a prostate cancer. And here you can see the diffusion sequence, and here the long-b, which is a derivative of the diffusion sequence, and all of these are serving as biomarkers; biomarkers to tell us that disease is present and I'll illustrate in a minute with the long-b after treatment, biomarkers to show us the disease is indeed gone.

Dr. Mark Emberton:

Such a high probability lesion, they're almost invariably Gleason 3 + 4 lesions. It's remarkable just how constant they are. This individual had pattern 4 at 30%, so a greater burden of pattern 4 by volume, and indeed proportion. None of the other biopsies were positive, just as in this case. How you treat the lesion doesn't matter, the case we described used cryotherapy, this uses IRE or NanoKnife electroporation, so instead of using ice you're using high voltage electricity, takes about half an hour to do. All done as a day case procedure, and the post-treatment MRI that we do in about a week shows just how well the prostate responds to the energy exposure.

Dr. Mark Emberton:

Not only has the cancer gone and been replaced by non-vascularized tissue, in this case, but the rest of the prostate has been preserved as I'll illustrate here and as I'll illustrate in just a second. If we leave it now for six months, let the prostate heal nicely, I think it's very hard to tell that this patient has been treated. If you didn't tell the radiologist that this patient had an anteroseptal treatment, I don't think they would know. The patient hardly knew afterwards in that he was continent, had good erections, ejaculated in antegrade manner, and his PSA had plummeted from above six to less than two.

Dr. Mark Emberton:

Here's the long-b and you can see the biomarker effect playing out. There's no evidence at all here of any disease in the left anterior part of the prostate that I showed you earlier. And I think this is a very quick, relatively cheap, noninvasive way of assessing disease control, and I suspect this is something we'll debate in just a second. Why do we get such good outcomes? Well, because we preserve key structures; side effects are due to collateral damage, whether that be by radiotherapy or surgery. Here we preserve the sphincter, we preserve the bladder neck, and indeed we preserve the neurovascular bundles by using spatial specificity to treat the bit that matters and preserve the parts of the prostate that are healthy.

Dr. Mark Emberton:

So, who's eligible for focal therapy? You want a discrete lesion, as I've illustrated, you want to have disease that merits treatment, clinically-significant prostate cancer, though exactly what constitutes that, I think it's debatable. Increasingly, I am of the view that disease that you can see is clinically-significant, disease that you can't is not. You need to apply a margin, as in all cancers. It's good if the patient has a high utility for preserving genitourinary function in terms of motivation, and there's always an awareness and acceptance of the uncertainties and an awareness and acceptance of the salvage strategies, and we're learning more about that as we go along.

Dr. Mark Emberton:

What's been remarkable about focal therapy is the consistency of the results, irrespective of patient selection, energy type, and the way that the outcomes have been derived. Basically, incontinence goes away and 90 to 95% of patients keep erection sufficient for penetration, though about a third of patients will use some Viagra or equivalent thereafter. And about 85 to 90% of patients can expect to be free of clinically-significant disease at the time of evaluation. Now that time evaluation, as in this study, was relatively early, but the outcome studies are now going out to five years and indeed some just beyond, though the numbers of events aren't huge.

Dr. Mark Emberton:

We've got high-quality randomized data to show that this is safe and well-tolerated. When you compare a focal therapy, which in this case was a hemiablation study in the men that were randomized to it, against active surveillance, you can see that the functional outcomes were indistinguishable. This isn't about case selection, this is a randomized study, and so men can expect to have quite a bit of their prostate treated but keep their erections compared to their counterparts, and actually keep or indeed improve their urinary symptoms with time.

Dr. Mark Emberton:

In terms of complications and early side effects, of course, treating the prostate, sticking needles into it results in some moderate events; bleeding, dysuria, infections, but they are short lived and what's really interesting is that there was no increase in the severe or life-threatening complications compared to active surveillance. So, focal therapy is extremely well-tolerated and extremely safe in this large, multicenter, international study using sites that had very little experience of focal therapy. So, in summary, ladies and gentlemen, focal therapy has emerged as a new class of therapy which now commands a legitimacy in terms of patient acceptance, academic, harm reduction, health economic. Focal therapy has forced an order of precision in terms of the risk stratification that was hitherto missing.

Dr. Mark Emberton:

So active surveillance didn't change the way that we evaluated men, focal therapy has because focal therapy is driven by information on location, "Where's the cancer, and how confident can I be that there is no clinically-significant cancer elsewhere?" And this is just a reminder, although it seems we've been debating this for a long time, we are at the beginning of a story. Most of the focal therapy is done with technologies that were developed in the 1930s; ultrasound, cryotherapy. Cryotherapy has a longer history, actually, and we're just getting into the era where we'll be evaluating treatments that have been designed for the task, which I think will be transformative.

Dr. Mark Emberton:

What do you need? Exceptional imaging, real partnership with your radiological colleagues; they become your new best friends, near-perfect risk stratification. If you're getting upgrading at radical prostatectomy against your biopsy results, your risk stratification is poor. You've got to get within 95% precision in terms of predicting what's going to be in that prostate. Otherwise, you will fail at focal therapy because you will be making risk stratification errors. You need to be an expert at the management of energy sources; this is not easy. This is a skill, and it's a skill that's not particularly well taught, nor is it integrated into many of the residency programs.

Dr. Mark Emberton:

And like all good practice, you need to be committed to long-term follow-up with registries and the publication of studies. And I think this is probably the most important bit, I think we're now in the era where we should be offering focal therapy to properly evaluated men, where we know that focal therapy can be delivered to a good standard and to a very high quality. And I would argue, and this is my big assertion, that it may be the key defining quality of centers of excellence and that they can offer a very good comprehensive range of choices for the men that includes a range of focal therapies for those men that indeed are eligible. Thank you very much.

Dr. Andre Abreu:

Thank you so much for your excellent presentation. We go straight for the considerations from Dr. Carroll as a counter argument; pro radical treatment. Please, Dr. Carroll.

Dr. Peter Carroll:

Andre, thank you very much. Very much enjoyed Mark Emberton's talk and I do agree that comprehensive centers need to offer patients a comprehensive suite of opportunities. So: Focal Therapy; Always, Never or Only Sometimes? I do want to comment on this issue focal therapy in lieu of active surveillance in lower-risk patients. I agree that surveillance can be burdensome in some patients, it may not be practical in some patients; I was giving a talk in China one time and they said, "Peter, doing surveillance at UCSF may be fine, but here in China to do repeated MRIs, biopsies, it certainly wouldn't be acceptable in patient population," and focal therapy is less morbid in whole-gland treatment.

Dr. Peter Carroll:

I do want to comment on the study that Mark showed them the randomized trial; it wasn't a big trial. It was still, I think, a couple hundred patients, I've talked to the FDA on this trial, and the trial design in my opinion was wrong. It was surveillance versus focal therapy, in the time of progression, patients were offered whole-gland treatment. The better trial would've been surveillance versus focal treatment; at a time of progression, consider focal treatment. And this is a series from UCSF looking at this whole issue in patients with low-volume disease three-three, or limited-volume three-four be candidates for focal treatment. So, we have over 2,200 patients in surveillance serial biopsies, so we actually looked at this, "Based on biopsies, what number of men might be candidates for focal treatment?"

Dr. Peter Carroll:

On the first biopsy, It was higher, about 75% of patients, but in fact you needed a second biopsy in order to accurately identify patients who'd be good candidates for surveillance. And this includes if you assume the patients who have negative biopsies; again, 20% of patients in surveillance, at any single time will have negative biopsies, but if you assume those patients might be candidates for surveillance then about 60% of patients may be candidates of focal therapy. That is, they progress in the dominant lesion. So, again, for these patients that we're talking about, these lower volume lesions they do progress in the dominant lesion. I agree with Mark that a visible lesion is more likely to progress, it doesn't reach statistical endpoints significance in our studies, but that's because we have MRI, genomic profiling, and PSA density, but it does come close. I think Mark is wrong when he says these patients don't do well on surveillance, they actually do. Even when you treat these patients, at two to five years, the outcomes are very similar, so surveillance is about timing of treatment.

Dr. Peter Carroll:

Don't set the bar too low, this patient could've been treated with anything. Maybe, not treated. I just got off a call reviewing grants for the Prostate Cancer UK, CyberKnife, there's a lot of things happening right now for a patient population like this. In my opinion, the battle for prostate cancer will be won or lost by treating disease which is at risk to the patient. So these are generally higher volume, higher grade tumors. The cancers we've been showing here are generally, again, generally favorable intermediate-risk patients.

Dr. Peter Carroll:

Well, in my mind, "Focal Therapy; Never, Always, or Sometimes?" The answer is sometimes. I do think there's a role for focal treatment and it should be considered, and we are having increased numbers of patients who come to us asking about focal therapy. To Mark and the Panel, "Who would you do or not do focal therapy on?" What about this whole issue of apical cancers? T3A, is that okay to do? What about high-grade cancers? Primary pattern 4 or 5. What about germline mutations; are you carrying a germline mutation? BRCA 2? Should these patients undergo focal treatment? And what about the whole issue of unfavorable genomics? These genomically very complex, but appear to be focal cancers, are these candidates for focal treatment? And I think the panel will discuss this.

Dr. Peter Carroll:

My big worry about focal therapy. And again, we do it more and more commonly. It distracts us from confronting the real issue of over-detection and under treatment. And I want to be sure that, as urologists, we don't always focus on treating the primary lesion, but we should be the most active participants in saving lives that could be lost, so developing predictive not prognostic biomarkers. I mean, who responds to radiation or surgery or focal therapy? Advanced imaging. There's this is explosion in the use of theranostics. This deal is changing rather rapidly and I'm talking about theranostics for the primary tumor. And then new therapies; T cell therapy, implantable pulmonary vaccines; these things are happening and I want to be sure that we play as an important role on that as we do in applying therapy only to the prostate, whether it be surgery, radiation, or focal treatment.

Dr. Peter Carroll:

Lastly, we were kind of talking about minnows here, and I do think focal therapy, it's not exponential, it's incremental. And again, I want to be sure that we don't distract ourselves from these higher volume, higher-grade lesions that really require more and more of our attention. With that, thank you very much.

Dr. Andre Abreu:

Excellent points and arguments. Now we go straight to Dr Mark Emberton for his considerations in rebuttal, please.

Dr. Mark Emberton:

Well, thank you very much. So, I'll respond to some of the things that Peter said. I think you can all see that the common ground is growing, as I said at the beginning, and I think we're all in agreement that focal therapy should now be part of comprehensive prostate cancer care, but delivered responsibly, and delivered in line with the risk stratification that we're offering these men. And I think we are getting beyond the era where we offer men all options because our risk stratification was poor; this is the era of PSA trust biopsy. We've got an array of risk stratification technologies now that all of us are using to different degrees, and that means that we can stratify risk. And that means that we should be able to prioritize treatments, and give the heavy-duty treatment surgery and radiotherapy and perhaps systemic therapy for really advanced disease, not to treat the people that don't need treating, but offer minimally invasive treatments that are well-tolerated for those individuals that conform to those types of therapy.

Dr. Mark Emberton:

So, I see a stratification of therapies now as a product of our very, very evolved risk stratification. If we don't do that, I think there's a huge amount of waste in terms of the test that we're throwing men if we're going to say to them, "Well, actually, you choose," and I don't think we will have progressed. I think the discussion around active surveillance is really interesting, but it's a complicated one, I think. I think active surveillance and focal therapy are less in competition and more complimentary. You could argue that the best patient for focal therapy is a patient who's been carefully watched for many years, who's had a lesion that has slowly been growing that transforms from Gleason 3 + 3 maybe to a Gleason 4 + 3, over time verified by biopsy, and in which we're aware that the background prostate, because we've had the opportunity to look at it, has remained stable.

Dr. Mark Emberton:

So, we've got a growing unifocal lesion that's getting worse by radiological progression, perhaps by chemical progression, and histological progression, and we can treat it in the knowledge that there'd be no secondary or tertiary lesions developed over the last five to 10 years. And so, you can see just how complimentary the two approaches work. We try and defer treatment, and now we've got a treatment that we can apply that is extremely well-tolerated for those individuals. However, there's a bind with active surveillance and focal therapy, and I alluded to this in my talk. When you see a lesion, you meet it for the first time, you obviously don't know how long it's been there, but it will never be smaller than the time that you first see it. And you can observe these lesions; lesions will progress, as we've illustrated, and so if you defer focal therapy, you will have to treat more prostate, you will have to extend your margins, and that will begin to eat into the functional reserve of that individual, particularly if they're starting to lose erectile function.

Dr. Mark Emberton:

So, there's a really interesting, important discussion to have when you meet a patient like today's patient who's got Gleason 3 + 4, or low-volume Gleason 4 + 3, which looks unifocal. Do you go in now or do you observe until the lesion progresses and then treat? I'd be really interested what the panelists. And let me just finally respond to the cases that might not be suitable for physical therapy, so this was Peter's last slide. I think we're getting better at apical; there was a paper published last week by Phil Stricker from Sydney showing really good extreme apical treatments using special techniques and special measurements. And in fact I spoke to him last week, so we're going to share the technique and I'm going to do the same.

Dr. Mark Emberton:

T3A is not a problem; you just put your energy source outside of the prostate. I'm doing more and more Gleason 4 + 5, T3A disease for men who are 85 or something like that really well, characterized PSMA PET negative, outside the prostate, because they want to avoid two years of hormonal therapy and radiotherapy. And remember if they do fail, we still have that available, but they can have their treatment in half a day. In fact, I did such a patient earlier on today and he's gone home already; it's evening in the UK now. So, I'll stop there, and I really look forward to the questions and the discussion, and indeed the challenges from some of the panelists. Thank you very much.

Dr. Andre Abreu:

Excellent. Thank you. Really excellent thoughts from both of you. I will just finalize presenting this case and we will open for debate with the others. So, this is just to summarize; 63-year-old with Paris 5 on the MRI, no suspicious for extraprostatic extension, he underwent a targeted and systematic biopsy twice that show Gleason 7 in the left side only with 3 + 4 in cribriform pattern. All other biopsies were negative. We assessed the risk of node invasion, that was 2.47, and although we know that MRI underestimate the size of the lesion in final histology, there are manuscripts from our group and from others showing that when we combine MRI information with biopsy information we actually can be more accurate and better select these patients for focal therapy.

Dr. Andre Abreu:

This patient, actually, was candidate for cryoablation, that's what the discussion was with the patient, that's what he wanted, and that's how we do cryoablation here at USC; we use free-hands technique, we don't use the grid template. This is our technical details that we can discuss later. So, these are the intra-operative pictures, you can see the lesion here on ultrasound, pre-cryoablation, then how I plan to place the needles around the lesion, and how the needles are actually placed. And this is starting the ice ball that you actually cover the lesion plus margins. This is the final aspect of the ice ball, you see the right lobe there is untreated, the urethra, in the left lobe there is completely treated, and this is the sagittal view of the same patient.

Dr. Andre Abreu:

At six months of follow-up, this patient returned with a PSA of 2 that represented 65% of PSA reduction from the beginning. Here, he was continent, he was continent from the very beginning, from the get-go after removing the catheter that I removed in seven days. He's IPSS was nine from one, SHIM score was 17 from 24, there were no nodes, the patients was doing well. And here you can see the ultrasound, there is no Doppler signal to that area and the prostate shrank considerably. And his PSA dropped 65%, which is in agreement with 70% or so that we saw from our initial series of patients undergoing cryoablation.

Dr. Andre Abreu:

In one year post-cryoablation, left cryoablation, this patient returned. He was doing well; incontinent, IPSS now was four, SHIM score was six and I said, "This is something weird here because you were potent before." And he said, "Actually, I have no partner." So, when you evaluate the patients, be sure that you use a proper questionnaire because SHIM score is not the best question to evaluate sexual function. On the EPIC questionnaire, this patient had erections firm for masturbation, and not on the days he had ejaculation, that was kind of a half of a volume before. His PSA was continued going down, at this time at one year was 1.2, that correspond to 79% of PSA reduction. This is the ultrasound at one year and then can see again there is no Doppler to this area.

Dr. Andre Abreu:

And here's the MRI; at one year MRI, that how the MRI was. There was the lesion, we can't see the lesion anymore. The prostate has shrunk, mostly in the right side of the prostate has shrunk. And nevertheless, we do biopsies for these patients routinely, and what you see here is the initial biopsy that we did at the diagnosis that we create this cartography, and this same biopsy, so just a little lighter color same like this. Then what we are doing now, as the MRI was negative, we are doing 3D TRUS with 3D TRUS fusion. So, the initial biopsy is now fused with the current ultrasound, and based on this, we can sample same areas. Of course, it's not completely precise because there is a shrinkage on the left side, but this is the best we can do in terms of revisiting patients on focal therapy. We sample other areas that were not sampled before, and all of these biopsies they all came back negative; everything was benign, just we're seeing the target areas, there was no malignancy, just some inflammation fibrosis and hemosiderin. That's what we see after ablation. This of course was just one case, but we presented our series, 160 patients. Majority of them have intermediates and-

Dr. Tom Polascik:

Andre, we need to introduce our other speakers.

Dr. Andre Abreu:

Yeah. In five-year, free survival was 85%, in radical treatment free survival, 89%. More patients, majority of them are continent. Now, going back to the panel, I would like to introduce Professor Laurence Klotz; a Professor of Department of Surgery in the University of Toronto, Chief, Division of Urology; and Professor Herb Lepor, Professor and Chairman of Department of Urology at NYU, New York University. So, now, please have your considerations. There was a lot of debate on active surveillance, if active surveillance should be offered for these patients or not, if a patient with Gleason 3 + 4 cribriform pattern visible, lesion Paris 5, would be candidate for surveillance or not?

Dr. Herbert Lepor:

So, I think the goal of treatment has pretty much been stated, we want to prevent prostate cancer mortality and metastasis, and preserve quality of life. So where are we with the quality of life consideration? Because I think that's the real advantage of focal therapy. So, we just sent in a paper, I imagine those that's on the panel will probably be reviewing it, so I'll give you a preview. We didn't have any incontinence in our patients and I think what's really important when we look at quality of life, we stratify according to their baseline presentation. So, in terms of LUTS, this patient doesn't have LUTS, so we can't improve upon their LUTS. If you look at guys who come in with marked lower urinary tract symptoms, we've shown dramatic improvements with focal therapy.

Dr. Herbert Lepor:

And also, looking at erectile dysfunction, I used to think that the focal therapy really had no adverse impact, but it does. And I think, as Andre showed, in this patient if you start with the SHIM at 24, you go down to 17, you're still functional. Now, if you look and you just aggregate all the data together, if you got 60% of the patients who had ED, you can't make them worse. But I would say the patient who comes in with moderate ED, with a SHIM of around 13/15, that person is likely to have some functional impairment which for him would be significant. And in terms of assessing oncologic control, what do we want to know? I think we want to know if you have clinically-significant prostate cancer. We published our experience, we biopsied everybody at six months following an MRI, and we only had one out of 60 that had clinically significant prostate cancer. So, in our series, we don't do a biopsy at six months but I would say, as you're getting started, I think you have to prove first that you have good oncologic control before you stop assessing your patients early on.

Dr. Herbert Lepor:

And in fact, we still do an MRI, but you really wonder that necessity because the positive predictive value was only 16%. So, I do believe that at six months, with properly selected patients and good technique, that you don't have to do the imaging and biopsy. At two years, we're beginning to see about 10 to 15% in-and-out-of-field recurrences, so I do believe that as time goes on, we are going to have to critically assess oUr oncologic control. And I think we have to prove that imaging and PSA or PSA velocity or density, that this can be used as a proxy for oncologic control, but we have to do the reflex biopsies in order to show that.

Dr. Herbert Lepor:

So, what about I believe as far as long-term oncological control? I think if you come in and you're curable, you will not lose that opportunity if you're carefully followed. I think at five years, my prediction and sort of based upon our early experience, about 30% will need reablation, 10% whole-gland therapy. We want to know 20 years, like the Scandinavian trial, how does focal therapy measure up? We'll see. And I would say, and I'll leave this in closing, there're so many things that I think can be added to the conversation, but I'm not conflicted in whether this patient does a radical or focal therapy. And we have rather extensive, and I think credible, outcome data. And if I had this patient sitting in front of me, and I gave them what I feel is an honest expectation, I would say about 2/3 would pick a focal therapy and 1/3 would pick a radical, and I don't think many would choose an act of surveillance partly because I would not be enthusiastic about it for all that we've discussed.

Dr. Laurence Klotz:

Thanks for the opportunity to participate, and I think those were really great presentations. Most of what was presented, I think I certainly agree with and most of us would. The way I frame this whole issue, and it's a little bit like the active surveillance story in retrospect, maybe 15 years ago. You have the concept and the application, and I think in our world, whether it's a new surgical technique or diagnostic technique, you can have a great application but if the concept is flawed, it's not going to fly and the converse is also true. And I thought, actually, Peter's comments were mainly around the concept and Mark's were mainly around the application. I'm just going to address those two things separately.

Dr. Laurence Klotz:

As far as the concept, three points; number one, I think everyone on the line, including Peter who was perhaps unhappily saddled with defending surgery, we all buy this concept but it is by no means widely accepted and I think that's a key point. The last overview of this topic that I saw, which was in European Urology Focus by Bates et al was resoundingly negative. Focal therapy should only be undertaken in the context of a clinical trial, essentially. Also, the AUA guideline also reflects that view. So, first of all, I still think this is something where there's a struggle for acceptance, just as it was with surveillance, initially.

Dr. Laurence Klotz:

The second thing is there's one conceptual aspect of focal therapy that bothers me and it's received very little attention. We don't really have time to talk about it, but this is the equivalent of, in radiation, what's called accelerated repopulation. It's well-known in radiation; if radiation therapy is incomplete, it's interrupted for whatever reason, comorbidity, the disease accelerates and progresses. And my concern with this whole area is that if we under-treat a patient, he has more disease than we anticipate, there's disease at the margin, the injury response may alter that phenotype and turn an indolent disease into a more aggressive one. So that, to me, is a conceptual aspect of this that has to be addressed.

Dr. Laurence Klotz:

As far as the technical aspects, I think that the key point which has been alluded to and I just want to emphasize that this is an emerging and evolving area, and there are so many new trends and facets to this that warrant exploration, just a couple of them. The combination, for example, of focal therapy with immunotherapy, focal treatment as a immune stimulant is a very unexplored area. The technique, for example, of HIFU; there is a debate in the field, there's been some recent publications on this, the value of double-treating or even having overlap of three areas so that the core focal lesion is actually treated two or three times, may give a better result. So even the technique is an evolution; the role of contrast-enhanced ultrasound, for example, of micro-ultrasound, the value of a second treatment, so for example the French approach to HIFU was very much to treat once and then retreat almost half of the patients. Just a different way of approaching it, but ultimately may give better results. So, I think we're talking about a kind of application of treatment modalities that are still very rapidly evolving and need to be evaluated.

Dr. Laurence Klotz:

And then finally, I slightly want to take issue with Peter's concluding comment; Peter, you said, "The battle will be won or lost by the treatment of disease which is a risk to the patient." But we know from the history of prostate cancer that part of that battle is not aggressively over-treating a lot of patients who don't need it because the baby will be thrown out with the bathwater as almost happened with PSA due to concerns about over-diagnosis and over-treatment. And I think one of the facets of this therapeutic approach we have to be careful of is what you could call the snake oil medicine concept where you have an innocuous therapy that really doesn't harm the patient, which is great, but if it's applied widely to diseases that don't require treatment, we will be heading again down that pathway of over-treatment, and we for sure do not want to do that. So, this was a case of intermediate risk, totally appropriate, but we have to be careful about once again embarking on that whole over-treatment scenario with a more innocuous therapy. So, thank you all again.

Dr. Andre Abreu:

There are some questions from the audience that were responding on the chat, and we are happy to respond afterwards. I have one question for actually Dr. Lepor that I think you should speak more; what is the pathway for the future of focal therapy? Is adjuvant, neoadjuvant treatment, better imaging; how do you see this? Is it theranostic, how do you see this? You have three minutes.

Dr. Herbert Lepor:

No. I'll even take a little less time so we have other questions. But my biggest concern is compliance with follow-up. So, we tried to publish our five-year experience, and I had myself calling the patients, calling their primary care doctor; we did everything to try to maximize our compliance, and I still had 20% of patients that were just off the radar, and we had already followed them meticulously for two years. So, my biggest concern is a patient accepts focal therapy because we've convinced them that they need a minimally-invasive-like treatment for their cancer, and then they feel that they don't need to follow-up. And what I really do believe what we have to do, and I see that lacking because if you look at so many of the five-year outcomes, what they don't show, what they don't report is how many patients have been lost to follow-up, and I bet if they did, there would be a majority of those cases.

Dr. Herbert Lepor:

And so, what I feel, it's our responsibility to select patients, this is not simple. That we really maximize our technical approach to the disease, but what I think we also must commit to following patients. And I think as Peter said, I don't think today we can assume that a negative MRI and a decreased PSA is equivalent to the lack of clinically-significant prostate cancer, so I figure we need to do the meticulous oncologic control to validate that.

Dr. Andre Abreu:

Excellent.

Dr. Tom Polascik:

I wanted to thank everyone for participating today. This is a great discussion. As you can see, we have lots more to talk about. I just wanted to make a comment about the Focal Therapy Society. We are trying to get together with registries, we are going to be launching a registry so we can look at outcomes, we'll be hopefully running clinical trials, and we've been putting together consensus reports to try to get some answers to these important questions. Our next Masterclass Webinar will be February 26th on Robotic Partial Nephrectomy with surgeons Dr. Ravi Munver and Ronald Boris, with Dr. Ketan Badani moderating.

Dr. Tom Polascik:

Again, we encourage everyone who is not already a member to join the Endourological Society. If you want to join the Focal Therapy Society, it's a single membership since we are partnered with the Endourological Society, so please join. Your dues provide many Member Benefits including the full-text online access to the Journal of Endourology and Videourology. Details are available on the website. Our next in-person meeting is planning to be held September 23rd through 25 in Hamburg, Germany. Again, thank you for participating. Have a nice rest of your day.