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Melanie Cole (Host):  Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole and today, we’re discussing focal therapy for prostate cancer. Joining me is Dr. Ashley Ross, he’s an associate professor of Urology at Northwestern Medicine. Dr. Ross, it’s a pleasure to have you join us today. Before we get into this topic, briefly tell us about yourself as you are new to Northwestern. Give us a little bit of background, your expertise and how you came to Northwestern Medicine.

Ashley Ross, MD, PhD (Guest):  Thank you very much. So, I’m a Physician Scientist. I completed my MD and my PhD in Biochemistry and Molecular Biology at Johns Hopkins Hospital in Baltimore. And then stayed on there, in Urology for training both in Residency and then as Faculty. My interest was almost exclusively in prostate cancer both in the laboratory and at the bedside. Eventually I became an Associate Professor and Head of the Urology & Prostate Cancer Program at Johns Hopkins. I then relocated to Texas, joined Texas Oncology and Texas Urology Specialists, continued my practice in prostate cancer and was the Head of the Mary Crowley Cancer Research Center which was an early trial development center in North Dallas. The Polsky Institute was created a couple of years ago. It was a big opportunity, a big push forward for Northwestern Medicine and for Urology at Northwestern to both increase clinical care but also to innovate new technologies; both ones that are surgical based but also ones that are based on biologics and immunotherapy. And so it was a big opportunity and I was recruited up and I’m very excited to join the faculty at Northwestern and to push forward a lot of advancements in urologic oncology.

Host:  Well thank you so much for telling us about yourself. So, now speak about the role of focal therapy in the management of prostate cancer. Tell us the rationale as a middle ground as it were and some of the challenges in applying such an approach to the treatment. Is it due to the multifocal nature of this disease? Tell us a little bit about the rationale.

Dr. Ross:  So, prostate cancer is as most of the audience knows is a very common malignancy of men and it also has a wide range of features in terms of how aggressive it is. Over the last couple of decades, and certainly in the last decade, we’ve been more accepting of active surveillance meaning watching sort of lower risk, favorable risk prostate cancers and we’ve been refining how we treat more aggressive prostate cancers. Meaning like ones that are obviously going to cause problems for the gentlemen within the next five years. But there is as you mentioned, sort of this middle ground where there’s disease that looks a little bit too aggressive to watch or has features in which we think it would be risky to watch and it might progress quickly in the next several years, but disease that also appears to be confined enough that it might be amendable to a curative treatment without as many morbidities.

The prostate of course lives next to the neurovascular bundles that control erection, on top of the rectum, near the bladder, near the urinary sphincter and the questions in treatment is how can we do that in a way that reduces the morbidity to the gentlemen. What’s happened over the last, again five to ten years, really in the last five, has been kind of very good advancements in imaging of prostate cancer with MRI. There’s been more molecular correlates to disease so understanding how much a disease will progress, but we’ve been able to sample the prostate better to know like what is the actual burden of disease within the prostate and that all together, brings focal therapy into the range of possibilities.

We can identify patients that don’t seem to have multifocal disease. We can identify patients that have disease that seems too risky to watch and then a lot of the technologies are allowing us to target the disease better. Now those are still emerging. There’s some technologies like freezing therapy or cryoablation which has been around for a long time. It has been repurposed and used in the OR and the clinic for focal therapy for some time, in my practice for over five years. There’s some other emerging therapies, laser based therapies, photodynamic therapy, high frequency ultrasound therapy that have been studied to various extents and that all are being used to various extents in and outside of clinical trials.

But the middle ground is this patient that still has favorable risk features; however treatments might result in cure without significant urinary or sexual morbidity and delay might require more aggressive treatment if performed a year or two later and that is sort of the sweet spot of focal therapy.

Host:  What a comprehensive answer. Thank you so much and it’s really an exciting time to be researching and practicing this. Who do you see it gaining traction with? Tell us a little bit about patient selection.

Dr. Ross:  Great question. So I think you have to bring all the modalities to bear. So, the patient selection is – originally when I started focal therapy, about five or six years ago, my selection for patients was patients that had unifocal disease as seen by MRI and also on their biopsy, patients that did not have high grade disease and specifically, I looked for older patients, patients that were 65 and older because most of the time, when I would think about salvaging the focal therapy, meaning like it failed, which about 10% of the time, you’ll have disease on the contralateral side within five years, you may have disease on the same side recur as well. I was going to salvage those patients with radiation if I didn’t know how difficult the surgery would be.

There’s been some changes over time. Still I think it’s most appropriate in patients with higher volume low grade disease either Gleason Grade Group 1 which is three plus three equals six or Gleason Grade Group 2, three plus four equals seven. So favorable intermediated and low grade disease. Still it’s appropriate that they only had disease on one side of the prostate, although, you can make some exceptions for well-localized disease on the other side as long as it is away from critical structures. But I think that we can move the patient selection into a slightly younger cohort because we’ve seen both in my hands and also in literature, that salvage surgeries are possible after focal therapy. We’ve also seen the outcomes in my mind look acceptable to be trying on the younger patient population.

The final thing I would say is that one of the interests of focal therapy is beyond sort of doing this on an expanded population as we’ve advanced, we can also look at moving the technology into the clinic instead of the OR. It doesn’t really have to do with patient selection, but it does have to do with the patient selection in terms of like who would be doing this. When we were doing it in the OR originally, sometimes radiologists were doing it in the interventional radiology suite but I think there’s really a role now for the urologist if we can bring this into clinic, have it done without anesthesia with just regional or local anesthesia and there’s been some initial practice of that, then there’s going to be a large role for the urologist.

Operationalizing that will take a little time. But I think that one of the goals of the Polsky Center and Northwestern is to really lead the charge in bringing this technology into clinics so it can be done effectively but also efficiently for the patients.

Host:  Is there anything you can tell us about outcomes or the efficacy of focal therapy?

Dr. Ross:  Yes, I mean the question has a few caveats. So, what’s happening currently, is that there’s multiple different focal therapy modalities. There is cryoablation, like I talked about, photodynamic therapy, high frequency ultrasound therapy. There’s also been multiple different treatments sort of planning’s. Some people will do what’s called True Focal which they will treat just the area of interest that has cancer or in which they think it has cancer. Some people will expand that into hemi-ablation or basically treating a whole half of the prostate. And sometimes, this makes the ability to track which outcomes difficult to sort of ascertain.

But there’s been a couple of studies that have been done both in terms of clinical trials and also in terms of well-kept prospective registries and there’s also obviously our personal experience. So, in terms of like the clinical trials that are out there, probably the largest randomized controlled trial was a study using photodynamic vascular therapy which is you basically give a chemical to the gentleman that’s only activated at certain wavelengths of light. Then you put a probe into the prostate where you think the disease is, you activate that chemical and it ablates the cancer. The trial, which was called the TOOCAS trial or PCM301 was an international multi-institutional randomized controlled trial of this vascular photodynamic therapy versus active surveillance. And what it showed was that at two years if you look at progression on active surveillance, at two years, while the people who didn’t get any therapy progressed about 60% of the time; the people who progressed who got the photodynamic therapy, only progressed about 30% of the time.

They found that the freedom from radical therapy for these guys at four years was 53% were free of radical therapy at four years versus 24% for people who had just surveillance. So, the hazard ratio or how many times better for having focal therapy versus not, and the lower the number the better, was about 0.3. So, it was like three times better if you take into account some components of time. They also saw similar erectile dysfunction and similar incontinence rates whether you watched the man, or you give them the focal therapy. So, that trial was a very well done kind of large effort. One of the criticisms was that a lot of the people on the trial had lower grade cancers, so would this work in higher rate cancers or lower volume cancers. But it definitely gave us a very good signal that this is sort of coming in the future.

In the UK, where they had a program using a lot of high frequency ultrasound and a focal therapy program using that; they had a very well done prospective registry. And there, they used more aggressive cancers including these intermediate risk cases. And what they saw was that if they did the focal therapy and these registries, then at five years, about 88% were free from disease progression, so failure free survival was 88%. And in terms of this is expected, but in terms of people having metastases, the metastasis free survival was about 98% at five years.

They have already reported their continence, meaning the man’s ability to hold their urine and the continence rates were nearing 100%. Erectile dysfunction hasn’t really been reported by them, but they collected that data and were awaiting it. So, these couple studies, and then my own clinical experience, really suggests that with the appropriate kind of persnickety patient selection which really means having excellent MRI to local the disease, we are starting to look at Northwestern add PET imaging also to rule out higher grade disease or occult disease. With really good patient selection and localization, and technologies and people who do this all the time; but I think in the future, kind of a rolled out to almost the community at large that gets trained on it; the focal therapy really has acceptable if not very favorable outcomes and it is going to be a standard, I think a standard treatment.

There was a cross-sectional survey that was done about three years ago or so of different urologists and they asked them how many of you think that focal therapy is going to be a standard option and it was 70%, kind of across the board that it’s going to be a standard option. I agree with that and the preliminary data are very promising for that. But like you have mentioned a couple of times, patient selection is key and the only way to really do that is to have top notch imaging which in the community, I think is still developing. In academic centers, it’s pretty locked in. But I think that’s one area where you really have to know where you are going to get your MRI, how are you going to do your targeting biopsy and mapping. Are you confident in that you are treating what you’re treating and if that’s so, then are you confident in the modalities you’re using and a lot of them have been proven at this point. Some of them are still in trials. And then how you follow these people afterwards.

I know I’m long-winded but I’m going to say one more thing. Which is that in addition to developing the focal therapy in multiple modalities to that focal therapy, cryoablation, laser therapy, et cetera; another kind of focus in the area is well maybe you don’t have to do a focal therapy at all. Like you said, because these might be multifocal. Should we be pushing innovations like immune based therapies, like hormonal access inhibitors on these candidates, ones that have good safety profiles? And at my previous centers, I had run clinical trials using immune based therapies for example. At Northwestern, we are going to be establishing a trial using a hormonal based therapy that looks a little bit safer and less toxic than previous therapies. So, you can treat the whole gland. Again, in the sweet spot of patients where you want to do it with the least amount of morbidity possible. And those are the favorable intermediate risk patients primarily and some of the high volume low grade patients.

Host:  Absolutely fascinating Dr. Ross. As we wrap up, what will you be working on at Northwestern Medicine and what else should urologists know about focal therapy and what you’re planning to do at Northwestern?

Dr. Ross:  A couple of things. So, the general urologists out there, they should note that this is emerging. I don’t think it’s yet there for widespread dissemination and prime time use. They should watch it closely. They should keep up with the field and know that there are centers of excellence that are kind of pushing the envelope forward and look at it as an option for some of their patients. But it’s still emerging. At Northwestern, where we want to lead the charge, I think beyond evaluating newer technologies, one of our focuses is that there is a lot of evidence around these things working. And the question is how do we now bring the technologies into the clinic to go from the OR suite or the interventional radiology suite into clinical practice so you can decrease not only the morbidity but the life disruption for the patient? How are we going to look at some of the follow up for these men, so not just selection and the newer imaging modalities like PET imaging and different ways of doing MRI but also how do we follow these people long term and how much do they need to be followed to be established as cure?

Can we use genomics and different molecular features of their prostate cancer and their benign prostate tissue to predict who might fail distance from the focal therapy? So, who has the worst soil in the prostate? And those are the efforts we really want to push at Northwestern and additionally like I mentioned briefly, some of the other clinical trials for the same men but may not be using focal therapy but also using low morbidity techniques. And our hope with focal therapy is to develop it and then sort of package it for the urologists out there. So, have available options for their patients now but then sort of develop it and refine it and have it operationalized so that we can roll it out to local urologists and they can look at us as a resource of what do I need to do this effectively and can it safely be done in my practice in my clinic. Because as kind of the theme of our talk, in the next five years, I have no doubt that this is going to be a standard therapy for the correctly selected patients.

Host:  Thank you so much Dr. Ross. What a great segment. So much information. Thank you for coming on and sharing your expertise with us today. And that concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient, or for more information, please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I’m Melanie Cole.