Focal therapy for prostate Ca: Ready for prime time?

Focal therapy has emerged as a treatment strategy for low-risk prostate cancer that bridges the gap between definitive whole-gland treatments and active surveillance, although long-term data are limited. In this interview, John W. Davis, MD, discusses the advantages and limitations of focal therapy, the ideal candidate, and what current guidelines say about its use. Dr. Davis is professor of urology at the University of Texas MD Anderson Cancer Center, Houston. He was interviewed by Urology Times Editorial Consultant J. Brantley Thrasher, MD, professor of urology at the University of Kansas Medical Center, Kansas City.

Please define focal therapy for prostate cancer in its current format.

I think it’s important look at two different, related concepts. The first, which I think is the most critical, is agreeing on what is focal and what is not. Three strategies have been tested in various forms. One is true lesion-directed therapy, which assumes the patient has a positive MRI and an ablation source will be directed at it, plus or minus a defined margin, and that’s probably going to be surgeon dependent. The other two-hemiablation and “hockey-stick” ablation-are not necessarily historically image guided. There is published experienced with both approaches in patients with a low-volume, unilateral biopsy.

Dr. John Ward of MD Anderson worked on the hockey-stick approach over 10 years ago. He found that by studying radical prostatectomy specimens, if you had a patient with unilateral cancer and wanted to address the dominant and most of the secondary tumors, it was necessary to treat the affected side completely and the anterior contralateral side. You might say that shouldn’t be called focal therapy because it’s subtotal therapy, and that’s a fair criticism. Although I haven’t seen data on it, I would imagine it would affect how much residual PSA you will be measuring when you’re treating 25% versus 75% of a gland.

The second concept where there is less controversy involves seven ablation sources: cryotherapy, high-intensity focused ultrasound (HIFU), laser ablation (which assumes real-time MR monitoring), photodynamic therapy, irreversible electroporation, brachytherapy, and radiofrequency ablation.

When you mention laser ablation, what type of laser are you talking about?

They are not identical to holmium or GreenLight type applications for benign disease. These are termed “laser interstitial thermotherapy” that are either continuous wave or pulsed. The mechanisms are the same-thermal coagulation, vascular damage, and finally, cellular damage.

What are the perceived advantages of focal therapy?

The one that is the least controversial is quality of life. Compared to standard, full-gland treatment with surgery or radiotherapy, patients will have less reduction in sexual function and possibly fewer irritative side effects. That probably applies to the range of focal and subtotal approaches I mentioned. There’s plenty of literature on cryotherapy with hockey stick showing that if you leave one entire posterolateral zone alone, patients will have fairly reasonable maintenance of sexual function.

Obviously patients need to be well-selected candidates in terms of prostate size, lower urinary tract symptoms, and pelvic anatomy. In other words, the selection is similar to that used for brachytherapy.

Next: What are the limitations?

What are the limitations? One that comes to mind that I’ve always been concerned about is men with a large gland, whom I’m hesitant to treat with radiation therapy or brachytherapy. Do we see the same limitation with focal therapy?

Regarding men with large glands, that may be a little more technique based. In cryotherapy and brachytherapy where templates are used, there will probably still be an upper limit of prostate size; ie, my comment regarding brachytherapy selection. In the laser and some of the other procedures that are perhaps more in-bore, MRI-based, you probably can be a little more creative about what you can access. The techniques are evolving and in some cases premature; ie, some patients may have an Artemis robot-driven biopsy, and yet their actual treatment is somewhat freehand the way it’s commonly applied.

Are there other limitations? For instance, what about bleeding and incontinence?

Those events are going to be favorable and similar to what is seen with active surveillance. Keep in mind, though, that even an active surveillance cohort will show very subtle declines in sexual function over time, but that is very minimal and probably just related to aging.

One criticism may come from high-volume surgeons who live in a world of constantly seeing image results and pathology results in the circle of planning therapy. Specifically, MRI is an estimation of what’s going on in the prostate. It does not have the precision yet that people want it to have. One particular paper in the Journal of Urology (2017; 197:320-6) used a modeling system of what a full radical prostatectomy specimen looks like, similar to 3-D printing. This was used to carve out what the MRI was showing. In their method, the authors found almost 80% of the tumor volume was outside of the line you would have drawn around the tumor based on the MRI.

Other experts debate that methodology (J Urol 2017; 198:1436-37), and that’s not for us to referee, necessarily. But high-volume surgeons know very well that MRIs can be off. That’s where the templates may make a difference. If the future is really lesion-driven therapy, we’re going to have to image better to not make a mistake. Otherwise we’re going to have to treat a lot of unaffected areas.

Whom do you consider the ideal candidate for focal therapy today?

The same question applies to whether or not we should be using biomarkers in prostate cancer, such as Prolaris or Oncotype. If you apply those to low-volume, Gleason 6 tumors, there aren’t many events already so it’s difficult for the biomarker to affect long-term endpoints. The same dynamic exists with focal therapy. If you apply it to a Gleason 6 tumor, you’ll have a hard time finding an oncologic benefit. You may be able to simplify patients’ monitoring compared to active surveillance, but you’re not going to be able to affect prostate cancer mortality.

There’s some potential for selecting Gleason 7 patients, especially those with favorable-risk, intermediate disease. These are mostly patients with Gleason 3+4 disease that can be reasonably defined in imaging and can be treated with the idea of converting their disease to a low-volume Gleason 6 tumor. If you do truly lesion-directed therapy, some satellite non-significant tumors will probably be ignored. You will have detectable PSA to interpret and you’ll probably still have to do some biopsy- and image-related follow-up testing.

The weakness of active surveillance for some patients is that they feel like they’re just waiting around for something bad to happen as opposed to proactively changing it. For focal therapy, I think most experts in the field-and some Delphi consensus panels have been published on this (Prostate Cancer Prostatic Dis 2017; 20:294-9)-have defined the intermediate, especially favorable intermediate-risk patient, as the ideal patient. I don’t think the choice of focal therapy has to be age dependent, but older age and comorbidity might make more sense.

Are we really treating these patients emotionally, or do we have good outcome data suggesting we’re making a difference with focal therapy in patients with Gleason 3+4 low-volume cancer?

The data will take time. I would lean on the surveillance outcome data from Dr. Laurence Klotz because, even in his series, the Gleason 3+4s typically have a slow pathway but when they hit that 10-year mark and beyond, there tends to be an uptick on conversion to therapy. The mortality statistics are still very low, but to the extent that frequency of biopsies could be reduced and quality of life maintained, that’s where you could probably carve out a benefit. Would biomarkers help in that space? Maybe. There is potential there as well.

Next:What do the guidelines say?What do the AUA/ASTRO/SUO guidelines say on the topic?

The guidelines on localized prostate cancer were announced and discussed at the 2017 AUA annual meeting and were published this year in two parts in the Journal of Urology(2018; 199:683–90 and 2018; 199:990–9). The guidelines basically recommend that focal therapies are not standard and really should be done on a trial. It would be fair to say a trial can be somewhat loosely defined. One definition is a direct comparative trial, which would be the best, and the lack of comparative evidence was what the AUA panel was concerned about.

A trial could also include a registry. A recent Journal of Urology paper discusses the creation of a national online registry by a group of experts (J Urol 2018; 199:1488-93). At this time, there are no data in the publication, but it shows the defined and agreed-upon endpoints of focal therapy that practitioners should be recording. From that, clinicians can start crafting questions. 

Because the guidelines state that focal therapy is actually not one of the standard treatments yet and we don’t have Level 1 evidence, what would you tell practicing urologists about counseling their patients and referring them to an academic center?

The AUA Office of Education, under Dr. Victor Nitti’s direction, has wrestled with this for a couple of years. Dr. Nitti’s question to the Laparoscopic, Robotic and New Surgical Technologies Committee, of which I am a member, is, should we be teaching focal therapy and how? We’re trying not to promote a head-in-the-sand mentality and ignore it, but we’re trying to be reasonable. We’re promoting the idea that urologists should be very aware of the science, the modalities, and how to integrate focal therapy in the discussion with standard therapies.

We’re not to the point of doing a giant live-demonstration how-to course and explaining how to roll it out in your practice. Without a doubt, patients will go online to read about this and have questions, so you should be expert on this topic. I work at a big tertiary cancer center and when I tell patients what the standards are and where we are on alternative therapies, most of them choose the standard therapy-surgery, one of multiple radiation delivery methods, or active surveillance if they’re a candidate.

If you have patients who really want to pursue focal therapy, I would determine who in your community is doing this on a registry or a trial and develop a partnership in that direction.

Is knowing this information also a benefit because we have potential competing interests in this space, including interventional radiologists and possibly medical oncologists? Since urologists have been known as the experts and the champions of this space, is it important to refer within the specialty?

As someone who was part of the early wave of robotic surgery that clearly rolled out without high-level evidence, you could draw a parallel argument. Are we holding focal therapy to a higher standard than the other treatments? It’s a question that’s somewhat fair.

But part of the reason why we need to be strict about rolling out focal therapy is that the endpoints we’ve used in prostate cancer are very long term. If you do a robotic prostatectomy, you get a pathology report and perioperative outcomes, for example. If clinicians start applying focal therapy to aggressive disease, we don’t know what that means biologically; I’ve clearly seen people come back with metastatic relapse within 2 years. Perhaps that would have happened anyway, but if that is being done with no trial or comparative registry, there is potential for harm.

Next: What happens if focal therapy fails, and what PSA criteria are you using for recurrence?What happens if focal therapy fails, and what PSA criteria are you using for recurrence?

Regarding PSA recurrence, I don’t think there is agreement on it. I don’t think you can apply the Phoenix definition because that was developed out of full-gland radiation dosage. Most of it comes out of repeat biopsy and repeat imaging. In almost all the men I’ve treated for salvage, it’s been biopsy generated. The PSA may set the stage for how concerned we are, but all patients should probably undergo a 1-year biopsy, and these are the types of parameters the registries are working on.

The salvage HIFU and cryotherapy literature would suggest that, with experts doing the salvage therapy, urinary control is probably going to be OK. I do think sexual function will take a hit. With the less and less intensive, true lesion-directed focal therapies, we don’t know yet about adverse events with salvage therapy. Hypothetically their salvage surgery might be better. Then there’s the option, as in some of the older patients who have failed, to radiate. And some of these focal therapies can be repeated.

When we talked about measurement for recurrence, you said biopsy will be critical. We have a difficult time obtaining a Gleason sum in patients after radiation. Can we still use a Gleason grading system when we re-biopsy after using the focal therapies you mention?

Yes and no. Obviously some of those recurrences are going to be out of field and valid for that reason. With some of the infield recurrences, pathologists will hedge a little bit; they’ll give you a Gleason score but say there’s treatment effect there. We do have data from salvage radiation that, even if they can’t obtain a Gleason score on radiated patients, if they see residual tumor, it is usually real, not just dead cells.

I hear there are 5 Tesla and 6 Tesla MRI scanners out there now. Will imaging change this in the future?

I think imaging will have to improve if we’re going to move to a lesion-directed philosophy. We’re going to have to see a little better. These tumors are not perfectly round circles like they appear on an MRI. The real growths tend to be very scattered, so the better you can draw out a template, the better. As surgeons, we always struggle with the fact that when we see pathology results, the dominant tumor is not always the aggressive one. It can be the second or third largest tumor foci.

Do you have any take-home messages for practicing urologists about focal therapy? Where do you see it fitting into practice?

I think the AUA guidelines will help you to define standards versus alternatives, and I recommend being well versed in that. Have a plan for how you would refer patients or perhaps your group will have a designated expert. There will be how-to courses and trial workshops. The AUA currently is sticking to more of the educational plan. I think that’s what is sufficient for now. I think this is going to be a small but growing field.