Dr. Arvin George discusses state of focal therapy, outlines 2 clinical trials

In this interview, Arvin K. George, MD, gives an overview of the current state of focal therapy and also discusses 2 clinical trials evaluating new technologies in the space.

With emerging new technologies and evolution of current modalities, focal therapy for the treatment of prostate cancer remains a vibrant field. In this interview, Arvin K. George, MD, gives an overview of the current state of focal therapy and also discusses 2 clinical trials evaluating new technologies in the space. George is an assistant professor of urology at the University of Michigan, Ann Arbor. He was interviewed by Ardeshir R. Rastinehad, DO, system director for prostate cancer at Northwell Health, and the vice chair of the Smith Institute for Urology at Lenox Hill Hospital in New York City, New York.

How do you define focal therapy?

When I think about focal therapy, it encompasses a very broad category. When we get into the semantics of it, there's different terminology regarding partial gland ablation or subtotal ablation. What it boils down to is treating the cancer that we know exists, and generally it's the cancer that we can see, applying a margin around that treatment area to be able to destroy the presence of any clinically significant prostate cancer.

The advantages are really clear. It's the difference in side effects after treatment, and more specifically, the preservation of urinary, sexual, and bowel function. With our conventional treatments, I think that we have, to some degree, been punished for the side effects that arise from either surgery or radiation in an effort to be able to control a cancer that in some cases may not warrant such an aggressive treatment.

Ardeshir R. Rastinehad, DO, is system director for prostate cancer at Northwell Health, and the vice chair of the Smith Institute for Urology at Lenox Hill Hospital in New York City, New York

Ardeshir R. Rastinehad, DO, is system director for prostate cancer at Northwell Health, and the vice chair of the Smith Institute for Urology at Lenox Hill Hospital in New York City, New York.

One element I would like to clarify for our readers; when you say "see" the cancer, you're not referring to seeing by the naked eye. How do we visualize and detect prostate cancer today?

Our advances in cancer treatment have largely paralleled our advances in imaging. The better that we're able to see and identify the cancer, the better that we are able to offer more effective and more minimally invasive treatments. The cornerstone has historically been ultrasound, but that has shifted now to multiparametric prostate MRI. The ability to look at functional sequences, or the movement of water in tissue and blood flow to an area, has enabled us to both localize a prostate cancer and also better risk stratify it. If we can see it, we can biopsy it very precisely. Then we can understand, what is the true aggressiveness of that prostate cancer that that patient has? Moving forward, we have next-generation imaging, specifically PSMA PET, or prostate-specific membrane antigen, PET-CT or PET-MRI. This essentially is a radioligand that is targeted to the expression of prostate-specific membrane antigen that really improves the sensitivity and to a large degree, the specificity, of our cancer detection and staging.

In general, what are your optimal focal therapy candidates, and who do you consider to be enrolled into your trials? What type of patient are you looking for?

I think that varies geographically. In Europe and in Australia, they have accepted that we can treat higher risk patients. Within the US, we're a little bit more conservative. We're looking for a sweet spot—identifying prostate cancer that requires treatment or that has lethal potential, and secondly, ensuring that we pair the treatment with the disease aggressiveness. More

Arvin K. George, MD, assistant professor of urology at the University of Michigan, Ann Arbor

Arvin K. George, MD, says, "Our advances in cancer treatment have largely paralleled our advances in imaging."

aggressive cancer would require a more aggressive treatment. A less aggressive cancer may require no treatment at all. In the middle, we have a large proportion of patients in whom the vast majority may outlive their cancer. At this time, we're not able to reliably identify those men. So when you ask me, "what is the ideal candidate?" it would be somebody who has imaging-visible cancer, and that it is away from vital structures, it has the absence of high-risk features such as extracapsular extension or seminal vesicle invasion, and also that it is amenable to ablative therapy.

It's really exciting to hear that we're expanding the indications for focal therapy. As you know, the group with Mark Emberton [MD, FRSC (Urol), FMedSci], et al at University College London looked at this in their prostatectomy patients, and they found that almost 40% could have benefited from a possible focal therapy option. What are some of the commonly used focal therapies that are currently on the market for the general urologist to get into and start utilizing?

The 2 dominant technologies are cryoablation, which has been around since the 1970s, and also high intensity-focused ultrasound ablation [HIFU], which was FDA approved in 2015 for prostate tissue ablation. These have really served as the workhorses for ablative treatments for a couple of reasons. One is that they are in guidelines for salvage treatment after radiation. Two, they are now consistently reimbursed, making them financially viable and accessible for patients.

Geographically, the Northeast does not allow HIFU reimbursement yet. When you perform focal therapy, how do you follow these patients after you tell them that they have a lethal cancer, they may die from the disease, and they need some intervention? What are some of your metrics for treatment success?

In terms of follow-up, it's very similar to an active surveillance protocol. We rely on PSA [prostate-specific antigen], even though we may not at the current time understand the true aspects of where PSA fits in in surveillance. We know that going down is good and going up may be bad. We also rely heavily on imaging; specifically, looking at enhancement of blood flow within a treated area. And finally, biopsy—that histologic confirmation of the treated area showing that there is no viable or residual cancer—is really what's going to prove that we are delivering an effective oncological treatment. Those are the 3 key aspects of surveillance and follow-up. There are different intervals at which you can do it. In general, in my practice, I will biopsy a patient at 6 months post-ablation, I'll get a PSA every 3 months for the first year, and then every 6 months thereafter. I perform MRI as well. After the initial period post treatment, we can deescalate and reduce intensity in terms of imaging and PSA and biopsy. That, I think, is consistent with the US paradigm. In other countries, the paradigm is more of a for cause, so if there's a rise in PSA or persistent suspicious areas on MRI, that would warrant additional interrogation with a biopsy or potential repeat treatment.

As we know, this is a new and up and coming field. The Focal Therapy Society is a group of people who have been dedicated to fostering this technology and nurturing it going forward. You and others have helped design a registry to look at outcomes, so hopefully we have more real-world patient data from the community as well as academic practices to move this field forward. You are a PI on 2 new technologies that are emerging in the focal therapy space. Let's start with irreversible electroporation [IRE]. What is the mechanism? How does IRE work?

You're referring specifically to the PRESERVE trial, which is the pivotal FDA trial seeking 510(k) approval for prostate tissue ablation for IRE. IRE is the application of an electrical field across tissues between 2 electrodes. That generates pores in the cells and induces apoptosis. There are some unique potential advantages to IRE, including preservation of architecture. IRE preserves the scaffolding or connective tissue, so it can treat closer to the nerves across the urethra.

The second advantage is it's largely athermal. Because it's athermal, meaning it doesn't rely on either heat or cold to be able to destroy cancer, it is not going to be susceptible to mechanisms of failure such as thermal sink. If, for example, you are close to the dorsal venous complex, that is essentially warm blood that's going through, and then that can prevent you from achieving a lethal temperature. During cryotherapy, when you have a urethral warming catheter, that's going to preserve about 3 mm of tissue circumferentially around the urethra. It can be difficult to freeze deeply into that area if your tumor is there or if you need to achieve a margin in that location.

How many sites are currently open and what is the eligibility criteria?

For the current trial, there are about 7 to 8 sites that are currently active. The goal is to have a total of 20 sites that are actively accruing. A number of sites are working on their process to get approved and up and running. The criteria for this trial is image-directed targeted biopsy confirmed, Gleason Grade Group 2 and 3 prostate cancer. We do allow for a small volume or a single core of Gleason Grade Group 1, up to 6 mm outside of the treatment field.

Do you think a cognitive biopsy has any limitations when compared with MR fusion technology in stratifying the risk for patients undergoing focal therapy?

There are 2 aspects of this. The first aspect is, do you have an equivalent diagnostic potential for cognitive vs software-based or in-bore fusion biopsy? That has been demonstrated to be equivalent across most categories. In very large prostates and very small lesions, there may be benefits to software-based fusion, but largely, there has been a randomized trial that's been performed that randomly assigns men to either fusion-guided, cognitive, or in-bore biopsy, which really did not highlight any differences. Now, that's a different question than its ability to inform or guide treatment. I think there are some advantages because you can spatially understand the location of the cores that are positive and also non-targeted cores and whether they are spatially concordant with what was visible on MRI. It does offer some advantages, but often, when you apply both the treatment of the index lesion plus the margin, the goal would be for that margin to be able to help address any registration error or other factors that could limit your diagnostic potential otherwise.

My challenge with that is that when you work with multiple people, not everyone is the same cook in the kitchen. The fusion systems allow for video archiving and 3D data to be moved across the patient's care cycle, and I think that really has a benefit in understanding this technology. Those are the challenges that we deal with every day in focal therapy. We are one of the sites here at Northwell working with on the IRE trial. As we go through these technologies, how do you feel you can overcome the learning curve with adding these new technologies and the new approaches at different sites? How are you approaching this? How are you going to maintain quality in the trial?

For the trial, specifically, there are a couple of things. One is that your ability to perform fusion and your volume of fusion biopsies is going to help you immensely. Certainly being familiar with the transperineal approach, which is the technique in which the electrodes would be placed. There are training sessions that are available for both investigators and non-investigators that are hosted by AngioDynamics. There is also the ability to have online training sessions, where you understand the technology and the mechanism of action behind it, so that gives you that foundation. And then finally, learning from more experienced users. Prior to selecting a case, we have what is essentially a tumor board, where we review the case prior to determine whether it is an appropriate patient for the trial. Then also, we can help with treatment planning for more experienced users. My experience with IRE is quite limited, so I lean heavily upon other providers who have a lot of experience with IRE. You can have an expert clinician proctor available during your initial treatments to help facilitate getting over that learning curve.

What are potential adverse events associated with IRE?

The large proportion of them are going to be consistent with what you would see with any ablated modalities. Low grade would be hematuria or urinary symptoms, like urinary frequency, urgency, or lower urinary tract symptoms. There is of course a risk of infection. Epididymo orchitis is very common in ablation in general. You could potentially result in stricture, especially if you perforate the urethra. There is some thermal energy that will happen immediately adjacent to the probe. Being careful to maintain a safe distance away from the rectum would be important to prevent any rectourethral or rectoprostatic fistula. Those are the main adverse events from a procedural standpoint.

Then there are the functional side effects. That's going to be urinary leakage, which is relatively uncommon with any focal ablation on the order of less than 3% to 5%, even lower than that in most cases. Erectile function is an important aspect. A lot of times, the reason why patients seek focal therapy is to preserve their sexual function. I commonly tell patients there is no treatment for prostate cancer that will not affect your erectile function. Most of these ablative technologies will have the least impact on sexual function compared with the standard of care, radical therapies.

What is the study’s end point?

Biopsy is the ultimate end point. That biopsy at 12 months will let us know whether we have adequately treated that tissue and adequately ablated that tissue. There is a coprimary end point for safety in terms of adverse events, and also a number of secondary end points looking at functional outcomes; specifically, urinary leakage, sexual function, etc.

Let's talk about the VAPOR 2 trial. Can discuss that trial and how that technology works?

We're quite early in terms of development of the protocol. The trial will be called the VAPOR 2 trial. The name of the device is Vanquish. It is essentially water vapor ablation using radiofrequency energy to heat up water to the vapor state, and using that energy to be able to ablate tissue. It does conform to the capsule of the prostate. They have overcome the ability to just treat the transition zone and actually penetrate and go into the peripheral zone. It's the same concept for what we commercially use as Rezum for benign prostatic hyperplasia. Similar technology is now being applied for ablation of prostate cancer.

When do you think you're going to be enrolling your first patient in the VAPOR 2 trial?

That's a good question. I can't give you an exact date, unfortunately. We’re waiting on feedback from the FDA. Once we have some clarity on that, we'll have a better idea of when we'll be able to get started enrolling. Certainly, for any new company, the sooner the better in terms of getting started.

What impact do you think imaging will have on the future of focal therapy?

With regards to the future of focal therapy, I believe the future is bright. The reason I say that is because from a scientific perspective, every question still needs to be answered. We need to understand how PSA is well utilized, certainly how imaging is utilized, and whether we can rely on imaging exclusively or whether we need to continue to require histologic confirmation. I think that we will start expanding the indications into higher risk disease after seeing some of the real-world evidence and prospective series that have been published outside of the US. You alluded to a recent publication from approximately 20 to 22 sites within the UK performing Sonablate HIFU. They presented data from 13,079 patients with almost 15 years of experience with a median follow-up of 32 months. In those who had greater than 5 years follow-up; 82 months was the median follow-up for those patients. We're starting to get longer-term outcomes.

What's well established is that the functional outcomes are incomparable. There is nothing currently that would be able to exceed the outcomes of focal ablation with regards to continence and erectile function. Where we now have to maintain our focus is the oncological outcomes—identifying the right patient for the right treatment and generating that body of evidence. Again, I would like to stress the Focal Therapy Society's registry. The goal for that is to be able to accumulate our outcomes and our data. The FDA has signaled that they are more than willing to incorporate real-world evidence to help guide regulatory decisions. It is essential to not just do it, but also to do it and record your outcomes judiciously. We can certainly help facilitate that with the Focal Therapy Society.

When you try to identify the correct patient for trials and treatment, the challenge is that once patients hear about focal therapy, that's almost the only thing they want to hear about. Because the alternatives are surgery and radiation, with the incontinence and erectile dysfunction that are associated with whole-gland therapies, it poses a real challenge for a patient wanting to go down that route when these technologies are available. Patients might say, 'oh, that's just a little bit outside the prostate, you can still treat the area,' and some technologies can. The question is, is that an oncologically viable way to move forward? How do you let patients down when they have their hearts set on focal therapy? It's a tough position to be in, and unfortunately, in our space, they can always find someone that's willing to do it. How do you let them down?

It is extremely difficult because a lot of patients are coming to me, seeking that treatment in mind, but not looking at the big picture. Not everybody is the right person for this treatment. What I tend to tell patients is that it's important to understand that it's not the right treatment for every patient, and if you're not the right patient for the treatment, it's not going to align with the expectations. At the end of the day, this is a cancer treatment. As much as we need to preserve function, we need to ensure that we have an effective cancer treatment. The challenges being that guidelines, panels, and the [American Urological Association] and other associations ask for comparative evidence. It's extremely difficult to provide comparative evidence, first, because as you mentioned, it's extremely difficult to accrue 2 randomized trials for whole-gland vs focal ablation. Second, it's very difficult to find a common primary end point that can be achieved within a reasonable amount of time. Those are continued discussions. Currently, we are using biopsy as a surrogate, but certainly the avoidance of radical or whole-gland treatment, the development of metastasis or clinical progression, death from prostate cancer, these are all metrics that we will look at even though they are further down the line.

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