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Dr. Hashim U. Ahmed on Today’s Focal Therapy For Prostate Cancer

Dr. Ahmed is Professor and Chair of Urology at London’s Imperial College Healthcare.

His research focuses on prostate diagnosis using novel imaging and tissue biomarkers, prostate treatments that reduce the harms of traditional surgery and radiotherapy, and clinical trials and health technology evaluation.

Prostatepedia spoke with him about the current state of focal therapy for prostate cancer.

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What is focal therapy?

Dr. Ahmed: Focal therapy is about targeting the tumor within the prostate with a margin of normal tissue. The tumor is one that we believe that were we to leave it untreated, would progress, grow and spread, and impact the patient’s life at some point. By doing so, we avoid treating the entire prostate. We avoid damaging as much normal little tissue as possible. By damaging as little tissue as possible, we aim to maintain as much function as possible for that particular man, whilst at the same time treating the cancer that would otherwise cause problems in the future.

What are some of the various forms of focal therapy? Focal therapy is an umbrella term, is it not?

Dr. Ahmed: It is an umbrella term. I often joke that there’s almost like a catwalk of treatments that can be used for focal therapy. The traditional ones were cryotherapy, which freezes the tissue, and high intensity focused ultrasound (HIFU), which uses very focused ultrasound waves that heat up the prostate. You can use laser, which also heats up the prostate. You can use electrocution of the cells, which is called irreversible electroporation. There are now some new injectable drugs. You can inject hormone drugs or molecules that are activated by PSA, which then kill the prostate cells once they are injected into the prostate. There’s a lot of activity going on.

What I often say is that all of these different modalities are interesting. It’s good to see that commercial bodies are really interested in this field. That shows that the concept has real legs and everybody sees this as a big future, so that everybody’s crowding into the market. Ultimately, these are all tools, if you like— surgical instruments for me to do my focal therapy. No one tool can be applied to all tumors.

Let me take an example. If you had a big prostate with a tumor high up in the gland, there’s no way HIFU would be able to reach it. The ultrasound wave just can’t get that far. Even if it could, by the time it reached the tumor, there would be so much tissue it went through that it would lose its energy. For that particular tumor, an anterior tumor, something like cryotherapy is probably going to be better for that particular man than HIFU. A posterior tumor near the rectum, but contained in the prostate, probably does really well from HIFU at the moment, but could easily be treated in the future using these injectable drugs, if they’re to be efficacious.

Which form of focal therapy is best really does depend on where the tumor is, how big it is, and how big the man’s prostate is. Are there other characteristics within the prostate, for instance, like calcification, which means you can’t see the tumor? Those calcifications might, potentially, deflect the energy. There are a lot of other considerations, but there are quite a lot of things that you can use. I would say the two that are in pole position at the moment, just because they’ve been around for longer and therefore they have a lot of data, and the two that I use routinely in clinical practice, are HIFU and cryotherapy.

For which men is focal therapy usually an appropriate choice?

Dr. Ahmed: Firstly, focal therapy is a choice for the man who wishes to preserve or minimize his risk of genitourinary side effects like incontinence and erectile dysfunction as much as possible. You could argue that everybody wants that, but there are some men who will just have radical treatment and say to me, “I understand that I have side effects, but I just want it sorted out.” There are other men who prioritize minimizing the genitourinary impact that treatments have.

Focal therapy is also a good choice for men who have one index lesion. In other words, they have one tumor that is clinically significant, but at the same time have either no other tumors or one or two clinically insignificant cancers. In those men, we would target the main, biggest, or highest grade tumor because that is the one, studies have shown, that is likely to grow, progress, and metastasize if it was left on its own. The other, smaller, low-risk lesions are the type of indolent disease that a lot of men in the male population have that doesn’t need immediate treatment. You can monitor those after you’ve knocked out the main tumor, for instance.

You wouldn’t want to just knock out those one or two insignificant cancers while you were in there anyway because of potential side effects?

Dr. Ahmed: One of the reasons is it’s difficult to localize one or two millimeters of low-risk disease. In order to treat those, you’d have to end up treating a block of tissue. By the time you’d treated that block of tissue, or two other blocks of tissue, you’re probably at 70 to 80% of the prostate volume.

And if you do that, you might as well just target the whole thing?

Dr. Ahmed: You might as well just treat the whole thing because you’re going to cause as much damage. These small lesions are often not visible on MRI. They’re found on random, systematic biopsies, and you have no idea exactly where they are.

Another consideration is the characteristics of the lesion itself that we would want to treat. It could be one of two things: intermediate Gleason Grade 7, so 3+4 or 4+3. Or, there’s an increasing recognition that high volume Gleason Grade 6 is also something that is better treated immediately than monitored because that is also likely to progress.

For unfavorable, if you like, low-risk disease and intermediate-risk disease where there is one index lesion you can carry out focal therapy. If you can have intermediate-risk disease, which has two or three significant lesions, you would be better served having radical therapy.

What happens if a man gets focal therapy and later his cancer recurs? Can he go on to other subsequent treatments?

Dr. Ahmed: This is quite an important topic now. We know that following focal cryotherapy, focal HIFU, and some of the newer emerging focal therapy modalities that about 15 to 20% of men will either have residual or recurrent disease in the area that’s already been treated. Most of those men will be eligible to have a repeat session of HIFU or cryotherapy. Certainly in my practice, I tell men there is a one in five chance that we may have to repeat the focal therapy to the same area. Almost invariably, all men see that as just part of the intervention. I would argue having two treatments in a fifth of men is probably part of the treatment.

If they fail two treatments in that area, then they really should go on to have radical therapy, or a change in the type of treatment that you give. If the cancer has resisted 80 to 90 degrees centigrade temperature changes twice, or with cryotherapy minus 50/minus 60 degree centigrade twice, then that is an aggressive tumor. It probably has got a very aggressive blood supply and we need to change tacks.

There is a group of men who develop new lesions in untreated tissue. Some of those men can have another focal therapy, but most of them will go on to have radical therapy because their untreated tissue, if you like, has declared itself as unstable. It has a propensity to develop new tumors, and therefore, it would be better to treat the entire prostate.

About 15 to 20% of men over five to six years need a second focal therapy treatment. Overall, about 5 to 7% of men go on to have radical therapy, despite one or two focal therapy sessions. Now that is five to six-year data; we don’t have ten-year data at the moment, either from HIFU or cryotherapy. The newer modalities don’t even have five to six-year data.

Is it safe to say focal therapy is still an emerging option and that we still don’t have all the data?

Dr. Ahmed: I guess it depends on how you define that level of evidence. If we have to wait ten to fifteen years, then yes. If you argue that we’ve now got good five to ten-year data showing non-inferior cancer control, superior toxicity, or superior side effect profiles after focal therapy, then there are a considerable group of men who will accept the uncertainty of the lack of ten to fifteen-year data. They prioritize genitourinary function and they are not compromising their cancer control, at least at five to six-years median follow-up. And they can still have surgery or radiotherapy afterwards.

In the United Kingdom, in certain centers, focal therapy has been offered side by side with other radical therapies within the National Health Service, as part of the NICE, or National Institute for Clinical and Healthcare Excellence, approvals that we have.

What are some of the other controversies over focal therapy?

Dr. Ahmed: There are a number of controversies. One big controversy is this lack of ten to fifteen-year data. I was in the European Congress a couple of days ago. There was a Pro/Con focal therapy argument. I was pro and the person before me was con. He stood up and said, “We don’t have fifteen to twenty year data.” Five years ago, we didn’t have five-year data. A couple of years ago, it was you don’t have ten-year data. When we first started, they said well you don’t have any one year data on biopsies. This is the first time I’ve heard people stand up and say, well you don’t have fifteen to twenty-year data. It’s slightly amusing. It’s infuriating, as well, because the goalposts keep on changing. The long-term data will come; we’re collecting all the data in registries in the United States, the United Kingdom, and European centers. It’s all very robust data collection. We’re doing trials to see if men will accept randomization between radical and focal therapies. Those trials are tough. Men generally want to choose their therapy rather than allowing themselves to be randomized, but we’ll see.

Then the other controversies are around the areas that we touched on. What happens to the untreated tissue? So far, about 4 to 5% of men over the five to six years of median follow-up that we have in our series of several hundred cases have developed new lesions in untreated tissue. Now, those are probably just tiny bits of Gleason 7 tumors that the biopsy and MRI missed that then subsequently progressed. Some of them will be new lesions, but some of them will be disease that was missed in the first place, which declare themselves later. By ten years, it might be higher. So far it’s quite low.

One of the arguments against focal therapy is that this is a multi-focal disease. The untreated tissue is just going to show up with lots and lots of cancers, but that has not been the case, so that has been quite reassuring. The other controversy is around the point that MRI is not good enough and biopsy is not good enough. But I think both MRI and targeted biopsy are good enough. You can never be 100% in anything. If you look at breast mammography, the data shows that a negative mammogram can miss anywhere between 5 to 30% of breast cancers, yet we still use it as a screening tool. We all accept that nothing in medicine is certain. Then there’s concern about what happens to men who fail focal therapy. Can we remove the prostate, or are these men too scarred. What happens in terms of their cancer control? It’s early days yet, but certainly technically, removing a prostate after focal therapy is easier than removing a prostate after failed radiotherapy. It certainly is more scarred around the treated area, though. Does that mean men shouldn’t have focal therapy?

I would argue not because we’re giving radiotherapy to hundreds of thousands of men. It’s an accepted treatment modality, and if it does fail, it’s tough surgery afterwards. That is, unfortunately, the nature of the beast. When the first treatment fails, secondary treatments are always going to be a little bit more difficult, if not a lot more difficult.

It is difficult to perform that second surgery or men will have more side effects after their surgery?

Dr. Ahmed: The concern is both. If it’s more difficult to perform, then are they likely to suffer more side effects? And, as a result of the surgery being difficult, are we going to get more positive margins? Are they going to fail more often?

These are men whose tumors are going to be very aggressive by nature because, as I said, they resisted extremes of temperature, sometimes twice, and there are still a few cells. So they’re going to be pretty aggressive. The failure rates might be higher in that group, just because of the focal therapy paradigm. Just like radiotherapy, when you get radio-resistant cancers they are generally more aggressive and nastier cancers just by natural selection, if you like.

Do you have any advice for men who are considering focal therapy?

Dr. Ahmed: It’s very important when you are first diagnosed with prostate cancer not to rush into treatment. It’s important to do as much reading as you can and have consultations with urologists and radiation oncologists. If you haven’t been told about focal therapy, ask whether you’re suitable. You might get an answer that says, “Well, it’s not proven.” But if you are keen to explore it, you should definitely have a consultation with somebody who does focal therapy so that they can tell you first whether you are suitable, and secondly, what the outcomes might be in your case. I think every good focal therapist will share the uncertainties, as well as the certainties, around the treatment that they give.

If they’re not sharing those uncertainties, then see somebody else. It’s also very important that they quote their own data. That data, ideally, should be published in the public domain because that is a sign, first of all, that you’re being told the right outcomes for that surgeon or physician. Also, it’s a sign that physician takes their trade seriously and is constantly looking to see how they can improve, as well as sharing their data with their peers.

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Join A Trial On Focal Therapy For Prostate Cancer

Dr. Jim Hu is a urologic oncologist at Weill Cornell Medical College, where he serves as the Director of the LeFrak Center for Robotic Surgery and the Ronald P. Lynch Chair in Urologic Oncology.

Prostatepedia spoke with him about a focal therapy clinical trial that he’s running.

Join is to read the rest of this month’s conversations about focal therapy.

What is the context for your clinical trial?

Dr. Hu: If you look at breast cancer surgery about 40 years ago, for instance, some of the trials were done to demonstrate that a lumpectomy or a partial mastectomy in many cases was as good as removing the breast entirely. In prostate cancer, focal therapy or partial gland ablation is referred to often as the male lumpectomy.

The challenge for why there hasn’t been a partial gland approach with prostate cancer is the timeline of knowing differences in outcomes. If you took a whole gland versus a partial gland approach, you’re not going to see it as quickly as you might in breast cancer, where metastasis or death can occur in a shorter time. In prostate cancer, 95 percent of men who are diagnosed are still alive 10 years after their diagnosis.

In about 75 percent of men who are diagnosed, prostate cancer is multifocal, so even if on a biopsy you find it in one area, it’s not uncommon that when prostate is removed surgically, the pathologist detects prostate cancer in multiple areas. That’s also been a barrier to the use of partial gland treatments in prostate cancer, and multifocality is less common in breast cancer.

When you’re treated for prostate cancer, the blood test biomarker to determine whether you’re free of cancer is the prostate-specific androgen (PSA). In contrast to other cancers, when you’re treated for localized disease for instance, you don’t do CAT scans or X-rays to see if something has grown back or spread because the PSA is going to become detectable before there’s any radiographic signs of a recurrence. Therefore, if you only treat part of the prostate, the part that’s untreated, the normal prostate is going to continue to produce PSA. Therefore, the PSA is not going to be a meaningful marker of cancer recurrence with partial gland ablation. There are many unknowns in terms of how we should follow these patients who have partial gland ablation approaches.

What has driven the greater interest or the increased realization of partial gland ablations? MRIs are done commonly in the United States when men have an elevated PSA as a biomarker or as a predictive test beyond an elevated PSA of what the biopsy may show. This may help them forego a biopsy, but MRI’s increased sensitivity or accuracy for finding significant cancers is about 70-80%.

Fusion-guided platforms take the MRI and fuse them to the ultrasound, which allows us to better pinpoint where the suspicious area is within the prostate. These fusion-guided platforms have enabled a more accurate diagnosis within the prostate. This has led to the application of these MRI ultrasound fusion platforms to deliver energy to kill cancer cells that have been confirmed in those areas. In other countries around the world, there has been availability of one of the partial gland approaches, high-intensity focused ultrasound (HIFU).

Before 2015, when the FDA approved HIFU for treating prostate cancer in this country, it was pretty common for men who were seeking partial gland treatments to fly overseas and pay out-of-pocket for these treatments.

We know that HIFU kills prostate tissue, but we don’t know what the outcomes are for prostate cancer, and therefore, the FDA has not given a prostate cancer indication. You can’t market it as treating prostate cancer, and because of the absence of comparative data to other treatments, Centers for Medicare & Medicaid Services (CMS) will not reimburse the full amount for prostate cancer treatment currently.

Other insurances follow the lead of CMS. It’s an interesting time. There is a need for comparative effectiveness research for clinical trials that compare this new treatment option of partial gland ablation to established methods of surgery, radiation, or active surveillance.

What can patients expect to happen in the trial?

Dr. Hu: In our trial, you have an MRI and a biopsy within 6 to 12 months after you get partial prostate gland ablation. There may be a tendency for people to get treated and never come back, assuming that the treatment was successful. This would almost be like receiving a placebo and not wanting to receive bad news if cancer returns.

Typically, a clinical trial means that we’re offering a treatment to a patient. We don’t really know the long-term outcomes. Therefore, there is a defined follow-up. Participants agree to get treated so that we can study this and clear up some of the uncertainty for others in the future, and so that we can detect a cancer recurrence earlier with structured follow-up. Data and outcomes are tracked as they occur, or prospectively to ensure complete collection of outcomes. We want a control group in which the patients get standard treatment and we want an experimental or an intervention group who receives the new or novel treatment. This balances differences in characteristics such as age, race, other medical issues such as diabetes, cancer characteristics, etc.

The challenge with trials in prostate cancer is that few men would agree to having their fate based on randomization. If we said to your average American man with prostate cancer that we’ll flip a coin, and if it’s heads, you’ll receive partial gland ablation, and if it’s tails, you’ll get surgery, they wouldn’t go for it.

This is reinforced by 11 randomized trials in localized prostate cancer that have failed to recruit. In this case, its also a bit of comparing apples to oranges in the sense you’re comparing treating part versus treating the entire prostate. Therefore, the side effect profiles are different in terms of incontinence, erectile dysfunction, and so forth.

It’s a space that needs more studies because there are many men who are interested in this technique.

One of the unfortunate aspects with men travelling overseas for HIFU is that we don’t know what they’re getting. We know of instances in the United States where practitioners are marketing a laser approach to prostate cancer, and men are paying $25,000 out-of-pocket, but there are too many unknowns.

Another example is laser treatments of prostate cancer which are advertised online or on billboards. These need to be studied thoroughly. Unfortunately, the out-of-pocket nature of non-coverage by insurance distorts incentives with out-of-pocket payments for new technologies that are unproven and may not be studied thoroughly in that fee-for-service environment.

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Dr. Scott Eggener on Focal Therapy for Prostate Cancer

Scott Eggener, MD, an internationally known robotic and open surgeon, specializes in caring for patients with prostate, kidney, and testicular cancers.

He is the Director of the Prostate Cancer Program and Co-Director of the High Risk & Advanced Prostate Cancer Clinic at University of Chicago Medicine.

Prostatepedia spoke with him about focal therapy for prostate cancer.

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Why did you become a doctor?

Dr. Scott Eggener: I came around to medicine later than most people. I always had an interest in science and math. The combination of being able to use those skills to help people out and to have a component of life that combines clinical care with research was ultimately the attraction that led me down this path.

Have you had any particular patients whose cases changed either how you see your own role as a doctor or how you view the art of medicine in general?

Dr. Eggener: I try to learn regularly from my patients. The overwhelming majority of cases are fairly routine from a medical standpoint, but what makes my role fascinating are the unique elements of their background or hobbies and getting to know them.

As far as memorable experiences, there are so many standouts from both the really heartwarming celebratory side and the profoundly depressing side. When you have a practice that focuses exclusively on cancer, you’ve got the highest of highs and the lowest of lows.

What is focal therapy? Where does it fit into the spectrum of treatments available to men with prostate cancer today?

Dr. Eggener: Focal therapy is a dense topic. The bird’s-eye view is that, traditionally, any treatment of prostate cancer localized to the area of the prostate is focused on the entire prostate. Unfortunately, the prostate is in ground zero of the pelvis where there are a lot of other important structures. Any treatment, even when done by a very experienced specialist, poses a risk of short and long-term side effects. The first and most important fork in the road is whether the cancer even requires treatment. Active surveillance, monitoring the cancer, is a very attractive approach for many men with an extremely low-likelihood of cancer-related problems.

The concept of focal therapy is to only treat the part of the prostate that has the cancer and leave the rest of the prostate alone with the utopian dream of limiting the risk of cancer-related problems while trying to optimize the quality of life and minimize exposure to side effects. It’s analogous to women with breast cancer. There was a time when every woman with any type of breast cancer had a radical mastectomy. Through good science, clinical trials, brave patients, and data nowadays, somewhere between 65 and 80 percent of women get a lumpectomy. We’re in the very early stages of determining whether a similar strategy is safe and smart for some men with prostate cancer.

There are different forms of focal therapy: are some forms more effective than others?

Dr. Eggener: There are literally about a dozen different ways of ablating a part of the prostate.Focal therapy is a concept of treating part of the prostate. There are a lot of different mechanisms of trying to destroy parts of the prostate. There is not enough comparative data to say A is better than B or C is worse than D. There are some focal therapy interventions that have been studied relatively rigorously. Most have been studied in small populations of men. None have sufficient longterm follow-up, and none have ever been sufficiently compared to surgery or radiation therapy, which are the conventional and time-tested treatment options.

Is that one of the controversies over focal therapy—that there’s not enough long-term data to know which is better or not?

Dr. Eggener: There are a gazillion different reasons why focal therapy is controversial. Number one is that focal therapy turned the whole paradigm on its head in that prostate cancer is typically multifocal where about three-quarters of men with prostate cancer have multiple cancers within their prostate. Reflexively, a lot of people feel the entire prostate needs to be treated.

What we know based on elegant studies is the overwhelming majority of those other cancers within the prostate are not destined to cause any problems. There are many prostate cancers that are indolent, and if they are destined to cause problems, it’ll be years or decades down the road. Some people are fundamentally opposed to the concept of treating part of the prostate. There isn’t enough high-quality, long-term data to show whether the focal therapy paradigm is beneficial for certain men.

Conceptually, it’s supposed to be helpful, but until we have proper clinical trials, that’s just speculative. That is why there are dozens of clinical trials. Hopefully, one day we’ll have quality data. There have been a lot of companies interested because it’s attractive to patients.

The FDA has recently gotten more engaged. There have been multiple public meetings with the FDA trying to figure out how best to evaluate focal therapy. There is a swell of interest, but it’s going to take thoughtful investigators to provide the data. Unfortunately, as you know, in the landscape of prostate cancer there is often a lot of enthusiasm without data supporting it. Unfortunately, there are always charlatans willing and capable of putting the cart before the horse.

Is there anything about focal therapy that would prevent a man from getting a later treatment—i.e. a radical prostatectomy or radiation therapy?

Dr. Eggener: Conceptually, the plan is to do focal therapy and it doesn’t necessarily burn any bridges. Theoretically, the more time that passes there is an increasing chance that in certain men the cancer can spread elsewhere in the body, although if you select men well for focal therapy you can minimize those risks. Depending on the type of focal therapy that’s used, some have close to no impact on the efficacy of future treatments. There are other forms of focal therapy that are more aggressive and would impact the possibility of doing surgery or radiation in the future.

Do you have advice for men reading this who might be considering focal therapy?

Dr. Eggener: It’s exciting conceptually but we’re still in the very early stages of properly evaluating this approach. There are a range of practitioners who will offer focal therapy from very thoughtful prostate cancer experts with very selective criteria, clinical trials, and tempered enthusiasm to those on the other end of the spectrum—people who are one trick ponies who believe nearly every man they see might be a candidate for focal therapy.

My advice to people is if you’re newly diagnosed with prostate cancer and think focal therapy might be an attractive option for you, seek out someone who has expertise in prostate cancer who offers focal therapy amongst many other options and can thoroughly discuss the knowns and unknowns.

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Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

“Interest in focal therapy is fueled by the promise of cancer control with fewer side effects than are seen after radiation or radical prostatectomy. From the patient perspective, this is certainly an attractive option. As a result, we have seen the development of an increasing list of approaches to focal therapy.

There are a number of issues that make critical evaluation of the various focal therapies problematic. First, with the exception of a recent trial that involved laser, randomized clinical trials are absent. There is even a controversy about what is the best control group. The laser trial just mentioned used an active surveillance control group. The second approach would be to randomize against surgery or radiation therapy. The major problem is that such trials have proved nearly impossible to run because of poor accrual. For this reason, I suspect that focal therapies are most likely to find a clinical niche as an alternative or add-on to active surveillance.

Another issue is that we lack trials that randomize between two different focal therapies, so it is difficult to know what approach to recommend for a given patient.

For example, cryosurgery and high intensity focused ultrasound (HIFU) have both been around for many years and have never been directly compared in a clinical trial. In developing focal therapies, it is currently common practice to treat a group of patients with a new technology and then follow those patients over time. Results are reported after 1, 5, and 10 year follow-ups and comparisons made to historical results with radiation or radical prostatectomy.

However, we have long known that such comparisons with historical data are often unreliable. As mentioned above, a better, more time efficient approach would be to test focal therapies as an alternate or add on to active surveillance rather than as an alternate to radical prostatectomy or radiation.”

Join us to read this month’s conversations about focal therapy.