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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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Can You Self-Manage Your Symptoms?

Dr. Sarah Hawley is keenly interested in decision-making among cancer patients and physician-patient communication. She recently completed a study that looked at using automated voice-response technology to help veterans self-manage erectile dysfunction, urinary incontinence, bowel incontinence, and general loss of vitality after prostate cancer treatment.

Prostatepedia spoke with her about her study and its implications for men with prostate cancer.

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How did you come to focus on decision-making in cancer patients? Why patient-physician education?

Dr. Sarah Hawley: I have had a long-standing interest in cancer outcomes and delivery, growing out of my doctorate program. My postdoctorate program was in the area of cancer care delivery and quality and studying access. As part of that, I became interested in how decisions that patients make, both on their own and in collaboration with their providers, influence the care they get. I noticed that even in similar health systems there were groups of patients who got different types of care. Some people get too much care; some people are not getting enough care.

I became really interested in the role that the decision-making process plays in that. Could that be a potential mechanism for improving access and outcomes for patients? Part of that is the patient-physician communication process and the patient-physician-caregiver communication process. Many patients have loved ones who join them in making these very difficult and challenging decisions.

How did you come to be working with patients from the Veterans Administration?

Dr. Hawley: I’ve been on the faculty of the University of Michigan and an investigator in the Ann Arbor Veterans Administration (VA) center for clinical management research since 2004. When I came to this position, it was a joint position. I had not worked with veterans before. I had not worked in the VA system before, but I was really excited about the chance to study communication and decision making in the Veteran population.

As part of my career over the last 10 or so years, I’ve been able to do similar projects, both within and outside of the VA, and I have looked at veterans and non-veterans. It’s been very rewarding to be able to do that in both settings.

How common is prostate cancer among veterans?

Dr. Hawley: Obviously, the veteran health system is predominantly male. Although that has been slightly changing, especially in more recent years, it still predominantly services male patients. Prostate cancer is the most common cancer in veterans. Lung cancer remains the most commonly diagnosed cancer outside the VA.

Approximately 12,000 veterans are diagnosed with prostate cancer every year. Most of those men have early-stage prostate cancer, partly because of the use of PSA screening to identify potential prostate cancer as opposed to identifying later-stage cancer, which has metastasized. This means that the patient has to make a treatment decision about how to manage his cancer: surgery, radiation therapy, or, increasingly, active surveillance, which is an active management strategy without any medical intervention. That is a complicated and difficult decision and one that veterans face daily.

Talk to us about the study you did on self-managing symptoms after prostate cancer treatment.

Dr. Hawley: To do this study, we took a jump from the decision-making side of things to the survivorship side of things. A patient who has received a cancer diagnosis—of any cancer— makes a treatment decision early on: surgery or radiation. As I mentioned, in prostate cancer there is now the option of active surveillance. Early-stage prostate cancer is very survivable. Most of the patients live and thrive into survivorship.

However, many of them have received surgery or radiation. Both of those treatments have side effects, which are very present in the first few months following treatment. A lot of these side effects remain issues for men for months, and even years, following their diagnosis. Patients then transition from that initial treatment phase into survivorship. But there’s no clear time point when that happens. They are released back into their regular follow-up care and do quite well except for these symptoms.

Programs do not really exist, either within or outside of the VA, to help men who are dealing with these long-term symptoms.

The symptoms can include urinary and sexual symptoms. They can have problems with incontinence and pain with urination. Men can have impotence. There are also some bowel problems that men experience and general health or vitality issues.

Those are the grouping of symptoms that we were interested in trying to help improve in this long-term survivorship population. Again, this is a group that hasn’t really been the target of many interventions. All of these symptoms, to some extent, can be self-managed. There is a trajectory of less serious to more serious symptoms.

One of the things that we try to do is help the patient understand when the symptom is so serious it may need a consultation with a specialist.

How was your study structured? How many patients did you have?

Dr. Hawley: We developed an intervention, which was based on some prior work that our team had done, using automated voice-response technology: you get a phone call and can interact with the phone system, not a person on the other end. We used that approach to measure symptoms using an established measure of prostate cancer symptoms. The EPIC, or the expanded prostate cancer index, is an established measure that assesses urinary, sexual, bowel, and general health.

We programmed that into an automated system and allowed men to interact with it. After that interaction, they could choose through the automated system one of the symptoms that they felt they wanted help with. We then mailed them a tailored newsletter with information about the symptom they had chosen to focus on and what they could do at home. We also included information about when it’s more important to seek specialist care.

We also had a component of the newsletter that focused on coping. Some patients deal with these symptoms for a long time. Whether we can actually improve the symptom or not, we felt it was important to offer coping strategies based on cognitive behavioral therapy.

The intervention consisted of four automated phone call assessments followed by a newsletter over a four-month period.

What did the control group get?

Dr. Hawley: They got one newsletter, which focused on general symptom self-management. Symptoms can be self-managed. Be aware of that. These are things that you can do at home. You can talk to your physician if things get worse. The newsletter wasn’t tailored to a symptom of their choice. It didn’t include the coping strategies based on behavioral therapy approaches.

What did you find?

Dr. Hawley: The overall study was a randomized control trial. We enrolled men from four VAs and randomized them online to one of those two groups. At five months, we evaluated their symptoms using the EPIC, their confidence and their ability to manage symptoms, and then some secondary outcomes related to how they viewed cancer and their outlook. What we found in the overall comparison between intervention and control arm was a slight signal in some of the intervention measures of being better than in the control measures but nothing was statistically significant.

When we did a more detailed analysis we saw a positive effect in the intervention arm in each area that men chose to focus on. That was really exciting to see.

It suggests that this intervention can be useful in helping men improve their symptoms over time. We also found that the patients themselves thought the intervention was extremely positive. We had extremely good participation and experience rates, even in the intervention arm, which did require a fair bit of work with four phone calls over four months. We had really positive reports among the participants at the end of the intervention; they found it useful and helpful.

We even found positive reports in the control arm as well. We think some of this is probably a reflection of the fact that there just is not a lot available for this population. To be offered help, and to identify that there’s a problem and that the VA is interested in trying to help support prostate cancer survivors was genuinely appreciated by all participants, even if they only received the nontailored newsletter.

What are the implications of this study?

Dr. Hawley: An intervention like this shows promise for helping improve symptoms over time if tailored to an area of focus that the patient desires to focus on. We would like to look at this in a bigger sample and match interventions, control and a choice of symptom, which we weren’t able to do in this study.

Interventions like this are very well received in prostate cancer survivors in the VA. Enrollment rates were good. Persistence with the intervention was good. Fidelity to the intervention was good. There’s a need for some kind of program for prostate cancer survivors to help them get through these debilitating symptoms.

There’s always further work to be done. We would love to continue to refine the intervention and then perhaps roll it out to some type of dissemination or implementation study to see if we could continue to see an improvement for these patients.

What do you think are the obstacles to implementing something like this across the entire Veterans Administration?

Dr. Hawley: The obstacles are the same for any system the size of the VA. It’s more of a technology system challenge, I think, which is always there for any health system. I think if it were solved, veterans would use it.

Do you have any final thoughts for patients about self-managing symptoms?

Dr. Hawley: Management of symptoms is possible. Self-management is one way to manage symptoms, and for some better than others. I encourage patients to keep having conversations with their providers if they’re not satisfied with the management that they experience.

Finally, I’d like to acknowledge the critical input of Dr. Ted Skolarus, Section Chief of Urology at the Ann Arbor VA. I would also like to acknowledge the study team in Ann Arbor, as well as the 4 study sites—the VA Ann Arbor Healthcare System, the St. Louis VA Medical Center John Cochran Division, the Louis Stokes VA Medical Center, and the VA Pittsburgh Healthcare System University Drive Division.

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