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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.

Not a member? Join us to read the rest of this month’s conversations about focal therapy for prostate cancer.


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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.


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Join A Clinical Trial For Biochemically Recurrent Prostate Cancer

Dr. Rahul Aggarwal is an Associate Clinical Professor of Medicine in the University of California, San Francisco Genitourinary Oncology and Developmental Therapeutics programs. He’s keenly interested in developing novel therapeutics and imaging strategies for men with advanced prostate cancer.

Dr. Aggarwal is a Co-Investigator in the ongoing Prostate Cancer Foundation’s Stand Up To Cancer-funded West Coast Dream Team prostate cancer consortium.

Prostatepedia spoke with him about his clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer.

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What is the thinking behind your clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer?

Dr. Aggarwal: This trial is for patients with prostate cancer who previously had what we call a radical prostatectomy, or the prostate was removed, as their primary treatment and then subsequently had evidence of cancer recurrence as indicated by a rising PSA. We’re specifically looking at patients with a PSA that is rising quickly with a PSA doubling time of nine months or less.

We know that this group of patients is at risk for subsequent development of metastases as well as at risk for prostate cancer-related mortality. One standard treatment approach is to use intermittent hormone therapy, which can suppress the cancer for a period of time. Inevitably, though, the cancer becomes hormone or castration-resistant.

Once that happens, patients have fewer treatment options remaining and a shorter prognosis.

The main goal of the study is to use some of the more potent hormonal therapies that have been developed, including Zytiga (abiraterone) and Erleada (apalutamide). and apply them to this situation to see if we can durably suppress the patients’ prostate cancer in a finite period of treatment. Rather than treating indefinitely, we treat everyone on the study for 12 months, and then we stop and let their testosterone levels recover and any side effects related to hormone therapy stop or lessen. Hopefully, we can see long-term control of patients’ PSA levels or maybe for some prevent the need for future treatment.

In this way you would also lessen some of the side effects associated with these treatments?

Dr. Aggarwal: Exactly. Then the total duration, or percent time, spent on hormone therapy would be shorter. Even though we’re giving more potent hormone therapy, this would actually translate into less overall treatment and less medical burden from a side effect perspective. Some of the other studies that have come out using medicines like Zytiga (abiraterone) and Erleada (apalutamide) in the hormone sensitive or castration resistant settings do seem to suggest there is a benefit to giving these medicines earlier in the treatment course. I think it fits with what we’re seeing in terms of the general trends in the use of these medicines and the management of prostate cancer.

What can a patient expect to happen step by step if he ends up participating?

Dr. Aggarwal: The treatment phase of the study consists of monthly visits for a year in which patients are getting hormone injections. Then it is a randomized study, so in the standard of care arm men would be getting the hormone injections alone once a month for a year. Then there are two experimental, or investigational, arms with added hormonal therapy. One arm has added Erleada (apalutamide). The third arm adds Erleada (apalutimide) plus Zytiga (abiraterone).

Patients have a two in three chance of being on one of the added hormonal treatment arms.

This is an open label trial, meaning there is no placebo. Everyone will get active treatment, so there’s no risk that their PSA levels won’t go down. Every patient responds initially to hormone therapy, or nearly everyone. We see patients monthly for hormone treatments. We evaluate them for side effects. At four or five time points throughout the study, we have patients fill out questionnaires regarding their symptoms. We do want to understand from a patient perspective what quality of life and symptoms are like during the course of treatment.

After one year of treatment, assuming the PSA is not rising, patients will then enter a follow-up phase which we try to make easy. We check patients’ PSA and testosterone levels once a month, but we don’t require any mandated in-person visits to allow more flexibility for those who live far away from the study center where they were treated.

At the time that the PSA rises to above 0.2, that’s the cut off for what we call PSA progression, which is the primary endpoint of the study. After that treatment is per the discretion of the patient and treating doctor. We still follow patients long term for metastases free and overall survival. The treatment options at that point are completely up to whatever is decided upon between the patient and his doctor. It’s flexible on the backend too if his PSA were to rise.

Join us to learn more about Dr. Aggarwal’s trial and how to participate.


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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Clinical Trial: Exercise For Metabolic Dysregulation After Prostate Cancer

Dr. Christina Dieli-Conwright is an Assistant Professor of Research in the University of Southern California’s Division of Biokinesiology and Physical Therapy.

She’s particularly interested in understanding physiologic mechanisms and designing exercise interventions for cancer patients.

Prostatepedia spoke with her about her clinical trial.

What is the thinking behind your clinical trial?

Dr. Dieli-Conwright: This study spawned from my interest in the side effects and changes that patients were experiencing as they underwent treatment. For some of the more prevalent cancers like breast, prostate, and colorectal cancer, there is literature to provide evidence that individuals are experiencing what I broadly call metabolic dysregulation, which encompasses things like gaining weight, insulin resistance, elevated inflammation, and elevated blood pressure.

Whether they have metabolic dysregulation before diagnosis or whether it develops during treatment, they are at higher risk for experiencing diseases like heart disease, diabetes, and obesity. In prostate cancer in particular, when men are prescribed androgen deprivation therapy, there are side effects to that therapy that lead to metabolic dysregulation.

If you look at individuals who exercise who have not had cancer, we know that exercise can successfully offset metabolic dysregulation. It can improve insulin resistance. It can reduce body composition changes, etc. We wanted to apply exercise to this particular population so that these patients may also experience the benefits of exercise.

If a man who’s reading this ends up participating, what can he expect to happen step by step?

Dr. Dieli-Conwright: This is a randomized controlled trial. Individuals will be randomized to either the exercise group, and receive a 16-week, 3 times a week exercise program immediately, or the delayed controlled group. Everybody eventually gets the exercise program, but the “exercise group” gets it first. The delayed controlled group gets the program 16 weeks later.

We ask them to come to our facility, which is here at University of Southern California, to exercise. We pair them one-on-one with a certified cancer exercise trainer. They perform both aerobic and resistance exercises for about one hour every time they come. They perform the exercises in an interval circuit training, high-intensity manner. We’ve done that so that we can really challenge the metabolic systems for energy balance that have been shown to be more effective at targeting metabolic dysregulation as to opposed, for instance, just walking on a treadmill for 60 minutes.

We do a number of tests at the beginning, middle, and end of the 16 weeks. Those tests involve a blood draw so that we can measure glucose and insulin, as well as triglycerides, cholesterol, and markers of inflammation. We measure blood pressure, waist circumference, and body composition so how much muscle and fat the patients have. We also measure bone density. We do a battery of what we call physical function tests: how fast can the man climb upstairs? How fast can he walk six meters? How many times he can sit to stand? We do what we call a cardiopulmonary exercise test to test their maximal fitness and we do a series of strength tests to see how strong their muscles are.

We give them a packet of questionnaires about quality of life, fatigue, depression, and other cancer-related symptoms.

We are measuring the whole gamut of health outcomes even though our main focus is on insulin resistance and metabolic dysregulation simply because that’s the precursor to diabetes and heart disease.

We retest those measures at Week 8 and Week 16. We do follow participants after the 16-week period is over. Regardless of what group they were in, we check on them four months later to see how they’re doing.

Are there any specific eligibility criteria that you want to call attention to?

Dr. Dieli-Conwright: The main thing is that they’re over the age of 18 and that they have been on androgen deprivation therapy for the previous 16 weeks. That’s just so that we can allow the medication to stabilize the hormones. We also look to see whether or not they have been exercising regularly. If they are highly trained from a fitness perspective, then they are not eligible, so we do actually look for people who are relatively sedentary who are not participating in a structured exercise program already. We do that because we are trying to reach out to people who may be at a higher need for these interventions.

Do you care if a man has had surgery or radiation for prostate cancer?

Dr. Dieli-Conwright: No, we do not, as long as the surgery or radiation is completed. If they’re actively on radiation or actively on chemotherapy we would wait until that treatment is done. Often we get calls from patients who are very enthusiastic and eligible, but then tell us they’re starting radiation next week. We have to wait until that treatment is over and they’re cleared by their oncologist for exercise.

Is there anything else you’d like patients to know either about this trial in particular or about exercise for cancer patients in general?

Dr. Dieli-Conwright: We’ve had a number of patients participate already. It’s been very successful. It’s safe. It’s feasible. Everybody’s enjoyed the program. We’ve had very high compliance to date—almost 100%.

But it’s a strong time requirement—3 times a week for 16 weeks—so I would just say that if anybody is interested, even if it’s just a small amount, to contact us. We have very flexible scheduling times and can accommodate exercise almost 24/7. We have a large staff and a number of trainers who are eager to help. We try not to turn anybody away because of scheduling and try to work around work schedules if that’s a concern.

We would love to take more patients.

Subscribe or download our February issue to read more about this trial.

 


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Clinical Trial: Cardiovascular + Lifestyle Interventions For Prostate Cancer

Dr. Darryl Leong is a cardiologist and Assistant Professor in Medicine at Canada’s McMaster University. He’s particularly interested in the prevention, identification, and management of cardiovascular disease in those with complex diseases. He is also leading the development of a clinical research program for the evaluation and treatment of cardiovascular disease in patients with cancer at Juravinski Hospital.

Prostatepedia spoke with him about the RADICAL-PC clinical trial, which is a randomized intervention of cardiovascular and lifestyle risk factors in prostate cancer patients.

Why did you become a doctor?

Dr. Leong: Within a generation, our society has added 20 years of lifespan. This is consistent whether it’s in wealthy countries like the United States and Canada or in developing countries. We have been really successful in a short time at prolonging people’s lives, and so the science that went behind that was really interesting to me.

When you look at the history of the world, in hundreds of millions of years, I don’t think any species has seen such a lengthening in their life expectancy in such a short period of time. I hope to build on that with our research and help to improve not just life expectancy but also people’s quality of life.

Would you tell us about the thinking behind your clinical trial?

We read some papers that came from the United States and Europe that suggest two things. First, men with prostate cancer seem to have quite a high risk of developing cardiovascular disease, heart attacks, and strokes during the course of their follow-up.

Second, there might be a link between (hormonal) androgen deprivation therapy (ADT) and the occurrence of these sorts of cardiovascular events. So, our thoughts turned to cardiovascular disease and prostate cancer. We proposed a study to the charitable organization Prostate Cancer Canada that supports research to understand why this link exists. We were fortunate enough that Prostate Cancer Canada agreed to fund our proposal, and so that’s how we came to study over 2,000 men with prostate cancer in Canada.

We’d like to expand this research internationally because we know that what happens in one country may not necessarily reflect what’s happening in another country. We have ongoing efforts to try to expand.

What will you be doing in the study? Should a man reading elect to participate what can he expect to happen?

Dr. Leong: One level of involvement, which we would ask of anyone who is interested in being involved in the study, is that we collect information about you, and we follow up with you over time. We hope that period of time will be at least another three years. If we are successful in getting more funding, we’d like to make it long term.

At the beginning, we collect information about health, cardiovascular disease, and risk factors that people have today, as well as information about physical characteristics, muscle strength, fitness, and a range of factors like that. Then we follow up with folks over the years to see if people develop cardiovascular disease or heart attacks and strokes and what predisposes people to these complications.

In addition to monitoring for cardiovascular disease, and because this is an opportunity to see whether we can make a difference to the cardiovascular disease rates in men with prostate cancer, we decided that people within the RADICAL-PC who give consent would be randomly allocated into one of two groups.

One group would receive usual care. Their medical care would not be changed at all. They would continue to see their general practitioner and their cancer specialist. The other group would be allocated to see a cardiologist on top of their usual care. The cardiologist would be instructed to provide very focused interventions to reduce cardiovascular risk. So, this is a trial built into the RADICAL-PC trial to see whether or not we can reduce cardiovascular events in these men.

Are there any specific eligibility criteria?

Dr. Leong: The criteria are simple. All we ask is that they’re over 45 years of age, and that either their prostate cancer has been diagnosed within the past year, or they’ve started hormonal therapy within the past six months or have a plan to start it in the next month.

To learn more about this trial, read our February issue.


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Join A Clinical Trial: Casodex (bicalutamide) + Metformin

Dr. Marijo Bilusic is the director of the National Institutes of Health (NIH) Hematology Oncology Fellowship, and an Associate Research Physician in the Genitourinary Malignancies Branch, Center for Cancer Research,

National Cancer Institute (NCI). He’s keenly interested in tumor immunology and in developing prostate cancer treatments using novel target agents, therapeutic cancer vaccines, antibodies or immune modulations.

Prostatepedia spoke with him about a trial he’s running that looks at men with prostate cancer on Casodex (bicalutamide) with or without metformin.

Not a member? Join us!

Would you walk us through the thinking behind your trial looking at Casodex (bicalutamide) with or without metformin?

Dr. Marijo Bilusic: A former prostate cancer patient of mine had had surgery and his prostate was removed. Then his PSA kept rising, and he was not very keen about hormonal therapy, which was recommended by other oncologists he’d seen before me. I met him, and we talked about what to do. “We’re just going to observe you for now,” I said. “Try to exercise, lose some weight, and make healthy lifestyle changes. We’ll see you back in three months, and we’ll see what your PSA’s doing.”

In three months, he came back, and his PSA was 50 percent less than before. It went from 4 to 2.

I was impressed. I asked him, “What did you do?” “I followed your instructions.” “Lots of people follow my instructions,” I said, “but I’ve never seen anybody have PSA decline just with exercise and diet change. Any other changes from the last time we met?”

“I’ve also been taking metformin,” he said. “I read that metformin can help people with prostate cancer and asked my primary care physician to prescribe it, even though I was not diabetic.” It’s important to note that metformin is not something that we would recommend to prostate cancer patients outside of a clinical trial, yet. That’s why we’re running this study-to learn more about how metformin works and who it may work for.

I was surprised, and grew curious about a potential link. After that, I did a literature review. I found one population based observational cohort study that included around 38,000 men with prostate cancer and diabetes from Ontario, Canada. Authors reported that metformin treatment was associated with decreased prostate cancer mortality: 24% reduction for each additional 6 months of metformin use while use of other anti-diabetic medications did not significantly decrease mortality. This was a very interesting study. Two prospective studies tested metformin in non-diabetic patients with prostate cancer. First enrolled 42 patients with castration resistant prostate cancer who were treated with metformin, 1,000 mg twice daily. Two patients had ≥ 50% PSA decline and in 23 patients (52.3%) had a prolongation of PSA doubling time. Another study enrolled 24 men with newly diagnosed prostate cancer that were treated 500 mg of metformin three times a day before the surgery (neoadjuvant treatment). Metformin reduced

Ki67 proliferation index by 29%, compared to the baseline biopsy, meaning that the cancer became less aggressive with metformin use of about four weeks. That was very interesting.

Nobody knows how metformin works, exactly. Some studies have shown metformin also could help patients with breast cancer and pancreatic cancer, and also observational studies have shown decreased risk of the incidence of cancer, suggesting that metformin can help prevent cancer.

Though we are still trying to understand how metformin works, we do know it’s inexpensive and it’s very safe. Instead of having a treatment of prostate cancer that costs more than $100,000, it would be great to have one that costs only a couple of dollars. We’re not there yet, but we’re hopeful that this trial and others like it will help us continue to learn more about how to best treat prostate cancer.

To learn more about when metformin may work, we came up with the study design to test metformin in combination with Casodex (bicalutamide), an FDA-approved agent for prostate cancer. We selected Casodex (bicalutamide) because testing of this combination using animal model showed the synergistic effect of Casodex (bicalutamide) and metformin. The side effects profile is much better than from Lupron (leuprolide), so we thought that would be a reasonable alternative for people who have biochemically recurrent prostate cancer with rapidly rising PSA.

What can patients expect to happen in the trial?

Dr. Bilusic: First, we have to make sure they’re eligible. When they contact us, we determine if they have a biochemical recurrence, which we define as somebody who’s had prostatectomy followed by two rising PSAs above 0.2. If PSA doubling time is between three and nine months, those patients are potentially eligible for this trial.

We are also looking for people who are not diabetic, but they should have a BMI of 25 or more because the mice models we tested were obese, and one of the side effects of metformin is weight loss. We did not want to give somebody who is skinny to start with a drug that makes them lose weight. Eligible participants should also not have their testosterone suppressed by hormonal therapy. We don’t allow prior hormonal therapy, unless it was given during the primary treatment as an adjuvant or neoadjuvant therapy.

Those are the main inclusion criteria: BMI more than 25, no history of diabetes (hemoglobin A1C should be less than 6.5), testosterone more than 150, no prior hormonal therapy, and PSA doubling time is three to nine months. Then we’ll do a CAT scan and bone scan to confirm they don’t have metastatic disease.

Once we determine they are eligible, we randomize them to one of the two groups. One group (control arm) will receive observation for two months, followed by Casodex (bicalutamide) alone for 6 more months. The other group will receive metformin alone for two months, followed by a combination of metformin and Casodex (bicalutamide) for 6 months. Because Casodex (bicalutamide) doesn’t deprive testosterone, people have normal levels of testosterone, or sometimes higher levels. The total duration of treatment is 8 months or 32 weeks.

They come here to the NIH clinical center once a month, where we do blood work, a doctor evaluation, and we provide medication. During the trial, in addition to regular blood work, we research blood at the start, at the beginning of cycle three, and at the end of the trial. We’re trying to understand the mechanism of how metformin works.

I know that you supply the medication, but are there any fees associated with participating in the trial?

Dr. Bilusic: No, there’s really nothing else for the patient. Everything is provided, and all the care here at the NIH Clinical Center is free. Once a patient is enrolled on one of our protocols, we also support their trip to the NIH Clinical Center, so patients can come from all over the United States. We also provide a stipend for a hotel if they have to stay overnight. And we give them a meal voucher.

Subscribe to learn more about Dr. Bilusic’s trial as well as others.