Conversations With Prostate Cancer Experts

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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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Cardiovascular Disease + Prostate Cancer

Dr. Pedro Barata is an Assistant Professor of Medicine at the Tulane Cancer Center. He’s keenly interested in genitourinary tumors with a particular focus on clinical trials.

Prostatepedia spoke with him recently about the intersection between cardiovascular disease and prostate cancer.

Not a member? Join us to read the rest of this month’s conversations about heart health and prostate cancer.

Why do we even talk about cardiovascular disease when it comes to prostate cancer? It doesn’t come up with lung cancer, so why does it in prostate?

Dr. Pedro Barata: When we think about cardiovascular events, it’s actually a growing topic in this field. As treatments get better and better, patients live longer. Some develop cardiovascular events because they just live long enough to experience those long-term toxicities.

In regard to prostate cancer, it’s usually in relation with hormonal therapy. For context, prostate cancer is a hormonally driven disease, and so its tumor growth depends on androgens. We’ve been using surgical castration or androgen deprivation therapy (ADT) to treat men with prostate cancer for several decades. We have been doing this to treat prostate cancer since the guys who discovered this got a Nobel Prize for it in the 60s. There’s a clearer connection between cardiovascular disease and ADT.

Explanations for this increased risk include metabolic changes, such as hyperglycemia, or dyslipidemia, and factors in relation with arteriosclerosis. This has been an ongoing discussion, to determine why ADT is correlated with increased risk for a cardiovascular event and what we can do to prevent that. We use ADT in localized disease combined with radiation therapy. We use it in the biochemical recurrence space. We use it in the advanced setting. And we also have other therapies called novel androgen inhibitors, such as abiraterone or enzalutamide, to explore this pathway. All of these hormonal manipulations give an increased risk for cardiovascular events.

On the other hand, there’s radiation, which is not a strong risk factor in prostate. In the majority of the cases, we end up not irradiating the chest, and so you don’t have an increased risk for cardiovascular events as compared with lung cancer or breast cancer where radiation is given to the chest, especially to the left side where the heart is. So, the risk for cardiovascular disease is mainly in ADT, novel androgen therapies, androgen pathway inhibitors, and chemotherapy to a much lesser extent.

What would you say to a man who’s reading this and doesn’t already have preexisting cardiovascular disease but has been prescribed ADT?

Dr. Barata: The risk is different depending on the patient. It is different when you have someone who already has preexisting cardiovascular risk factors such as high blood pressure or diabetes, for instance. Because we need to use ADT to suppress testosterone levels, the advice is always to go back and control cardiovascular risk factors in the best way possible. That usually includes getting the primary care physician involved in the care. He should have good blood pressure control, good diabetic or glycemic control, and he should focus on diet and exercise. Those are the factors that we can act on, and we can reduce or minimize the increased risks caused by treatment.

So you could address things as they come up?

Dr. Barata: Exactly. In the clinic on a day-to-day basis, apart from talking about prostate cancer, we talk about which risk factors are present, which are not, and what we need to pay attention to. We usually talk about these five things: ADT, diet, bone health, exercise, and good control of cardiovascular factors.

Every time I see a patient who is at moderate or high risk for cardiovascular events, I usually engage a cardiologist with a focus on oncology. They calculate the risk in a more objective manner. When we are concerned about the treatments we’re considering and their cardiovascular risks, involving a cardio-oncologist is a good way of making sure we don’t miss anything.

There are some data, which are not very strong, that suggest that an antagonist has a lower risk compared with an agonist in causing cardiovascular events. This is not settled yet, but there is a large Phase III trial going on to answer the question. Right now, we don’t have a preference. If it turns out that an antagonist correlates with the lower risk for cardiovascular events, then we’ll change our practice, and we’ll start using the antagonist as the treatment of choice.

Do you know who’s running that trial?

Dr. Barata: The trial is called PRONOUNCE. The collaborators of the study are Memorial Sloan Kettering and Duke Institute, and it’s sponsored by a pharma company. It’s still open. It’s a trial comparing the cardiovascular safety of degarelix, which is the LHRH antagonist, versus leuprolide, which is the LHRH agonist, in patients with advanced prostate cancer and cardiovascular disease. (See Prostatepedia February 2019 for a discussion with Dr. Matthew Roe about this trial.)

I predict it might be closed soon because it’s been open to accrual since 2016. We hope to have a result in the next 24 months.

What about after ADT treatment?

Dr. Barata: Fortunately, we cure a lot of patients with prostate cancer. Every time we deliver a treatment that cures but increases the risk for cardiac events, we should let the patient know that their risk doesn’t go away.

Because we deliver hormones for a short period of time for prostate cancer, that’s not as important as it is for other cancers. In testicular cancer, for instance, we follow patients to make sure that we have cardiovascular risk factors under control. So it’s important that survivorship programs for prostate cancer be mindful of cardiovascular events.

Does the impact that ADT has on prostate cancer last even after the ADT has been stopped?

Dr. Barata: We don’t know. In the localized setting, the duration of ADT is relatively short. For instance, if you have intermediate risk prostate cancer, you usually deliver six months of hormones, and if you have a high-risk disease, you treat them for two to three years. We have no long-term data showing the long-term impact on cardiovascular events for patients treated with three years of hormones, where you suppress testosterone for three years. We do know that, if you have advanced prostate cancer, you are usually in a long-term ADT, meaning continuous suppression, and that can last for five or more years. That’s where there’s more data.

If a person has diabetes or a prior history of cardiovascular problems, their primary care physician should be engaged to make sure that, even though we are done with treatments, we are still paying attention to preventable cardiovascular risk factors, like blood pressure, exercise, and diet.

Do you have any advice for men either going into prostate cancer treatment or already undergoing treatment?

Dr. Barata: There’s frequent toxicity in patients diagnosed with GU tumors in general, and prostate cancer is more associated with ADT. Ask your treating physician about your specific risks. What can you do to prevent or minimize cardiovascular events in the future? Is there a role for a cardio-oncologist, a cardiologist with a focus on oncology, on your healthcare team?

Not a member? Join us to read the rest of this month’s conversations about heart health and prostate cancer.