Prostatepedia

Conversations With Prostate Cancer Experts


Leave a comment

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.

 


Leave a comment

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.


Leave a comment

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.


Leave a comment

Which is better for your heart: Firmagon or Lupron?

Dr. Matthew Roe is a Professor of Medicine at Duke University’s Clinical Research Institute (DCRI), the Faculty Director of the Global Outcomes Commercial MegaTrials program, and the Director of their Fellowship Program. (The DCRI’s databank is the world’s oldest and largest cardiovascular database.) He has participated in the leadership and conduct of numerous clinical trials focused on therapies for acute coronary syndromes and chronic cardiovascular disease. He is keenly interested in clinical trials’ operational conduct as well as in national and global academic collaborations.

Prostatepedia spoke with him recently about a clinical trial he’s leading that looks at the cardiovascular safety of Firmagon (degarelix) versus Lupron (leuprolide) in men with prostate cancer.

Not a member? Join us!

What’s the thinking behind your clinical trial comparing cardiovascular safety of Firmagon (degarelix) versus Lupron (leuprolide) in patients?

Dr. Roe: Years ago, a number of studies were done that showed a potential signal for increased cardiovascular event risk among patients with known cardiovascular disease who were receiving androgen deprivation therapy, the standard of which is Lupron (leuprolide). Eventually, there was a document released by professional societies, including cardiology professional societies and urology professional societies and a black-box warning on the label of that drug, that there is the potential that patients with known cardiovascular disease who receive this therapy could have an increase in cardiovascular risk. That therapy is used to treat advanced prostate cancer and has known benefits there. These professional societies were trying to set up a shared decision-making model with prostate cancer patients and their physicians to better understand if this therapy should be used, and if so, how should they monitor it.

Then Firmagon (degarelix) was developed as a different type of androgen deprivation therapy with a different target, having similar efficacy in treating prostate cancer. Some post-hoc analyses suggested that patients who receive Firmagon (degarelix) might have a lower risk of cardiovascular events when they have known prior cardiovascular disease while receiving this drug as treatment for prostate cancer.

All these studies that were done were retrospective studies that weren’t meant to answer that question.

The trial we’re conducting, the PRONOUNCE Study, was designed as a prospective rigorous randomized trial to compare those two treatments among patients with prostate cancer, to understand if there is a lower cardiovascular risk with Firmagon (degarelix) versus Lupron (leuprolide).

What can a patient expect to happen during the trial?

Dr. Roe: A number of sites in the United States and other countries are participating. In those sites, urologists or oncologists who treat patients with prostate cancer are evaluating their patient population whom they’re considering treating with androgen deprivation therapy.

If they meet their eligibility criteria for the trial, they discuss the trial with them. If the patient is eligible and he chooses to participate, then he is randomly allocated to receive Firmagon (degarelix) or Lupron (leuprolide) for 12 months. The therapy is provided to him as a study participant. He will be seen every month during the study to do a check in and assess whether or not he has experienced a cardiovascular event and to optimize his background treatment therapy for both prostate cancer and cardiovascular disease.

I work at the Duke Clinical Research Institute. We’re the academic coordinating center, working with the sponsor Ferring Pharmaceuticals to help design, run, and conduct the study. This is a collaboration between academic experts and the sponsor. We have a steering committee of academic experts—cardiologists like myself, urologists, and prostate cancer oncologists to work together to conduct this study.

Are there any specific eligibility criteria that you’d like to call attention to?

Dr. Roe: Yes. We are looking for patients with prostate cancer who meet the criteria to receive androgen deprivation therapy. I’m not going to go into the exact details, but the trial is for those eligible for advanced prostate cancer treatment. These would be people who would not be receiving a prostatectomy or radiotherapy treatment. These patients have to have a known history of prior cardiovascular disease, which we confirm. We work with the study sites to implement that confirmation, because urologists and oncologists treating patients with prostate cancer aren’t really experts in cardiovascular disease.

We work with them to ensure that they’re meeting those criteria and that they’re treating patients appropriately. In many cases, a cardiologist will work with the site investigator, who is an urologist or an oncologist, to help conduct the study.

I’m sure there are quite a few men with advanced prostate cancer who also have cardiovascular disease.

Dr. Roe: Yes. It’s estimated that about 35-40 percent of men with advanced prostate cancer will have a known history of cardiovascular disease, partly because both conditions are common in older age. That is one of the strongest risk factors for both prostate cancer and heart disease, so we see the convergence of those two conditions.

If someone reading this is interested, who should he contact?

Dr. Roe: We do have at least 30 or so sites in the United States. If someone is interested, he can contact me directly and then I can put him in touch with the right people. One of the challenges is that only a certain number of physicians who treat patients with prostate cancer would be interested in participating and being investigators for the trial, so matching them with patients around the country is always a challenge. We are happy to help patients who are interested in participating have that opportunity, even if their local doctor may not be the one who’s the investigator.

Is there any fee for patients to participate?

Dr. Roe: No. They receive reimbursement for their travel to come to and from the clinic for their visits. They receive the therapy that they’re getting, Firmagon (degarelix) or Lupron (leuprolide), for free. There are no costs for the patient; they just have to volunteer their time. We recognize that and we share information with the patient.

At end of the day, we will share the information from the study directly with the study participants, to help them understand their contribution and what it means going forward. We overtly honor the volunteerism and altruism of the patients.

Is there anything else you’d like patients to know, either about this trial in particular or the context in which it occurs?

Dr. Roe: If a patient who has advanced prostate cancer and known cardiovascular disease is being considered for androgen deprivation therapy, it is important that he speak with his cardiologist. (Presumably, both a cardiologist or cardiovascular specialist and an urologist or oncologist would treat him.) He needs to ensure that all the providers have a discussion about what the best and safest treatment would be before therapy begins. Obviously, this trial is not completed yet so we don’t have any answers. In the meantime, it is certainly in the patient’s best interest to ensure that his providers are communicating and trying to jointly determine the right approach.

Not a member? Join us to read more about cardiovascular disease and prostate cancer?