In February, Prostatepedia spoke with Dr. Mark Moyad about heart disease + hormonal therapy.
How much of a problem is cardiovascular disease in men newly diagnosed with prostate cancer?
Dr. Mark Moyad: It’s arguably the number one cause of death in prostate cancer patients. It’s the quiet elephant in the room. Men have to be as concerned about cardiovascular disease as they are with their prostate cancer diagnosis.
Do some prostate cancer treatments, like hormonal therapy, increase the risk of cardiac disease?
Dr. Moyad: Whenever people ask me that, I almost always say it doesn’t matter. Because we already know that cardiovascular disease going into Androgen Deprivation Therapy (ADT) is the number one cause of death in men.
So even if ADT doesn’t increase risk, I’m already going to treat that patient as if he were at high risk for a cardiovascular event. I’m still going treat this person as if he’s just as likely to die of a cardiac event.
You have to think heart-healthy as much as ADT-healthy before the first injection. It doesn’t mean we’re downplaying the prostate cancer. It means that life is a game of probability, so in order to beat the odds you need to do everything possible to reduce your cardiac risk to zero. If you do that, it takes care of all the other business that you’re worried about.
Dr. Snuffy Myers talks about bone metastatic prostate cancer, as discussed in the November 2015 issue of Prostatepedia.
Learn more about American Institute For Diseases of the Prostate.
(The interview with Dr. Himisha Beltran that Dr. Myers discusses in the video appeared in Prostate Forum Volume 17 # 2.)
In October’s Prostatepedia, we’re talking the impact diet, exercise and lifestyle can have on prostate cancer.
Dr. Daniel Galvão, a Professor of Exercise and Sports Science and Co-Director of the Edith Cowan University Health and Wellness Institute in Australia, is crusading research into how exercise influences prostate cancer patients’ quality of life, ability to weather treatment side effects, and time to progression.
Prostatepedia spoke with him recently about the exercise program he recommends for prostate cancer patients.
Prostatepedia: Let’s start by talking a little bit about you: where you trained and the focus of your current research.
Dr. Daniel Galvão: I’m an exercise physiologist. My background is in clinical exercise science. I did my Bachelor in Physical Education degree in Brazil, Masters in Clinical Exercise Science at the University of Queensland, Australia and a PhD in Exercise Science and Prostate Cancer at Edith Cowan University, Australia.
My research interest is in applications of exercise as medicine for the prevention and management of prostate cancer treatment side-effects and survival. I always had a lot of interest in the aging process and the health issues older men face. Of course, prostate cancer is a major clinical issue. I was very interested in exercise gerontology—exercise in aging and was mentored by a leading international Exercise Gerontologist Prof Dennis Taaffe during my time at the University of Queensland, Australia. This was a natural link to prostate cancer where I was very fortunate to be mentored during my doctoral studies by international leaders and close colleagues today Professor Robert Newton and Clinical Professor Nigel Spry, where we brought the disciplines of exercise science, gerontology, and clinical oncology and prostate cancer together as the basis of our future work aiming to answer meaningful research questions in this novel field of exercise-oncology.
At the time I was doing my PhD, this approach was extremely novel. We used resistance training, or strength training, an anabolic exercise mode in men undergoing therapy for prostate cancer. In particular, men treated with androgen deprivation therapy (ADT), a well-known type of therapy that suppresses testosterone. ADT, or hormonal therapy, is an important tool to control prostate cancer. It is used across a range of different settings from men with local aggressive disease to men with advanced disease. Hormonal therapy leads to a number of side effects that can substantially affect quality of life: erectile dysfunction, muscle loss, a potential increase in cardiovascular and metabolic complications, and loss of bone mass.
Our intention was to trial interventions such as exercise as medicine to offset or mitigate these issues and toxicities. This was really the first study looking at physiological and physical outcomes in patients on hormonal therapy. That study was published nearly ten years ago; it has been quite an influential study in the area.
Prostatepedia: Can you talk about the study design?
Dr. Galvão: It was a single cohort pilot study—single arm, and a relatively small study. We were testing the feasibility and efficacy of exercise in these men. Can patients do it? Can they tolerate resistance training while receiving testosterone suppression? Is it safe? Is it effective?
We found that exercise was indeed safe. Exercise didn’t change levels of testosterone, which could potentially be a concern for clinicians. (If the aim of therapy is to reduce testosterone, we don’t want to raise testosterone with exercise.)
At the same time, there were no injuries and no adverse events. Patients were able to substantially improve muscle strength. This translated into improvements in functional performance for activities of daily living. They were able to do things during the day more easily than they could before. They also substantially improved their quality of life.
We subsequently extended this study and undertook a randomized controlled trial that was published in the Journal of Clinical Oncology back in 2010 that combined resistance training with aerobic training which also extended the work from our colleagues in Canada (Prof Segal). Aerobic training is walking, cycling, or running. We combined the two exercise modalities in a comprehensive clinical trial. There were two arms: an arm of men who did exercise while on ADT and a control arm of men who were only on ADT without exercise.
We looked at a range of different parameters. For the first time, we reported that exercise could actually stop muscle loss which can be clinically meaningful and relevant to patients. Normally, you lose one to two kilos or two to four pounds during the initial nine months in the first year on ADT. Patients in our study were able to gain nearly two pounds of muscle on therapy. That is a clinically important change for patients. In addition, men in the study substantially improved their muscle strength.
They improved their aerobic capacity or aerobic fitness, which is an important predictor for cardiovascular mortality. The result is that they have an improved cardiorespiratory reserve capacity.
Patients also improved their dynamic balance. If these men fall, because they have low bone mass and low muscle mass, they have a greater chance of fracture and subsequent complications. By improving balance and function, they have a decreased chance of falling, and if they do fall, a reduced chance of fracture. That is important.
During the course of these studies, we undertake objective measurements of changing physical capacity and function, but we also look at other aspects of the patient. In this particular study, patients improved their vitality quite substantially with statistically and clinically meaningful changes. We also reduced their levels of fatigue by roughly 30%. (A third of patients on ADT experience significant levels of fatigue; patients were actually reducing fatigue with exercise.)
Another interesting finding from that study was that patients also reduced a marker of inflammation called C-reactive protein (CRP), which is potentially linked to cancer progression. Systemic inflammation was reduced.
Prostatepedia: What does all this mean for patients? Is there a specific program you recommend for men on hormonal therapy?
Dr. Galvão: We recommend patients aim for 150 minutes of moderate aerobic exercise per week. This could be broken down into five sessions of thirty minutes, for example. In particular for men on ADT who experience loss of muscle and adverse metabolic effects, resistance training is critical. We think the best prescription for men with prostate cancer is resistance AND aerobic training.
Aerobic training targets the cardiovascular system and metabolic outcomes such as blood pressure parameters, cholesterol, etc. Resistance training targets the musculoskeletal system to preserve muscle, preserve physical function, and improve muscle strength. We think the combination is probably best for men with prostate cancer.
We also have a trial whose results we haven’t published yet. We’re looking at the data at the moment. In that study, we compared different exercise modalities: the combination of resistance training plus aerobic training against impact loading, which is a more sophisticated type of prescription. Our results should be published soon where we incorporate aspects of impact loading as part of their training regimen with the aim to prevent bone loss.
But what we know today and is well established is that the combination of resistance training and aerobic training in men with prostate cancer is quite important and it is currently the recommendations of the American College of Sports Medicine and American Cancer Society.
Prostatepedia: Should men on ADT seek out a professional who can help them design an exercise program that is right for them?
Dr. Galvão: Exactly. These are just general recommendations. Ideally, you want to see a clinical exercise physiologist and have him or her develop an individualized program. Many men with prostate cancer have comorbidities and you want to make sure it is okay for you to exercise. For instance, make sure your blood pressure is under control before you initiate an exercise program.
Our general recommendation is 150 minutes of moderate aerobic activity, but some patients may benefit from a more or less intense program. We also recommend two days a week of resistance training—i.e. lifting weights. But you have to make sure you have the right technique and the right prescription to ensure a safe environment and derive the benefits we expect.
Having said that, the benefits of exercise far outweigh the risks. We say it is important to have a proper prescription and proper supervision, but it’s also important not to create too many barriers to exercise, otherwise it becomes too difficult. The benefits are huge.
We use the term ‘exercise is medicine’. This means using exercise to treat and help patients. Exercise is Medicine is an initiative launched in 2007 by the American College of Sports Medicine, which has rapidly gathered acceptance within the health and medicine field and has been expanding globally.
Prostatepedia: Do you have any ongoing studies currently enrolling?
Dr. Galvão: We have several ongoing trials: a particular study looking at men with bone metastases. Traditionally, all of these exercise studies have been done in patients with local disease. Patients whose prostate cancer has spread to bones are usually excluded for clinical trials on exercise because of concerns about fractures and the bones becoming very weak.
We designed and published pilot work and are now completing a larger trial that uses an exercise program with modular components. We target patients bone mass—those men who normally would be excluded from an exercise trial. We’re designing prescriptions that don’t target the zones that have cancer. For instance, if someone has a lesion in their proximal femur or lumbar spine, we’re using exercise for the upper arms instead.
This is actually quite interesting, because a lot of men deteriorate very quickly when they have bone metastases. Some of these men will be on other drugs in addition to ADT, like Docetaxel or chemotherapy agents. We’re trying to understand if exercise can also be prescribed in this setting.
Another study that we’re running at the moment looks at improving sexual health in men with prostate cancer. We’re using resistance and aerobic training as a way to facilitate improvements in sexual health in all prostate cancer patients, post-therapy including those on ADT.
We also recently completed a study as part of Dr. Favil Singh’s PhD work on pre-operative exercise undertaken several weeks before prostatectomy — to improve body composition, reduce body fat, and potentially improve outcomes in terms of continence and sexual health. We call this prehabilitation: getting patients exercising before they have surgery so that they deteriorate less after surgery. These are patients already scheduled for surgery. There is usually a window of six to eight weeks between scheduling and the actual procedure. This preliminary study is showing great promise to use exercise medicine to potentially improve patient outcomes post surgery.
Prostatepedia: What about men on active surveillance?
Dr. Galvão: This is a very interesting and novel area from an exercise science perspective. There has been some great early work undertaken by the group at UCSF using intense lifestyle interventions. Larger trials are needed to confirm and expand on these early studies. Exercise might have a role in delaying progression of the disease. What is really well established in the area of prostate cancer is that exercise plays a major role in mitigating the effects of ADT and radiation therapy.
Prostatepedia: What about older men who completed prostate cancer therapy?
There is a study we recently published in European Urology. This was a long-term study, which was novel because most exercise studies are short term. Most of the patients were 70 or older. A lot of the other trials looked at men in their 60s. We had 13 exercise clinics in Australia and New Zealand. There were 100 participants who were randomized. This is quite a lot for a lifestyle/behavioral change exercise trial.
We looked at the role of exercise in patients who had completed therapy. We looked at men five years post-diagnosis after they’ve had a combination of ADT, radiation therapy and bisphosphonates. Some of these men have late effects of therapy.
We compared ways of delivering exercise in this prostate cancer population—either supervised with an exercise physiologist or by just giving patients educational materials about physical activity. After six months, the group that had supervised training was doing a lot better than those who only received educational materials. After six months, the group that was supervised graduated to an at-home exercise program. By twelve months, they were able to maintain a lot of the changes that they had attained at six months with the home program. This is important, because you can’t have all patients come to an exercise clinic; it’s just not feasible. What we’ve shown is that it is possible to provide initial supervision and then have patients carry on the activity at home.
Prostatepedia: Does the program include aerobic and resistance exercises?
Dr. Galvão: Yes, the prescription was similar to that of the previous trial published in the Journal of Clinical Oncology: a combination of resistance and aerobic training.
Prostatepedia: Is there anything else you think patients should know about exercise for prostate cancer patients?
Dr. Galvão: It is important to keep in mind that we’re talking about controlling symptoms and potential toxicities. What is very interesting and exciting in this area of exercise oncology and prostate cancer is that now we have studies indicating that there might be a protective effect after a prostate cancer diagnosis. Patients might have a protective effect in terms of all-cause mortality and prostate cancer-specific mortality. There is about a 50% reduction in risk of all-cause mortality and about 60% reduction in prostate cancer specific death if prostate cancer patients are more physically active, in particular intense type of activities. This means they are less likely to die from any cause and less likely to die from prostate cancer specifically. This report comes from the Harvard Health Professionals’ Follow-up study that was published a few years ago in the Journal of Clinical Oncology.
It is of interest that this work was recently replicated by a group in Sweden: a study of 5,000 participants also showed that more physical activity has a protective effect against all-cause mortality and prostate cancer-specific mortality. These data from observational studies report associations and form an interesting basis for undertaking randomized clinical trials.
What is also interesting is that we and other researchers are trying to understand mechanistically how this protective effect is actually taking place. Is it inflammation, the endocrine system, or growth factors? We don’t understand what leads to this potential protective effect.
For example, a few years ago a group in Sweden looked at blood serum from healthy adults who had undertaken aerobic training acutely for one hour. They put the blood serum into prostate cancer cell lines and found that the aerobic serum seems to reduce the proliferation of prostate cancer cells. This was an in-vitro experiment, in the lab. It’s difficult to translate this to humans at this stage, but it provides pre-clinical evidence and it is encouraging when combined with observational studies pointing to similar directions.
Prostatepedia: Is there any downside to exercise for prostate cancer patients?
Dr. Galvão: It is hard to see any downside.
Dr. Snuffy Myers talks about the impact diet, exercise and lifestyle can have on prostate cancer, as discussed by Dr. Stacey Kenfield and Dr. Daniel Galvao in the October 2015 issue of Prostatepedia.
Learn more about American Institute For Diseases of the Prostate.
Dr. Snuffy Myers talks about testosterone levels during hormonal therapy, as discussed by Dr. Laurence Klotz and Dr. Daniel Suzman in the September 2015 issue of Prostatepedia.
Learn more about American Institute For Diseases of the Prostate.
Dr. Snuffy Myers talks further about using Taxotere in men who have been newly diagnosed with metastatic prostate cancer.
Dr. Snuffy Myers talks further about inappropriate testing + prostate cancer.
In August’s Prostate Forum, we’re talking about advanced prostate cancer with Dr. Philip Kantoff and Dr. Himisha Beltran.
Here’s Dr. Myers’s introduction to the issue:
In this issue, we’re featuring conversations with two investigators making major contributions to our understanding and treatment of advanced prostate cancer.
Dr. Philip Kantoff has long been one of the major clinical investigators involved in prostate cancer research and is now Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. While our conversation with him covers a range of topics, I suspect two are of great interest to our readers.
The first issue involves the impact of statins on prostate cancer. As Kantoff points out, there are sound retrospective studies showing a correlation between statin use and improved effectiveness of hormonal therapy. We now have a potential mechanism for the effect of the statins. From multiple studies, we know that one way the cancer cells can resist hormonal treatment is to take up DHEA sulfate and convert it to dihydrotestosterone. Dr. Kantoff and his team have shown that statins reduce the uptake of DHEA sulfate by prostate cancer, eliminating one potential mechanism of hormone resistance. At this point, enough is known to design a Phase 3 clinical trial randomizing patients to hormonal therapy alone versus hormonal therapy plus a statin. While we await the results of such trials, it certainly makes sense to use statins for their approved purpose–to lower elevated cholesterol in patients in whom diet and exercise are not sufficient.
Both Dr. Kantoff and our second interviewe, Dr. Himisha Beltran, are both heavily involved in using gene sequencing to characterize the changes that can make advanced prostate cancer difficult to treat.
I am particularly interested in the work Dr. Beltran has done to characterize neuroendocrine prostate cancer. This is a form of prostate cancer that has traditionally been difficult to treat. Fortunately, this has been a relatively uncommon form of prostate cancer.
However, as the intensity of hormonal therapy has increased, the frequency of neuroendocrine prostate cancer has increased. In fact, in the laboratory, testosterone removal has been shown to foster the development of neuroendocrine prostate cancer. This is why Dr. Beltran’s work is so important as it has led to the discovery of new drug targets that may improve treatment of neuroendocrine prostate cancer.