Dr. Stacey Kenfield is an epidemiologist in the Urology Department at the University of California, SF who explores through her research how dietary and lifestyle factors impact both the risk of aggressive prostate cancer as well as the risk of prostate cancer progression. Prostatepedia spoke with her about her findings as well as a large clinical trial she’s directing with Movember that looks at the impact of exercise in men with advanced prostate cancer.
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Why did you become an epidemiologist?
Dr. Stacey Kenfield: I’ve been an epidemiologist for over 12 years. The opportunity to help men with cancer improve their quality of life and survival with the disease continues to drive me to do the work that I do. Our group strives to translate our research findings and to implement clinical trials to learn how to help men adopt the behaviors that we study, as well as to learn more about the mechanisms driving the relationships.
We’ve continued to engage men with our clinical trials, but also now educate patients who visit our urology clinics and the community who want to know what they can do once they’ve been diagnosed with cancer. We’ve continued to do our research, believing that our results on lifestyle can be used as adjuvant therapy to primary treatment of prostate cancer, and can also help formulate tailored management tools to improve prostate cancer survivorship.
What do we know about the impact of diet on prostate cancer?
Dr. Kenfield: A number of studies indicate that specific dietary factors prior to diagnosis are associated with the risk of developing aggressive prostate cancer. We also know from studies performed in men with prostate cancer that many of these same factors are associated with the progression of disease and the risk of dying from prostate cancer. Some of these factors include cooked tomatoes, due to the fact that there’s more bioavailable lycopene in cooked tomatoes versus raw tomatoes.
We also know from studies that lycopene seems to inhibit prostate cancer growth and development of aggressive prostate cancer. Another factor is fish, which is possibly beneficial due to an anti-inflammatory effect. We’ve seen that fish with especially high levels of Omega-3 fatty acids, such as salmon, sardines, mackerel, and herring, are beneficial for reducing risk of the more aggressive forms of prostate cancer.
Another factor that we believe is important is to reduce one’s intake of processed meat. Processed meat has pre-formed compounds called N-nitroso compounds. It also has nitrites, nitrates, and added salt, which seem to have cancer-promoting properties.
There has also been a lot of research on dairy and calcium in prostate cancer. In general, most studies agree that higher intakes of calcium at levels of more than 1000 milligrams per day increase one’s risk of developing prostate cancer. We want to emphasize that men with or without prostate cancer need to consume some calcium for general health, just that it should not exceed 1000 milligrams per day. For example, a cup of skim milk has about 300 milligrams of calcium and a cup of yogurt about 450 milligrams. Getting some calcium from your diet is still incredibly important for overall health.
What about getting some of these nutrients in supplement form? I know lycopene and Omega-3 fatty acids are available as supplements. What do you get from the diet that you don’t get from supplements?
Dr. Kenfield: To be honest, a lot of our studies have been focused on whole foods.
I published a study back in 2015 on supplemental selenium intake showing that high doses of supplemental selenium are associated with about a 2.6-fold increased risk of prostate cancer mortality in men after diagnosis. Both the American Cancer Society, the American Institute for Cancer Research, and others discourage people from getting their nutrients from supplements, because the data do not suggest that it’s beneficial. In all likelihood, it could cause harm if you’re taking high dose supplements; so we recommend getting your nutrients from food if you can.
Are these all factors that you would recommend for both men who don’t have prostate cancer as well as those who have already been diagnosed?
Dr. Kenfield: There are a few factors that potentially impact prostate cancer progression that have been studied recently. Plant-based fat–like nuts, plant based oils, canola, olive oil, and avocados—have been studied after a diagnosis of prostate cancer and shown to have a beneficial impact on the risk of lethal prostate cancer. Another food that we’ve focused on is cruciferous vegetables like broccoli, cauliflower, and kale. These foods have components that detoxify carcinogens that could be helpful for stopping cancer cells from growing and can also cause cancer cell death.
I’ve already mentioned tomatoes, fish, and processed meat. We also recommend that men avoid high-fat dairy like whole milk, which has been linked to a higher risk of dying from prostate cancer.
What about red meat versus chicken?
Dr. Kenfield: We focus on recommending people eat lean protein sources, so this would be skinless poultry and fish, rather than red meat, which has been associated with other chronic diseases.
What about pork?
Dr. Kenfield: We have not been recommending pork specifically. We focus on just lean protein— chicken, fish, legumes, beans, and other sources of protein, like soy.
What about organic free-range meat? Do you have any comments about the importance of hormone-free meat?
Dr. Kenfield: This has not been studied. It’s a little bit harder to study organic or free-range meat in the types of data that we collect from our patients. That question is not regularly added to our food frequency questionnaires, so it hasn’t been looked at in detail.
What impact does exercise have on prostate cancer—both on the risk of getting prostate cancer and on the risk of progression once you’ve been diagnosed?
Dr. Kenfield: A number of studies have suggested that physical activity, especially activities done vigorously—i.e. cause sweating; deeper, quicker breathing; and cause your heart rate to increase—are associated with a reduced risk of lethal prostate cancer. Early studies from our group conducted in two independent cohorts of men with prostate cancer showed that vigorous activity of 3 or more hours a week in one study and brisk walking for 30 minutes or more on most days in the other study had substantial benefits on reducing one’s risk of dying of prostate cancer, or from progression from prostate cancer, respectively.
More recent studies suggest that slightly lower levels, about four hours of walking or two hours of jogging, had some benefit. There was a fourth study that showed that you may see a benefit after just one hour of exercise per week. Overall, the data suggest that exercise is beneficial, both for the prevention of advanced prostate cancer, as well as reducing one’s risk of progression from the disease. Any aerobic exercise seems to be better than none; there is some benefit. I think for prostate cancer, one should really strive to do some of that activity at a vigorous level.
You’re talking about cardiovascular exercise. What about resistance or strength training? Has anyone looked at that?
Dr. Kenfield: There have been a number of studies, mostly focused on men on hormone therapy (ADT), that show resistance exercise offers improvements in muscle strength and certain quality of life metrics. There have been trials that focused on both aerobic and resistance exercise; those studies have reported benefits, including gains in muscle strength, improved fitness, improved balance, and less fatigue. So both resistance training and cardiovascular training are helpful.
What about lifestyle factors like not smoking and stress management. How do those factors impact prostate cancer?
Dr. Kenfield: We’ve recently developed a lifestyle score to look at the combined risk of lifestyle factors on the development of lethal prostate cancer. In addition to the dietary factors that I just mentioned (high intake of tomatoes and fish and low intake of processed meat), we also looked at high levels of vigorous activity or brisk walking, not being obese (a body mass index or BMI<30), and not smoking. This included people who had never smoked or people who had quit ten or more years prior. We created a score, which has six factors. We found that men who had 5 or 6 of these healthy lifestyle factors versus 0 or 1 of the factors had a 68 lower risk of lethal prostate cancer. That is statistically significant. This was done in the Health Professionals Follow-up Study (https://sites.sph.harvard.edu/hpfs/). In the same paper, we looked in the Physicians’ Health Study (http://phs. bwh.harvard.edu/phs1.htm). Many of the same variables are collected there, so we had a six-factor score and found a very similar reduction in the risk of lethal prostate cancer there. Most of the data used were collected before prostate cancer diagnosis, and up to the point of either having an outcome of lethal prostate cancer or to the end of the follow-up study. Currently, we’re looking at what lifestyle pattern after diagnosis offers the most benefit.
How are all these different lifestyle factors weighted? For example, is it more important not to smoke than to have an appropriate BMI?
Dr. Kenfield: In a separate publication on smoking, we reported that current smokers had a 61 percent increased risk of progression, which is PSA progression, as well as a 61 percent increased risk of death from prostate cancer. There is also a strong benefit for vigorous activity compared to some of the other dietary factors that have a more modest benefit. When we looked at each factor separately that are part of the score, vigorous activity had the greatest impact on prevention –we estimate that 34% of lethal prostate cancer would be prevented if men exercised vigorously regularly. I think focusing on not smoking and exercise would be critical for both prostate-specific outcomes as well as overall health and the main chronic diseases that men and women tend to die of, like heart disease.
Can you talk to us about the thinking behind the clinical trial that you’re running?
Dr. Kenfield: Some smaller clinical trials in men with prostate cancer, mostly at earlier stages of disease, have suggested that there are significant benefits to exercise on quality of life and functional outcomes. We also see from the observational research that there is an association between exercise and lower risk of clinical outcomes (I mentioned those findings above.) But we don’t know if exercise is beneficial in men with advanced prostate cancer. That was one of the critical reasons why Movember decided to fund INTERVAL (INTense Exercise foR surVivAL), a large global trial focused on advanced prostate cancer with the primary endpoint of overall mortality. We’re also interested in many secondary endpoints that need to be explored further, including exercise’s impact on progression-free survival, skeletal-related events, and other quality of life outcomes.
We really want to understand the mechanisms behind the associations, so we’re studying exercise’s effect on inflammation, insulin, glucose metabolism, androgen biosynthesis metabolism, and other pathways. We are collecting blood and urine in the study to look at mechanisms of exercise.
What can men expect to happen, step-by-step?
Dr. Kenfield: The trial is specifically examining whether a supervised exercise program versus a self-directed exercise program improves overall survival in men with metastatic castrate-resistant prostate cancer. If men are eligible, they will complete exercise tests at baseline. They’ll have their blood drawn, provide a urine sample, complete surveys, and then they’ll be randomized to either a one-year supervised aerobic and resistance exercise program that basically tapers over that year to another year of fully self-managed exercise, meaning exercise that you do on your own.
The other group is randomized to self-directed exercise. They will receive guidelines on how to do exercises on their own. During the two-year study, patients will complete exercise testing at various time points. We’ll ask them to complete surveys related to their lifestyle habits and quality of life. Each month, both groups will receive psychosocial support in the form of newsletters focused on different topics relevant to men with prostate cancer.
When you were describing the self-directed program and guidelines, my very first thought was that I’ll bet half those people aren’t even going to complete the exercises. The risk of a self-directed program is that you won’t do it if you don’t have any accountability built into the program.
Dr. Kenfield: Currently, we don’t know if supervised exercise will affect the outcome or not, and there is no evidence of superiority of one exercise strategy over another. Both groups are really important to the success of the trial. The information each participant provides will help investigators determine what levels of activities may be beneficial for men with advanced prostate cancer.
What kind of patients are you looking for?
Dr. Kenfield: We’re looking for men with metastatic prostate cancer whose disease has worsened on standard hormonal therapy. This is termed metastatic castrate-resistant disease. Patients are eligible if they’re receiving treatments in this disease phase, like Taxotere (docetaxel), Zytiga (abiraterone), Xtandi (enzalutamide), or they can be treatment naïve, meaning they’re not on these drugs yet. If a man has metastatic prostate cancer, the study coordinators will check the other study clinical criteria.
Men must be able to travel to one of the study-designated exercise facilities at least twice a week for nine months. That’s a requirement for someone who is randomized to the intervention arm. This tapers over time, but that’s a critical component of the study because we are trying to have men do supervised exercise with one of the exercise physiologists associated with the study.
Where are the study locations?
Dr. Kenfield: We have study locations in the USA, Canada, Australia, Europe, and we’re opening in China. Right now, we’re open at 12 sites; 10 other sites are in startup phase and 10 others are in feasibility stage. The study is continuing to grow, and we plan to have it continue at least through 2024.
That is a massive study.
Dr. Kenfield: I’m directing the study coordination center, based at UCSF. We have collaborators at Edith Cowan University; Dr. Nicholas Hart directs the exercise coordination center and manages the exercise testing and training for participants from Perth, Australia. At the study coordination center, we’re in charge of new site activations, patient recruitment, clinical data collection, the study databases, and data monitoring for every site, as well as the behavioral support and psycho-social support programs that are part of the study.
Do you have any thoughts for men with prostate cancer either about the INTERVAL study that you’re running or about diet, exercise, and lifestyle choices in general?
Dr. Kenfield: Please consider joining the INTERVAL study and contacting us if you are interested and think you may be eligible. We sincerely hope that men, regardless of arm assignment, will experience some benefit from participation. And finally, to summarize, a healthy diet, not smoking, and regular exercise are critical components to reduce your risk of developing lethal prostate cancer, and may possibly prevent or delay prostate cancer progression.
We’ve seen that adopting more of these behaviors could lead to greater benefits. As I mentioned before, many of these lifestyle factors are critical for reducing the risk of other chronic diseases like diabetes, obesity, hypertension, and heart disease. Death from cardiovascular disease is still the leading cause of death worldwide in men with prostate cancer, so it’s really important to consider making these changes, not just for your prostate cancer, but also for your overall health. It will impact a lot of other aspects of your life.
Does hormonal therapy exacerbate the cardiovascular disease that many men already have?
Dr. Kenfield: Yes, hormone therapy has been linked to increased risk of insulin resistance, an increase in body fat, and decreased muscle mass. Some of these metabolic changes could lead to increased risk in developing other health problems, like diabetes and heart disease. It’s really critical that men who are on ADT or hormone therapy are exercising to counteract some of these negative effects of the drugs.
Would you say that every man with prostate cancer should be exercising?
Dr. Kenfield: Yes, I would. Our studies have focused on men with prostate cancer adjusting for the treatments that they’re on.
Would you go as far as saying that every man—even if he does not have prostate cancer–and woman should be exercising?
Dr. Kenfield: Yes.
Cardiovascular disease is the leading cause of death in women, too, is it not?
Dr. Kenfield: Yes, it is. It’s helpful to have support. Have somebody in your life that encourages you to adopt these healthy behaviors, even if it’s just a colleague or a friend. I’d encourage everyone to find someone who can help motivate them to live healthier.
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