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Join A Clinical Trial: Exercise + Advanced Prostate Cancer

S Kenfield_UCSFDr. 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.

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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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Obesity, Exercise + Prostate Cancer

Dr. Stephen Freedland is a urologist at Cedars-Sinai in Los Angeles, California and the Director of the Center for Integrated Research in Cancer and Lifestyle, Co-director of the Cancer Genetics and Prevention Program and Associate Director for Faculty Development at the Samuel Oschin Comprehensive Cancer Institute.

Dr. Freedland believes in treating the whole patient, and not just a man’s prostate cancer.

Prostatepedia spoke with him about the link between BMI, exercise, and prostate cancer.

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Have you had any patients whose cases have changed how you view your role as a doctor or how you view the art of medicine?

Dr. Stephen Freedland: I think you go into medicine because you want to – at least for me – cure disease. That implies that there’s some state of perfect health. People come in to see me and they are not in a perfect state of health. You want to restore them to this perfect state of health. I now understand that there is no such thing as a perfect state of health. We perceive a perfect state of health to mean you have no diseases. However, you’re still at risk for certain diseases. Perfect implies you can’t do any better. I don’t think that’s the case. I think we can always do something better.

I changed from a physician whose goal was to cure disease to a life coach in many ways. I help move people from less healthy states to healthier states, but it’s not a black or white thing. I don’t cure disease and then go on to the next patient. I continue to work with them, hold their hand, be a counselor, a life coach, a shoulder to cry on, someone to slap a high five when they do have a success.

I had all those experiences yesterday in my clinic. A patient gave me a hug. He called me his angel, slapping high fives with another patient, and then one patient was practically in tears because he did not have such a good prognosis. To be able to ride the rollercoaster of life with patients is a phenomenal honor. It’s a lot of responsibility, but there is nowhere else in the world that I’d rather be.

That’s an interesting perspective. It’s more like seeing people when they’re healthy to help address diseases and issues as they come up rather than having people only come to you when they’re sick…

Dr. Freedland: An ounce of prevention is worth a pound of cure.

That’s a nice segue into my first question: what do we know now about the role of BMI, exercise, and prostate cancer risk?

Dr. Freedland: BMI has been much better studied. It is very clearly delineated that elevated BMI increases the risk of aggressive prostate cancer and increases the risk of dying of prostate cancer. That’s pretty incontrovertible at this point. You’ll see a study here and there that says the opposite, but the totality of the data is pretty convincing in that regard.

Exercise is a little harder to study because you can’t simply measure it the way you can measure someone’s height and weight and know what their BMI is. You need to ask them how much they exercise. Is it vigorous exercise? Is it nonvigorous? Are you doing an hour at a time? You can get 1,000 or 10,000 steps during the day, or you can go run on the treadmill and get 10,000 steps in a half hour. It’s very different.

Collectively, I would say the data seem to suggest exercise and particularly vigorous exercise may be beneficial to prostate cancer risk, but again, that is not nearly as codified nor as consistent and clear as the link we see between BMI and bad prostate cancer.

What impact does BMI or exercise have on risk of prostate cancer progression?

Dr. Freedland: Elevated BMI increases the risk of progression, recurrence, spread to metastatic disease, and death of prostate cancer whereas exercise, again, particularly vigorous exercise, seems to be preventive for progression. But, again, this is not as well studied and is based on a handful of exercise studies. The role of BMI is pretty well established.

A lot of men on androgen deprivation therapy (ADT) struggle with weight gain and muscle loss. What are the implications of this relationship between BMI and aggressive prostate cancer or exercise and aggressive prostate cancer for those men?

Dr. Freedland: As you said, ADT induces weight gain. You get muscle loss. There’s one study from our group that showed obesity at the time of ADT increases the risk of progression to castrate resistant disease. Surprisingly, it’s not been well studied. Let’s say you decide to go on a diet and not gain that ADT weight. We’ve actually shown a low-carbohydrate diet induces 25 pounds of weight loss despite being on ADT, so the weight gain is preventable. We do know that.

What we don’t know is impact of that weight gain on progression. Is gaining all that fat mass and losing muscle bad for your cancer? Intuitively, it should be. I mean, that just stands to reason from almost everything we know about prostate cancer and metabolism, but we haven’t proven it. We have not proven that if you can prevent those things, you can prevent or delay prostate cancer progression.

It certainly has an impact on cardiovascular disease, doesn’t it?

Dr. Freedland: Presumably but, again, it has not been studied in men on ADT. We do know exercise can preserve muscle function and quality of life. We know its impact on cardiovascular markers, but actually showing that exercise prevents cardiovascular disease in men on ADT has not been shown.

What we do know is that ADT will increase the risk of diabetes by about 40%. There’s data to suggest it may increase cardiovascular disease, but it’s controversial in that, if you look at really well done Phase III trials where men either got hormones or didn’t, you see no difference in cardiovascular deaths. Those are men on Phase III trials, selected to be healthy, and followed closely by their doctors. I think what we can say is, in highly selected patients, hormones are probably safe if you follow the patient closely, but in unselected patients, they probably do have cardiovascular effects.

That’s interesting what you just said: followed closely. Are you saying that people who are on clinical trials are just by nature of being in a clinical trial followed more closely than people who are not?

Dr. Freedland: Absolutely, I mean, there’s actually data to suggest that patients on clinical trials who are randomized to the control arm, i.e. standard of care, do better than patients not on the clinical trial who got the exact same treatment. Being on a trial, even if you don’t get that fancy experimental drug, still has benefits.

What does all this mean for patients? Should BMI be a priority for all men, including men who have prostate cancer?

Dr. Freedland: Correct. BMI is the strongest lifestyle link with prostate cancer. I see patients all the time ask me what should they eat. Should they take this supplement? Should they do that? Should they take this herb?

I say: just lose weight. That’s the one thing that we know. To me, it makes the most sense to focus on getting people to lose weight. How to lose weight is a challenge. Everybody has a difference of opinion. Part of it is picking a lifestyle and sticking with it. The word diet literally means way of life. The word is Greek in origin. We need to pick a way of life that’s sustainable, that’s going to work for you, and is going to help you to lose weight. The one common thread I see among all of the diets to a certain degree is reducing simple sugars—cookies, cakes, candies. There is not a diet that I’m aware of out there that says, “Nah, don’t worry about it. Eat all the cookies you want.”

You mean there is no chocolate cake diet?

Dr. Freedland: Correct. The low-fat, the whole-food plant-based folks will say eat all the vegetables you want. The low carb people will say eat all the meat you want. But all of them agree, even though they’re almost diametrically opposite, that cookies aren’t good.

What would you say about exercise? Would you tell men to prioritize BMI over exercise?

Dr. Freedland: To me, they go together. Do you know what the number one cause of death in men is?

Cardiovascular disease.

Dr. Freedland: Cardiovascular disease. What’s the number one cause of death in men with prostate cancer?

Cardiovascular disease.

Dr. Freedland: Cardiovascular disease. To me, if I can use a man’s cancer to scare him into eating right, losing weight, and exercising, I’ve probably done him a lot of good. Whether I’ve helped the cancer or not, in my mind, isn’t as important. Even if the exercise won’t help his prostate cancer, I’ve definitely done good from a cardiovascular point of view. To me, eating right and exercising go hand in hand. I don’t think you can focus on one over the other. Are you going to wear your pants today or are you going to wear a shirt? You need both, right? You’d look silly going around the workday without either one of those.

I guess it’s hard to lose weight without exercising.

Dr. Freedland: Amazingly, it’s not that hard to lose weight without exercising. Exercise is not a great way to lose weight. It’s a great way to get fit. It’s a great way to get healthy. Not a great way to lose weight. Not that it makes weight loss worse, but it actually doesn’t help weight loss much. Weight loss ultimately is about eating less.

Right, eating less than you spend, right?

Dr. Freedland: Correct, taking in less than you burn, and that’s where the whole-food plant-based diet comes in. You’re eating a lot of filling food that’s not calorie dense. It fills up your stomach and you feel full, even though you haven’t taken in a lot of calories.

You can also go to low-carb, which is very calorically dense. Fat and protein fill you up more than carbs, so you end up losing weight. There’s a lot of different ways to go about losing weight. There are general low fat diets. There’s Weight Watchers. There’s a lot of ways to lose weight. But exercise is something you do for your health, not to lose weight. The problem is that a lot of people start exercising to lose weight and then get frustrated and give up. You don’t exercise to lose weight. You exercise to get healthy. You eat less to lose weight.

Do you think discussions about BMI and exercise should be a part of every prostate cancer patient’s initial meeting with a doctor, whether he has low-risk or aggressive cancer?

Dr. Freedland: I think it should be a discussion with every patient at every visit regardless of the diagnosis. It should be part of a wellness visit, a hypertension visit, a high cholesterol or a BPH visit, or a prostate cancer visit. I think it needs to be integral. We need to not think of ourselves as prostate cancer doctors, or bladder cancer doctors, or whatever the case may be. We need to think of ourselves as doctors.

Most patients have more than one disease anyway. If you treat just the prostate cancer, then you’re ignoring the cardiovascular disease.

Dr. Freedland: Correct. It doesn’t mean we need to manage the cardiovascular disease and manage the blood pressure, but we need to be aware of it. We all went to medical school. But there’s more to a patient than his PSA and Gleason score.

Any final advice for men about obesity and prostate cancer?

Dr. Freedland: I always keep in mind the age-old adage: genes load the gun, but lifestyle pulls the trigger.

Join us to read the rest of this month’s conversations about diet, lifestyle, and prostate cancer.


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Diet, Exercise + Prostate Cancer

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This month, Prostatepedia talks about things you can do to help yourself—diet and exercise.

Dr. Snuffy Myers frames this month’s conversations for us:

There is a clear consensus that it is a good idea to get thin and exercise. First, it is good for your general health as it reduces the risk of hypertension and diabetes as well as the cardiovascular complications associated with both of these diseases. Exercise has also been shown to preserve cognitive function and is beneficial for common neurologic diseases like Alzheimer’s and Parkinson’s.

Second, exercise helps minimize the side effects of most of the treatments used for prostate cancer. Finally, as several interviewees discuss, exercise is associated with a lower risk of death from prostate cancer.

In my experience, it is not difficult to convince prostate cancer patients that they should exercise. However, it is very difficult for patients to initiate and maintain an exercise program that is comprehensive and vigorous on their own. It turns out that it is very important to join an exercise facility and get professional guidance. Ideally, you would have a personal trainer tailor your program to your abilities and needs. However, this can be expensive. A sound alternative is to attend group exercise sessions. Water aerobics classes are very gentle on knee and hip joints and practical for even very obese patients. Spin or indoor cycling sessions can offer a very intense cardiovascular workout with less risk of knee or hip trauma than running. Resistance exercise is important and, done properly, weight lifting has a relatively low risk of injury. However, most patients do not know how to squat or deadlift properly, so professional supervision is again important.

In his conversation, Dr. Stephen Freedland states that successful weight loss requires a diet that the patient can stick with long term. I would add that a diet is more likely to be successful if you believe in it yourself. In other words, there is a strong placebo effect.

This is not to say that anything goes. A diet based on cured meats, cookies, and cinnamon buns would not be healthy and would not promote weight loss. Some low carb diets do end up including cured meats like bacon.

In my clinic, we ended up recommending a Mediterranean diet as most patients found that easy to maintain over a period of years. The major pitfall was that some patients overate foods like pasta, leading to overly high carbohydrate intake. As a result, we emphasized moderate carbohydrate intake.

Charles E. Myers, Jr., MD

 


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Imaging In Community Practices

Dr. Rodney J Ellis is a Professor of Radiation Oncology at the University Hospitals of Cleveland and a radiation oncologist at Case Comprehensive Cancer Center.

He spoke with Prostatepedia about how prostate cancer imaging is used in community settings and how it is impacting patient care.

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Prostatepedia: Why did you become a doctor?

Dr. Ellis: I was seven when I told my parents I was going to be a physician when I grew up. They said, “Oh, Rod that’ll be really nice.” No one else in my family had gone to college, so they didn’t really expect that it was likely to happen.

I thought it was cool that my family doctor, who delivered my brother and me, had his wife in his office; they ran the office together. I thought that’d be really nice to work with my wife and run our own business.

Once I got to medical school, I realized that doctors do a lot of work that’s controlled by the insurance companies, and I became less enamored with primary care medicine. When my grandfather and an uncle developed cancer, I became more interested in oncology. It made me focus on how cancer impacts families. I had an opportunity to do a rotation in radiation oncology and met the mentor who taught me so much, which changed what I wanted to do in life.

That’s how I ended up in radiation oncology, initially working with monoclonal antibodies to image cancer and direct where you place radiation, either in the operating room with brachytherapy or intraoperative radiotherapy.

Over the last 20 years, as the field has blossomed, we’ve developed even better techniques for dose painting and giving high doses in regions. Largely, that’s been the focus of my academic career.

Have you had any patients who stood out in your mind as having changed either how you see your role as a doctor or how you practice the art of medicine?

Dr. Ellis: Yes, especially since advanced imaging has come out and over the 20 years that I’ve been doing it. Sometimes, when I see a patient in long-term follow-ups, I think, “Wow, the advanced imaging we used actually predicted death from prostate cancer the day I saw him, but I just didn’t know it those ten years ago.”

When I look at the new imaging today and how it’s changing what we’re doing, I think we’re truly personalizing medicine.

I’ve seen numerous patients where I could determine whether their cancer was curable based on an image. If it is curable, does it change how you may image that patient? More often than not it may. For maybe one in three cases, it does nothing for you. You do the image, and the good news is it didn’t show any spread of disease. The bad news is it didn’t show any localization of the disease either. The test didn’t really help us; it just didn’t resolve the questions we had. For about two-thirds of my patients, it adds to their care. New data from ASTRO this last week shows in the Locate trial that even negative studies may have significant changes though, such as staying in surveillance versus aggressive local therapy if a study is negative.

What kinds of imaging studies do you use currently with your patients?

Dr. Ellis: I use standard imaging, whether that’s bone scan, CT scan, or MRI. We’ve been very image-based in our approach to treat prostatecancer for many years. Currently, we use a lot of MR-based imaging and the functional imaging of MRI to look at these within the prostate gland. The dilemma for patients is whether there is any disease outside of the prostate gland. Much of the literature that I’ve published over the last two decades worked with the previous imaging agent that was FDA-approved for looking for spread of prostate cancer called ProstaScint. We’ve published on that with ten-year data showing that it was able to predict deaths from prostate cancer. It was useful for helping to select where to give higher doses within the prostate gland, when giving radiation to improve cure rates. That’s been largely improved upon with newer imaging agents, both the Axumin PET scan that is currently FDA-approved and the C-11 Choline that’s available at Mayo Clinic.

Worldwide, there’s a lot of interest in PSMA-based PET imaging. That is the same molecule that ProstaScint looked at years ago, only now the marker is looking on the surface of the cell rather than on the cytoplasmic, or internal surface, of the cell. This has greatly improved the PET agent over the previous generation products.

What are some of the limitations that you face?

Dr. Ellis: Prostate cancer is non-uniform. All the cells are not going to be alike. They’re going to metastasize or develop different traits at different times. We can image some cells nowadays with Axumin PET. That looks at the synthetic amino acid that gets picked up more commonly by prostate cancer, but it may be applicable for some other cancers as well.

On the other hand, some cancers express PSMA, and may show up with a PSMA-based PET. Not all cancers show up with one or both, so we don’t know which agent is best for which particular patient.

The biggest limitation right now is that the only one that’s FDAapproved is Axumin PET. As a member of the National Comprehensive Cancer Network (NCCN) Prostate Board, I’ve looked at it and made recommendations to add that for standard imaging. The board has also made recommendations that, as newer agents come out, they should be considered as well.

How are these newer imaging studies impacting treatment?

Dr. Ellis: Well, I can give a great example. We had an add-on patient today who had been treated with hyperthermia in Germany, which progressed locally. We had treated him with proton therapy into the prostate, and for a while, he had responded to therapy, but his PSA had started rising.

Today, he came in for follow-up, and we did an Axumin PET this morning. I’m waiting for the results to be read by the radiologist. But on my review, it looks like he’s got a solitary metastatic focus that lights up in the right chest, adjacent to his airway. The question now is what to do in that setting. If you’ve got one site of metastatic disease that’s a clear distance from the prostate, the standard of care is to go on to hormonal therapy and give additional agents either orally or systemically for metastatic prostate cancer.

One of the opportunities these new agents may open up for us is to treat limited metastatic disease—or oligometastatic disease, which means that mets are present in only one, two, or a few sites—with radiation or other techniques to ablate that tissue and potentially prolong life for those patients.

Are these newer imaging studies, such as Axumin PET, available in every community?

Dr. Ellis: I think that Blue Earth, the company that’s been promoting that agent, is doing a great job of getting it out further into the community. The limitation with most nuclear medicine studies is the half-life of the agent. In other words, from the time you make it to the time you use it, it decays. The second it’s made, its half-life is in minutes, so it can only be used locally in the facility where it’s made. In Axumin’s case, it’s about three hours from the time before it becomes too weak to use in imaging.

They’ve got to start producing it in more areas and be able to get everyone who needs the image within a three-hour radius. The reality is that they may never be able to reach everywhere in the United States with that kind of a radius.

Well until that happens, do a lot of patients travel to you or other locations in the United States to get the scan? Are they coming on their own, or are they being referred by their doctors?

Dr. Ellis: It’s a little bit of both. It’s a fairly new agent, so I don’t think there’s a lot of patients who are aware of it yet. I’m a member of their speakers’ bureau, so I’ve got a bias. I can be honest and say yes, I’ve been working with the company to promote and let people know about it. They are still getting the word out, so a lot of patients don’t know about it yet.

I have started to see patients come specifically to ask if we do the test. I don’t know how many are coming directly to me versus how many are coming to our nuclear medicine department, where the test is done, but we are certainly using it much more frequently today than we were using previous imaging studies.

What about the doctors? Are they routinely referring patients to you? Is there any trouble finding people who can read the results of these scans?

Dr. Ellis: Urologists, the primary caretakers for many of these patients, are becoming acutely aware of all the data that’s coming up worldwide on PSMA-based imaging with PET scan. They’re interested in nuclear medicine scans and cutting edge technologies to image their patients. What people aren’t really sure of is what to do with that information yet, so there’s more work that needs to be done to categorize the patients for the appropriate treatment.

Medical oncologists are starting to become aware now; certainly, the radiation oncologist is aware. Yes, there’s more work to be done teaching the physicians.

So, we’re gathering more information, but we’re still not sure what to do with that information?

Dr. Ellis: Right. And we’re not sure whether it’ll impact every patient, that’s the problem. Is it going to be useful for every patient? Of course not. Will it change it in a large majority of patients so it becomes clinically significant? We think so. Right now, it’s only FDA-approved in patients that have had prior therapy. They have had prior radiation, surgery, or systemic therapy, and we have a reason to think that the therapy failed. Then, you image them.

But it is even more interesting to know, in the patient who is newly diagnosed, will these agents be used to help us see exactly where the cancer is located and to make a decision between surgery or radiation, and whether they will be used to make a decision about where to radiate.

Are there any studies now looking at Axumin PET in newly diagnosed patients?

Dr. Ellis: I believe the company is certainly interested in investigational studies in answer to that question. I would have to defer to them about which studies are currently open and active.

Do you still educate patients about imaging studies?

Dr. Ellis: That is a huge part of what I do. And the best way to do that is publications. Publications get out there, and they don’t go away. People read them, and they learn about these studies from trusted sources. But until publications can get done, going out and doing person-to-person education or webinars are other ways to get the word out.

Do many patients ask about imaging studies, or is it something that you tell them about?

Dr. Ellis: Both. I think there’s an educated group of patients out there now, more so than 20 years ago, when I started my practice. It’s probably information from the internet. Everyone has access to the internet. If you search for prostate cancer and start spending some time, you’ll come across the imaging data. They bring those questions in.

If you look at the changes in diagnostic medicine, imaging, and genomics, we have all this new information, but we’re still grappling with what to do with it and what it means.

Dr. Ellis: Yes. We’re wrestling with all the information that’s coming and how to best assimilate all that information for an individual patient.

Do you have any last thoughts about imaging studies, either for people newly diagnosed or facing recurrence?

Dr. Ellis: I would like to see more people lobby to get advanced imaging approved for newly diagnosed patients. Unfortunately, many of those patients don’t have access to it, and I’d like to see the people who are doing clinical research present their data to help support that, if there is emerging data to do so.

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Dr. Thomas Hope: New Directions in Prostate Cancer Imaging

Thomas Hope, MD, of UCSF and the San Francisco Veterans Affairs Medical Center, is keenly interested in novel imaging agents and therapies for prostate cancer and neuroendocrine tumors.

Prostatepedia spoke to him about novel imaging for prostate cancer.

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What are some of the newer imaging techniques available across the globe? How do they work, and when are they used?

Dr. Hope: I do a lot of radiopharmaceutical imaging. We inject radioactivity into people, and then we image it with a positron emission tomography (PET) scanner to locate where the radioactivity has gone. We label these small molecules (proteins) with the radioactivity and use those proteins to target different places in the body. In this case, we try to figure out where prostate cancer is.

There’s been a whole host of developments over the past 20 years of increasingly improved detection strategies for prostate cancer. The old-school fluorodeoxyglucose (FDG) PET imaging technique has been around for 30 years in the United States, and they have used sodium fluoride worldwide for just as long. For bone imaging, sodium fluoride can tell you where obvious metastatic bone disease is. FDG is actually the stable for the majority of PET/ CT imaging we do in the world, but it’s used primarily for other cancer types that are hypermetabolic or use a lot of glucose. When prostate cancer is in the earlier stages, it typically does not use a lot of glucose.

There’s been this hole in prostate cancer treatment for patients with biochemical recurrence. These are patients who have undergone definitive therapy and have a rising PSA. Neither of those two imaging modalities really help them. But a couple of new agents have been developed.

Choline-based agents, such as fluorocholine and C-11 choline, have been used in the United States and Europe. The Mayo Clinic brought choline C-11 to market in the US. Those radiotracers are certainly better than FDG PET or sodium fluoride PET in localizing particularly soft-tissue metastases, but they fail at lower PSA values.

When your PSA gets below one, you really don’t see much disease, and the studies are also quite difficult to interpret. The next imaging agent, is Axumin (fluciclovine). Fluciclovine is another amino acid tracer, just like C-11 choline, that’s used in biochemical recurrence. It was FDA-approved two years ago and has been used fairly frequently with biochemical recurrence. It’s probably, in my mind, equivalent to choline imaging. Fluciclovine itself is not really used outside of the United States because, if you have the availability of other radiotracers, you wouldn’t use fluciclovine. Yet in the United States, fluciclovine has become the mainstay because it is reimbursed by Medicare and readily available. Prostate specific membrane antigen (PSMA) compounds have been developed by a number of groups and companies over about ten years. The big change came with the gallium PSMA-11 compound, which is a small molecule that was first developed at the University of Heidelberg in Germany. Gallium PSMA 11 is a unique compound in that it wasn’t patented. No company controlled it, and so any site that wanted to use it could just sign up and get the precursor delivered to them. Very quickly, a large number of sites around the world started using PSMA-11 to image patients with prostate cancer. It is not approved in many counties, although technically, it is approved in Switzerland and Israel. Outside those countries, it is used on a compassionate-use basis. In the United States, it is being used under Investigational New Drug (IND) authorization from the FDA. The fact that it was so quickly adopted and widely used led to a huge number of articles in the literature.

In addition to PSMA-11, there is a whole host of other PSMA compounds. Gallium PSMA-R2 is being developed by AAA, DCFPyL is being developed by Progenics, PSMA-1007 is being developed by ABX Chem. There is a whole family of PSMA compounds coming to market on the back of the experience of PSMA-11. There are questions as to which is better, and although there is not a lot of head-to-head literature published, it’s fairly clear that PSMA 11 is better than, for example, the choline radiotracers and fluciclovine. The question is: how do these other PSMA tracers rate against one another? In my mind, they’re much better overall as a class, but I’m not sure there is a huge difference between them in terms of detection activity. We’ll find more about that as things progress.

You said the PSMA compound is widely available because it was not under the auspices of a specific company but that it is not approved everywhere. Does that mean that patients can get access to it, but it is not necessarily covered by their insurance?

Dr. Hope: You have to go country by country, so it gets complicated. In the United States, for example,

PSMA-11 is not owned by a company, and there’s no company paying for clinical trials. Centers like ours are running trials through Investigational New Drug (IND) authorization, which means it’s being studied in clinical trial aiming to get FDA approval. In the United States, everything is done under a clinical trial. There are a couple of methods to pay for the studies. There are a few insurance companies that will pay for these imaging studies under a trial setting. But I would say that the majority do not, and patients end up having to pay out of pocket.

The FDA allows you to use a cost recovery mechanism if you are acquiring data to eventually support an NDA application, and that’s how the majority of these studies are paid for. There are other institutions that use research funds in order to have a small number of studies performed. The two major institutions in the United States are UCSF and UCLA, and each uses cost recovery mechanisms and billing patients’ insurance companies directly in order to perform the study.

Are the studies expensive?

Dr. Hope: Yes. I would say they range between $3,000 to $5,000 apiece, so they’re quite expensive. There is clearly an ethical dilemma in having patients pay for an imaging study that’s not FDA-approved. What do you do with that? I think it is a reasonable approach as long as the institutions are actually using that data in the way that they state they are, which means that it’s up to us to use the data to get the agent approved. If the data isn’t used productively to get the drug approved so that insurance companies will pay for it, then I have an issue with the ethical aspect of it. As long as I’m doing the work, then it may be reasonable, although different people might disagree.

I’m sure there is a wide range of opinions.

Dr. Hope: There’s no right answer. For example, two weeks ago, we went to the FDA for our pre- NDA meeting and presented all of our data, which we are doing in collaboration with UCLA. The FDA was very positive and said that we had enough clinical data to support an NDA application, which is pretty exciting. Hopefully, we can get the drug approved within the next 6 to 12 months.

How have these newer imaging techniques impacted how we treated prostate cancer? We’re detecting smaller and smaller amounts of cancer earlier and earlier. What do we do with that information? How is it changing how we treat patients?

Dr. Hope: These newer techniques are changing current patient care. But is that actually improving the outcome? For example, if you have a low PSA, and your PSA is 0.2 after radical prostatectomy, the standard treatment is to radiate the prostate bed and maybe the pelvic nodes. Now you get a PSMA PET, and it shows a node somewhere over here. So, now the radiation oncologist zaps that PSMA-positive node. Everyone thinks we did a good job, and maybe we did. But we just don’t know.

What we don’t understand fully is whether or not PSMA PET is the tip of the iceberg. If you have a PSMA positive node, are there many nodes we do not see, or does it mean that those nodes are the extent of the patient’s disease, which we can potentially cure if we hit it? Right now, the care is changed in maybe over 50 percent of patients who get a PSMA PET, but whether that change in care or treatment planning has improved outcomes, no one has a handle on that yet. There are some clinical trials starting that use varying radiotracers. The question in the community is: how does PSMA PET impact this care, and does that change improve the outcome of the patient who we’re imaging?

Is it just a matter of time before we answer this question?

Dr. Hope: Yes, but it is not that straightforward. You cannot take a cohort of patients who got PSMA PETs, check what happens to them, and conclude that things got better. You have to do it in a trial setting with a cohort of patients who do not get PSMA PETs and a cohort who did, and see if there’s a difference between the two. Otherwise, there are a lot of biases if you have a one arm study. You cannot tell if the patients have improved outcomes for other reasons or even how you compare the data. You really do need a randomized trial in order to demonstrate this improvement in outcomes.

That will come, but those trials will take a very long time to perform. These drugs will all be approved well before the length of time that these trials take to perform. This becomes a big issue. If you have an imaging agent, and we all believe it’s better than the previously existing ones, how do you randomize patients to not get it once it is FDA-approved? We are going to face difficulty showing that PSMA PET improves patient outcomes because we are going to be bottlenecked based on the availability of agents in the near future.

That’s an interesting position to be in.

Dr. Hope: It has happened in imaging over the years. Take sodium fluoride PET, which was never approved. It was grandfathered into FDA approval. No one ever did any clinical trials showing impact and outcome, and that is why Medicare has chosen not to reimburse sodium fluoride PET CT. This has happened over and over again.

It is mainly because imaging trials are unique. Drug trials must have outcome benefits as the endpoint in order to obtain approval. Imaging trials only need to show that we saw something we thought we would see. For example: “I think there is prostate cancer, I looked at a cohort of patients, I biopsied them, and the biopsies came back as prostate cancer. Therefore, this imaging study is good.” But that doesn’t work in a therapy world. Therapy data is a lot stronger.

Do you have any thoughts for men considering travel to get one of these newer imaging techniques or participating in a clinical trial if it’s not available in their community?

Dr. Hope: That is a hard position to be in right now. Think about it in a different setting. Let’s say you were at your institution, and you were thinking about participating in a clinical trial for an investigational therapeutic agent. Most men would not travel too far outside their institution for that therapy. With PSMA PET, patients are traveling all across the country for this agent and paying out of pocket for it. It’s an unusual circumstance. Two years ago, it would not have occurred to people to do this.

I think in the United States, you have to think about the cost and the marginal benefit. It really depends on your PSA. It depends on discussions with your oncologist or urologist in terms of where you are and what type of therapies you are thinking of. Outside of imaging studies, there are therapeutic aspects of PSMA targeted radionuclide therapy. That becomes a much bigger issue. Outside of the United States, the vast majority of sites that offer it do so outside of trial settings.

There are potential huge ethical issues with doing that. Sites are treating patients with therapies that have significant toxicities, and that data is not being collected prospectively, is not being reported, and the trial is not being done in a way that will lead to data that will help us determine what to do with patients moving forward. Centers should run clinical trials and publish results so that we learn, but there’s a large number of centers around the world offering some of these agents out there to treat patients with limited to no follow-up.

It’s really important that, if we’re going to treat patients with a non-approved drug, the trial or the setting where it’s administered does so in a way that leads to actionable, usable information for the community at large, and not just the individual institution or patient.

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Should You Travel For Prostate Cancer Imaging?

This month, Prostatepedia is talking about newer imaging techniques for prostate cancer. As our ability to image prostate cancer becomes ever more precise, controversy over what to do with this newer information is coming to the forefront. Also at stake are whether or not American insurance companies will pay for newer scans. When a man’s insurance doesn’t cover an imaging study, many patients with the financial means are paying for the scans themselves and often traveling to sites within and outside of the United States.

When your PSA begins to rise after initial treatment, you have what is called a biochemical recurrence. If you’re scanned with one of these newer imaging techniques—the Gallium-68 PSMA, for example—and discover 1 or 2 spots of metastases, you have what is called oligometastatic disease.

Prostate cancer experts are divided on how to treat men with only a few metastases. Traveling—and paying out of pocket—for a scan when doctors are still grappling over what to do with any information such a scan would reveal—may not be the wises course of action. Unless, of course, you understand that the scan results may just be interesting information for you and your doctor to consider and will not necessarily change your course of treatment immediately.

Drs. Thomas Hope and Stefano Fanti help us place PSMA imaging and the controversies mentioned above within the context of conventional prostate cancer imaging and treatment. Dr. Fanti’s offers us the European perspective: imaging has been more widely available in the United Kingdom and continental Europe. Many Americans are now traveling to these countries to obtain newer imaging studies. Dr. Nina Tunariu, of the United Kingdom, talks about whole body MRI as a way of staging prostate cancer. She also offers a note of caution for Americans traveling abroad for scanning.

Dr. Rodney Ellis talks about how newer imaging techniques are changing the treatment landscape at the community level. UsToo offers the support group network and patient advocacy’s view of how imaging impacts prostate cancer diagnosis, staging, and treatment.

And finally, Mr. John Moore talks about his prostate cancer journey and the experience of traveling from his home in North Carolina to California for imaging studies.

The bottom line is that more information is always useful. Newer imaging techniques are detecting cancer in smaller and smaller amounts. How to treat these small amounts of cancer is still under debate, especially since the side effects of prostate cancer treatment can be particularly difficult for many men. If you have the means to obtain a newer scan, do so: but understand that there are controversies over the meaning of their results within the global prostate cancer community. A frank and open discussion with your doctor about what you’ll do with any information you learn before you get scanned is the wisest course of action.

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Imaging Prostate Cancer

In November, we’re talking about imaging prostate cancer.

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Dr. Snuffy Myers frames this month’s discussion for us.

Our ability to image prostate cancer metastases has improved dramatically over the past few years. CT and bone scans, which have been the standards for decades, typically image a cancer mass larger than 1 cm (0.4 inches). Newer imaging techniques have lower limits that approach 1-4 mm. Dramatic changes like these have a way of disrupting the status quo.

The current guidelines for the treatment of metastatic prostate cancer are based on clinical trials where metastases were detected with CT or bone scans. Do these treatment guidelines still hold for metastases too small to be found by CT or bone scan, but detectable with the newer, more sensitive imaging techniques? There are reasons to suspect we might begin to detect prostate cancer at a different stage in its evolution.

The concept of cancer dormancy is commonly used to explain a long interval between initial treatment with surgery or radiation and subsequent appearance of metastatic disease. For both breast and prostate cancers, more than 10 years can pass between treatment with curative intent and the appearance of detectable metastatic disease.

Several mechanisms have been identified that can lead to cancer dormancy. Two of these mechanisms might result in cancer masses potentially detectable by the newer imaging techniques. First, cancer dormancy can result when the cancer mass fails to attract a blood supply and thus is starved of both oxygen and food. The second is that cancer dormancy can result from ongoing immune attack on the cancer. Both mechanisms can allow cancer masses above 1 mm that overlap with the lower limit of the newer scans.

Cancer dormancy is associated with greater resistance to cytotoxic chemotherapy and hormonal therapy. The implication is that we may increasingly detect prostate cancer metastases that pose no immediate threat to the patient because they are dormant. Additionally, these metastases may respond poorly to standard treatment options. All of these factors would argue for caution in making treatment decisions based on the newer generation of scans.

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