Diet and Supplements for Men with a Rising PSA

Diet and Supplements for Men with a Rising PSA

David’s given me a very difficult task, one is it’s the last lecture of the day and the second is to try to show you that there is some evidence for using diet supplements and herbs, not the herbs that have just become legalized here in Colorado, but some herbal compounds that may be helpful in your practice and as mentioned, this does come up every day. I’d like to start out with a case, and this is actually a real case of actually a medical oncologist who had a radical prostatectomy five years ago for a Gleason-7 prostate cancer, multiple cores were involved, the presurgical PSA was 5.9, margins were negative, lymph nodes were negative, seminal vesicles were all clear, but there was some extracapsularly extension in one area. Over the past four years his PSA has been undetectable. He’s had an excellent quality of life, he’s had normal erections, he’s had no leakage, and he wants to keep it that way. Over the past year he’s been monitoring his PSA every four months, his PSA had gone to 0.01, up to 0.05, and is now 0.09. Someone got an MRI, I wouldn’t have gotten an MRI in this gentleman, I wouldn’t think there’d be anything to see, but an MRI was done for the pelvis and the pelvis was clear with no visible abnormalities. What would you do for this patient? Would you consider hormones? Would you do something that I’ve coined “active holistic surveillance” using some dietary supplements, maybe changing his lifestyle, and his diet? Would you now consider him for salvage radiation therapy or would you just kind of say, you know what, let’s just watch and wait? You haven’t necessarily failed biochemically, you don’t have a 0.2, so maybe we’ll just watch you. What do you think?

So let’s see, no one’s giving him hormones. Most people are watching and waiting, very few are going to pursue an active program for him, and about one-third of you would do salvage radiation therapy, which I think is probably if you polled most radiation oncologists, that probably would be somewhere around 70% that are going to offer him salvage radiation therapy.

So with that, as many of us know, 35%, one-third of men, which is surprising, and I think this is probably still true despite robotic surgery and despite IGRT, I think over the 10-year period patients will have a rise in PSA. Not all these patients will have cancer, especially the radiation patients. We’ve biopsied a lot of these men and they don’t have cancer, but they will have a rise in PSA, which does make them rather anxious, and I think that there may be a role for implementing some dietary strategies, physical activity, and stress reduction, which may help and reduce progression of these cancers and prevent them from needing additional radiation therapy or hormone therapy as we’ve heard in Dr. Gomella’s talk about the potential adverse events. We all know those from hormone therapy. Can we delay it? Of course there is a risk here. The risk is is that we have a window of an opportunity where a patient may be curable using adjuvant radiation therapy perhaps. Are we willing to risk that window and watch these patients? And for the surgical patients that have a rise in their PSA, we’re basically down to these three options.

You’re either going to have radiation, you’re going to have hormones, or you’re going to go on to some form of surveillance. I think that surveillance, from what I see right now in my practice using these dietary interventions for surveillance are really the low-risk prostate cancer patients for surveillance or the patients that have had a rising PSA after radiation therapy or surgery that don’t want to have additional therapy. Then for the radiation patients, there’s the whole list of things; salvage cryotherapy, which we’ll talk about tomorrow in a debate with James Eastham about whether or not that’s a better modality than salvage radical prostatectomy. There are a few centers now that are doing salvage brachytherapy in patients that never got seed implantation, perhaps even doing this in a focal manner. Salvage HIFU, there is an ongoing trial right now in the United States and hopefully those results will show beneficial and modality will be FDA approved, hopefully within a year or two. Then of course there is hormonal therapy whether you do it continuous or whether you believe in the intermittent approach, then just watching these patients with surveillance.

What about this approach of incorporating some dietary strategies? I think it may be reasonable for these patients that have had radiation therapy or surgery for the slow-rising PSAs maybe the patient now is out a few years, like the patient that I just presented that has other comorbidities, and men that we “believe”, and this is quotes here because we’re really basing this on the clinical parameters, our gut instinct, does this patient really have localized disease based upon things like a prolonged PSA doubling time, a long interval from primary treatment, and what are some of the PSA parameters, PSA kinetics, the imaging modalities, the quality of life? Then the question is can diet and vitamins play a role for these patients?

Fish oils; so I thought fish oils was great. I take fish oils and many of you will take fish oils, but for prostate cancer patients I was also telling my patients I think fish oils is great. The reason I thought it was great is that it had a lot of health benefits; reducing cardiovascular disease and stroke, it could enhance your immune system, reducing inflammation, especially if you have a high triglyceride level, over 500, there is a prescription medication Lovaza, that is indicated for these patients with high triglyceride levels, and even some reports showing that it can improve brain health and it may have an effect on cancer.

So I thought this was great until about six months ago. Six months there was a paper that was published in The Journal of National Cancer Institute from Fred Hutchinson Cancer Center that looked at patients, and this was not a prospective, independent trial, it was patients that were on the SELECT trial. We all remember the SELECT trial, the NCI trial looking at the role of vitamin E and selenium to see if we could prevent prostate cancer. What they did is they took patients from that trial, their blood level, one blood level, and they looked at the plasma level of these omega-3s in the blood and compared it to patients that had prostate cancer, to those patients that did not, that were control patients. In fact the patients that had very high levels of omega-3 levels in their blood actually had a much higher rate of developing prostate cancer.

There was no information on the eating habits. We don’t know anything about whether or not these high levels of phospholipids in their blood was actually due to supplements. We don’t know anything about that. There were no supplements that were given in this trial. Again this was just a randomized trial in the community looking at vitamin E and selenium. Do we really think that an omega-3, that these are the trigger points? There are a lot of communities, especially countries that eat a lot of fish. We always go back to the Japanese countries where they eat a lot of fish, they take in a lot of soy, and they have the lowest incidence of prostate cancer what we believe around the world.

There was some hype. There was some pushback about this, but there was a lot of media hype about omega-3s and the nutraceutical industry was certainly up in arms about it. Mayo Clinic still came out and said “eating fish, great for your heart”. The American Heart Association said “research has shown that omega-3 fatty acids decrease the risk of arrhythmias, which of course can lead to sudden death and omega-3 fatty acids also decrease triglyceride levels and slow down the rate of atherosclerotic plaques and can have an effect on blood pressure”.

So what do we do? What do I do? What did I do? Well I think for now I’ve told my patients to stop taking in all these fish oil supplements. I think it’s probably best that the patients just go to eating a few servings of fish each week unless there is in their blood, and I do obtain their triglyceride levels in their blood, and if they have very high triglyceride levels, then I do suggest that they seek advice from their internist and go onto Lovaza. The fish that have the highest amounts of omega-3s; sardines, wild salmon, and anchovies, and flax seed oil also has a high amount of omega-3. That’s pretty much the omega-3 area.

The other area of interest, and what I’m going to do over the next 15 minutes or so is just go over some of the areas that I think have caught the media’s attention, caught your patient’s attention, and there’s some evidence either for or against it to try to help you to see if this can have an impact on your practice. What about vitamin D and prostate cancer recurrence? There is tremendous amount of literature on vitamin D in a wide variety of cancers showing that the further that we go from the equator, the lower levels of our vitamin D and the higher rates of breast cancer, prostate cancer, and colon cancer. We take in vitamin D through the sunlight and as well we take in vitamin D through our intestinal tract, through milk products, and again through fish.

As you see on the bottom, the more vitamin D we have in our blood system, it can increase bone mineralization. I have all of my patients that are on hormonal therapy, I get vitamin D levels on them. I don’t know if any of you do that in your practice, but I would suggest that you do that, especially for your patients that are on hormone deprivation. It can have an effect on your immune system and as well as on the tumor microenvironment, inhibiting cellular proliferation and inducing differentiation and also inhibiting angiogenesis.

There have been studies out of Harvard, Ed Giovannucci that showed in a 50,000-men study that the lower the vitamin D if you reduce your vitamin D, you will increase your risk of a number of different cancers. I look around in my community and I see the kids in my community, nobody’s outside anymore. Everybody’s inside, going on the computer, this Facebook factor. This has been associated with lower levels of vitamin D. In fact I did a study when I was at Colombia a couple of years ago in The Journal of Urology 2011 where I looked at about 2,500 patients in the urology clinic and about 68% of them were deficient in vitamin D, having a value of less than 30. In fact, almost half of them were frankly deficient less than 20. Vitamin D deficiency is more common in younger patients, in African American patients, and maybe a predisposing condition for prostate cancer. It is extremely common in the urological center, at least in the center at a major urban center when I was at Colombia.

This was a trial looking at patients, a small trial. The problem with a lot of these nutraceutical studies is that many of them are not randomized, many of them are not placebo controlled, and many of them are of short duration and short number. This study out of Stanford, 21 patients with a rising PSA, after surgery or radiation giving them the active form of vitamin D, calcitriol with naproxen, which is an antiinflammatory agent, did show that you could extend the PSA doubling time. This was the endpoint. A lot of the nutraceutical studies, that’s really what their endpoint is, especially when you’re looking at patients that have had radical prostatectomy. They could extend their PSA doubling time in this particular trial.

What I would recommend, and what I do for vitamin D, and again I do obtain vitamin D levels on all of my patients that are on active surveillance, whether it be in the recurrent cases or in primary is to get a baseline vitamin D level. Then you need to restore about 1,000 units of vitamin D, that’ll give you just a bump up of around 10. Most people in the field believe that the therapeutic range is somewhere between 40 and 50. I have not had any problem going straight to 5,000. If you look in the vitamins, if you’re on multivitamins and you look at how much vitamin D is in your vitamin capsule, it’s about 200 units of vitamin D. I will start with 5,000 per day and then repeat the vitamin D in three months.

Here’s the story on red meat. A lot of the studies have come out looking at obesity as an independent predictor of aggressive prostate cancer. The Hopkins group as well showed that patients that are obese, have a higher body mass index at the time of radical prostatectomy, have more adverse features and are more likely to have a PSA recurrence in the postoperative period. Is it red meat? Is it what’s in the red meat? Is it hormonal agents that are in the red meat? Eric Klein at the Cleveland Clinic has looked at this and he felt that the higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer. It appears that it’s not just the meat. If you grill the meat excessively, if you barbeque it, if it’s black, if it’s charred, you know what I’m talking about, it tastes great, but the problem is, it’s liberating these heterocyclic amines and polycyclic aromatic hydrocarbons that are formed when you over-grill it. This has been found in men when they did a FFQ, a food frequency questionnaire. The men that had higher meat consumption had more rates of aggressive prostate cancer and lethal prostate cancer.

So then we go to the other side. Maybe we should just go to all vegetarian diet? There is a lot of studies looking at these particular vegetables, and these don’t taste that great. Maybe you should grill these. Broccoli, brussel sprouts, kale, and red cabbage, and these cruciferous vegetables there have been a number of studies that show that if you take in more cruciferous vegetables during the week, that you may be able to reduce PSA and prostate cancer recurrence. Epidemiological studies have shown that, and actually there have been studies looking at prostate biopsies at tissues before and after a 12-month broccoli rich diet. I actually offer my patients, there’s a broccoli seed extract pill, some people just don’t like broccoli and don’t want to take broccoli every day. But the men that have been on the broccoli rich diet had changes, molecular changes in their DNA, cell cycling signalling, and affecting the insulin signalling, and the insulin receptors, and it appears that we can reduce inflammation and it can cause several signalling pathways associated with inflammation and reducing carcinogenesis in the prostate.

Should you go to a whole-food, plant-based diet? Has anybody in this room tried this or recommended it to your guys or have men come into you and said you know what my PSA is going up, I’m just going on plants, I’m just going to eat vegetables all day, I’m not going to have any animal protein? This is very difficult for men. I can tell you that guys become grouchy, the wives are complaining to me. I say look I didn’t put them on this, this is what they wanted to do. They don’t like it. A lot of men need animal protein. You can try. Some of the patients have tried this and tried to stabilize their PSA like this. I’ve recommended and have done a study with an herbal study called Zyflamend, it was made by a company called New Chapter, which is now bought out by Proctor and Gamble. It’s the number one herbal supplement in the United States, sold for inflammation. These herbs here, these 10 herbs all have low levels of cyclooxygenase activity and they are incorporated into a pill, and there are a number of products that are out there that are like this. I actually found out about it anecdotally because patients were telling me that they were taking this for their knees or their shoulder and their joints were better, but also their PSAs were going down, so we spent a couple of years in the lab. Actually I’m not going to bore you with all of the molecular results that we had. We did a study with patients that had PIN and were able to show that we could reduce prostate cancer development in the patients that took these herbs and reduce their PSA value, which is of course very important to a lot of men. There really is no adverse features here. There’s really no side effects as long as you take these herbs with food, otherwise you can get a GI upset.

This was a study that was done recently, actually a few years ago. Again a six-month study, just looking at adding just plant-based diet to patients that have recurrent prostate cancer following radiation therapy or surgery. Just taking in plant-based foods and finding if there’s a relationship between the rate and the rise of PSA. What they found was that the men that did do this actually their PSA rise decreased when compared to the pre-study PSA and it provided some preliminary evidence again that perhaps going more to a plant-based diet, getting away from the red meats may have an effect on PSA progression.

This was done a little bit more elaborately in 2012 in a randomized trial, randomizing patients who have had again a recurrence after radiation therapy or prostatectomy to an intensive diet with staying away from meat, going more to a plant-based diet, physical activity, meditation, and more fruits and vegetables in their diet, and then looking again at the PSA values and PSA progression. Decreasing meat and dairy consumption while increasing the consumption of whole grains, soy beans, soy products, etc. as well as exercise. More than 30 minutes of moderate intensity exercise, I don’t know if you encourage patients to exercise in your practice, a lot of the guys clearly need it. There’s been a tremendous—there’s a few studies that show that it can have an effect on BPH and voiding symptoms, exercise as well as the potential obviously for reducing cardiovascular disease and for prostate cancer development. Again small study, 47 men, randomized, but in the intervention group, the intervention group experienced decreases of 39% in saturated fatty acids, and in the men increasing their consumption of fruits and vegetables 56% experienced no rise in their PSA. Again these are men that have had radiation or surgery, rising PSAs, more than half of the men had no rise in their PSA that went onto this diet.

Pomegranates, pomegranate juice, pomegranate extract pills have also been used and have been studied in randomized fashion. There is peer-reviewed articles, there’s probably about 25 of them right now, some of them are basic science work showing that there’s been in vitro studies, in vivo studies that you can interfere with some of the inhibition of fairly aggressive prostate cancer cells, PC3. You can interfere with the delaying S phase, and then in mice you actually prevent and prolong their survival and reduce PSA.

This was a randomized trial just published, it was 2013. One of the groups, it was a multicenter trial led by Hopkins looking at a pomegranate extract pill, POMx. This was not a placebo-controlled trial, it was basically a study in men that had a rising PSA, it was double-blinded that either had radiation or surgery, you couldn’t have a higher than a Gleason-8, PSAs were still under five, no evidence of metastatic disease, no prior hormone therapy, basically again just saying what their PSA doubling time. They weren’t sure what the right dose was, should it be 1 gram or 3 grams of this POMx. It is available. If you go on Amazon.com, I did it a few hours ago just to see how much it was, it’s about $24 a month. It’s 104 patients that were enrolled. This is the extract, not the juice. There was a prior study that was published by Alan Pantook at UCLA looking at pomegranate juice in these patients. This is the extract pill. It was associated with a more than six-month increase in PSA doubling time. Again, no side effects; no side effects at all. You can see here that the majority of patients, even in the low dose, but in the higher dose, the 3 grams here of POMx that these are their PSA doubling times. The majority of them, only a few patients actually lowered their PSA doubling time. The majority of these patients had extension of their PSA. If you believe that PSA doubling time extension will extend life, then you probably think that this is reasonable and maybe should start your patients on this prior to adjuvant or salvage radiation therapy.

I have a number of patients that are low risk patients that I’ve queried my IRB database at my center. These are non-treated patients, low risk patients, monitoring their PSAs every three months at least for the first two years, get an MRI at baseline to make sure that they are what I believe to be a candidate for surveillance. If there’s any evidence of extracapsular extensions, seminal vesicle involvement, even a capsular bulge then I don’t feel that they should be going onto surveillance. But if their MRIs are clear, then they would get another MRI in a year and follow them by PSA. They get put on a diet, which is a diet that has no red meat, but they are allowed chicken and fish, a lot of broccoli and herbal compounds, vegetables, the cruciferous vegetables, the pomegranate extract pills, and some lycopene pills, exercise, PSA monitoring every three months. I do genomic testing on them. I found this to be very helpful. I like the MDX testing, the genomic testing, and if their GPS scores come back pretty low and I feel that they are by NCCN either very low or low risk prostate cancer patients, then they go on to this protocol.

This is basically the diet; getting off of red meat, more cruciferous vegetables, no sugars, try to get into more green tea, taking more green tea than coffee, reducing dairy, no fried foods, trying to exchange with soy to cow milk, and red wine, which has the highest amounts of resveratrol, they like to know that they can have the pinot noir that has the highest amount. That’s the urology wine of choice, that’s pee-no more, that’s now they remember that.

One hundred twenty one patients, the average age was 64, we have some young patients here that are diagnosed with, and I’m sure you’ve seen this in your practice, early stage disease. I think the genomic testing is reasonable, MRI, and for two cores of a Gleason-6, all the cores have to be less than 50%. They may not want to go on for radical prostatectomy or definitive therapy. Most of the patients we’re treating are Gleason-6’s, 87%, but we have a few patients here that do have a Gleason pattern 3+4. I’ve been doing this for quite a while in my practice, so some of these patients are out 17 years, but the average right now on surveillance is almost five years. Right now only a very few of the patients have dropped out. I do not, you can criticize me for this, I do not rebiopsy these patients unless their PSA goes up. Up to me means a PSA that has doubled in a year. I don’t do as Memorial does and I know Hopkins do, they do confirmatory biopsies, I don’t. As long as the MRI stays clean, 3.OT, multiparametric MRI, I follow them with PSA, MRI, quality of life symptoms, and digital exam. Unless their DRE changes or their MRI changes or their PSA changes, I just follow them. Then these are the types of treatments that we have a big Cyber Knife program at our hospital and some of these patients have gone on to that.

Soy and soy products, taking the data from Japan and looking at the incidence of prostate cancer around the world, we thought well maybe it’s soy. So maybe our patients will take more soy in their diet. There’s a lot of controversy about soy, the isoflavones there’s four of them, genistin is the most active. You look at the chemical structure of soy, it looks like estrogen. So patients are concerned, am I going to start developing gynecomastia or am I going to lose my sexual function, is it going to affect my testosterone level?

These are the areas where you can take in soy. These are the food compounds. If you look at our diet, the Western diet, it is significantly lower the amount in the blood and the urine of isoflavones that we take in versus the Asian or the Mediterranean diet.

I thought soy was great. I recommend it for all my patients. This just was published in JAMA and Herb Lapour and Tinasia and NYU group was part of this multi-centered trial looking at a soy beverage in patients that had rising PSA after radical prostatectomy. I don’t know if any of you have seen this trial. It was a soy protein supplement versus placebo, 177 men at high risk for recurrence after radical prostatectomy. They started giving them the soy beverage almost immediately, like four months after surgery when they thought that these patients were at high risk for failure and they continued this up for two years. They did a PSA every two months and every three months thereafter. Their failure, their cut point, I think because they didn’t want to lose the window of opportunity for salvaging them with radiation was a PSA cut point of 0.07. Well, this wasn’t a great result. There was really no difference when you’re taking this soy beverage. Now does this mean that patients that are untreated shouldn’t take in some soy, I don’t necessarily know if you can extrapolate that, but in this particular trial, this was a randomized trial, the only knock on the trial was that the placebo was this high-dose sugar pill with cassine, which some of the people in the nutraceutical world have said oh that can cause prostate cancer, why did they use that as the placebo? I can’t really knock the study. I think that the study was well done and there was no statistically significant difference between the soy beverage and the control.

The other area that’s gained a lot of interest is in lycopene’s or stewed tomatoes. You have to actually stew or cook the tomatoes in order to incorporate the lycopene into your blood and make it biologically active. It is the most prevalent carotenoid and a very high prevalent antioxidant. This study was just published last month so you probably haven’t seen it, out of the group from Harvard where they looked at 49,000 health professionals and they did again this FFQ. They went back and they asked these 49,000 men through a food frequency questionnaire how much carotenoids or lycopene have you taken in? What they showed, and this was just published in JNCI, higher lycopene intake was inversely associated with total prostate cancer and more strongly associated with lethal prostate cancer. Higher lycopene was associated with some of the biomarkers indicative of less angiogenic activity that may be interfering with proliferation and angiogenesis. If you look here, if you take in the highest quartile of lycopene, which is usually around three to five servings of stewed tomatoes a week, your risk of advanced prostate cancer and lethal prostate cancer was significantly less than if you took in a very small amount of lycopene in your diet.

There was study by Maha Hussain at Wayne State looking at lycopene and soy in the treatment of patients with prostate cancer who again had recurrence following local definitive therapy with 71 patients who were randomized to receive a tomato extract capsule containing 15 mg of lycopene or a soy capsule alone. What was shown, and this was pretty remarkable, that 95% of the patients in the lycopene group actually achieved stable disease by basically saying that they had a stable PSA and in the patients who took the soy capsule it was 67%. There was again no adverse events, you don’t see any adverse events typically with most of these nutraceuticals. The data showing that lycopene and soy may have activity in prostate cancer.

For the most part that’s it. Patients can come with you with stacks of information from the internet about all different types of herbal compounds, but for the most part this is what I think is in the literature that is reasonable. Do I think that overall in doing this on a day to day basis that diet and supplements can stabilize PSA rises? No doubt it can in a subset of patients, and especially for patients that are low-risk that are on surveillance. I’ve taken more of an active surveillance, a holistic approach incorporating diet, supplements, exercise. But I tell patients it’s not a cure, your cancer is not going to go away. This is something that you can live with and whether or not these low risk cancers are really cancers and should be defined as cancers is up for another discussion. Do I think that we should consider diet and lifestyle for our patients undergoing active surveillance? Yes. Do I think that salvage radiation should be used for selective patients? Yes and from what I can see, from what was presented earlier here and from the randomized trials, there’s no doubt that if we get these patients in earlier the better, but there is a risk. Neil presented some interesting data about the risk, the acute and the late toxicity of salvage radiation, and I think that the erectile dysfunction is higher than is reported. I honestly do. I’ve seen that. I think that guys that—I agree with urinary incontinence, that I haven’t seen salvage radiation affect their continence once they’ve gained continence, but it clearly can have an impact on their erections. Do I think that we should monitor other things beyond PSA like vitamin D, like C-reactive protein level for inflammation? I certainly do.

I think that just keep in mind that not all patients with a PSA rise after definitive therapy will develop metastasis. Adjuvant and salvage radiation can cause short and long-term problems as has been shown. There’s usually no immediate or urgent need to start radiation and so we must be mindful. Sometimes we should remember a famous hypocratic oath which is—I guess not. Can I get the famous quote? No. The quote was “let food be thy medicine and medicine by thy food”. Thank you very much.

Do we have time for one last question? I was given the task of writing two questions, so I might as well just give that to you. A 74-year-old male undergoes a prostate biopsy for a rising PSA of 4.2-5.1 in the last year. He has a BMI of 28 and underlying cardiac disease, which require the placement of a stent a year ago. He remains on Plavix, his AUA score is 12, he has no erections, a 12-core biopsy shows two cores, Gleason-6, 20% and 10%, his density is 0.13. So by NCCN criteria he would be a very low risk prostate cancer because his PSA density is below .15, Gleason-6 in two cores and less than 50%. He has a 3.0 TMRI, didn’t show any lesions, and a clean capsule. If the patient decides and you are agreeable that he’s going to go on surveillance, would you recommend any of the following; diet and lifestyle, vitamin D, pomegranate, lycopene’s, none of the above, all of the above? So all of the above, okay very good. Yeah 82% said all of the above, which is what I would do, and diet and lifestyle changes.

Well I hope that was helpful and thank you very much for your attention.

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