The mantra of heart health being tantamount to urologic and prostate health was highlighted in the opening chapter of this book and most other past written sources from this author [4].

Men have a consistently lower life expectancy in the USA and in most countries around the world and have a higher morbidity and mortality from heart disease, hypertension, cancer, and diabetes [5]. Yet it must be reiterated that heart-healthy changes are tantamount to overall men’s health improvements, regardless of the part of the human anatomy that is receiving attention, including the penis and the prostate [6, 7]. Heart-healthy changes need to be advocated to men concerned about prostate cancer because it places probability and the overall research into perspective. Triaging preventive medicine for men’s health is providing probability-based advice via evidence-based medicine and can impact all-cause mortality as well as potentially prevent prostate cancer.

One of the more fascinating features of large randomized clinical trials, especially for primary prevention, is that they appear to reflect the current health status and risk issues of not only the subjects being tested, but also perhaps the general population. The largest, most recent, and arguably the best-designed US and worldwide pharmaceutical-based cancer primary prevention trials for the prevention of prostate cancer exemplify the urgency for a different or changing perspective. For example, results of the Prostate Cancer Prevention Trial (PCPT) seem to have garnered attention and controversy regarding the use of finasteride daily versus placebo to reduce the risk of prostate cancer [8–11]. The debate over finasteride abounds, but another observation from this trial has not received adequate exposure in the medical literature. Over 18,000 healthy men were included in this randomized trial, and five men died from prostate cancer in the finasteride arm and five men died of prostate cancer in the placebo arm. However, 1,123 men in total died during this primary prevention trial [8]. Thus, prostate cancer was responsible for approximately less than 1 % of the deaths, while the majority of the overall causes of mortality were from CVD and other causes [8, 12, 13]. Additionally, the mean BMI, systolic blood pressure, and total and HDL cholesterol were the following: 27–28 (50 % overweight and approximately 25 % obese), 138–140 mm Hg (pre-hypertensive), and 212 mg/dL and 42–43 mg/dL (dyslipidemia or at risk). Despite 85 % of men with no history of CVD, approximately 50 % of the men reported some level of erectile dysfunction (ED) [12].

The international dutasteride high-risk prostate cancer prevention trial known as REDUCE (Reduction by Dutasteride of Prostate Cancer Events) had somewhat similar issues to the North American PCPT in terms of overt controversies [14–16], but what was not questioned, discussed, or even debated was the BMI and several other abnormal CVD parameter issues mentioned earlier were similar in the two trials. For example, on average men in REDUCE were overweight (BMI of 27–28) [14]. There were 8,231 men randomized and after the 4-year trial in this group of men there were 147 total deaths, primarily from cardiovascular events and none from prostate cancer. Of further note, men in the placebo arm of PCPT with low cholesterol (<200 mg/dL) had a 59 % (p = 0.02) apparent reduction in risk of being diagnosed with aggressive prostate cancer (Gleason 8–10) compared to men with high cholesterol (>200 mg/dL) [17], and men with coronary artery disease (CHD) at baseline in REDUCE were found to have a significantly higher risk of a prostate cancer diagnosis, and this included low-grade (OR = 1.34, p = 0.02) and high-grade cancer (OR = 1.34, p = 0.09) [18]. These notable but less recognized observations do not intend to belittle prostate cancer or these trials utilizing a specific chemoprevention agent, but again it places the overall risk of morbidity and mortality in a more proper perspective. Men inquiring about the advantages and disadvantages of finasteride and dutasteride for prostate cancer prevention need to be reminded that the number 1 risk to them in general is CVD, and in both clinical trials the researchers found good indications that heart health was tantamount to prostate health.

Whatever appears to improve heart health also appears to simultaneously improve prostate health. Encouraging patients to do whatever is practical and plausible to reduce their risk of CVD to as close to zero should be the mantra. This should provide the greatest potential to not only reduce the risk of prostate cancer, but other disease morbidity and even impact all-cause mortality. It is interesting that most major behavioral risk factors for CVD morbidity and mortality today appear to be correlated with a higher risk of prostate cancer or aggressive prostate cancer and/or fatal prostate cancer. For example, smoking is the single largest preventable cause of death and disease in the USA with approximately 443,000 deaths still occurring per year from tobacco-related disease, and approximately 20 % of adults smoke, which is a number that has remained constant the past several years [19, 20]. Smoking has been associated with a higher risk of being diagnosed with prostate cancer in recent meta-analyses [21], a higher risk of aggressive prostate cancer, and dying from prostate cancer [22, 23]. Similarly, obesity is associated with a higher risk of aggressive and fatal prostate cancer [24], and this is why it is no longer surprising that a higher risk of recurrence occurs posttreatment for prostate cancer [25]. It is also plausible that obesity is associated with a lower risk of localized prostate cancer, and a higher risk of advanced disease due to the artificial lowering of PSA or hemodilution impact associated with this condition [26, 27].

Weight gain ancillary issues abound. For example, ongoing evidence suggests an increased risk of certain cancers with insulin resistance, and this may include aggressive prostate cancer [28–31]. Increased growth factors occur with increased insulin levels, but long-term diabetes may result in insulin, IGF, and androgen reduction, which may be correlated with a lower prostate cancer risk in the short term (“diabetes paradox”) [31]. The dramatic increase in the diabetes epidemic [32], along with the known 2–4 times increased risk of CVD events in diabetics over nondiabetics [33], should make type 2 diabetes prevention strategies a priority for simultaneous prostate cancer prevention. Only 15 years ago, 3 states in the USA had a diabetes prevalence of 6 % or higher, but now all 50 states in the USA have a rate of at least 6 % or higher [32]. Six states have rates of 10 % or more, along with Puerto Rico, and currently 19 million people in the USA have diabetes and 7 million are undiagnosed. Perhaps prostate cancer prevention strategies can help to modestly curb this epidemic. Exercise (aerobic and resistance) and dietary (caloric reduction) and other lifestyle changes have been shown to significantly prevent diabetes and metabolic syndrome in normal and high-risk individuals better than pharmacologic therapy [34–38].

Hypertension is a primary risk factor for CVD and stroke and almost a third of the US adult population has this condition [39]. Hypertension increases with age to approximately 70 % of individuals 65 years and older. Hypertension is a contributing factor in one out of every seven deaths, and 70 % of individuals who have a first heart attack or stroke have hypertension [40]. Treating hypertension has been correlated with dramatic reductions in the incidence of stroke (40 %), heart attacks (25 %), and heart failure (>50 %) [41]. However, the correlation between prostate cancer risk and hypertension and/or antihypertensive medications is weak [42]. Yet high blood pressure as part of a continuum of unhealthy parameters, such as observed with metabolic syndrome (central obesity, dyslipidemia, and insulin resistance), is becoming a potential risk factor for prostate cancer and other prostate issues [43]. It is also well known that alpha-blockers, originally discovered for blood pressure control, are now one of those most effective treatments for men with prostate issues (BPH) and lower urinary tract symptoms (LUTS) despite not having consistent positive or negative impacts on prostate cancer risk [44, 45]. In order to maintain prostate health, it is critical to prevent or control hypertension.

Regular vigorous exercise (3 h or more per week) is a potential strategy to significantly reduce prostate cancer death after diagnosis and simultaneously reduce all-cause mortality to a similar degree (50–60 %) in these same patients compared to men that perform only 1 h or less exercise per week [46]. Thus, it should not be a surprise that exercise may also contribute to a slightly lower risk of prostate cancer, from a review of past studies including a recent summary of 22 studies published over the past 12 years [47–49]. Patients should be told that the profound reduction in blood pressure, diabetes, depression, dyslipidemia, cancer, CVD, fatigue, obesity, and multiple other conditions would arguably be enough to garner exercise a Nobel Prize if it were a drug [4].

Patients should also be informed of the potential for exercise to profoundly enhance the effects of conventional medication. This has been a constant source of difficulty in the past to explain intuitively that one needs to continue to exercise daily despite utilizing an effective prescription drug. A truly novel prospective 10-year study of over 10,000 adults (mean age of 58 years) from the Veterans Affairs (VA) Medical Center in Palo Alto, CA, and Washington, DC, should help in educating men with dyslipidemia on the ancillary effects of exercise [50]. Researchers found a lower risk of dying from any cause when on a statin (cholesterol-lowering drug), but this was not the noteworthy news. Participants in this study had received an exercise test between 1986 and 2011. Over 2,300 patients died during this time and the risk of dying was significantly greater in the group that did not take a statin drug compared to those that did, but again this is also the noteworthy news. Next, researchers looked at the fitness level of those based on exercise testing and the use of a statin drug. The risk of death further decreased with fitness or improved health from exercise far beyond what the statin drug alone could provide. Men that were most fit in this study were able to reach slightly more than nine MET (metabolic equivalent tasks, a measure of the intensity of your exercise; higher numbers are better) peaks on an exercise machine, and this group experienced a 70 % reduction in overall mortality compared to the least fit! However, men who could do just 7.1–9 MET did almost as well (59 % reduction); even those who were able to perform 5.1–7.0 MET experienced a 36 % reduction! This is the noteworthy news! Think about this the next time a discussion with a patient occurs on the benefits of exercise in addition to proven conventional treatments. Again, the clinician reading this chapter or patient needs to ponder and appreciate what a 70 % advantage in reducing the risk of dying from all causes beyond what is already being provided by a lifesaving drug really means (arguably an immediate Nobel Prize in medicine)! A person gets 1 MET for sitting on the couch and breathing, 3–5 MET for just moving or carrying golf clubs, and 5–7 MET for a light jog or hike or brisk walk, and 7–9 MET for more intense exercises. A 10-min mile is approximately equivalent to 10 MET. In fact, exercising 30–60 min/day basically allows many individuals to reach this exercise capacity. Researchers also looked at men not taking statins and their fitness levels compared to other men not taking statins and found that the most fit had a 47 % reduction in the risk of overall mortality compared to the less fit [50]! This study also shows that individuals who simply cannot tolerate these drugs when everything has been tried should at least be exercising regularly to get some notable benefits. It should also be kept in mind that this is now the second paradigm-type study of men in medicine or urology that demonstrates the impact of exercise on proven health-promoting medicines. In the erectile dysfunction (ED) chapter on lifestyle changes, the clinical trial of PDE-5 inhibitors in association with exercise over 3 months was discussed, and the profound improvements that occurred for most ED parameters, including libido (an indication never approved by the FDA for PDE-5 inhibitors), were reviewed [51]. The mean age and BMI of the participants were 50 years and 27 (overweight), respectively. A significant improvement was observed in all aspects of the IIEF-15 except the orgasm domain for men who exercised 3 or more hours a week compared with the non-exercise pill-only group. Erectile function, confidence, sexual desire, intercourse satisfaction, and total satisfaction were all significantly improved in the exercise group taking PDE-5 medication over the PDE-5 alone group. Thus, the clinician today has wonderful motivating resources or research to utilize in discussions with patients. Whatever the drug utilized, it could be argued that exercise improves the efficacy of these conventional agents.

Thus, virtually every heart-healthy parameter of lifestyle change has now become associated with prostate health or prostate cancer. Obesity, a lack of exercise, high cholesterol, hypertension, glucose intolerance, inadequate diet, excessive alcohol intake, tobacco, etc. have all been linked to abnormal prostate health [4]. For example, Table 7.1 is a quick overview of general lifestyle changes, situations, or parameters that have been associated with the risk of prostate cancer and abnormal prostate issues, and all of them also impact cardiovascular risk [4].

Firstly, I have always had a policy of reducing dietary supplement intake before conventional medical treatment, especially surgery and radiation [4]. There are quality-control and blood-thinning issues that are virtually impossible to anticipate or predict. For example, small amounts of some dietary supplements could impact or increase the risk of bleeding events in some rare situations, including fish oil, which could have a qualitative effect on platelets, and no test is currently available to predict coagulation issues. A dose of fish oil as low as 1,800 mg/day in combination with a statin (another partial blood-thinning agent) significantly increased the risk of minor and serious bleeding events (subcutaneous, epistaxis, fundal, and cerebral hemorrhage) in one of the only randomized long-term clinical trials to ever address this issue [52]. The number of overall events was small compared to the control group (105 vs. 60; p = 0.006), but the results in some of these rare cases were and could be catastrophic. In addition, when allowing the intake of herbal products that could also contain natural blood thinners (“coumarins,” similar to coumadin) without identification on the bottle, the risk clearly outweighs the benefit for most patients. Thus, after complete recovery, or 1–2 months, potentially restarting dietary supplementation is an option. Clinicians should explain this safety issue with compassion because in my experience when it is handled without this approach, it can generate a response that does not encourage compliance from the patient, but rather conspiracy due to the lack of perceived general knowledge of CAM for healthcare professionals.

I have always been opposed to men taking megadoses of supplements when getting radiation treatment for prostate cancer unless they potentially mimic what could have provided benefit in the area of conventional medicine (e.g., cholesterol- or glucose-lowering or control, potential radiosensitizers) [53–57]. Taking numerous dietary supplements with radiation treatment does not appear to improve results and may in rare cases reduce efficacy, but more research is needed. Again, it is my opinion that no dietary supplement will improve the results of radiation treatment in my lifetime unless researchers try to copy what already might be working in the prescription drug world to improve outcomes after localized treatment, for example, aspirin, metformin, or statins (cholesterol lowering) [4, 53–57].

A retrospective review in utilizing the following dietary supplements with prostate cancer radiation treatment was published [58]:

A total of 134 men were treated with radiation therapy for primarily localized prostate cancer, and 69 patients received these high doses of dietary supplements. A total of 77 received hormone therapy, and all of the men on dietary supplements continued to use them for at least 24 months after radiation was completed. The follow-up period postradiation was 71–79 months. No significant differences were found in the patients receiving radiation alone in terms of pretreatment PSA, PSA nadir, time to reach nadir, and follow-up. Similar findings occurred in the group of men receiving hormone therapy. There was also no difference in urinary or sexual function between the men treated with hormone therapy in the dietary supplements group compared to the no supplements group. This study reflects the current thinking and past human radiation studies in cancer in terms of a lack of minimal or profound ancillary impact.

Why have patients risk even a 1 % chance that the supplements or CAM they are utilizing could compromise their conventional treatment success or cure? If a patient accepts the potential for cure or control of his prostate cancer with a conventional option, then to compromise this option even remotely undermines the very reason the patient chose this option with the doctor and the team he trusts in the first place. This needs to be explained compassionately and carefully, and in my experience most patients will accept this philosophy. When looking at the past two decades of cancer and radiation treatment and rigorous randomized trials that have been done in certain cancers with supplements like vitamin E and head and neck cancer, there were negative effects on treatment outcomes, especially in those with other unhealthy behaviors such as tobacco use [59–62]. Even though side effects may have been reduced, it came at the expense of treatment efficacy. There is also a concern with hormonal tumors and the ability of dietary supplements to provide cancer protection and simply worsen survival [63].

One counter argument to this thought is that the patient only wants to further enhance treatment outcomes or reduce side effects since there are efficacy issues with any conventional treatment for prostate cancer. This is true, but this is the point where lifestyle changes can be emphasized. The average weight or body mass index of a man with prostate cancer patient receiving surgery or radiation in the USA today classifies him as overweight or obese, and other comorbidity issues abound [4]. In other words, I find it interesting that reducing weight or waist size, aerobic and resistance exercise, improvements in diet, eliminating tobacco use, normal to low cholesterol or cholesterol reduction (statins), perhaps aspirin (for aggressive tumors), and controlling blood sugar (glucose) look more promising today to improve conventional treatment for prostate cancer than at any time I can remember in urology. Thus, I explain to patients compassionately that if they are trying for a prostate cancer cure, the smartest thing they can give their treating doctor and team is the gift of trying to become as healthy as possible before, during, and after treatment to only further increase the chances of success. For example, meta-analysis of aerobic exercise along with prostate cancer treatment and after treatment has found a reduction in fatigue [64]. Resistance exercise (weight lifting) just 2–3 times a week during and after radiation treatment also appears to provide quality-of-life benefits and a reduction in fatigue [65, 66]. Additional reduction in body fat and triglycerides and improvements in strength may also occur [66], which could translate into added treatment efficacy benefits and a reduction in cardiovascular disease (CVD).

Another common question over CAM and radiation for prostate cancer is the type of diet needed to reduce toxicity or enhance treatment effects. Yet, this has not been adequately addressed in clinical studies and there is considerable controversy. The primary mode of thought for a long time has been the use of a low residual (soft diet, generally low in fiber)-based diet during the entire time of radiation treatment, which could theoretically reduce bowel toxicity. One older retrospective observational study found a lower rate of gastrointestinal issues in men being treated for prostate cancer with radiation therapy compared to men that were not placed on this diet. The problem with this study is that whole pelvic radiation techniques were used and radiation treatment and targeting has changed dramatically since this time period [4, 67]. A brief review and partial summary of this older diet is listed in Table 7.2.

However, a randomized prostate cancer trial that included the reduction in insoluble fiber (a bulking agent) and lactose worked no better compared to the control diet [68]. And another retrospective observational study of 739 patients with no change in diet compared to 105 patients placed on a fairly strict antiflatulent diet to reduce intrafraction prostate motion actually found a significant increase in clinically relevant intrafraction motion increase of 43 % of those on the dietary intervention compared to 19 % (p < 0.0001) of the control group [69]. The authors theorized that the change in diet may have caused bowel patterns to adjust or be altered dramatically and perhaps no change in diet during radiation treatment may be a better option. This is a philosophy that appears to make sense and should be discussed with patients. This same research group conducted a double-blind, placebo-controlled randomized trial of 1,000 mg of magnesium oxide per day or placebo during the treatment duration of intensity-modulated radiotherapy (IMRT) with the goal to reduce bowel changes that could impact intrafraction prostate motion [70]. No difference compared to placebo was found (46 patients per arm), and the secondary endpoints suggested a trend toward worse quality of life and more potential toxicity in the magnesium oxide group, but the differences were not statistically significant.

Another issue is that IMRT and other sophisticated and well-targeted techniques today may simply negate the effects of any dietary changes in prostate cancer patients undergoing radiation therapy. It is for this reason that I am ambivalent in recommending dietary changes for men undergoing radiation treatment for prostate cancer. Perhaps the older low-residue or soft diet is still an option, but this discussion must be balanced with the newer data, which suggests no difference in potential treatment outcomes. However, there is some suggestion that diarrhea can be reduced utilizing or continuing the use of a psyllium fiber agent, which should also be discussed as a possible option [71, 72]. In other words, if a patient is already utilizing 1–2 teaspoons, for example, of psyllium or another soluble (and perhaps insoluble) fiber source, then continuing it throughout the period of radiation could provide some preventive advantages. More research is needed on the impact of insoluble fiber, but many heart-healthy food sources of fiber contain both types. Again, the data are so weak in this area of prostate cancer research that the conversation and decision should be doctor and patient determined, keeping in mind that no approach has more data compared to another at the current time.

One of the most surprising findings from a large phase 3 dietary supplement study occurred in the 1990s when the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial, a randomized 2 × 2 factorial prevention study of 50 mg of alpha-tocopherol and/or 20 mg of beta-carotene on over 29,000 male chronic smokers, was stopped [73]. Subjects receiving beta-carotene had a significant increase in lung cancer incidence and overall mortality compared to placebo. This study was designed originally because a plethora of epidemiologic research suggested beta-carotene could reduce the risk of lung cancer [74]. Yet, soon after the ATBC stopped, the Carotene and Retinol Efficacy Trial (CARET), another phase 3 randomized study of 30 mg of beta-carotene and 25,000 IU retinol in individuals with a history of past or current smoking or asbestos exposure, was also stopped for precisely the same reasons as ATBC [75]! A significant increase in lung cancer diagnoses and overall mortality occurred in the supplement versus the placebo arm. The third large prevention trial of beta-carotene, the Physicians’ Health Study (PHS), did not show anything positive or negative, but PHS was not just conducted in smokers [76]. A total of 11 % were current and 39 % were former smokers, and 50 mg of beta-carotene was utilized every other day and the median blood level was 1.2 μg/mL, which was far lower compared to the median blood level in ATBC (3.0 μg/mL), or CARET (2.1 μg/mL). In other words, researchers received a real indication that an excess of certain supplements or antioxidants in certain populations could potentially increase the risk of cancer and early death. This was again a substantial change in the paradigm of thinking that really impacted my thoughts and beliefs forever.

Current and former smokers should be reducing their supplemental intake of beta-carotene regardless of their prostate cancer status. In fact, the results of the Age-Related Eye Disease Study 2 (AREDS2) phase 3 randomized trial were released years later, and they only highlighted the problem of overexposure of certain nutrients in some populations [77]. This clinical trial found that fish oil does not reduce the progression of macular degeneration. However, in this same trial the group that was utilizing 15 mg of beta-carotene in their supplement had a significant increase in the risk of lung cancer (23 vs. 11 cases or 2.0 % vs. 0.9 %; p = 0.04), and most of the lung cancer cases were in former smokers. This finding was from secondary randomization excluding individuals who were smokers. It is now highly plausible that higher doses of beta-carotene dietary supplements (15 mg or more) increase the risk of lung cancer in former and current smokers. Former smokers should check their supplements to make sure they contain little or no beta-carotene. Current smokers should stop smoking and not ingest beta-carotene as a dietary supplement. Eating healthy foods high in beta-carotene has not been a safety issue in former and current smokers—only the supplements. I believe this is what is known as level 1 evidence that a dietary supplement in the wrong population of men and women can cause harm. Thus, with this in mind, perhaps one of the greatest examples in medical history that more is not better in terms of supplementation can be derived from urology and prostate cancer prevention, and this is known as the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

The ATBC, CARET, and AREDS2 dietary supplement trials were a surprise, but what would come next was an even more definitive sign that less is more, even in healthy individuals, when dealing with certain supplements. This would be especially true in populations already replete with these nutrients. SELECT randomized over 35,000 men into four groups: high-dose vitamin E (400 IU/day), high-dose selenium [200 micrograms (μg)/day], combination of vitamin E and selenium, or placebo [78]. The rapid time period to reach full recruitment was unprecedented; thus, it seemed that participants and healthcare professionals were both enthusiastic to test the theory that high-dose antioxidant supplementation could prevent prostate cancer (the primary endpoint) and perhaps other conditions. Yet, the trial was terminated early, after a median of 5.5 years, due to a lack of efficacy, although at the time a nonsignificant (p = 0.06) increased risk of prostate cancer in the vitamin E arm and type 2 diabetes in the selenium group (p = 0.16) was observed. Therefore, indications of a lack of effectiveness and potential harm existed in this healthy group of men.

And, to the credit of the SELECT research group, participant follow-up continued (54,464 added person-years), which provided more clarity about any further health impact after dietary supplement cessation [79]. What was revealed in this follow-up period was a concern and perhaps changed the perception of a lack of potential harm with dietary supplements in healthy populations forever. A significant (p = 0.008; HR = 1.17) increased risk of prostate cancer was found in the vitamin E group, but not in the selenium or combination intervention arm. More concerning is that the risk of Gleason 7 or higher disease was greater for the three intervention arms compared to placebo, but did not reach statistical significance in any group. The HR and p-value for Gleason 7 and higher disease compared to placebo was 1.16 (p = 0.20), 1.21 (p = 0.11), and 1.23 (p = 0.08) for vitamin E, selenium, and the combination. The increased risk of prostate cancer with vitamin E began to emerge after only 3 years and was found to be consistent for low- and high-grade disease types. It could be argued that had the trial been allowed to continue for several more years, there would have been a statistically significant increased risk of Gleason 7–10 prostate cancer in all groups except the placebo arm. This is speculative, but a trending plausible scenario.

The negative results from SELECT cannot be explained by bias or increased biopsy rates, but suggest that the dietary supplements themselves are the issue, and the confidence intervals have only continued to narrow over time [79]. Secondary endpoints that included other cancers and cardiovascular events did not find statistical differences compared to placebo with this additional analysis. This is indeed good news in light of such negativity from ingesting what many pundits would have perceived as benign over-the-counter dietary supplements.

Yet, the SELECT should still address the following question: Are any of the SELECT results a surprise when reviewing the history of these and other nutritional interventions in large dosages? It could easily be argued that not only were the results somewhat expected, but again they could have been even more disconcerting over time if the trial continued. And, even if any of these interventions would have prevented prostate cancer, it is highly questionable whether they would have still provided a tangible clinical advance in clinical medicine. Why? The controversy that plagued high-dose vitamin E and selenium supplements from past clinical trials was the lack or even negative impact these interventions have on the number one cause of death in men and women, cardiovascular disease [80, 81]. Even a past potential increased risk of all-cause mortality had been a concern with high-dose vitamin E supplementation based on meta-analysis [82].

One could argue that the synthetic vitamin E supplements utilized in the SELECT were the reason for negative findings, or in other words the classic “natural versus non-natural” debate, and this is a debate that often arises in meetings I attend. Yet, this cannot be the case because several past trials of “natural” vitamin E-derived supplements in high dose showed no overall effects [81, 83], and even a significant increased risk of specific cardiovascular events such as heart failure or hospitalization for heart failure from one large randomized trial [83]. So, it is highly doubtful that the form or type of vitamin E would have provided alternative results.

One might also argue that the frequency or daily use of vitamin E led to the negative observation and less frequent or intermittent dosing would have provided a better benefit-to-risk ratio. This also appears to be a weak argument because another large randomized trial of vitamin E and prostate cancer risk in healthy men, the Physicians Health Study II (PHS2), found no impact of 400 IU of vitamin E every other day compared to placebo [84], but a significant increased risk of hemorrhagic stroke was observed [85]. Additionally, for such an adverse event to occur in a completely healthy population from a primary prevention trial is concerning enough. One also has to ponder why two independent large phase 3 clinical trials (SELECT and PHS2), primarily initiated in the USA, utilizing high-dose vitamin E supplements for testing prostate cancer prevention were allowed to be conducted simultaneously at such an enormous financial burden with similar clinical endpoints. Why not conduct just one randomized trial and save a plethora of resources, time, enthusiastic volunteers, and money for another future and perhaps more relevant chemoprevention trial?

Some could argue that the dosage of vitamin E might have been the real issue or even the lack of adhering to phase I, II, and III trial principles, and this has some potential merit that I have agreed with for some time, along with other controversial issues from the initiation and design of SELECT [86]. One primary justification for SELECT was the Alpha-Tocopherol, Beta Carotene (ATBC) trial, which demonstrated a 35 % risk reduction of prostate cancer risk with vitamin E from a secondary endpoint, but the dosage utilized in ATBC was only 50 IU (approximately eight times lower compared to SELECT) and a higher rate of hemorrhagic stroke was also found with this lower dosage [73]. Men in ATBC were also chronic, 36 years on average, smokers, and continuous tobacco users are well known for multiple nutrient deficiencies, not just vitamin E [87]. Less than 10 % of SELECT males were smokers [78, 79], which leaves one to ponder the outcome of this trial if a lower, scientifically more evidence-based defendable dose had been utilized, or if a phase 1- and 2-type study was completed first, similar to conventional medicine protocol, before moving right to a phase 3 trial [88]. For example, why even the belief that more is better—400 IU trumps 50 IU? Isn’t this one stereotype or prejudice applied to some patients that utilize a multitude of non–evidence-based dietary supplements? Since there were data to suggest that 50 IU of vitamin E might prevent prostate cancer in what researchers considered tantamount data to a phase I or II clinical trial, then, again, what is the justification for utilizing 400 IU in the phase 3 trial? This would not have seemed permissible if this were a conventional drug clinical trial in terms of dosage alterations based on past potentially effective prostate cancer prevention data [86]. In other words, PCPT or REDUCE would never, in my opinion, alter the dosage used in those trials because the past phase 1 and 2 data suggested the appropriate dosage to use in the phase 3 trial. Why treat dietary supplements differently?

Healthy and primarily non- or former smoking men (85 % of the participants) from a unique randomized trial (Supplementation en Vitamines et Mineraux Antioxydants or SU.VI.MAX) utilizing substantially reduced doses of vitamin E (30 IU) and other dietary supplements, including selenium, in combination (100 mg of ascorbic acid, 6 mg of beta-carotene, 100 μg selenium as enriched yeast, and 20 μg zinc gluconate) demonstrated the potential for notable benefit for prostate cancer prevention but also harm for men with higher baseline PSA levels [89, 90]. This trial included 13,017 healthy French adults and found a difference or potential benefit for men (n = 5,141, age 45–60 years, 35 % nonsmokers, BMI of 25) in terms of a significant reduced cancer incidence and overall mortality and nonsignificant 18 % reduction in cardiovascular disease, but these benefits were not found for women (n = 7,876, aged 35–60 years, 55 % nonsmokers, BMI of 23) in this same trial. Perhaps this is due to the lower baseline blood levels of antioxidants (especially beta-carotene and vitamin C) found in men compared to sufficient concentrations and more healthy behaviors and parameters found in women participating in this trial. Testing individual, multiple, or combination lower or reduced dosage, or what the authors cited as “nutritional” dosages of nutrients, appeared to be safer and perhaps more effective compared to larger dosage in those that appeared to have a lower intake of these nutrients from their diet and/or lifestyle. Less is more.

Other cited controversies by advocates of vitamin E supplements will arguably continue through time. For example, the modicum of positive data for the primary form of vitamin E derived from food, gamma-tocopherol, could have been tested as a dietary supplement based on some preliminary past evidence [91, 92]. Not only is this preliminary and would need phase 1 and 2 data, which it does not enjoy, but there is also some preliminary evidence to suggest that it could also have negative effects in excess [93]. Again, smokers with nutritional deficiencies have the most to benefit in this situation. Smoking cessation should be a more prominent goal over arguing and researching specific dietary supplementation in the dwindling population of current smokers that could be effective for prostate cancer prevention. And using data from smokers to equate what would happen to nonsmoker and former smokers is, again, a difficult argument.

What about the past issues with selenium dietary supplements? The impact of high-dose selenium supplements on cardiovascular and overall health from past clinical trials was arguably as concerning as past vitamin E clinical research [94] and included a potential significant increased risk of type 2 diabetes and non-melanoma skin cancer recurrence [95, 96]. Interestingly, this increased risk of skin cancer recurrence was the final conclusion surrounding the primary endpoint analysis of the landmark randomized selenium supplement trial (Nutritional Prevention of Cancer), which was utilized to justify initiating SELECT [95, 97]. In other words, it appeared that some researchers were more fascinated by the secondary endpoint reduction in prostate cancer risk compared to the primary endpoint increase in skin cancer risk.

A question to ponder in the first chapter of this book and when dealing with patients is: Why attempt to prevent prostate cancer with high-dose interventions that may actually increase the risk of other primary causes or even the number one cause of morbidity and mortality in men or women, regardless of its potential for a favorable impact on prostate cancer or another chronic disease? Again, primary prevention trials are simple excellent reflections of the current health status of populations from where recruitment originated. For example, the Prostate Cancer Prevention Trial (PCPT) and SELECT morbidity and mortality rates from cardiovascular events (primary causes of death in these two trials), regardless of the group assignment, were notable [8, 78, 79] and continue to demonstrate the ideal prostate cancer chemoprevention agent needs to potentially and simultaneously reduce the risk of cancer and some aspect of cardiovascular disease. This would appear to at least represent an advance in medicine, and not a lateral shift.

One of the most important lessons to learn from SELECT, and somewhat in defense of the researchers and designers of SELECT itself, was the chance of launching an externally uncontaminated clinical trial by the time of randomization was impossible. This is due to a novel phenomenon that I have termed the “over-antioxidation of the population.” Interestingly, baseline serum selenium status in SELECT was 22 points higher (135 ng/mL vs. 113 ng/mL) compared to comparative trials from the 1990s in the USA [78, 79], which essentially equates to a population of men that are no longer deficient in this antioxidant or nutrient before they even begin to ingest selenium as a supplement. How could this occur?

In the USA and in multiple countries around the world, I have observed countless multiple nutrients being added to a diversity of foods, beverages, and supplements such as multivitamins, foods, and beverages at an uncontrolled rate over the past decade as preliminary research highlights some potential preliminary benefits in various laboratory and/or observational studies. This appears to be helpful in marketing and profit, but not for science, research, and safety. When any nutritional deficiency trial is designed and initiated over several years, the depleted participants being tested will now arguably be replete with the nutrients being tested even before the trial commences. This was one of the most important lessons of the SELECT that should be constantly taught and discussed among future healthcare professionals, researchers, and clinical trial designers. This should pose a serious challenge for any further nutrient prevention or treatment trial in the Western world. It is also my belief that multiple future supplement or nutritional interventional trials, including vitamin D, will also suffer from the same SELECT over-antioxidation or overexposure controversy, dilemma, or fate. Currently, it will be difficult to ever recommend any individual supplement of vitamin E or selenium to men trying to prevent prostate cancer, men with prostate cancer, men being treated for prostate cancer, or men that were treated for prostate cancer. If a supplement can increase the risk of prostate cancer in very little time, it can be argued that it can encourage the growth of existing prostate cancer in an even shorter time period, which is simply what occurred in the SELECT.

It could be argued that the lessons of the selenium and vitamin E trials are as lucid now as ever before in medicine, and these individual supplements should be abandoned in prostate cancer at these dosages. There is no further need to spend more time and resources on these compounds in prostate cancer or perhaps most of urology. However, this should not be construed that they have no place in rare situations in medicine where the benefit may outweigh the risk (similar to a prescription medicine). For example, 800 IU of d-alpha-tocopherol or vitamin E has been uniquely found to potentially benefit some nondiabetic non-cirrhotic NASH (nonalcoholic steatohepatitis) patients with aggressive histology from a major 96-week-duration phase 3–like clinical trial known as “PIVENS” (Pioglitazone versus Vitamin E versus placebo for the treatment of nondiabetic patients with Nonalcoholic Steatohepatitis) [98, 99]. Since there are few treatment options for this subset of patients, many expert reviews suggest the benefit outweighs risk [99]. Additionally, there are major phase 3 clinical trials with selenium ongoing, for example, to prevent bladder cancer recurrence (SELEBLAT; Selenium and Bladder Cancer Trial) [100], which may or may not change clinical practice based on the eventual outcomes.

Based on the lesson learned from the SELECT, my full-time career in CAM and urology, and beyond, it has now become difficult to ignore three heart-healthy interventions that arguably appear to be more promising than any costly interventions that might selectively and precisely prevent prostate cancer, or any CAM option used for ancillary treatment. Cholesterol-lowering (statins) medications, aspirin, and metformin all continue to garner attention for being cost-effective, generic, generally safe, and heart healthy in the appropriate risk-stratified population (middle-aged and older men) [53–57, 101–107]. These heart-healthy agents have unique mechanisms of action that potentially reduce the number one cause of morbidity and mortality in men and women and may provide ancillary benefits in those being treated for prostate cancer, including reducing side effects of some standard treatments [107].

Statins or cholesterol-lowering medications may be associated with a lower risk of aggressive prostate cancer [108, 109] and could also be a partial explanation for noteworthy mortality rate reductions from prostate cancer in some countries such as the USA [110, 111]. Since most statins are now generic, the lost cost of these products is another attractive feature. It is disappointing that no prostate cancer prevention trial or ancillary treatment trial has been completed with cholesterol-lowering medications, but several studies are being proposed and initiated based on latest US government data [112]. It is also appealing that statins have side effect prognostic markers, for example, liver and muscle enzyme tests that can predict toxicity.

Aspirin may also reduce the risk of prostate cancer mortality, but these data are preliminary [55, 56, 101]. However, aspirin toxicity is more difficult to predict in clinical practice because hemorrhagic strokes, ulcers, or gastrointestinal bleeding events do not have laboratory tests to precisely predict outcomes. Still, based on cost and history of reducing the potential risk of colorectal cancer in high-risk patients [113] or hear disease, it should be of interest to potentially recommend in some prostate cancer patients that already are candidates for aspirin use based on their medical history.

Metformin is beginning to receive adequate attention in multiple cancers, and this generic low-cost drug, actually derived from the French Lilac, has over 100 clinical trials being designed and initiated in cancer [114]. In fact, the following cancers are currently testing metformin with and without conventional treatment:

Preliminary observational research is impressive and requires further investigation with this gluconeogenesis and growth factor inhibitory and heart-healthy agent. For example, researchers at Sloan-Kettering in New York conducted a retrospective analysis of 2,901 consecutively treated patients for prostate cancer and radiation therapy, and 157 were using metformin, 162 were diabetic and not using metformin, and 2,582 were nondiabetic [57]. Mean age was approximately 70 years, and they were utilizing metformin for about 5 years at an average dosage of 500 μg twice a day (1,000 μg total). Prostate cancer–specific mortality (PCSM) rates were significantly reduced for those on metformin (2.7 %) compared to diabetic non-metformin (21.9 %) and nondiabetic patients (8.2 %). A total of 16 % compared to 33 and 25 % developed a PSA recurrence. Metformin use was associated with a reduction in the development of CRPC compared with diabetic non-metformin patients. Further analyses revealed that the largest benefit to metformin use appears to be in the high-risk recurrence group or those with more aggressive disease likely to return after regular treatment, and also a significant benefit in overall survival occurred with metformin use compared to the other groups. Metformin with conventional radiation treatment could reduce recurrence, distant metastasis, the risk of death from prostate cancer and all causes, and reduce the risk of developing CRPC. Only 157 individuals used metformin in this study but it was interesting enough to garner ongoing interest. The other potential health benefits of metformin are also interesting, such as the ability to promote neuronal growth in the brain and improve memory in laboratory studies, and this drug activates atypical protein kinase C-CBP pathway that directs neural stem cells to differentiate into mature neurons [115].

Statins, aspirin, and metformin (SAM) are not CAM, so why discuss these three interventions in this book? It is because they share many features that serve as teachable lessons including generic, low cost, originally derived from natural sources (fungus for statins, willow bark for aspirin, and French Lilac for metformin), good overall safety profile, and heart healthy. These three interventions provide a paradigm for what to achieve or potentially investigate in the area of CAM and prostate cancer, urology, and medicine. In fact, CAM options that tend to mimic the effects of one or more of these three interventions have the most potential to be utilized for prostate cancer prevention and ancillary treatment in my experience [116]. For example, statins were originally derived and extracted from red yeast rice (see section on “Red Yeast Rice” in this chapter), which is also a dietary supplement with an adequate history of cholesterol reduction. These are the types of CAM options that would be my primary choice to test in a clinical trial and that I believe have the most to offer along with conventional treatment for prostate cancer.

Since 5-alpha-reductase (5-AR) inhibitors have some adequate clinical research that they prevent nonaggressive prostate but may increase the risk of a rare aggressive prostate [8–10], it is not unusual for some advertisers of BPH supplements to suggest a preventive favorable effect with BPH supplements. Yet, despite some suggestion that the mechanisms of action of many of these herbal BPH supplements are somewhat similar to 5-AR inhibitors, this has not been proven. And, PSA reduction or prostate cancer prevention has not been consistently demonstrated with these agents [117–124]. It is my opinion that BPH CAM options do not prevent or treat prostate cancer and may have some weak 5-AR effects in large dosages in some cases. Regardless, despite men taking these supplements for “prostate health,” and in the hope of prostate cancer prevention, it should be reiterated that this is not accurate.

However, flaxseed has some preliminary evidence that it could be used as an ancillary option for the treatment of BPH and cancer [125], but these trials utilized dietary flaxseed powder (30 g/day, or 3 rounded tablespoons) for prostate cancer and dietary and supplemental flaxseed for BPH [126, 127]. Flaxseed is one of the largest sources of plant omega-3 fatty acids (alpha-linolenic acid or ALA) and it is high in fiber. Some of the plant omega-3 (ALA) from flaxseed can be converted into marine longer chain forms of omega-3s (ALA into EPA, eicosapentaenoic acid) by the human body. The conversion rate is not predictable and is low in some cases, but there are exceptions. For example, flaxseed oil has been shown in some studies to increase blood levels of marine EPA by as much as 60 % [128].

The Lyon Diet Heart Study (one of the first published Mediterranean diet studies) is the one of the only randomized clinical trials completed with ALA supplementation that was actually designed not just observe laboratory changes, but actual clinical solid cardiovascular endpoints [129]. However, the actual source of ALA in this famous study was a canola-enriched margarine, which was given to recent heart attack patients along with a variety of other dietary changes. The group of patients getting the ALA margarine had a significant (p = 0.001) 65 % reduced risk of cardiac death and nonfatal heart attacks. Also of interest was the 35 % increase in blood levels of EPA in the margarine group. It appears that canola or flaxseed or other sources of the plant omega-3 fatty acids have a good history of being heart healthy, but most of the positive studies have utilized dietary sources of plant omega and not supplemental sources. Again, this should be reiterated to patients excited about any of these plant omega-3 products (further information on omega-3 is found under the “Fish Oil” section of this chapter).

Three omega-3 fatty acids have been shown to improve heart health and overall health [130, 131]. The primary omega-3 from plants again is known as ALA. The other two usually are derived from marine or fish and fish oil supplements and are known as EPA and DHA (docosahexaenoic acid). ALA can be converted into the body into EPA and some EPA and be converted to DHA. Again, as mentioned earlier, these three omega-3 fatty acids are not mutually exclusive. For example, in one of the most notable prostate cancer neoadjuvant or presurgical randomized clinical trials, men that consumed foods high in ALA (flaxseed powder) had significant increases in their blood EPA levels [125]. Yet, the data or research with fish oil to reduce the risk of prostate cancer or aid in treatment is inconsistent and should not be recommended for this purpose. There is a plethora of preliminary past data to suggest that fish oil may be beneficial for a variety of health conditions including:

The problem with all of this positive preliminary data is that when it has been subject to some phase 3-like clinical trials, the effect of fish oil has been similar to placebo. For example, no impact of fish oil was found in a large trial on macular degeneration progression (AREDS2) [77], as well as a more definitive primary prevention heart health clinical trial in high-risk patients [146], or for prevention of postoperative atrial fibrillation [147], and from a comprehensive meta-analysis [148]. The positive data on fish oil for reducing the risk of prostate cancer mortality is derived primarily from dietary (not pills) observational studies [149]. In other words, perhaps the American Heart Association (AHA) recommendations are the most accurate for prostate cancer prevention and after diagnosis in terms of potential benefits and how to approach the issue of fish oil. Fish is an outstanding lean source of protein, one of the highest natural sources of vitamin D, and one of the highest natural sources of omega-3 fatty acids (EPA and DHA), which is why the AHA recommends two servings of oily and fatty EPA and DHA rich fish (salmon, anchovies, mackerel, sardines, trout, herring, etc.) and plant sources of omega-3 (this fact often gets missed) [150]. AHA also recommends 1,000 μg of fish oil for those with heart disease or those trying to reduce high triglycerides (the one FDA-approved indication). Thus, there is some indirect indication that select patients on androgen-deprivation therapy (ADT) could benefit from fish oil supplements in terms of muscle maintenance and triglyceride reduction [137, 140], which is discussed later in the chapter. Otherwise, most patients trying to prevent or treat prostate cancer with conventional therapy do not need fish oil supplements but should be encouraged to eat fatty and oily fish for heart health. Some patients claim that fish oil provides ancillary benefits, for example, a reduction in muscular or arthritic pain (anti-inflammatory), which helps them reduce their intake of pain medications, which is an area where the benefit may of course outweigh the risk.

A fairly extensive overview of the history of folic acid is provided in this section in order to construe specifically who or who does not qualify for these supplements. The reader will notice that folic acid provides a powerful preventive role in certain areas of medicine, especially obstetrics and gynecology, but in other areas such as prostate cancer, the results are controversial and concerning based on its mechanism of action and clinical results. This is also true for other B vitamins in high dosages and multivitamins that harbor higher dosages of B vitamins including folic acid.

Folate or folic acid is a B vitamin, and some B vitamins can be recognized by their assigned numbers such as B₁₂ (cobalamin), B₆ (pyridoxine), B₂ (riboflavin), and B₁ (thiamine) [151]. Other B vitamins are also known for their alternative nonnumerical names such as niacin (vitamin B₃), pantothenic acid (vitamin B5), biotin (vitamin B₇), and even folate (vitamin B₉). Folate is found in numerous diverse healthy nutritious food and beverage products [152]. Folic acid is actually the synthetic form of folate that is found in dietary supplements and added to some grain products, which are also known as “fortified foods.” Folate is water soluble, hence the requirement for essentially daily or regular ingestion to maintain optimal serum (range: 5.4–40.0 ng/mL) and/or red blood cell (range: 280–903 ng/mL) concentrations [153, 154]. The primary benefit of folate is for the primary and secondary prevention of neural tube defects (NTDs), such as spina bifida [155–159], whose name was derived from the Latin words that translate to mean “split spine” [160]. The neural tube forms, shapes itself, and closes within the first month of conception, which highlights the need for folic acid consumption by the mother before and immediately after conception [161]. Research also preliminarily suggests that other medical conditions in the newborn, such as preterm birth, congenital heart defects, and other organ abnormalities such as orofacial cleft malformations, could be at least reduced to some significant degree by folic acid [162].

Experts recommend 400 micrograms (μg) of folic acid daily, which is a small amount in general (approximately 400 millionths of a gram), and it is 600 μg/day in pregnancy and 500 μg/day during lactation [163]. There are also a variety of other situations, conditions, and medications that may increase the demand for folate or the strict adherence to daily consumption of this compound. For example, a short partial list includes the following:

For example, women taking AEDs are generally recommended to take 4,000 (or 4 μg) of folic acid daily because these medications are folic acid antagonists and have been shown to significantly reduce the absorption and efficacy of folic acid and increase the risk of NTDs [168]. Some experts also recommend that obese women take 800 μg/day of folic acid because research also suggests that lower amounts, such as 400 μg/day, may be clinically insufficient to maintain normal serum or RBC levels of folate [174].

Since folic acid requires regular ingestion for efficacy, it would be optimal to consume the recommended amount from a combination of diverse healthy food sources and from supplementation from an over-the-counter or prescription pill. Folic acid has no known side effects from food or pill sources when taken at the recommended dosages for women and should be taken with a meal to improve absorption and tolerability [162]. It is also of importance to mention that taking B vitamins in supplemental form, especially B₂, can cause the urine to turn a harmless fluorescent yellow color that could be concerning to an individual who had not been informed about this potential side effect.

Approximately half of all pregnancies in the USA are unplanned; thus, many women of childbearing age can potentially benefit from folic acid [176]. Folic acid is also beneficial for all individuals when consumed on a daily basis because it reduces the risk of macrocytic anemia [161, 177, 178]. Historically, there has also been a concern that folic acid supplementation can “mask” a vitamin B₁₂ blood deficiency (approximately less than 300 pg/mL) [163], which also potentially can be further identified utilizing additional costly serum tests known as “methylmalonic acid” and “homocysteine.”

However, there is minimal evidence to suggest that these tests are necessary, consistently supportive, or that the B₁₂ potential “masking” concern is valid or an evidence-based issue [163]. Part of the reason may be due to the fact that only 6 μg (compared to 400 μg for folate) is needed to satisfy the RDA for B₁₂, which is easily obtained today in many foods, beverages, and multivitamins.

Focusing on healthy foods that contain a high amount of folate and taking a multivitamin or another pill daily with folic acid is one of best immediate methods to improve deficient or insufficient folic acid levels. For this reason, a list of healthy diverse food sources that contain an unusually large amount of folate (approximately 50–100 μg or more per serving) and other healthy compounds for the body are listed below [163, 179]:

Folic acid plays such a strong role in maternal and child health that it is perhaps one of the greatest preventive success stories in public health and preventive medicine, and it is utilized primarily as a dietary supplement. In fact, the potential novel benefits with folic acid appear to continue with more research. For example, there is now some observational data that suggest it has potential in contributing to a lower risk of autism or severe language delay at older ages [180, 181].

Folic acid is involved in cell division or DNA and RNA synthesis, and several effective anticancer and other drugs from methotrexate, 5-FU, and trimethoprim-sulfamethoxazole arguably work by reducing the efficacy and utilization of folate [178]. These drugs can block dihydrofolate reductase, which is needed by folic acid to become active. Thus, it has been concerning in the past that excessive amounts of folic acid could theoretically increase the risk of some cancers, especially prostate cancer.

A large-scale meta-analysis has reviewed all of the randomized trial data on folic acid and other B-vitamin supplementation to reduce the risk of cardiovascular disease, cancer, or impact all-cause mortality [182]. It concluded that there was minimal to no impact of these supplements in reducing the risk of these conditions. In other words, currently it does not seem to impact the risk of most chronic diseases, despite the fact that it can reduce blood homocysteine levels by at least 25 %. Still, folic acid supplements may increase or encourage the growth of a variety of common tumors and precancerous lesions or polyps in high-risk individuals [183]. The cancer that receives the most attention in terms of a potential increased risk from folic acid is prostate cancer [184, 185]. Serum levels of folic acid also appear to be increasing in the elderly such that unmetabolized folic acid (UMFA) has become a concern in men and women [186]. UMFA may have the ability to cause immune suppression and is a reflection that aging along with fortification of foods does not require large intakes of folic acid from other sources.

Still, the controversy over the clinical significance of a potential increased risk of prostate cancer will and should continue without any resolution in the near future. A meta-analysis of randomized trials found a significant increased risk of prostate cancer [187]. Arguably, another larger meta-analysis of randomized trials in cancer suggested that there was no risk and that past meta-analysis were influenced by a higher rate of cancer from one clinical trial [188], where prostate cancer incidence in the folic acid arm was probably increased due to chance [184]. Although these researchers make a compelling argument for this case, the problem with this theory is that most of the major trials looking at prostate cancer incidence still found at least nonsignificant increases in risk that cannot be disregarded due to chance, and this is confirmed by another recent meta-analysis [189], including some recent population studies [190]. Still, there are also some data that will challenge this notion [191], which further enhance the nebulousness and controversy on this subject.

Yet, the sum of the data on folic acid is simply not demonstrating primarily a neutral or reduced effect, only an increase risk overall and the argument is whether or not it is statistically or clinically significant. This argument tends to miss the forest over the tree in men’s health and especially prostate cancer, and until the risk is justified there has been no sound benefit for most men in taking higher doses of supplemental folic acid on overall health and wellness.

Thus, clinicians should not encourage supplemental folic acid use, especially in the elderly and in other cases such as men with a history of cancer concerned about fertility, despite some minimal positive or just non-impressive data in the area of fertility itself [192, 193], because other supplements are safer, just as effective, and do not appear to require megadosage (like folic acid) for a clinical impact. Some of the early and only clinical trials that involved folic acid were using dosages such as 5 μg/day (along with zinc), which is 12.5 times the recommended daily intake [192]. Again, food sources of folate can be recommended, because these have not been concerning overall, but the concentrated nutraceuticals do not follow the mantra right now of benefit exceeding risk. It appears that folic acid may even find some place in medicine in men’s health in some future trial, perhaps eye health, but again will the benefit outweigh the risk?

Multivitamins are arguably the most concentrated and readily available form of B vitamins such as folic acid for men. Despite minimal scientific evidence, multivitamins are the largest selling and utilized supplements in the USA [194]. They are also the primary supplement utilized by men in notable prostate cancer screening studies [195], male health prevention trials or observational studies [13, 196], and by male physicians [197]. Why, because it is not a plethora of clinical research that could be propelling these sales? Perhaps it is the perception compared to the reality, but until some higher-quality evidence finds some realistic benefit with these supplements in megadoses, the potential for harm when taking them in excess (two or more pills daily) seems concerning [198]. For example, an increased risk of advanced and fatal prostate was found in one of the largest prospective epidemiologic studies of multivitamins (NIH-AARP study), and the greater use of other supplements was also associated with an even greater risk [199]. Men that were free of cancer were evaluated in this prospective cohort study selected from the 3.5 million AARP, 50–71 years old, who lived in one of the following six states or two of the following metropolitan areas, including:

Individuals were sent a baseline questionnaire and asked how often they used three types of multivitamins in the past year leading up to filling out the questionnaire. Men were placed in the category of either never use, casual use (0–6 times a week), consistent use (7 times a week), or heavy use (more than 7 times per week). Men were also asked about the dose and frequency of individual vitamin and mineral supplements. The mean age of the men and BMI was 62 years and 27 (overweight), about 50 % of the men were physically active three or more times a week, 60 % were former smokers, and the average vitamin D intake was approximately 200 IU a day. About 5 % of the men in this study were heavy users of multivitamins (total of 13,854 men), and overall multivitamins were the most commonly ingested supplements (51 %), followed by vitamin C (40 %), vitamin E (37 %), and calcium (22 %). During 5 years of following the men in the NIH-AARP Diet and Health Study that included 295,344 men, a total of 10,241 were diagnosed with prostate cancer. This included a total of 8,765 localized and 1,476 advanced cancers, and 179 cases of fatal cancer (after 6 years of follow-up).

Overall no association was found between the use of multivitamins and the overall risk for localized prostate cancer [199]. However, an increased risk of advanced and fatal prostate cancer was found for the men reporting an intake of more than seven times a week for multivitamins. This concerning information was found to be even stronger for men that were heavy users of multivitamins and those who also had a family history of prostate cancer and/or who took additional individual supplements including beta-carotene, selenium, and zinc. For example, men that took multivitamins more than seven times a week had a nonsignificant increased risk of advanced and fatal cancer 1.3 and 2 times higher than the men never taking these pills, while men getting one multivitamin a day had a nonsignificant similar risk for advanced prostate cancer (to nonusers) and a 10 % lower risk of fatal prostate cancer compared to the nonusers of multivitamins. Men ingesting individual selenium supplements and more than seven multivitamin pills a week had an almost (p = 0.054) significant 5.8 times higher risk of fatal prostate cancer. Men with a heavy use of multivitamins and also taking individual vitamin E or folic acid or other supplements (beta-carotene and zinc) had 1.6 to as much as 4.4 times the risk of fatal prostate cancer. The highest risk of fatal prostate cancer was found for the high-dose supplement takers and men with a family history of prostate cancer (16.4 times the risk of fatal prostate cancer). Let’s review the findings in a simplistic table that shows the increased risk of advanced and fatal prostate cancer for men that were “heavy” users (more than seven times per week) of multivitamins from Table 7.3.

Lower doses of vitamin E were associated with less risk of getting prostate cancer overall including (none showed statistical significance) [199]:

Another concern found in the study but apparently not statistically significant was that men in the high-use multivitamin group consumed almost 100 calories more per day than the other men in the lower supplement intake groups. A piece of positive news was for the men that never took multivitamins or those that took 1–6 multivitamins a week because they experienced no increased or decreased risk. Perhaps the best news from this study that did not receive much attention was for men taking one multivitamin a day, which represented the largest numbers of men followed for fatal prostate cancer in the study. Men had a 10–20 % reduced risk of fatal prostate cancer in this group—the only group to demonstrate a lower nonsignificant risk of dying from prostate cancer in this study.

Several other large male observational studies have found somewhat similar results [200, 201]. It is interesting that some studies in breast cancer has somewhat mirrored these negative findings [202, 203]. Multivitamins are also replete with higher doses of B vitamins, which have also recently been found to potentially have no impact on health or increase the risk of prostate cancer from the largest and most recent meta-analysis of clinical trials [182, 185]. Some might argue that this is all due to reverse causation, and patients with more advanced and aggressive disease are perhaps more likely to take more vitamins and minerals as witnessed with some other cancers [204]. Regardless of the side of the argument that one supports, there is no consistent suggestion of benefit with a greater intake of multivitamins, and since there is a suggestion of either no impact or serious harm, it would have been prudent to wait for more clarity from more clinical studies [205].

Perhaps some level of greater insight was provided again in the SUVIMAX randomized, placebo-controlled trial that included several vitamins and minerals at very moderate or low dosages not usually utilized in clinical trials [89] and commonly found in children’s formulations from my experience (mentioned earlier in the chapter). It appeared that taking a low-dose multivitamin minimally based formula could provide a potential benefit for some men. The researchers from this study suggested that men benefited because they had lower levels of these vitamins and minerals in their blood from less than optimal dietary patterns at the beginning of the study compared to the women that consumed a more healthy diet on average. A follow-up secondary observation to this study (8.8–9 years) found that this multivitamin reduced the risk of prostate cancer by 48 % in men with a low PSA (less than 3), but in men with a higher PSA, a multivitamin may have been associated with a higher risk of being diagnosed with prostate cancer [90]. In other words, if a man has an elevated PSA he should be careful about taking dietary supplements to reduce risk. This multivitamin did not impact PSA or IGF levels, suggesting that risk was impacted by other methods. It was also interesting in this study that older age (mean age of men, 51 years), higher body mass index (BMI), and men with higher PSA levels had significantly increased risks for prostate cancer. Side effects from the low-dose multivitamin were similar to placebo. Limitations in this study were prostate cancer as a secondary endpoint and no information was collected on family history of prostate cancer. It was this trial that suggested it would be wise not to still consume anything larger than a children’s multivitamin or one adult multivitamin per day until some clinical trial can demonstrate that greater intakes are beneficial.

The most definitive trial to determine the impact of multivitamins on overall male health and prostate cancer would be the result of the first ever randomized primary prevention US trial of adult men known as the “Physicians Health Study II” (PHS2) [206]. This trial would arguably provide level 1 evidence to determine whether utilizing a multivitamin has merit in men’s health with regard to total cancer and cardiovascular risk. PHS2 was a randomized, double-blind, placebo-controlled trial known, which included 14,641 healthy male physicians at least 50 years or older (average age of 64.3 years) [207]. A total of 1,312 of these men had a history of cancer at baseline. The study began in 1997 and continued to June 1, 2011. Men consumed one daily multivitamin (Centrum Silver) or placebo, and the primary endpoints were the total number of cancer cases and cardiovascular events diagnosed between the multivitamin and the placebo group. Men were followed for a median of 11.2 years, and there were 2,669 men diagnosed with cancer during this study, and over half the cases (1,373) were men diagnosed with prostate cancer, and there were 210 cases of colon cancer. Men taking a multivitamin daily compared to a placebo had an 8 % reduction in being diagnosed with cancer that was statistically significant (p = 0.04). The daily multivitamin had no positive or negative statistical impact on prostate cancer, colorectal cancer, or other major cancers. There was no significant reduction in the risk of dying from any cause including cancer when the multivitamin was compared to the placebo. However, the daily multivitamin was associated with a significant 27 % (p = 0.02) reduction in the risk of being diagnosed with cancer in the 1,312 men with a history of cancer. The researchers of this paper concluded their article by saying “In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.” Researchers also commented profoundly in the discussion section an important clinical take-home point, which was “The reduction in total cancer risk in PHS II argues that the broader combination of low-dose vitamins and minerals contained in the PHS II multivitamin, rather than an emphasis on previously tested high-dose vitamins and mineral trials, may be paramount for cancer prevention.”

There were other fascinating findings from this study. For example, the physicians utilized in this study were for the most part one of the healthiest participants of a primary prevention trial I have reviewed [207]. Only 3–4 % were current smokers, and most were near a healthy weight or BMI, 60 % exercised regularly, 80 % drank alcohol in moderation, red meat intake was low, and fruit and vegetable intake was generally 4–5 servings per day. Why didn’t this multivitamin significantly lower the risk of one major type of cancer like prostate or colon cancer? The answer is that multiple cancers were nonsignificantly reduced compared to placebo, and when they were all added together the results became significant or robust enough with all the cases, but one specific cancer did not necessarily provide a large significant risk reduction. For example, although the following specific cancers never reached statistical significance, there was a reduction in risk with the multivitamin compared to placebo in cancers such as:

In fact, there was almost a statistically significant reduction in cancer deaths, which were reduced 12 % (p = 0.07), but one has to ponder what would have occurred if the study were permitted to continue for several more years.

The side effect rate with the multivitamin in PHS2 was similar to placebo overall, and in terms of gastrointestinal symptoms and most other adverse events [207]. Men were more likely to report getting rashes on the multivitamin (7 % increased risk that was significant, p = 0.03), and a 10 % significantly (p = 0.01) higher risk of reporting epistaxis, but there was a 9 % significant (p = 0.02) lower risk of hematuria with the multivitamin compared to the placebo. Otherwise and overall there were no side effect concerns including bleeding issues.

It was interesting that men with a personal history (“baseline history”) of cancer when they began the study had a 27 % reduction in the risk of being diagnosed with another cancer (p = 0.02), and when eliminating the men that were diagnosed with leukemia or lymphoma the risk reduction was 34 %, but the reduction in risk of prostate cancer was 44 % in these men and this almost reached significance (p = 0.07) [207]. So, in reality it is potentially possible that some men (those with a history of being diagnosed with another cancer) may reduce their risk of being diagnosed with prostate cancer if they take a multivitamin. Men that had no history of cancer at the start of the study experienced no significant reduction (adjusted HR = 1.00) in the risk of prostate cancer.

Subgroup evaluation, albeit primarily nonsignificant, also provided some interesting findings or trends; for example, men with a parental history of cancer appeared to receive no benefit (p = 0.02 for the interaction—the only significant subgroup finding), but again those with a baseline/personal history of cancer may have received a benefit [207]. Men 70 years or older at baseline experienced an 18 % reduction in risk of cancer in the multivitamin group compared to placebo, and men that were in their 50s or 60s only received a 0–4 % reduction (p = 0.06 for interaction). Men that were of normal BMI had a slightly better risk reduction in the multivitamin group compared to men that were overweight or obese. It is also interesting that in the small group of current smokers, there was a 28 % nonsignificant reduction in cancer risk in the multivitamin group compared to the men that smoked but received the placebo. Men consuming seven or more fruits and vegetables daily appeared to benefit slightly more compared to those that consumed less. This finding, if accurate, may address the constant question I receive in lectures, which is the need for a multivitamin (or not) based on a strong history of already consuming a healthy diet with many nutrients. Perhaps, if the multivitamin does not contain megadoses of different items there appears to be no harm. Again, this is difficult to discern and, of course, during any subgroup analysis, the possibility for chance findings increases, but still this was interesting.

The most disconcerting result of the PHS2 appeared to be the criticism in the media from some medical experts. Some conventional doctors suggested that these findings, an 8 % significant reduction in total cancer, were not adequate enough to consume a multivitamin, or alternative statistics showed no difference. Some alternative medicine experts appeared to take the position that had another more appropriate megadose multivitamin supplement been used, there would have been a more profound risk reduction. It felt as if there were a polarizing game of politics being played out with conventional and alternative medical experts. Personally, there are three critical observations that were not objectively debated, and the first was that any pill with a similar side effect of a placebo that can reduce the risk of cancer over a little more than a decade and costs the consumer minimal money, arguably pennies a day, is worth a discussion and a consideration for use. Second, as is the mantra of this book, what was the impact of this multivitamin on the number one cause of death in men and women (cardiovascular disease)? There was no impact on cardiovascular events, except there was a significant reduction in the risk of fatal myocardial infarctions with the multivitamin over the placebo [p = 0.04], which may or may not have been due to chance because of the small number of total events of this secondary endpoint [208]. Regardless, this multivitamin passed one of my primary requirements of any CAM (heart healthy or no impact on heart health and cannot be heart unhealthy). This should give the clinician another reason to feel comfortable discussing and potential recommending this low-cost, single-pill multivitamin. Third and final is the forgotten fact that the Centrum multivitamin used in this clinical trial might surprise clinicians and patients because it was the one commercially available in the 1990s when the study started. The diverse ingredients and dosages of the multivitamin used in PHS2 can be found in Table 7.4 [207].

There appear to be few adult male or female multivitamins available in the USA today that have such low levels of the vitamins and minerals used in the PHS2. It is for this reason I believe that taking a children’s multivitamin for an adult man is the only recommendation I am comfortable with currently if a man wants to utilize a multivitamin. In Table 7.4, the dosages of most ingredients are generally low that they exemplify what is found in most children’s multivitamins today from my experience. Another option would be to take Centrum Silver and accept the fact that some small changes have occurred in the number of nutrients offered and the dosages. The average adult multivitamin currently in the USA could reach as many as 4–5 pills, while the children’s multivitamin also increases in size. The adult multivitamin utilized in the USA when I was a teenager (Unicap from Upjohn) was the size of the children’s multivitamin today and had approximately eight ingredients. Again, sizes and dosages in the USA have appeared to increase so dramatically that the PHS2 study, in my opinion, actually suggested that a children’s or low-dose multivitamin is safe for men and may reduce the risk of cancer, especially in older men. Thus, currently this is how I answer or discuss the question with individuals that seek my advice on what to take if they have or have not been diagnosed with prostate cancer.

Personal efforts to initiate a large-scale randomized trial of cholesterol-lowering agents have been unsuccessful to date. Many designs, including the evaluation of lipid reduction for the prevention of prostate cancer in average and high-risk patients, for men with prostate cancer on active surveillance, or as a neoadjuvant or adjuvant treatment, have been proposed over the past 20 years. Minimal interest in such a trial has been due to multiple obstacles, including perceived lack of a compelling scientific rationale, concerns over unpredictable toxicity, lack of funding, corporate instability, competition from generics, and a perception that other micronutrients (vitamin E, selenium, etc.) may be of more interest [209–211].

The field of dietary supplements has evolved and offers new opportunities for clinical trials to replace some pharmacologic agents that are not readily donated or funded for clinical trials. Red yeast rice extract (RYR) is a dietary supplement that competes with low-dose lovastatin, pravastatin, and simvastatin in terms of potency, and is a realistic alternative for statin-intolerant patients [212–216].

RYR is a traditional Chinese herbal medicine first mentioned in 800 ad in the Tang Dynasty for blood circulation [217, 218]. It is produced by the fermentation of the fungal strain Monascus purpureus Went (red yeast) over moist and sterile rice. RYR is a common dietary compound and food colorant utilized in multiple Asian countries. In China, Japan, and several other countries, it is utilized as an additive and preservative for fish and meat. It has a strong red color, flavor, and aroma; thus, it is also utilized as a flavoring product in a number of recipes and dishes, and it is also used for brewing red rice wine. RYR is also known by multiple synonyms as a food product, including Hong Qu, Hung-Chu, Ang-kak, Ankak rice, Red Mold Rice, and Beni-Koji. It is also known as “xuezhikang” as a dietary supplement intervention in the medical literature.

Dr. Akira Endo found in the late 1970s that a Monascus yeast strain naturally produced a substance that inhibits cholesterol synthesis to block cell wall synthesis of bacterial intruders and named it “monacolin K” [219]. This compound was later isolated and is now known to be of the same molecular structure as lovastatin, the first marketed statin drug. Thus, theoretically RYR is the first known statin used in medical history. Like RYR, a fungus, three of the first prescribed statins utilized in the USA were derived from fungi (lovastatin, pravastatin, and simvastatin) [212, 220]. The amount of monacolin K in any capsule should equate to the amount of lovastatin it contains. For example, if a patient utilizes three capsules from a commercial product that contains 2.5 μg of monacolin K per capsule, then 7.5 μg lovastatin equivalent could be expected in terms of LDL reductions. There are at least 10 identified monacolins in RYR (K, J, JA, K, KA, L, LA, M, X, and XA).

Unlike numerous dietary supplements or CAM products, RYR has a vast amount of clinical data that would arguably give it FDA approval if it were treated as a drug. A meta-analysis of over 9,600 patients in 93 randomized trials involving three different commercial variants of RYR was published [221]. The mean reduction in total cholesterol, LDL, triglyceride, and increase in HDL was, respectively, the following: −35 μg/dL (−0.91 mmol/L), −28 μg/dL (−0.73 mmol/L), −36 μg/dL (−0.41 mmol/L), and +6 μg/dL (+0.15 mmol/L).

Xuezhikang was the commercial RYR product evaluated in a large, randomized, placebo-controlled clinical trial with robust endpoints [222, 223]. The China Coronary Secondary Prevention Study (CCSPS) enrolled 4,870 participants (3,986 men, 884 women) with a previous myocardial infarction (MI) and a baseline mean total cholesterol, LDL, triglyceride, and HDL of approximately 208 μg/dL (5.38 mmol/L), 129 μg/dL (3.34 mmol/L), 165 μg/dL (1.85 mmol/L), and 46 μg/dL (1.19 mmol/L). Subjects received RYR 600 μg twice daily (1,200 μg total, monacolin K 2.5–3.2 μg/capsule) or matching placebo and followed for 4.5 years. The trial was conducted from May 1996 to December 2003 in 65 hospitals in China. The primary endpoint was nonfatal MI or death from coronary or cardiac causes. Secondary endpoints included total mortality from CV disease, total all-cause mortality, need for coronary revascularization procedure, and alterations in lipid levels. Fasting blood samples were drawn at baseline, 6–8 weeks after randomization, and at 6-month intervals. The mean LDL reduction compared to placebo was 18 % (p < 0.001).

Two interim analyses occurred, and the second one demonstrated a significant difference for the primary endpoint [222, 223]. A total of 98 % of the participants completed the study. Multiple clinical endpoints were significantly reduced with the exception of a nonsignificant reduction in fatal MI. Lipids were significantly reduced as well as a 56 and 33 % reduced cancer mortality (p = 0.01) and all-cause mortality (p = 0.0003). Potential anticancer benefits found in the overall trial with RYR were also found among the elderly (significant reduction in cancer deaths) [26, 36] and included a 51 % reduction in cancer incidence [224]. No serious adverse events were observed during this trial. Total adverse events and treatment cessation numbers were similar for RYR and placebo. The number needed to treat (NNT) to prevent a primary endpoint over the 4.5 year duration of the trial is 21, which compares with any prevention trial (primary or secondary).

Laboratory studies suggest that RYR has direct effects on androgen-dependent LNCaP cells and androgen-independent cells over expressing androgen receptors [225]. RYR inhibited prostate cancer growth compared to a prescription lovastatin. And whole RYR inhibited proliferation to a greater extent than monacolin K and pigment-enriched fractions isolated from RYR (p < 0.001). This suggests that other monacolins or ingredients apart from monacolin K in RYR may also have activity against prostate cancer. RYR also significantly reduced androgen-dependent and androgen-independent xenograft tumors in SCID mice (p < 0.05) [226]. Intact whole RYR again provided more inhibition than monacolin K alone. RYR also significantly (p < 0.05) reduced gene expression of several androgen-synthesizing enzymes (AKR1C3, HSD3B2, and SRD5A1) in both androgen-dependent and androgen-independent tumors. A significant (p < 0.001) correlation was observed between tumor volume and serum cholesterol. Identical findings have been demonstrated in colon cancer cell lines [227]. RYR has pleiotropic actions on a variety of pathways and markers beyond LDL cholesterol [228–231], which is similar to statin drugs and could have an impact on prostate cancer proliferation and progression [232, 233].

The active surveillance (formerly known as “watchful waiting”) population is ideal for an initial prostate cancer clinical trial of RYR [108, 234, 235]. Repeat biopsy, PSA kinetic data, and even imaging can be achieved without the interference of other treatments. Such a trial has been initiated in Toronto, Canada, by this author and Dr. Laurence H. Klotz, MD, and is known as “REALITY” (Reduction in Active Surveillance Lipid Indices Through Yeast of red rice). Men will receive 3,600 μg daily of RYR with a potency of monacolin K that is approximately 2.5 μg per capsule (600 μg of RYR per capsule) based on previous clinical trials. It is expected that compliant participants will experience a 20–35 % LDL reduction [236, 237]. Active surveillance patients will be followed for at least 1 year and have at least two biopsies in this 12-month period. Level of LDL is not predictive for response, and therefore will not be an eligibility or inclusion criterion.

Quality control (QC) with RYR is an issue that needs to be considered [238, 239]. Different commercial products of RYR have different concentrations of monacolins. Some contain a potentially harmful by-product of yeast fermentation known as “citrinin” [239]. Obviously, citrinin needs to be eliminated and monacolin K specifically reported for any clinician to feel comfortable utilizing this product for clinical trials or just patient care. The irony in the U SA currently is that manufacturers of RYR are not allowed to standardize monacolin K levels because it suggests a drug mimic, which the FDA could enforce. This ruling makes little sense because it only confuses the clinician and patient when trying to find a suitable alternative to statin drugs.

Contraindications for RYR should be at least identical to lovastatin, including hepatic or renal abnormalities, and allergies to yeast or fungus. RYR should be taken with or especially after meals, since lovastatin absorption is significantly improved under these circumstances [240–242]. Higher concentrated fiber sources such as pectin or oat bran should not be consumed with RYR because of the potential for the reduced absorption of monacolin K.

Overall, RYR has been a safe product in clinical trials and could be a good proxy for statins in a prostate prevention or ancillary treatment trial. Hopefully, more agents that mimic potentially effective prescription drugs will be available in the near future. The need is great because safe chemoprevention of prostate cancer, for example, appears to have hit stasis. And other agents for neoadjuvant or adjuvant use are costly and have their own set of toxicity issues.

Vitamin C supplements at a dosage of 500 μg compared to placebo were found to be safe in a large randomized US trial primarily addressing this issue, but it did not have any impact on prostate cancer risk [84]. This clinical trial ended any excitement for vitamin C as a stand-alone prostate cancer preventive agent. On the other hand, there has always been interest in vitamin C given in IV form in megadoses to cancer patients because in the alternative medicine arena this is not uncommon. One of the first ever phase 1 dose-escalating trial of IV vitamin C to determine if it is safe and if it could inhibit the growth of cancer cells in 24 patients with advanced forms of certain cancers was already published [243]. This was a safety and tolerability study using cohorts that were sequentially infused with 0.4, 0.6, 0.9, and 1.5 g vitamin C/kg body weight three times a week over a 90- to 120-min period. Patients had normal renal function. The average duration of treatment was 10 weeks with a maximum of 30 weeks. Median age was 61 and 24 patients with advanced tumors that had originated from various localized sites (breast, head and neck, liver, lung, lymphoma, ovarian, pancreatic prostate, renal, sarcoma, etc.) were included. No patients had an objective treatment response and all patients eventually progressed. There was a suggestion of physical quality-of-life maintenance for patients that completed this study. The recommended phase II dose will be 1.5 g/kg along with first-line chemotherapy for advanced stage non–small cell lung cancer based on safety and practicality. Intravenous vitamin C given in large doses appeared to be safe and free of toxic effects, including kidney stones, but provided no treatment impact by itself. Perhaps in combination with conventional therapies, and used earlier in the course of the disease, there may be a better chance of a treatment response or simply a quality-of-life response. The impact of these IV vitamin C treatments on increasing oxalate levels and kidney stone risk is controversial [244], and with the dietary supplements in large doses there is a realistic concern in the healthy patients at doses of 1,000 μg or more [245].

One option is to switch to a calcium ascorbate oral form of vitamin C (ascorbic acid) for patients that want to take oral vitamin C [4]. Our past research suggested a minimal or reduced oxalate change in the pill form (it was not tested in an IV form). Yet in individuals with advanced cancer, the argument over oxalate should not be as paramount as whether or not there is a quality or quantity of life benefit. This question needs to be further answered because these infusions are usually not of a low cost to the patient from my observational experience. Case studies abound in terms of potential benefits in select cancer patients [246], but strong clinical research has not yet supported the routine use of this method in most cancer patients. More answers in this area are really needed now, but currently the decision should be between the patient and the clinician he or she trusts until more research is conducted.

Vitamin D appears to have as many issues as multivitamins or any other dietary supplement for prostate cancer when some clinicians and patients want to believe that more is better. The tendency for patients to ingest higher amounts of this supplement is enticing, but in the area of prostate cancer vitamin D has not been consistently impressive, and several studies of no impact or potential harm have been demonstrated at higher blood levels [247]. Vitamin D is important for bone health, but the amount needed has been embellished and exaggerated. Vitamin D tends to mimic the function of a hormone, which is why caution should be followed because the potential for a U-shaped risk curve does exist (similar to alcohol and other hormones) for male health [248]. Perhaps indirect evidence is providing some clues because one of the largest and longest randomized trials in women found that excessively high blood levels of vitamin D from supplementation compared to placebo were actually associated with an increased risk of falls and fractures [249]. The normal level of vitamin D should arguably be from 30 to 40 ng/mL (75–100 nmol/L) based on expert opinion from a review of past clinical trials accessing multiple outcomes [250]. A total of 1,000 IU (25 μg) of vitamin D is adequate to increase blood levels of vitamin D over time (5–10 ng/mL or more over 6–12 months), and a suggestion of outright deficiency (less than 10 ng/mL or 25 nmol/L) from consistent reliable blood testing may lead to slightly greater intakes. However, even vitamin D blood tests have a history of uncertainty based on the assay utilized (RIA, ELISA, HPLC, etc.) [251, 252]. Monitoring vitamin D in men, especially higher-risk bone loss patients—for example, men on ADT for prostate cancer—may be appropriate, but in general for men’s health the vitamin D test may provide more harm than good until more tangible clinical endpoints are followed in healthy individuals [252, 253]. Even a large-scale high-dose trial (100,000 IU in general over 18 months) to prevent upper respiratory tract infections in otherwise healthy adults showed no benefit over placebo [254]. Perhaps it was the lack of patients with deficient levels that caused these findings, or it could be that vitamin D blood levels are simply a marker of healthy behavior rather than this vitamin’s impact itself [4]. A young, lean individual, with no prediabetes or diabetes, a low cholesterol, and who consumes fish and exercises outside regularly is more likely to have a higher blood level of vitamin D compared to an older, physically inactive obese or prediabetic or diabetic man with a high cholesterol level [4, 255–259]. One of the best indicators of a lower vitamin D level is weight gain because vitamin D remains in adipose tissue instead of blood circulation. So, is it really the vitamin D supplement providing the majority of the benefit for men’s health or the finding that higher vitamin D levels could be found on average in more healthy men? I believe it is more of the latter observation, but this does not imply that individuals with overt deficiency would not benefit from supplementation.