Eat your carrots

A December 2014 Chinese meta-analysis of prior studies on carrot consumption and prostate cancer reported that while there were some inconsistent results it nevertheless found an inverse relationship, i.e. eating more carrots cut the risk of getting prostate cancer.  Importantly, it found a dose-response relationship -- for every 10 grams of carrots per day consumed there was a 5 percentage point reduction in relative risk. If this holds for sufficiently large increments of consumption and if the association is causal then given that a small/medium/large carrot weights 50/61/73 grams (see [hannaone]) one could reduce one's risk by 25%/30%/36% by consuming a small/medium/large carrot per day. The abstract of the study can be found here: [Pubmed: 24519559]

The existence of a dose-response relationship is one of the Bradford Hill criteria of causation. See: Bradford Hill Criteria of Causation on this blog.

Nutritional Supplements and Prostate Cancer

[Updated August 17, 2015]

Literature Review

A 2015 survey of nutritional approaches to prostate cancer published in BMC Medicine contains a table of approaches for which the authors found research. See table 1 in [Full Free Text of paper].

UK NCRN POMI-T Study

A 2014 six month randomized placebo-controlled double blind UK study published in Prostate Cancer and Prostatic Diseases of a mixture of polyphenols (pomegranate, green tea, turmeric and brocolli) with 199 prostate cancer patients on Active Surveillance or Watchful Waiting found that the treatment arm had an increase in PSA of 14% vs. 79% for the control arm (lesser increase is more favorable). The paper notes that the study received no funding from the manufacturer of the supplement. [Full Free Text of Paper] [Cancernet UK Charity info] [video interview with researcher Robert Thomas] [Manufacturer's FAQ].

PSA Doubling Time. Note that a 14% increase in PSA over a 6 month period (as found in the treatment arm) represents a doubling time of 6 / log2(1.14) = 31.74 months whereas an increase of 79% over 6 months (as found in the control arm) represents a doubling time of 6 / log2(1.79) = 7.14 months. Thus the doubling time was 31.74 / 7.14 = 4.4x times longer in the treatment arm (higher is more favorable).

Disease Progression. MRI scans were not part of the protocol but many of the patients had them anyways as part of their routine medical visits and these scans were consistent with lesser disease progression in the treatment arm (as opposed to just a matter of just modifying the PSA kinetics).

Group Composition. The treatment and control groups were assigned randomly subject to assigning 2 patients in the treatment group for every patient in the control group. By chance the average age in the treatment group was 5 years less than the average age in the control group so statistical methods were used to adjust the results to correct for this difference. On other measured variables the two groups were statistically similar.

A 12 month US study on effects of pomegranate extract on rising PSA levels

A randomized double blind trial of pomegranate extract on 183 men with rising PSA after primary therapy published in Prostate Cancer and Prostatic Disease 2015 found no effect on PSA doubling time. It did find some indications that patients with the MnSOD AA genotype might benefit but this would require a further study to confirm. Some of the study authors received funding from the manufacturer of the extract. See [PMID: 26169045] [Full Free Text].

Key differences between this study and the UK NCRN POMI-T study are that:

• this study was performed after primary therapy whereas the UK study was performed on patients undergoing Active Surveillance and Watchful waiting.
• this study examined only pomegranate extract whereas the prior study examined pomegranate extract in combination with 3 other polyphenols.
• this study followed men for one year and the UK study for 6 months

Vitamin D Review

[August 4, 2011]

A review paper by Barnett and Beer that appeared in Urol Clin North Am. 2011 Aug;38(3):333-42 discusses the current status of Vitamin D research. [PMID: 21798396]. According to that paper it seems clear that vitamin D is involved in prostate cancer biology and that there is an anticancer effect in animals but it is much less clear whether there is a significant beneficial effect of vitamin D supplementation in humans. Below we outline the main points:

• geographic areas of low UV exposure have increased risk of prostate cancer
  
• in test tube and animal studies vitamin D has shown an anti-cancer effect
  
• because calcium tends to depress vitamin D it would be expected that if vitamin D were anti-cancer in humans then low calcium intake would correlate with lower risk of prostate cancer but of 12 recent studies 8 showed no relationship with calcium
  
• out of 13 studies 9 showed no association between low vitamin D and increased risk of prostate cancer
  
• some caveats are that the following may (or may not) be (a) it might be that the studies just cited did not have sufficient numbers of patients to detect a difference, (b) it might be that the effect of low vitamin D is to increase the risk of aggressive prostate cancer rather than increase the risk of prostate cancer
  
• studies relating genetic variations in Vitamin D genes and prostate cancer progression have been inconclusive
  
• multiple studies with calcitriol + chemo have resulted in lower PSA levels; however, a phase III trial was halted due to deaths in the treatment arm
  
• it may be that vitamin D therapy only works in certain targeted subgroups
  

In conclusion:

"At present, there are no consistent data to support high dose vitamin D supplementation for the average patient with prostate cancer for the treatment or halting of cancer progression. In addition, there are no data to support therapeutic use of vitamin D and its analogs in treating prostate cancer. Additional studies are needed to determine if higher doses of vitamin D supplements could benefit selected populations (ie, the elderly or patients with cancer) even if they may not be beneficial for the general population."

and for the average prostate cancer patient

"a recommended minimum of 600 IU of vitamin D per day, with testing at baseline to determine if additional supplementation is needed for deficiency levels (< 20 ng/mL) is reasonable."

WCRF/AICR Diet and Cancer Report

[Updated January 1, 2015]

The Report

A 5 year study by a team of 21 experts chaired by Sir Michael Marmot (Wikipedia) and sponsored by the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) has produced 500+ page report on diet, exercise and cancer, free to download at the Diet and Cancer Site ([report], [summary], [brochures]. Updates were released in 2010 (on breast cancer), 2011 (on colorectal cancer) and 2012 on pancreatic cancer. [updates]. It is expected that upcoming udpates will be available in 2013 on endometrial and ovarian cancers and on breast cancer survivors and in 2014 on cancers of prostate, bladder, kidney, liver and gallbladder. WCRF/AICR Timetable.

Modifiable Risk

The report is in agreement with the last WCRF report published 10 years ago that "about one third of all cancers are preventable ... by appropriate food and nutrition, regular physical activity, and avoidance of obesity". (page xxv) In particular,

"cancer is a disease of genes, which are vulnerable to beneficial or harmful mutation, especially over the long human lifespan. Nutritional factors are important in determining the likelihood of some mutations, as well as in changing the functions of genes even without mutation. However, both epidemiological and experimental evidence shows that only a small proportion of cancers are inherited. Environmental factors are most important and can be modified. These include smoking and other use of tobacco; infectious agents; radiation; industrial chemicals and pollution; medication and also many aspects of food, nutrition, physical activity, and body composition. Essentially this is good news. It means that healthy environments can stop cancer before it starts. The evidence also indicates that such environments, including the factors that are the subject of this Report, may be able to check the cancer process after it has started. ... The most impressive initial evidence showing that patterns of cancer are altered by environmental factors, and are not mainly genetically determined, comes from studies describing changes in the rates of different cancers in genetically identical populations that migrate from their native countries to other countries. Such studies consistently show that changes in the rates of some of the most common cancers, including those of the stomach, colorectum, breast, and prostate, can be remarkable, even over one or two generations." (pages 2, 4)

Methodology

The process followed to develop the report was to commission from scientific partners 20 independent systematic literature reviews (SLRs) using a common protocol (defined in a separate SLR Specification Manual) resulting in dose response curves (see Box 3.2 on page 52) and meta analyses displayed via forest plots (see Box 3.3 on page 53). The independence of the process was assured by separating the collection and assessement of the data and through the involvement of the peer reviewers. The process was developed by the Mechanisms Working Group headed by Dr. John Milner of the National Cancer Institute. Also see the business plan.

Judgments based on this work are displayed in matrices as well as an overview [Food Table]. The matrices and foldout categorize the strength of evidence in each case as convincing, probable, limited/suggestive, limited/no conclusion or unlikely to affect risk. Box 3.8 on page 60 and continued onto page 61 discusses the particular criteria that must be satisfied for each of these categories.

Prostate Cancer

For prostate cancer their assessment of the evidence is given in the matrix on page 305 and discussed on pages 305-309 which we summarize here:

• probable evidence supporting a decreased risk of prostate cancer for food containing lycopene (forest plot and dose response curve p. 104)
• probable evidence supporting a decreased risk of prostate cancer for food containing selenium (forest plot and dose response curve p. 110). [Note that in 2008 the SELECT trial found that selenium does not reduce the risk of prostate cancer. See [link].]
• probable evidence supporting a decreased risk of prostate cancer for selenium (matrix p. 179) [This has been overturned by the SELECT trial as in note above.]
• limited/suggestive evidence that pulses (i.e. legumes) decrease the risk of prostate cancer
• limited/suggestive evidence that foods containing vitamin E decreases the risk of prostate cancer (matrix p. 76) [This has since been overturned by the SELECT trial as in the note above.]
• limited suggestive evidence that processed meat (i.e. preserved by smoking, curing or salting or the addition of chemical preservatives) increases the risk of prostate cancer (matrix p. 116)
• probable evidence that diets high in calcium increase the risk of prostate cancer. (matrix p. 129)
• limited/suggestive evidence that dairy products and milk increase the risk of prostate cancer (matrix p. 129)

Note that they were careful to distinguish between food containing a substance and vitamins.

The report also says the following regarding the pathogensis of prostate cancer (Chapter 7, p. 306):

The disease usually develops slowly and dysplastic lesions may precede cancer by many years or even decades. Extrapolations from autopsy studies suggest that most men would have prostate cancer if they lived to be more than 100. [PMID: 12642065] The number of prostate cancers found incidentally at autopsy, which had been asymptomatic and not a cause of death, suggests that small, localised prostate cancers can remain unrecognised for many years before progressing to a clinically significant form. Men are more likely to die with, rather than from, prostate cancer. [PMID: 12672328] [PMID: 12096083] [Full Text] The increased prostate cancer incidence in first-degree male relatives of women who have early onset breast cancer suggests a genetic predisposition.[PMID: 14580253] [Full Text]. Some studies propose that this may be linked to the BRCA genes. [PMID:14709740] [Full Text]. Growth factors, particularly IGF, as well as androgens have also been implicated in the development of prostate cancers. Serum levels of IGF-1 can be associated with prostate cancer independently of PSA levels. [PMID: 12122101] [Full Text] High levels of testosterone promote cell differentiation, which could protect against the development of this cancer. Therefore, declining levels of this hormone in older age may contribute to the development of this cancer. [PMID: 1292595]

Regarding inheritance we note that "Of 100 men who present with PC 74% will have sporadic PC while 26% will have clustered PC, i.e. evidence of genetic clustering. Of the 26% having clustered PC, 81% will have familial prostate cancer, FPC, and 19% will have hereditary prostate cancer, HPC." (See page 9 of PCRInsights, July 1999 which references [PMID: 7853589].) Also a recent study on colorectal cancer, lung cancer, breast cancer, ovarian cancer and prostate cancer in families concluded that "cancer-specific survival in parents predicts survival from the same cancer in their children" [PMID: 17921068]
In November of 2014 an update was published with the following main conclusions. From their web site:

• "There is strong evidence that being overweight or obese increases the risk of advanced prostate cancer (being overweight or obese is assessed by body mass index (BMI), waist circumference and waist-hip ratio)."
• "There is strong evidence that developmental factors in the womb, childhood, and adolescence that influence growth are linked to an increased risk of prostate cancer (the taller a man is, the greater his risk of prostate cancer)."
• "There is strong evidence that consuming beta-carotene (either through food or supplements) is unlikely to have a substantial effect on the risk of prostate cancer."

Recommendations

The recommendations of the report are "are broadly similar to those that have been issued by other international and national authoritative organisations" (page xix) and their core is are summarized as the following in an AICR press release:

"Get and stay lean. Be physically active for at least 30 minutes a day as part of everyday life. Eat a diet that’s primarily composed of vegetables, fruits and other plant foods and limit meat. Limit or eliminate the consumption of alcohol."

More formally, the report has 10 recommendations which were unanimously agreed upon by the 21 experts:

1. Body Fatness. Be as lean as possible within normal range of body weight. (Aim for a Body Mass Index, BMI, between 21 and 23. Box 12.3 on page 375 gives a chart that uses height and weight and gives an assessment of overweight in various categories, normal or underweight or try this BMI calculator or this chart.
2. Physical Activity. Be physically active as part of everyday life. (Begin with 30 minutes brisk walking every day increasing increasing to 60 minutes of moderate or 30 minutes of vigorous exercise every day. Table 12.1 on page 377 quantifies exercise in terms of the Physical Activity Level, PAL, score.)
3. Foods and Drinks that Promote Weight Gain. Limit consumption of energy dense foods (Also see: [link].) Avoid sugar drinks. (That means avoid high calorie foods, fast foods and processed foods.)
4. Plant Foods. Eat mostly foods of plant origin. Eat at least 5 portions/servings (400g or 14 oz) of a variety of non-starchy vegetables and fruits every day. Eat relatively unprocessed cereals (grains) and/or legumes with every meal. Limit refined starchy foods.
5. Animal Foods. Limit intake of red meat and avoid processed meats. (People who do eat red meat should consume less than 500g (18 oz) a week and very little if any processed meats.) The meat industry has contested this point of limiting red meat and processed food while the WCRF/AICR has responded to the meat industry statement.
6. Alcoholic Drinks. Limit alcoholic drinks. If they are consumed limit consumption to no more than two drinks per day for men and one for women. (Despite the protective effect against coronary heart disease consumption of alcoholic drinks increases the risk of cancer and there is no level below which the risk is not increased.)
7. Preservation, Processing and Preparation. Limit consumption of salt and avoid the consumption of moldy cereals (grains) and pulses (legumes). Such mold contains cancer causing alfatoxins.
8. Dietary Supplements. Aim to meet nutritional needs through diet alone. (High-dose dietary supplements may be able to modify the risk of some cancers in specific, typically high-risk groups, but might have unexpected adverse effects when applied on a population basis. The report advises that supplementation be restricted to a clinical setting with medical advice.)
9. Breastfeeding. Mothers to breast feed their children exclusively for six months with complementary feeding thereafter.
10. Cancer Survivors. Cancer Survivors should follow the above recommendations for cancer prevention. (All cancer survivors should receive nutritional care from an appropriately trained professional.) In fact this recommendation seems to simply be a default as they were not able to find evidence to support much in the way of specific conclusions for cancer survivors.. With respect to food they stated "No conclusions can be derived from these results" (Chaper 9, p. 364), with regards to supplements they stated "The evidence from this review of trials does not show that micronutrient supplements have any benefits in cancer survivors. High-dose supplements may be harmful. Some micronutrients and other bioactive compounds are known to be toxic at high doses." (Chapter 9, p. 346) and with respect to physical activity they state that " Taken together, these trials provide some evidence for the benefit of physical activity on post-treatment quality of life in cancer survivors" (p. 347) but no evidence was found in favor of increased survival. Furthermore, with respect to prostate cancer Walter Willett of Harvard, who was a member of the expert panel has hypothesized that prostate cancer is different in younger and older men which, if confirmed, would certainly call into question the idea that the steps that reduce the risk of prostate cancer are the same as those which improve survival once one has it. See our previous post about this hypothesis [here].
    There are also three additional recommendations of foods to avoid that only apply to specific regions. These are mate (found in South America), Cantonese-style salted fish (found in southern China) and arsenic contaminated water (found in many places around the world). (See Box 12.5 on page 392.)

Miscellaneous

Energy Restriction

One intriguing point made in the report (see Box 2.5 on page 46) is that

Restriction of energy intake from food is the most effective single intervention for preventing cancer in experimental animals. It increases the lifespan of rodents, and suppresses tumour development in mice. In addition, energy restriction can suppress the pro-cancer effects of many carcinogens in experimental animal models. [PMID: 12525670] Energy restriction leads to a reduction in cell proliferation. [PMID: 12525670] This may directly inhibit tumour growth, and also indirectly reduce cancer development by reducing overall proliferation, thus reducing the chances for incorrect DNA replication, or by preventing damaged DNA from being replicated. Reduced metabolism results in reduced generation of reactive oxygen species, and therefore less exposure of DNA to damaging oxygen radicals. Dietary energy restriction reduces levels of circulating IGF-166 [PMID: 15599926] and insulin, which are growth factors for many cells, including breast cancer. [PMID: 15607540] IGF-1 stimulates progression through the cell cycle from G1 to S phase, and high levels of insulin increase production of IGF-1.13 Energy restriction also decreases expression of cyclins and cyclin-dependent kinases (CDKs), and increases levels of CDK inhibitors, leading to reduced Rb phosphorylation and inhibited cell cycle progression.139 Energy restriction also decreases other inflammatory markers.[PMID: 12525670] Conversely, increased glucose levels associated with increased energy intake are associated with increased DNA synthesis and levels of some cyclins and CDKs.[link] Energy restriction may also create a pro-apoptotic environment and reduce blood vessel density, as shown in premalignant and malignant breast pathologies. [PMID: 14587868] It may also activate other protective pathways, such as the activation of protein deacetylases. [PMID: 15254550] The data on energy restriction must be interpreted with caution, as all studies have been performed in experimental animals and there is an absence of epidemiological and mechanistic data in humans. Therefore the relevance of these findings in experimental animals to the human condition is not yet clear.

Other Reports

The panel also reviewed reports by other bodies giving nutritional recommendations (see Chapter 10); however, these tended to mostly be aimed at cardiovascular benefits.

Further Research

Chapter 11 lists a number of unanswered questions that further research may wish to pursue.

Expert Panel

Note that one of the expert panel members is Walter Willett of Harvard whose work was featured in an earlier post on this blog: Willett Divides Prostate Cancer Into Four . Another expert panel member whose work has been featured on this blog is Claus Leitzmann who worked on the study that is the subject of this post: Calcium Increases Prostate Cancer Risk in Smokers .

News Release

The following news release discusses the relationship between growth and cancer that the report discusses but which is not discussed here as it seems less related to prostate cancer.

Foldout

The [Cancer Process Foldout] is quite hard to read on screen so we have created a table based on it here:

	Pro-Cancer	Anti-Cancer
Fetal Expoxure	nutrient availability, fetal growth, material stress (infection, illness), maternal low protein
Body Composition	Obesity, Central Obesity, Adult Obtained Height, Metabolic Syndrome	Energy restriction
Cell Proliferation	n-6 PUFA, Insulin-like growth factor, Insulin, Leptin, Oestrogen, Obesity	Organosulphur compounds, Energy restriction, Flavonoids, Retinoids, Selenium, Indole-3-carbinol, n-3 PUFA
Carcinogens, other environmental exposures	Reactive oxygen species, Aflatoxin, N-nitroso compounds, Heterocyclic amines, Polycholinated biphenyls, inflammation, Phase I enzymes	zinc, curcumin, lycopene, Vitamin A, E, C, Flavonoids, Isothiocyanates, Selenium, Indole-3-carbinol, Energy restriction, Phase II enzymes
DNA Repair	Low folate, Malnutrition, Damaged DNA Repair	DNA repair, Selenium, Folate, Vitamin A, Coenzyme Q10

Failed aptosis
Aptosis, Genistein, Retinoids, Polyphenols, Vanilloids, Indole-3-carbinol, n-3 PUFA


Differentiation
Insulin-like growth factor
Epigenetics, Folate

Willett Divides Prostate Cancer into Four

Walter Willett has proposed that Prostate Cancer cases should be split along two axes: age (young vs. old) and aggressiveness (indolent vs. aggressive) giving four different combinations.

The thrust of the idea is that various nutritional recommendations have been shown to work in some of these groups but not in others. Lumping all groups together may mask an effect which occurs in one group but not the other whereas restricting attention to those groups where the nutritional recommendations work would be expected to better detect the effect.

Aggressiveness

Along the indolent/aggressive axis we have dairy and calcium consumption. High dairy consumption or high calcium consumption increases the risk of aggressive disease but does not pose a risk for organ confined disease. If one were to mix together indolent and aggressive patients one might miss the effect since it would not be present in the indolent ones. By restricting attention to the aggressive ones we would more likely detect the effect.

Age

Along the young/old axies we have a variety of supporting items:

• high body mass index reduces risk by 50% at age 21 but increases risk slightly at age 60
• hormones is a driving factor behind PCa in youger men while inflammation is a driving factor in older men (note: this has been disputed -- William Nelson suggests inflammation determines whether you get PC or not whereas hormones determine how aggressive it will be)
• as men age they tend to get heavier which in turn results in greater inflammation
• exercise reduces risk of prostate cancer among older men but not younger men consistent with exercise reducing inflammation
• lycopene has a relative risk of 67% for older men but only 89% for younger men. Again this is consistent with its ability to reduce inflammation.

Dividing men into a younger group and an older group would ideally be done based on a hormonal event paralleling menopause in women.

Note

According to in cites Walter Willett was the second most cited researcher in clinical medicine in the 1995-2005 period with 516 papers and 29,311 citations although citations to him tend to be in the area of Diabetes, not Prostate Cancer.

References

News item on Willett

Holick's July 2007 NEJM Paper on Vitamin D

[updated July 28, 2010]

Since the material below was written a good overview of the area was written up in the [July 26, 2010] which discusses benefits and toxicity. Also Holick has since written a book, The Vitamin D Solution.

Michael Holick of the Boston University has just published a review paper on Vitamin D deficiency in the July 2007 New England Journal of Medicine (NEJM). [PMID: 17634462]. The paper discusses the role of Vitamin D in many diseases but here we review the portion of the paper most associated with prostate cancer. Prior to reading the material here the reader may wish to review our post on Vitamin D and Prostate Cancer.

Before reading further Dr. Richard Lehman had these thoughts on the paper: "You are vitamin D deficient, very probably, and this is making your muscles ache, slowing you brain, thinning your bones and making you more likely to get cancer and heart disease. The secret of the Mediterranean is not its food but its sunshine. Or both. Go on, take your clothes off, get outside, and eat lots of oily fish, cheese, wild fungi and eggs. Abandon your miserable existence in the dark North and start living before it is too late. Alternatively, get a sunbed and take large daily supplements of vitamin D. It’s the elixir of life, according to this very thorough and plausible review."

• most tissues and cells in the body have a vitamin D receptor
• several can convert circulating vitamin D to active vitamin D
• vitamin D has a role in decreasing risk of cancer, autoimmune diseases and cardiovascular disease
• excess previtamin D3 is destroyed by sunlight so excessive sunlight exposure will not result in toxic levels
• D2 supplements are made from UV irradiation of ergosterol from yeast
• D3 supplements are made from UV irradiation of 7-dehydrocholesterol from lanolin. (My comment: perhaps one might be able to increase the Vitamin D they get from the sun by applying lanolin to the skin prior to exposure?)
• the active form of vitamin is regulated by parathyroid, calcium and phosphorus levels in the blood
• fibroblast growth factor 23 secreted from bone suppresses the synthesis of active Vitamin D
• the active form of Vitamin D:
  • increases calcium and phosphorus absorption in the kidneys and intestines
  • increases CYP24 which in turn inactivates both the circulating and active forms of vitamin D by turning it into the inactive water-soluble calcitroic acid
• deficiency is regaded by most experts as having a circulating vitamin D level of less than 20 ng/ml (i.e. less than 50 nmol/liter)
• as circulating vitamin D increases parathyroid hormone levels decrease until circulating vitamin D reaches 30 to 40 ng/ml (75-100 nmol/liter) at which point parathyroid levels level off (at their lowest point)
• intenstinal transport of calcium increases by 45% to 65% when vitamin D levels increases from 20 ng/ml to 32 ng/ml (50-80 nmol/l)
• 30 ng/ml can be considered an sufficient level for vitamin D and 150 ng/ml (375 nmol/l) can be regarded as a toxic level

Cancer

• people living at high latitudes are at increased risk for Hodgkin's lymphoma, colon cancer, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer and other cancers
• people living at high latitudes are more likely to die from these same cancers if they get it
• epidemiologic studies indicate that circulating vitamin D levels below 20 ng/ml are associated with 30% to 50% increased risk of colon cancer, prostate cancer and breast cancer as well as a higher likelihood of dying of those cancers if they get it.
• Levels of the active form of vitamin D are not associated with risk in colorectal cancer.
• one study showed a relative risk of 0.53 of colorectal cancer when 244 to 652 IU/day were taken
• it has been hypothesized that the active form of vitamin D can induce cell death in malgnant cells and can prevent angiogenesis

Requirements

• Institute of Medicine (see chapter on Vitamin D in their book) says daily intake should be 200 IU/day for children and adults up to 50 and 600 for adults over 50
• many experts believe that 800 - 1000 IU/day should be recommended for those without adequate sun exposure
• vitamin D2 is 30% as effective as D3 so three times as much is needed (Update: Although earlier work published in 1998 [PMID: 9771862] and 2004 [PMID: 15531486] seemed to support the lesser effectiveness of D2, since the NEJM paper came out Holick has specifically investigated this further and concluded that D2 is, in fact, equal to D3 in maintaining blood serum levels [PMID: 18089691] [Full text])
• one inexpensive method is to give patients 50K IU capsule of D2 once a week for 8 weeks followed by every other week after that.
• another method is 1000 IU per day of D3 or 3000 IU/day of D2
• another method is to give 100K IU of D3 once every 3 months. It was shown to maintain circulating D levels at 20 ng/ml or higher.
• additional considerations may be appropriate for those with kidney disease, malabsorption problems or those on anticonvulsants, glucocorticoids or other drugs involving the steriod and xenobiotic receptor
• exposure of the arms and legs for 5 to 30 minutes depending on time of day, latitude, season and skin pigmentation between the hours of 10am and 3pm twice a week is often sufficient
• most tanning beds emit 2% to 6% UV and can be effective in moderation
• exposure in tanning beds for 30% to 50% of the time recommended for tanning can prevent vitamin D deficiency and will have lower risk of skin cancer than a full exposure

Toxicity

• levels of vitamin D which are too high are associated with hypercalcemia (excess calcium) and hyperphosphatemia (excess phosphorus). 50K IU/day would raise circulating D levels to 150 mg/ml (374 nmol/l) and would be associated with such problems.
• doses of 10K IU/day for up to 5 months have not been seen to cause problems. See [PMID: 15225842] [full text] which in turn references [PMID: 12499343] [full text].
• certain disorders may predispose patients to be more susceptible to calcium levels which are too low or too high

Methods of Measurement

• assays for circulating D3 can be used to assess deficiency
• radioimmunoassays measure D2+D3
• liquid chromatography and mass spectroscopy can report D2 and D3 separately
• a combined total of D2+D3 of 30 ng/ml is generally sufficient

Lycopene, Selenium and Vitamin E in Combination for Prostate Cancer

[Updated January 3, 2010]

Note that since the information on this page was written a large scale study, the SELECT trial, concluded that selenium and vitamin E do not reduce the risk of prostate cancer (at least in the dosages used). See [SELECT Q&A]. Also a second large scale trial just reported that "individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily" did not prevent cardiac events (i.e. heart attack, stroke). [PMID: 18997197] [Full Text]. The November 20, 2008 New York Times' blog ran a story summarizing the latest news: [link]. Fleshner et al who performed the research below themselves announced negative results on the benefit of E combined with selenium and soy. [news release] at the 2009 AUA Annual meeting.

These negative results not withstanding in the following paper the same authors do hold out hope that further studies may still show benefits. See [PMID: 19997071].

Readers interested in nutrition and prostate cancer may also wish to read Zlotta's October 2008 comment [PMID: 18953448] [Full Text] and the following posts on this site:

Vitamin D and Prostate Cancer
Holick's July 2007 NEJM Paper on Vitamin D
Canadian Cancer Society Recommends 1000 IU/day Vit...
WCRF/AICR Diet and Cancer Report
Lycopene, Selenium and Vitamin E in Combination fo...
How Healthy Men Can Reduce Their Risk
Diet Soft Drinks
Longevity
Soy

In a 2007 ASCO presentation Neil Fleshner (who is also co-author of one of the free nutrition downloads, Prostate Cancer Nutrition and You listed in the right hand column of this blog) cites results in both mouse models and in human subjects where consuming a combination of:

• lycopene (50 mg/day)
  
• selenium (200 mcg/day)
  
• vitamin E (800 IU/day)

or the mouse equivalent virtually arrested prostate cancer development in mice and in only 4 weeks brought about improvements in progression markers in humans. A key observation of this study is that the combination of antioxidants is far more beneficial than treatment with any single antioxidant alone.

Human Trial

The human trial consisted of 50 subjects with prostate cancer divided into 5 groups: no supplementation, vitamin E group (800 IU/day), selenium group (200 mcg/day), lycopene group (50 mg/day) and a group given all three. After 4 weeks there was virtually no Ki67 staining (a proliferative marker) on the combination antioxidant group suggesting that prostate cancer was virtually arrested in only 4 weeks. In the single antioxidant groups only selenium showed an improvement over the control but nowhere near the combination treatment. Except for the combination group staining was seen in all groups. Also, there was dramatic upregulation of p27 in both the cytoplasm and the nucleus in the combination treatment. (p27 is a cell cycle inhibitor that is associated with prolonged survival.)

Animal Study

The animal study discussed was from a 2004 Cancer Research paper [FullText] [PMID: 1531393]. In that study 19 transgenic mice, bio-engineered to develop prostate cancer, were put on a standard diet and of the 19 mice 14 did, in fact, develop prostate cancer. On the other hand only 2 of 19 similar bio-engineered transgenic mice on the same diet but supplemented with lycopenes, selenium and vitamin E developed prostate cancer. The difference between 14 of 19 and 2 of 19 is highly statistically significant. The investigators also tried putting mice on a high fat diet (40% of calories derived from fat) in which case all 19 of 19 mice developed prostate cancer but only 3 of 19 whose high fat diet was supplemented with lycopenes, selenium and Vitamin E. The difference between 19 of 19 and 3 of 19 is also highly significant, statistically. One interesting observation that these numbers illustrate is that the antioxidants were not only beneficial in preventing prostate cancer but also largely blocked the negative effect of a high fat diet. There was no evidence of antioxidant-related toxicity in the mice given the antioxidants. The antioxidant dosages were provided in the human equivalent to 800 IU Vitamin E, 200 mcg selenium and 50 mg of lycopene per day.

A 2008 animal study that examined the effect of combined selenium and isoflavones on rats also concluded that taking them together had a large favorable effect on the amount later detected in the blood stream relative to separate administration of the two. See [PMID: 19000315] [provisional text].

Toxicities

Vitamin E. Although no toxicities were observed in this study,

• a meta analysis of other studies concluded that Vitamin E increased the risk of dying by 39 in 10,000 when taken at a dosage of 400 IU/day or more; however, the conclusion seems controversial and, in particular, some of the studies used multi-vitamins, not just E. See the related articles at the bottom of [link] for discussion on this study.
  
• the Womens' Health Study (WHS) concluded that cardiovascular disease increased among users of 600 IU/day of Vitamin E though the increase was not statistically significant. [link]
  
• The Heart Outcomes Prevention Evaluation–The Ongoing Outcomes (HOPE-TOO) patients in the vitamin E group had a significantly increased risk for heart failure and hospitalization for heart failure in the Vitamin E group. [link]

Lycopene. High levels of lycopene may have adverse effects in smokers and certain other groups. [link].

Selenium

.

• Diabetes. In a 7.7 year human trial subjects who took 200 mcg/day of selenium increased their risk of developing diabetes by 50% (incidence, 12.6 cases per 1000 person-years vs. 8.4 cases per 1000 person-years for controls). See [PMID: 17620655] [Full Text]. A probability sample done in the US determined that the quartile taking the greatest amount of selenium had a 57% greater probability of developing diabetes than the quartile taking the lowest amount of selenium (however, the quartiles were not monotonically increasing). See [PMID: 17392543].
• Toxicities not explored. In Bottom Line's "Why Doctors Don't Get Sick", Dr. Victor Herbert of the Mount Sinai School of Medicine in New York is said to have commented on the Harvard study that indicated selenium reduced the risk of advanced prostate cancer saying that the study failed to look at the incidence of other kinds of cancer, overall death and illness rates. Also there is little evidence that Americans are selenium deficient.
• More. For more on selenium see [link]. Dr. Marc Garnick (papers) of the Harvard Medical School has written a brief summary of the pros and cons of selenium here. There has been some speculation that selenium might hide rather than prevent prostate cancer.

Other

Doubts on Lycopene Effectiveness. A recent study of 28,000 men concluded that lycopene does not prevent prostate cancer [link] [PMID: 17507623] contradicting previous studies and the FDA has concluded that there is only a limited evidence of association between eating tomatoes and decreased risk of prostate cancer [article], [link]. Giovannucci speculates in [PMID: 17623795] [Full Text] that lycopenes may have more of an effect on later stage cancers when the initial studies that showed association were prevalent but that in today's environment of PSA testing and earlier stage cancer they may be less effective. That would account for the discrepancy in results. Fleshner's study suggests that there is still the possibility that it may be effective in conjunction with other antioxidants.

Another Combo - Brocolli and Tomatoes. Another animal study found positive effects from a combination of broccoli and tomatoes. In that study rats were fed the equivalent of 1.4 cups of raw broccoli and 2.5 cups of fresh tomato per day which had the effect of reducing tumor weight by about half relative to controls. 1 cup of tomato sauce or 1/2 cup of tomato paste would presumably be equivalent to the fresh tomato. See [article] and [PMID: 17213256].

Green Tea Combos. (1) Celebrex. Yet another combination study suggests that 200 mg of Celebrex, a COX-2 inhibitor, and green tea synergistically combine to reduce the growth of prostate tumors by 81% vs 42% for green tea extract alone and 57% for Celebrex along. [review] [PMID: 17332308]. (2) Citurs Juice. A Purdue in vitro (test tube) study concluded that mixing green tea with citrus juice (and to a lesser extent with citric acid, BHT, EDTA, ascorbic acid, milk, soy milk or rice milk) increased the catechin, i.e. active anti-cancer ingredient, recovery significantly. See Purdue press release and [PMID: 17688297] . (3) Soy. A Harvard study found that a combination of tea (either black or green) and soy had synergistic effects against prostate cancer in mice [PMID: 12566493] [full text].

Resveratrol/Quercetin combo. Resveratrol [PMID: 18439064] [PMID: 18414053] has anti-cancer effects against prostate cancer but is made less bioavailable in the liver through sulfation. It was found that this can be counteracted making the Resveratrol more bioavailable if quercetin, mefenamic acid (a non-steroidal anti-inflammatory, NSAID, marketed by Pfizer as Ponstel in the US and Ponstan or Parkemed elsewhere) or salicyclic acid (aspirin, also an NSAID) were simultaneously administered. [PMID: 10923862. Longevinex, a maker of a resveratrol/quercetin combo pill also has information on their site [link]. Note that some caution here is in order with respect to drug interactions. (1) "Older persons who mix alcoholic beverages with large doses of aspirin to self-medicate for pain are therefore at particularly high risk for episodes of gastric bleeding (19). In addition, aspirin may increase the availability of alcohol (31), heightening the effects of a given dose of alcohol. Chronic alcohol ingestion activates enzymes that transform acetaminophen (Tylenol and others) into chemicals that can cause liver damage, even when acetaminophen is used in standard therapeutic amounts (32,33). These effects may occur with as little as 2.6 grams of acetaminophen in persons consuming widely varying amounts of alcohol (34)." according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA): [link]. (2) red wine has inhibitory effects on cytochrome P450 which can result in magnifying the effects of other drugs the user may be taking which may have undesirable effects. [PMID: 11125847]. At higher dosages even more serious drug interaction problems can appear.

Vitamin E. Wright et al [PMID: 1754867] [review], looked at data from the NIH-AARP Diet and Health Study of 295,344 men filled out information on diet. 10,241 developed prostate cancer during 5 years of follow up. There found no connection between Vitamin E supplement (alpha tocopherol) use and prostate cancer risk but found a 32% risk reduction of advanced prostate cancer among the 20% consuming the highest among of Vitamin E (gamma tocopherol) in their diet vs the 20% consuming the lowest amount.

SELECT. There is a large scale 7-12 year cancer prevention study underway on Selenium and Vitamin E called SELECT that enrolled subjects between 2001-2004. See [link] and the references at the bottom of that page. It is expected that better information will become available with it.

Hypoxia-Inducible Factor. A team at John Hopkins has recently discovered that the mechanism by which Vitamin C acts in certain mouse tumors (though not specifically tested in prostate cancer) is to starve them of Hypoxia-Induced Factor (HIF). HIF is a protein that allows cancer cells to grow even in the absence of oxygen so by restricting access to this protein tumors cannot grow without oxygen. It is not known whether this work applies to human prostate cancer or to other antioxidants. See [PMID: 17785204] [John Hopkins news release].

Fleshner's study was previously mentioned on this blog in a revision to the post How Healthy Men can Reduce Their Risk. Even though an animal study and a 4 week study of 50 patients can only be regarded as suggestive, the steps are so easy to take and the results and the combination principle seem sufficiently intriguing that we felt it deserved its own post and so have expanded and moved that discussion here.

In [link] (also found [here]) Fleshner says he recommends 200 IU of vitamin E daily along with selenium to many of his patients who want to do something to lower their risk. "On one hand I am conflicted, because we don’t have the definitive data," he says. "But I have a history of prostate cancer in my family, and I take these agents myself, so I am not telling patients to do anything that I am not doing."

Also, Fleshner and Zlotta have just published a review [PMID: 17893870] on nutrition and prostate cancer in the journal Cancer. A review of that paper can be found here.

According to Medscape, Fleshner owns shares in Bioadvantex which makes supplements including Silexin, that contains lycopene, selenium and Vitamin E (plus other ingredients).

Vitamin D and Prostate Cancer

[updated February 12, 2008]

Readers may wish to first view the fascinating Vieth presentation which is one hour but worth it. (Unfortunately the Vieth presentation seems to be no longer online.) Also readers may wish to review the NIH Vitamin D Fact Sheet, four papers by Donald L. Trump ([bio]), Lisa Tseng, Gerry Schwalfenberg and Michael Holicks, the presentation by Kevin Cahill and the Wikipedia entry.

Garland et al [PMID: 16380576] reviewed 30 colon cancer, 13 breast cancer, 26 prostate cancer, and 7 ovarian cancer studies as well as several that assessed the association of the vitamin D receptor genotype with cancer risk and concluded that the "evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects." (This refers to all types of cancers, not just prostate.)

The Canadian Cancer Society is the first major country-wide organization to come out in favor of mass vitamin D supplementation (1000 IU/day in spring and winter for Canadians and all year around for those at increased risk) suggesting that other organizations many follow.

Vitamin D can be obtained from sunlight, fatty fish, shitake mushrooms and supplements and other sources. While it appears that the skin has self-regulatory mechanisms to prevent toxicity from vitamin D from sunlight if the vitamin D is derived from supplements it may take different pathways that could have an adverse affect on athersosclerosis. See Tseng [link] who suggests caution on supplements. Also note that getting Vitamin D from the sunlight involves sun exposure which does increases one's risk of skin cancer although according to a [presentation] by Reihold Vieth the increased risk of skin cancer is much less than the reduced risk of all cancers.

Evidence

The following is suggestive of a protective effect for Vitamin D against prostate cancer:

• People in northern climates, i.e. climates with less sunshine/vitamin D, have higher rates of prostate cancer.
• Blacks (whose dark skin requires more sunshine to get the same level of vitamin D as whites) have higher rates of prostate cancer.
• Cancer patients diagnosed in summer have better prognoses than those in other seasons (due to the protective effect of sunlight exposure).
  
• Calcium in dairy reduces vitamin D levels and higher levels of calcium consumption have been associated with higher rates of prostate cancer.
• Woo et al [PMID: 15749627] gave 15 prostate cancer patients 2000 IU of Vitamin D daily and found that PSA doubling time increased in 14 of the 15 with the median rising from 14.3 months to 25 months and initial decreases in PSA in 9 of the subjects. No adverse side effects were observed.
• Haojie et al [link] conclude that prostate cancer patients have low levels of Vitamin D.

See [PMID: 15868450] and [PMID: 12668278].

Vitamin D Pathway

The following sequence of chemical reactions occur (see [Vitamin D], [Calcium] and [Vitamin D Pharmacology] and [link]):

1. sunshine is converted to D3 in the skin (or D3 is ingested directly as vitamins or in food). D3 is also called cholecalciferol and can be obtained as a supplement without a prescription.
   
2. D3 is converted in the liver to the circulating form of vitamin D known as calcidiol or 25(OH)D3. This will circulate in proportion to the amount consumed or sunlight exposure with a half-life of 10 to 19 days. The circulating form is thought to have a beneficial effect itself [PMID: 15860261] in addition to contributing to its conversion in the following point.
3. The circulating form of vitamin D is converted in the kidneys to the active form also known as calcitriol or 1,25(OH)2D3. The active form has a relatively short half-life and is regulated by the parathyroid hormone so that a relatively stable level exists. The active form of vitamin D can be obtained as a prescription drug. Its current use in medicine is for patients with kidney failure or osteoporosis.
4. Vitamin D receptors (VDRs) on cancer cells interact with the active form of vitamin D suppressing the growth of cancer cells.
   

We can summarize the above with this diagram


sunshine -> D3 -> circulating D -> active D -> Vit D receptors


or in terms of names:


sunshine -> cholecalciferol -> calcidiol -> calcitriol -> Vit. D receptors


or in terms of symbols:


sunshine -> D3 -> 25(OH)D3 -> 1,25(OH)2D3 -> VDRs


The conversion of D3 to circulating D is called hydroxylation as is the conversion of circulating D to active D.

In [PMID: 1586845] it is hypothesized that prostate cancers lose the ability to convert circulating D to active D and therefore may rely on active D that is itself circulating. Note that consumption of calcium (e.g. dairy products) suppresses the active form of vitamin D and this could explain the observed unfavorable effect of calcium consumption on prostate cancer.

Intervention in the pathway could be at several points:

1. increase the load of D3 through supplements so that more of the active form of the vitamin D gets produced even if its not being converted efficiently (the first link points to such a study), or
   
2. rather than increase vitamin D attempt to increase the sensitivity of the Vitamin D receptors (VDRs) on the cancer cells to the vitamin D that is already there through phytoestrogens such as Resveratrol (thought to be the active ingredient in red wine). This study is about the latter approach in breast cancer but presumably this idea could also apply to other cancers: [link]

Tests

The most commonly found assay is the radioimmunoassay that detects the 25(OH)D2 and 25(OH)D3 forms of the circulating form of vitamin D. Its coefficient of variability is 12% to 18% for vitamin D levels in the 85 - 145 nmol/L range and 10% - 25% for vitamin D levels in the 20 - 62.5 nmol/L range. Another test is the competitive binding protein assay which detects 25(OH)D2 and often gives readings 30% higher than the radioimmunoassay. See [link].

Tests are available to measure blood levels of calcidiol, 25(OH)D3, and calcitriol, 1,25(OH)2D3. (These are two separate tests.) The ratio of the levels of these two tests would presumably reveal the efficiency of conversion of 25(OH)D3 to 1,25(OH)2D3.

Dr. Donald L. Trump says: "available data suggest that all men with prostate cancer should measure their 25(OH) D3 level and take enough supplementation to assure blood levels in the normal range. Since it takes 8-12 weeks for a steady state level of 25(OH) D3 to be achieved, D3 supplementation should be adjusted no more often than every 3 months, guided by blood levels of 25(OH) D3." [link]

Dosage

The Canadian Cancer Society recommends that Canadians take 1000 IU per day of Vitamin D in fall and winter and those at risk of not getting sunlight in the other seasons take it all year round. The American and Canadian Cancer Societies and a number of other prominent organizations agreed at a 2006 Vitamin D conference in Toronto that 2000 IU/day was safe [link]. In [Full Text] [PMID: 10232622] , Reinhold Vieth suggests that 4,000 IU/day may be a safe dose and, in fact shows a dose-response curve in which he has marked the levels at which various studies observed toxicity. One study observed toxicity at 10,000 IU per day but all other studies did not observe toxicity until even higher levels suggesting that even an intake of 10,000 IU might be safe. In a response Muskiet et al (2001) [PMID: 11722970] question whether there is evidence that more than 4,000 IU is needed to prevent disease. They suggest that since the excess is stored in fat tissue, 4,000 IU might be safe in the short run but could be a "potential time bomb with an as yet poorly understood detonator" in the long run.

In his PCAAT article Dr. Donald Trump suggests that if "blood 25(OH) D3 levels are raised into the 32-100 nmol/L level, PTH levels decrease and loss of bone density improves in most individuals. Whether this level (32-100 nmol/L) reflects the optimal or ideal for any individual is not clear." The 32-100 nmol/L levels that Trump mentions correspond to 8 to 40 ng/mL. In this 2006 survey [PMID: 16825677] [Full Text] Bischoff-Ferrari et al conclude that optimum serum (i.e. blood) levels of "25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L (36–40 ng/mL)".

In a report written by the University of Ottawa for the Agency for Healthcare Research and Quality. Effectiveness and Safety of Vitamin D in Relation to Bone Health found "a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose". Dose-response cannot be assumed linear if it were then this would imply that a 1000 IU/day would raise serum levels by 10-20 nmol/L or 4-8 ng/mL. See the dose response curve in the Vieth paper (the same paper cited above) for better insight into the relationship.

Be sure to review the deficiencies and toxicities section of this page and note that higher dosages only be taken with sufficient medical monitoring. Also people with kidney, liver or heart disease may not be able to handle Vitamin D supplementation at all.

Functions of Vitamin D

Vitamin D increases the blood concentration of calcium affecting the balance of calcium and phosphorus in the body. It also may have much other broader functions as well that are not yet well understood.

Other effects of vitamin D are:

1. Activates caspase-3
   
2. Activates caspase-9
   
3. Decreases ER-alpha
   
4. Decreases bcl-2
   
5. Kills mitochondria by means of a caspase-independent mechanism, resulting in cell death
   
6. Increases AS3, a protein which shuts off prostate cancer (and breast cancer) proliferation
   
7. reduces inflammation and prostaglandin secretion (which promote cancer cell growth)
   
8. down regulates the COX-2 (which promotes cancer cell growth) acting in a similar way to NSAIDs such as aspirin (and Vioxx which was taken off the market due to concerns about serious cardiovascular side effects and GI bleeding).
   
9. Vitamin D deficiency results in increased levels of parathyroid hormone and reduced bone density.

See [link] for first 6 and Kevin Cahill presentation for points 7 and 8.

Sources of Vitamin D

One can get vitamin D from sunlight, cod liver oil and supplements. The NIH Office of Dietary Supplements Fact Sheet gives additional sources.

Deficiency and Toxicity

"Vitamin D deficiency can lead to osteoporosis in adults or rickets (a bone disease) in children.

Too much vitamin D can make the intestines absorb too much calcium. This may cause high levels of calcium in the blood. High blood calcium can lead to calcium deposits in soft tissues such as the heart and lungs. This can reduce their ability to function.

Kidney stones, vomiting, and muscle weakness may also occur if you have too much vitamin D."

The above quote is from the Medline page on Vitamin D.

Vitamin D deficiency can result from insufficient sunlight exposure or insufficient consumption of vitamin D in the diet, liver disease or kidney disease or genetic defects in the body's vitamin D receptors. See [Mayo clinic].

According to an article by Dr. Trump mice genetically modified to have no vitamin D receptors exhibit low blood calcium, weak bones, hairless skin, abnormal muscle development, high blood pressure, abnormal heart muscle development, increased susceptibility to infection and increased susceptibility to blod clot formation.

Toxicity does not normally occur from sunlight exposure due to self-regulatory mechanisms in the skin; however, increased sun exposure does put one at increased risk for skin cancer; although, according to this Reihold Vieth presentation sun exposure increases risk of skin cancer by 1% - 2% but reduces risk of all cancers by 10% - 20% so it reduces overall cancer risk but much more than it increases skin cancer risk.

The self-regulatory mechanisms do not appear to exist when the vitamin D is consumed as through supplements. Since Vitamin D is fat soluble rather than water soluble, in principle, it can build up in fat stores to toxic levels. In an article by Lisa Tseng: "Concurrent with this rise in vitamin D ingestion in Canada, United States, Sweden, Israel, and England were the epidemic onsets of atherosclerosis and osteoporosis, which led Moon et al. to hypothesize that chronic vitamin D excess contributes to the development of these two illnesses. Moon and colleagues supported their postulate by citing 37 studies, some dated as early as 1945, which documented cardiovascular and skeletal effects similar to atherosclerosis and osteoporosis in humans and laboratory animals after high vitamin D intake. Subsequently, Haddad et al. showed in seven healthy human volunteers that while endogenously synthesized dermal vitamin D is transported on vitamin D binding protein and causes a more sustained increase in serum 25-hydroxy vitamin D, the orally administered vitamin D is absorbed from the intestinal tract via chylomicrons and carried in the circulation by lipoproteins such as VLDL and LDL, which may end up in the artery wall. This finding supports Fraser’s earlier speculation that the toxicity of orally acquired vitamin D might be due to its unnatural route through the body and, consequently, it is less finely regulated than endogenously synthesized dermal vitamin D."
[link]. Perhaps man evolved to regulate vitamin D from the sun since early man was constantly exposed to the sun but because consumption of large amounts of vitamin D through supplements is only possible with modern technology no similar mechanism evolved to regulate that.

In [PMID: 16598750] 2 of 37 patients taking vitamin D developed kidney stones.

In a February 2008 paper in Bioessays, Trevor Marshall writes that unlike getting vitamin D from the sun, vitamin D supplements may undesirably suppress immune function and supplements may actually block rather than enhance Vitamin D Receptor (VDR) activation: "the Vitamin D Nuclear Receptor (VDR) acts in the repression or transcription of hundreds of genes, including genes associated with diseases ranging from cancers to multiple sclerosis" and since we do not know the exact details of these numerous interactions they could include harmful ones. See [news] and [PMID: 18200565].

Because of the potential problems cited above it is important to monitor Vitamin D levels and urine calcium levels if consuming high dosages of Vitamin D.

Development of Vitamin D Analogues

The companies Cytochroma and Novocea Pharmaceuticals are working on analogues of calcitriol that avoid the side effect of hypercalcemia (excess calcium).

References

Gerry Schwalfenberg, Not Enough Vitamin D, Can Fam Physician 2007;53:841-854
[link]

Donald L. Trump, Vitamin D: More than a Hormone -- More than a Calcium and Bone Thing, Prostate Cancer Communication, Dec 2006, 22(4). [link]. Vitamin D and prostate cancer.

Marshall Protocol is a protocol based on Vitamin D for treating chronic fatigue syndrome (CFS). See: Marshall Protocol.

Although I have not seen it myself the book Peter J. Hyde, Sunlight, Vitamin D and Prostate Cancer Risk (ISBN: 1-4010-8258-0) is recommended by the doctor and urologist of Christopher Morash. See [link]

Lisa Tseng (2003) "Controversies in Vitamin D Supplementation", Nutrition Bytes: Vol. 9: No. 1, Article 3. [link]. Recommends getting vitamin D from sunlight.

Dr. Mercola discusses Vitamin D and sunshine: [Vitamin D and Cancer] [Vitamin D Deficiency]

Kevin Cahill, Vitamin D and Prostate Cancer, October 13, 2006. [link]

Reihold Vieth, Prospects for Vitamin D Nutrition, Calgary, Oct 13, 2005. Fascinating one hour presentation by a key researcher in Vitamin D intended for a lay audience. [link]. Also see Vieth's 1999 paper [link] and comments [link] and [link].

National Institute of Health Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. [link]

North American Conference on UV, Vitamin D and Health, Key Messages, March 8, 2006. [link]. The "Key Messages" coming from this conference have been endorsed by: American Cancer Society, American College of Rheumatology, Canadian Cancer Society, Canadian Dermatology Association, Dietitians of Canada, National Council on Skin Cancer Prevention (US), Osteoporosis Canada and the World Health Organization Collaborative Centre for the Promotion of Sun Protection. Also see [link] which discusses the document and provides a [link] to the Canadian Cancer Society's comments.

MS-Direct Vitamin D papers collection. See Vitamin D section at this [link]. A collection of online Vitamin D papers organized by Ashton Embry for MS patients (but some are applicable to prostate cancer too).

Charles Myers, Beating Prostate Cancer: Hormonal Therapy & Diet, 2006, pages 149 - 159. Myers recommends 4000 IU per day based on Vieth's 1999 paper (see above).

Canadian Cancer Society Recommends 1000 IU/day Vitamin D for All Adult Canadians in Fall & Winter

In [link] the Canadian Cancer Society is recommending that all adult Canadians take 1000 IU of Vitamin D daily in fall and winter while those at higher risk of low Vitmain D levels take the same amount daily all year round. The importance of this is that it is the first major cancer organization to recommend daily Vitamin D supplementation as a population-wide anti-cancer prevention strategy.

The Canadian Cancer Society later qualified their recommendation, saying to check with your doctor first.

Since the announcement Vitamin D has been flying off the shelves and Jamieson, Canada's largest vitamin maker with a 40% share of the Vitamin D market has seen sales temporarily spike to 8x their normal volume. See this article from Report on Business on Vitamin D sales in Canada and the Canadian Cancer Society's press release here:

08 June 2007

TORONTO - The Canadian Cancer Society is recommending a specific amount of Vitamin D supplementation for Canadians to consider taking. This first-time recommendation is based on the growing body of evidence about the link between Vitamin D and reducing risk for colorectal, breast and prostate cancers.

“The evidence is still growing in this area, but we want to give guidance to Canadians about this emerging area of cancer prevention based on what we know now,” says Heather Logan, Director, Cancer Control Policy, Canadian Cancer Society. “As we find out more we will update our recommendation.”

In consultation with their healthcare provider, the Society is recommending that:

Adults living in Canada should consider taking Vitamin D supplementation of 1,000 international units (IU) a day during the fall and winter.
Adults at higher risk of having lower Vitamin D levels should consider taking Vitamin D supplementation of 1,000 IU/day all year round. This includes people:

who are older;
with dark skin;
who don’t go outside often, and
who wear clothing that covers most of their skin.

“We’re recommending 1,000 IUs daily because the current evidence suggests this amount will help reduce cancer risk with the least potential for harm,” says Logan. “More research is needed to clearly define the amount of Vitamin D that will maximize health benefits.”

Logan explains that Canada’s geographic location was a strong factor in the Society’s decision making about the recommendation.

“Where a person lives is one important factor in how much Vitamin D they can produce from the sun. Because of our country’s northern latitude, the sun’s rays are weaker in the fall and winter and Canadians don’t produce enough Vitamin D from sunlight during this time.”

Research findings announced today add to the mounting evidence in this area. A study published in The American Journal of Clinical Nutrition found that taking Vitamin D supplements and calcium substantially reduces all-cancer risk in post menopausal women. Specifically, the researchers found that the higher the levels of Vitamin D in the blood, the lower the relative risk of developing cancer. As well, another study released in May, suggests that women who consume more calcium and vitamin D may be less likely to develop breast cancer before menopause.

In addition to taking supplements, people can get Vitamin D by exposure to the sunlight and in their diets. However, Logan cautions Canadians about relying too much on getting Vitamin D through exposure to sunlight.

“It’s important to remember that a few minutes a day of unprotected sun exposure is usually all that is needed for some people to get enough Vitamin D,” says Logan. “It’s not a good idea to rely solely on the sun to obtain Vitamin D. For some people, it’s possible that just a few minutes of unprotected sun exposure every day could increase skin cancer risk.”

Logan says a large-scale clinical trial would help provide more answers about the amount of Vitamin D needed to maximize health benefits, and the long-term risks, if any, of taking large doses of the vitamin.

“The Canadian Cancer Society is looking seriously at what we can do to make this research happen. We will also be talking to our partners about this. We need to keep building on our knowledge about this important area of cancer prevention.”

More research is also needed about the amount of sunlight exposure needed to achieve the optimum Vitamin D level.

The Society is not changing its SunSense guidelines, as skin cancer is the most frequently diagnosed cancer in Canada. The Society recommends that people reduce their exposure to the sun, particularly between 11 a.m. and 4 p.m. when the sun’s rays are the strongest. Use a sunscreen with a sun protection factor (SPF) 15 or higher and SPF 30 if you work outdoors or if you will be outside for most of the day.

At this time, the Canadian Cancer Society does not have a recommendation for Vitamin D supplementation for children. The research to date about the role of Vitamin D and cancer prevention has focused on adults.

The Canadian Dermatology Association recently updated its recommendations about Vitamin D supplementation. The association’s website says: “In order to lessen the health risks associated with skin cancer yet still reap the known and possible benefits of Vitamin D levels take 1,000 international units of Vitamin D supplements a day.”

The Canadian Cancer Society is a national community-based organization of volunteers whose mission is to eradicate cancer and to enhance the quality of life of people living with cancer. When you want to know more about cancer, visit our website www.cancer.ca or call our toll-free, bilingual Cancer Information Service at 1 888 939-3333.

-30-

For more information, please contact:

Kerstin Ring
Senior Manager, Communications
National office
Phone: 416-934-5664

Alexa Giorgi (French media)
Bilingual Communications Specialist
National office
Phone: 416-934-5681

Soy

[Updated June 3, 2008]

In favor of soy are the following:

1. Prostate cancer is lower in Asian populations that consume higher levels of soy. [PMID: 10332923] [PMID: 12869409] [PMID: 15945102]


2. Isoflavones (genistein, daidzen, equol) in soy can inhibit prostate cancer cells. [PMID: 17297558]


3. One human industry-funded study recorded a reduced risk of prostate cancer due to soy (although a second analysis found inconsistencies and little support for the assertion). [PMID: 15945102] [PMID: 15916986]


4. Soy is a good source of low fat protein allowing one to replace fatty red meats with a lower fat protein source. "Many soy products should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat." [PMID: 16418439]

On the other hand, soy:

1. is estrogenic, goitrogenic and may promote vascular dementia, thyroid cancer and other hormone cancers [PMID: 12060828] [full article] [Letter to FDA]


2. benefits in terms of reducing PSA rise are likely small in magnitude [PMID: 6682871]


3. "The efficacy and safety of soy isoflavones for preventing or treating cancer of the breast, endometrium, and prostate are not established; evidence from clinical trials is meager and cautionary with regard to a possible adverse effect. For this reason, use of isoflavone supplements in food or pills is not recommended." [PMID: 16418439]


4. soy may have drug interactions with 5AR2 inhibitors [internet discussion] which can also be found [here]. To understand the discussion there the reader may wish to review the model of prostate cancer discussed in [this post]


5. Even if it were beneficial for preventing prostate cancer or even if it were beneficial in earlier stage disease there remains the possibility that it could be detrimental for later stage disease. Although not a formal study, clinical observations by Dr. Leibowitz, a medical oncologist, were that he was able to reverse PSA rises in some patients by simply removing soy and phytoestrogens from their diet. See Dr. Leibowitz on soy. Also see Willet Divides Prostate Cancer into Four.

The Australian Cancer Council has reviewed the evidence and concluded that soy consumption as food as part of the diet is safe and may be beneficial for prostate cancer (although if it is the effect is small) but that in light of the potential dangers that supplements should be avoided due to the possibility that high dosages could be more likely to exhibit the negative aspects. Their report is not long, is easy to read and recommended. [link]


Other Sources

For a good overview read the above position paper by the Australian Cancer Council plus the sections on soy in the next two links.

Peter H. Gann & Edward L. Giovannucci, Nutrition & Prostate Cancer, Prostate Cancer Foundation, 2005. [link]

Natalie Ledesma, Nutrition and Prostate Cancer, 2004. [link]

FDA position on allowing health claims for soy: [link]

The following February 2008 paper reviews the benefits and research on soy: [PMID: 17923857] [Full text].

Free Downloadable Materials on Prostate Cancer

[Updated October 10, 2008]

The following books, booklets and book chapters are all free and can be downloaded from the internet. Note dates since medical advances may outdate some material. There is a Main section, a Single Topics section, a section for Nutrition and a section of Patient-Oriented materials which tend to be higher level and may lack references. Within the first Main and Nutrition sections the materials are listed in roughly descending order of usefulness (i.e. best first). Preference was given to material with greater depth of treatment, more recent, references to literature and pdf format. The materials in the Patient-oriented section tend to be comparable and so have been listed in date order with most recent first.

Main

- Endotext. Robert McLachlan, ed., Endocrinolgy of Male Reproduction, 2005, 118 pages. Best source in this list for in depth information. The link is to Chapter 10 of the endotext book on endocrinology which provides a review of many prostate cancer topics. Sections include Anatomy and Physiology, Natural History of Prostate Disease, Basic Science of Prostate cancer, Prevention of Prostate Cancer, Diagnosing Prostate Cancer, Prostate Cancer Treatment Options, Radical Retropubic Prostatectomy, Complications of Radical Retropubic Prostatectomy, Treatment of Post-Prostatectomy Recurrences, Radiotherapy and Systemic Therapies. HTML and PDF versions are given in these two links:
http://www.endotext.org/male/male10/maleframe10.htm
http://www.endotext.org/male/male10/male10.pdf

- NCCN Protocols. National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, 2008, 44 pages. Protocols for treating prostate cancer. A news article on outlining the changes in the latest release of the guidelines is available here. The guidelines themselves are here: http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf

- NICE. National Institute for Health and Clinical Excellence (UK). Draft guidelines for prostate cancer, 2007, 149 pages. First 15 pages provide a good summary of the entire document. http://guidance.nice.org.uk/page.aspx?o=444691

- NCI. National Cancer Institute, Prostate Cancer (PDQ(R)): Treatment, 2006. The NCI information is described in this link:
http://groups.google.com/group/alt.support.cancer.prostate/msg/2a68188ffa8a6fb6 and the information itself is provided in the first link as a single page or the following as mulitple pages: http://www.cancer.gov/cancertopics/pdq/treatment/prostate/healthprofessional/allpages/print
http://www.cancer.gov/cancertopics/pdq/treatment/prostate/healthprofessional

- PCF Advanced PC. Prostrate Cancer Foundation, Report to the Nation on Prostate Cancer: Advanced Disease, 2005, 64 pages. http://www.prostatecancerfoundation.org/atf/cf/%7B705B3273-F2EF-4EF6-A653-E15C5D8BB6B1%7D/PCF_ProfessionalGuide-2005.pdf

- Report to the Nation. Prostate Cancer Foundation, 2004, 96 pages. Note that this specifically refers to the 2004 edition. Different years are completely different in contents. Chapters on 1. Detection, Diagnosis and Prognosis, 2. Management of Local Prostate Cancer, 3. Androgen Deprivation Therapy, 4. Management of Bone Metastases, 5. Chemotherapeutic Options, 6. Emerging Therapies, 7. Management of Side Effects, 8. Nutrition and Prevention, 9. Therapeutic Strategies for Patients with a Rising PSA.
http://www.prostatecancerfoundation.org/atf/cf/%7B705B3273-F2EF-4EF6-A653-E15C5D8BB6B1%7D/PCF%20Monograph-final1.pdf

- Pilgrim/Crawford. Aubrey Pilgrim & David Crawford, A Revolutionary Approach to Prostate Cancer, 2002, 380 pages. Written by a patient, now deceased, and a urologist. http://www.prostate-help.org/books.html

- Leahy. Richard Leahy, Prostate Cancer Survival Decisions, 2002, 150 pages. Written by an engineer with prostate advanced cancer. http://www.cancer.prostate-help.org/download/leahy.pdf

Single Topics

- Jon Nowlin's Active Survellience Summary. This table summarizes entry and exit criteria for active surveillance (watchful waiting). (Note that another table appears in [PMID: 18037873] [Full Text] which is also the WW link on the Treatment line to the right.)

- Wassersug on Transdermal Estradiol. For advanced prostate cancer this article advances the viewpoint that Transdermal Estradiol can provide similar benefits to more expensive androgen suppression drugs and with less side effects (except as discussed) and cost. It is written by Dr. Richard Wassersug of the Department of Anatomy & Neurobiology, Dalhousie University, Halifax. Also see one patient's experience [here] and the warnings in Wassersug's article as well as this more recent [warning] which may or may not apply. Further information can be found in [PMID: 18422771] [Medscape] by David Douglas, [Medscape] by 3 UK doctors and on the PCa in Arizona site: Transdermal Scrotal Estrogen Patches (TSEP) by Fernando Premoli.

- There is also a collection of useful papers that are patient oriented but more technical than usual patient oriented materials on single topics in the PCRI papers (also referenced in the Links section to the right on the Mega: line).

- Guide to Biostatistics by Dr. R. K. Israni. An 11 page surprisingly easy-to-read non-mathematical outline of the main topics in biostatistics can be found here: http://www.medpagetoday.com/Medpage-Guide-to-Biostatistics.pdf. Topics include Study Designs (How Research is Classified, Terminology, Important Epidemiological Concepts), Descriptive Statistics (Measures of Central Tendency, Measures of Spread, Measures of Frequency of Events, Measures of Association, Terms Used to Describe the Quality of Measurements, Measurements of Diagnostic Test Accuracy, Expressions Used When Making Inferences About Data, Multivariate Regression Methods) and References.

Nutrition

- PCF. Peter H. Gann & Edward L. Giovannucci, Nutrition & Prostate Cancer, Prostate Cancer Foundation, 2005, 40 pages. Booklet reviewing nutritional research on prostate cancer. The greyed summaries can be read if you just want an overview. http://www.prostatecancerfoundation.org/atf/cf/%7B705B3273-F2EF-4EF6-A653-E15C5D8BB6B1%7D/Nutrition_Guide.pdf. A shorter link to this is http://tinyurl.com/2krst9
.
- UCSF. Natalie Ledesma, Nutrition and Prostate Cancer, 2009, 44 pages. Although not specifically in book form, this guide to nutrition is very much comparable in material discussed to some of the other nutrition guides in this list, reviews the research and has a cookbook section at the end. http://urology.ucsf.edu/sites/urology.ucsf.edu/files/uploaded-files/attachments/nutrition_and_prostate_cancer.pdf

- Princess Margaret Hospital. Challenging Prostate Cancer: Nutrition, Exercise and You, undated but appears to be 2007 or 2008. 102 pages. This new patient oriented booklet has been expanded to 102 pages and updated from the older 2000 twenty two page version. The older material is included in expanded chapters on diet and nutrition in Chapter 1, Supplements in Chapter 2 and the cookbook in Chapter 4. New chapters cover nutrition during treatment in Chapter 3, exercise in Chapter 5 and motivation in Chapter 6. Authors include doctors and medical personnel in urology, oncology, psychology, physiology, nursing and nutrition: John Trachtenberg, Neil Fleshner, Kristin Currie, Daniel Santa Mina, Andrew Mathew, Barbie Casselman, Paul Ritvo, Jane Irvine, Carol Lancaster. The older 22 page 2000 version is also avaliable: John Trachtenberg, Neil Fleshner, Carol Lancaster, Barbie Casselman. Eating Right for Life: Prostate Cancer Nutrition & You, 2000, 22 pages. For patients who already have prostate cancer (as opposed to preventing prostate cancer in healhty patients.) Collaborative work by a urologist, oncologist, nurse and nutritionist from Princess Margaret Hospital in Toronto. Cookbook section at end. No references. http://www.prostatecentre.ca/downloads/Challenging%20Prostrate%20Cancer%20PDF.pdf?seid=2051&mid=47

- World Cancer Research Foundation/American Institute of Cancer Research Report. Every 10 years the WCRF puts out a major report on nutrition and cancer. The most recent report was released in late 2007 and a summary of those aspects related to prostate cancer is summarized here together with links to the report itself.

- Barnard - Short. Neal Barnard, Healthy Eating for Life, The Cancer Project, 2004, 16 pages. For cancer, in general, not just prostate cancer but has a prostate cancer sections. Vegetarian eating: vegetables, whole grains, fruit and legumes. Focus on cancer prevention and survival for cancer patients. Recipies at end. http://www.cancerproject.org/resources/pdfs/HealthyEatingforLife.pdf

- Barnard - Long. Neal Barnard, The Survivor's Handbook: eating right for cancer survival, The Cancer Project, 2003, 148 pages. For cancer survivors (as opposed to preventing cancer.) Not specific to prostate cancer although there are sections on prostate cancer. Sections on low fat, fiber, dairy alternatives, replacing meat, meal planning,antioxidants and phytochemicals, immune-boosting foods, healthy weight andappendices on nutrition, breast and prostate cancer. Recipies at end. http://www.cancerproject.org/resources/handbook/survivors_handbook2004.pdf

Patient Oriented - Most Recent First

- The PC Charity. The Prostate Cancer Charity, Tookit, 2006. A collection of short downloadable publications on various prostate cancer topics for cancer patients. http://www.prostate-cancer.org.uk/info/publications_toolkit.asp#download

- VA. Dept. of Veteran Affairs (Australia). You and Your Prostate, 2006, 92 pages. Information for prostate cancer patients. http://www.dva.gov.au/media/publicat/2001/prostate/table_of_contents.htm

- NCI. National Cancer Institute, Treatment Choices for Men with Early Stage Prostate Cancer, 2005, 25 pages. http://www.cancer.gov/cancertopics/prostate-cancer-treatment-choices/PDF
An older version of this document co-authored with the US Too group and entitled Know Your Options: Understanding Treatment Choices for Prostate Cancer (2003, 48 pages) was the highest rated patient-oriented free document in a 2004 survey.

- PCF. Peter Carroll, Michael Carducci, Anthony Zietman, Jason Rothaermel, Report to the Nation on Prostate Cancer: A Guide for Men and Their Families, The Prostate Foundation, 2005, 130 pages. Overview of prostate cancer covering treatment options, side effects, nutrition, recurrence, hormone therapy, emerging therapies, clinical trials. Written by a urologist, medical oncologist, radiation oncologist and oncology nurse from UCSF, John Hopkins, Harvard and The Cleveland Clinic. Sometime after adding this PCF document we noticed that NJ Urology Associates mention it on their blog. http://www.prostatecancerfoundation.org/atf/cf/%7B705B3273-F2EF-4EF6-A653-E15C5D8BB6B1%7D/FINAL%20PCF_PatientGuide.pdf

- AstraZeneca. AstraZeneca, Understanding Prostate Cancer and Treatment Options: A Guidebook for Patients and Care Givers, 2005, 45 pages. AstraZeneca has written a high level patient-oriented booklet that covers diagnosis, staging and grading and the various treatment options (RP, RT, cryo, WW, hormones, chemo, clinical trials) together with the advantages and disadvantages of each. http://www.prostateinfo.com/patients/request/pdf/229327.pdf

- Queensland. Queensland Cancer Fund, (1) Understanding Treatment for Localized Prostate Cancer, 2003, 35 pages. (2) Understanding Treatment for Advanced Prostate Cancer, 2003, 35 pages. (3) Prostate Cancer - Sex After Treatment, 2003?, 17 pages. http://www.qldcancer.com.au/Prostate/Resources.html