Jacob Schor, ND, FABNO
May 7, 2019
I paused so long while talking with a patient the other day that we joked that maybe he needed to hit the ‘force quit’ button to get me going again. He’d asked me which multivitamin he should take to help slow growth of his prostate cancer.
I didn’t know what to tell him. I’m no longer sure whether these patients should even take a multivitamin.
Sure, there’s a 2012 study, the Physicians Health Study randomized trial of regular multivitamin use, that reported a modest but significant (8 %) reduction in total cancer incidence in men. The men with a history of prior cancer had a 27 % reduction in total cancer during the study. In particular there had been significant effect on risk of prostate cancer.  But research on nutrition and prostate cancer often conflicts from one study to the next. In one study a nutrient appears helpful and another the same substance seems harmful.
This confusing situation was summed up in a review paper by Pao-Hwa Lin, William Aronson and Stephen Freedland published in 2017. They stated that a “U” shape relationship may exist between folate, vitamin C, vitamin D and calcium with [prostate cancer] risk.”  Rather than a straight-line dose response relationship these nutrients may trigger a hormetic response in which their effect on prostate cancer changes with dose, initially hindering growth but then at higher doses promoting growth.
Folate as a good example of how confusing the data are. Half a dozen years back the National Cancer Institute’s website suggested that folate is a possible protective factor that may decrease the risk of prostate cancer, while folic acid, the synthetic version of folate used to fortify foods and contained in supplements, is a nutrient that may increase the risk of prostate cancer. This idea comes from the Aspirin/Folate Polyp Prevention Study, “… a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas… In a secondary analysis, the authors addressed the effect of folic acid supplementation on the risk of prostate cancer. …. Supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. However, dietary and plasma levels among non-multivitamin users were inversely associated with risk.”
If we look at recent research, we find three meta-analysis that will confuse us. Two of them reported that dietary folate was not associated with risk of prostate cancer. Yet in 2013, Collin reported that folate levels were positively associated with an increased risk of prostate cancer.  Tio and colleagues reported in their 2014 meta-analysis that they found no statistically significant association between dietary folate and prostate cancer. Nor did they find an association with total folate. However, they did find a significant association when they examined blood folate measurements. It didn’t matter how much folate one ate as food or swallowed as pills but only how much folate stayed in the blood. A third meta-analysis, published in 2014 by Wang et al, also found no association between dietary intake and risk, but it did report that serum folate was positively associated with risk of prostate cancer. 
A 2014 study reported on disease recurrence risk in men already treated. Dietary or total folate had no impact except in men who had been treated with surgery, and who had low folate intake; they had a 2.6-fold increase in risk of recurrence. No association was seen in men treated with radiation therapy.
Not all the research suggests folate supplements are bad; Roswell’s 2013 study reported that folate supplements were associated with a significant decrease in risk.  Of course, disease prevention does not tell us about disease recurrence or disease progression in men following a “wait and watch” routine.
I’m not sure we have a clear idea if folate is good or bad for these guys. My fallback position in such situations is that phrase about primum non nocere, while not Hippocratic in origin, I want to avoid anything that might increase risk. Multivitamins pretty much always contain folate.
Vitamin D is probably the best example of a hormetic U-shaped dose response. We’re all familiar with the studies that look at circulating vitamin D levels and prostate cancer risk. Nelson reported in 2017 that D deficiency (<20 ng/ml) is associated with triple the risk for aggressive prostate cancer in African American men. Then there are the papers that report higher vitamin D levels are associated with lower risk for prostate cancer, lower disease severity and lower cancer specific mortality. We are all familiar with these and other arguments that men with prostate cancer should take vitamin D.
The problem is that not all studies support this idea. It is easy to ignore studies that don’t support what we believe. If we notice them at all, it is to find fault. Chandler et al, couldn’t find an association between vitamin D supplements on PSA levels.  Nor did Skaaby et al or Holt et al find associations between vitamin D levels and prostate cancer risk. Gupta et al reported no association between vitamin D levels in 125 newly diagnosed stage-4 prostate cancer patients and their survival times.  Nor did Sawada’s 2017 case control study find vitamin D status associated with fatal prostate cancer. 
Some studies have actually reported a positive association between D status and prostate cancer risk. In 2014 Wong et al reported that in older men, lower vitamin D status was associated with lower risk of prostate cancer.  We should note clearly that in a 2014 meta-analysis, Xu et al reported a “… significant positive relationship between high level of 25-hydroxyvitamin D and increased risk of prostate cancer”. That is the opposite of what we expected to read. Meyer et al’s report is similar, that high vitamin D was associated with greater cancer specific mortality in this same cohort. 
The conflicting outcomes with vitamin D may possibly be the result of a hormetic effect creating a U-shaped relationship making it difficult to determine the optimal dose range for vitamin D when it comes to prostate cancer prevention and control.
A 2014 paper by Kristal et al is worth our attention because in their findings, “Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease.”.  These findings were similar to the earlier 2004 report by Tuohimaathat suggested an optimal range for prostate cancer prevention between 16-24 ng.ml.
We should note mention in passing, a 2016 paper on vitamin D and heart disease that reported a similar U-shaped curve in survival times with vitamin D, in which both low and high D levels were associated with an increased risk of death. Vitamin D levels <10ng/ml or >30 ng/ml tripled risk of dying during the study.
Granted, there are ardent proponents of the idea that more is better when it comes to vitamin D who find counter explanations for these reported U-shaped D response curves, but the striking contrast with what the research is suggesting and what many of us suggest to our patients, gives me pause. Until we have more certain data that our interventions don’t actually cause harm, shouldn’t we be more cautious? Is it good practice to dose every man with vitamin D?
If I decide to treat prostate cancer patients with vitamin D it is because we have a suboptimal blood level reported on a lab test and my goal is to reach the top of the U-curve, a point that may vary over time as research is published.
While many multis now contain vitamin D, I’ve wandered off topic; let me steer us back to the initial question on multivitamins. It’s unclear at this point that men with prostate cancer or at risk for recurrence will benefit from folate supplementation. There are other vitamins contained in multis that also concern me.
Remember how antioxidant micronutrients, in particular vitamin E and Vitamin C, were going to be the cure for most everything? Some of you may be too young to recall this era. Well for any of you older folks who haven’t been paying attention, randomized trials have done little to support this old notion.
Lippman et al reported in 2009 that in their “large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer.” 
Nor by the way did similar doses of vitamin E decrease risk of heart disease in women. 
The data on vitamin E in particular is no more straightforward than that on folate or vitamin D. Epidemiological studies and animal studies suggested that vitamin E would be protective against prostate cancer, but human studies have failed to confirm this. Several largescale intervention trials have yielded such disappointing results that the authors of one 2016 study wrote, “Whether vitamin E prevents or promotes cancer is a serious concern.” This is clearly not a “might help, won’t hurt” situation.
Wang et al reported in 2014 that in analyzing data from the Physicians’ Health Study II that taking 400 IU of vitamin E every other day and 500 mg of Vitamin C daily had no effect on risk for cancer and specifically for prostate cancer. 
Yet in a largescale trial in which over 29,000 smokers received what we would consider a very low dose of vitamin E (about 75 IU/day), supplementation was associated with lower risk of prostate cancer in general but with some rather complex clarifications.
Impact varied with body mass index (BMI) of the participants. Relative risk dropped 13% in overweight men [0.87 (95% CI, 0.77-0.98)], but appeared to increase risk in obese men [1.25 (95% CI, 1.01-1.55)]. Taking low dose vitamin E was also associated with a lower risk of dying from prostate cancer after the trial was over (RR, 0.84; 95% CI, 0.70-0.99). 
But then we have the frightening results from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in which high dose vitamin E significantly increased risk of prostate cancer and it looked as if vitamin E also increased the risk of high-grade disease. When Klein et al reported their results in 2011, men randomized to take vitamin E had a 17% greater risk of prostate cancer than those taking placebo. For those perhaps too young to remember this trial, it was quite large, with over 35,000 men randomized to take vitamin E, selenium, both or placebo, for an extended period. 
This is starting to sound like hormesis again. Low doses in the range of 75 IUs per day might provide benefit and slightly higher doses, 200 IU/day, did nothing and the 400 IU/day in the SELECT Trial were associated with trouble. We’ve been operating on the theory that more is better when it comes to E for a long time but perhaps we’ve been wrong?
Now there are valid seeming arguments that the particular form of vitamin E supplemented may make a difference but given the poor track record to date of predicting effects, I am becoming increasingly hesitant to bet on any particular theory until there is some compelling human evidence.
Let us assume that for many readers this sort of detailed study-by-study review gets tedious to read. [certainly, writing this is proving to be something of a marathon] So, let me skip over and simply say there is also good reason to believe that the effect of calcium on prostate cancer also varies with dose. And perhaps selenium. 
If this is the case, that many of the nutrients in multi-vitamins have hormetic action on prostate cancer, how do we know what the right dose should be? Too little could be a problem but so could too much. Could men already be getting adequate doses via their diet of these nutrients?
Let’s back up a step further and wonder where we got the idea that treating cancer with nutrient supplementation is a good idea? Cancer in general is a disease of excess nutrition. Caloric restriction lowers cancer risk and obesity increases it. Isn’t taking a multi kind of like an excess in nutrition? Wouldn’t it make more sense for cancer cells to go hungry than to force feed them with the nutrients needed to divide and grow? Why is it that we even believe that more nutrients the better?
This probably is left over from a time and a world where most people were both calorie-deprived and nutrient lacking. In that sort of world supplying missing vitamins and minerals could likely have near miraculous effect. Supplementation to those with deficiency historically has cured many diseases. Perhaps that era has passed us by. These days when major foods are fortified and most of our patient populations are amply fed, deficiency is not a common problem as it was in our profession’s earlier years.
We could end the article here, but I would be remiss if I neglected to mention the recent study on vitamin supplements published in the Annals of Internal Medicine in May 2019, while I was ruminating on this prostate and multivitamin question.
The full text of this new study is available online: https://annals.org/aim/article-abstract/2730525/association-among-dietary-supplement-use-nutrient-intake-mortality-among-u?doi=10.7326%2fM18-2478
Fan Chen and a group of American researchers from Harvard and Tufts Universities evaluated the association among dietary supplement use, levels of nutrient intake from foods and supplements, and mortality among U.S. adults. They followed a cohort of 30,899 U.S. adults for a median of 6.1 years during which time there were 3613 deaths including 945 CVD deaths and 805 cancer deaths among the group. Adequate intake “… of vitamin A, vitamin K, magnesium, zinc, and copper was associated with reduced all-cause or CVD mortality, but the associations were restricted to nutrient intake from foods. Excess intake of calcium was associated with increased risk for cancer death ….. and the association seemed to be related to calcium intake from supplements ….rather than foods.”
The bottom line was that “Use of dietary supplements is not associated with mortality benefits among U.S. adults.”  Taking a multi doesn’t change your risk of dying. Well duh, that didn’t come our right. You are not going to live any longer if you take a multi.
Taking a multivitamin didn’t seem to make a difference. Eating well enough to get minimum RDAs does make a difference.
Admitting this change of thinking doesn’t come easy but at this point I’m not seeing a compelling argument for men with prostate cancer to take multis. I’m still hoping that someone will tell me why I’m wrong.
Gaziano JM, Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012 Nov 14;308(18):1871-80.
Lin PH, Aronson W, Freedland SJ. An update of research evidence on nutrition and prostate cancer. Urol Oncol. 2017 Nov 3. pii: S1078-1439(17)30536-7.
Figueiredo JC, Grau MV, Haile RW, et al.: Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 101 (6): 432-5, 2009.
National Cancer Institute. PDQ Prostate Cancer Prevention. Bethesda, MD: National Cancer Institute; Date last modified 03/29/2012. Available at: http://www.cancer.gov/cancertopics/pdq/ prevention/prostate/healthprofessional
Rycyna KJ, Bacich DJ, O’Keefe DS. Opposing roles of folate in prostate cancer. Urology 2013;82:1197–203.
Collin SM. Folate and B12 in prostate cancer. Adv Clin Chem 2013;60:1–63.
Tio M, Andrici J, Cox MR, Eslick GD. Folate intake and the risk of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2014;17:213–9.
Wang R, Zheng Y, Huang JY, et al. Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies. BMC Public Health. 2014 Dec 29;14:1326.
Tomaszewski JJ, Richman EL, Sadetsky N, et al. Impact of folate intake on prostate cancer recurrence following definitive therapy: data from CaPSURE. J Urol 2014;191:971–6.
Roswall N, Larsen SB, Friis S, et al. Micronutrient intake and risk of prostate cancer in a cohort of middle-aged, Danish men. Cancer Causes Control 2013;24:1129–35.
Nelson SM, Batai K, Ahaghotu C, Agurs-Collins T, Kittles RA. Association between serum 25-hydroxy-vitamin D and aggressive prostate cancer in African American men. Nutrients 2016;9:pii: E12. http//dx.
Deschasaux M, Souberbielle JC, Latino-Martel P, et al. A prospec- tive study of plasma 25-hydroxyvitamin D concentration and prosate cancer risk. Br J Nutr 2016;115:305–14.
Galunska B, Gerova D, Kosev P, Anakievski D, Hinev A. Serum 25- hydroxy vitamin D levels in Bulgarian patients with prostate cancer: a pilot study. Clin Lab 2015;61:329–35.
Schenk JM, Till CA, Tangen CM, et al. Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014;23:1484–93.
Schwartz GG. Vitamin D in blood and risk of prostate cancer: les- sons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014;23:1447–9.
Chandler PD, Giovannucci EL, Scott JB, et al. Null association between vitamin D and PSA levels among black men in a vitamin D supplementation trial. Cancer Epidemiol Biomarkers Prev 2014;23:1944–7.
Skaaby T, Husemoen LL, Thuesen BH, et al. Prospective popula- tion-based study of the association between serum 25-hydroxyvita- min-D levels and the incidence of specific types of cancer. Cancer Epidemiol Biomarkers Prev 2014;23:1220–9.
Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL. Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis. Cancer Epidemiol 2013;37:666–70.
Gupta D, Trukova K, Popiel B, Lammersfeld C, Vashi PG. The association between pre-treatment serum 25-hydroxyvitamin D and survival in newly diagnosed stage IV prostate cancer. PLoS One 2015;10:e0119690.
Sawada N, Inoue M, Iwasaki M, et al. Plasma 25-hydroxy vitamin D and subsequent prostate cancer risk in a nested case-control study in Japan: The JPHC study. Eur J Clin Nutr 2017;71:132–6.
Wong YY, Hyde Z, McCaul KA, et al. In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of pros- tate, but not colorectal or lung cancer. PLoS One 2014;9:e99954.
Xu Y, Shao X, Yao Y, et al. Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol 2014;140:1465–77.
 Meyer HE, Stoer NC, Samuelsen SO, et al. Long-term association between serum 25-hydroxyvitamin D and mortality in a cohort of 4,379 men. PLoS One 2016;11:e0151441.
Kristal AR, Till C, Song X, et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014;23:1494–504.
Tuohimaa P1, Tenkanen L, Ahonen M, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004 Jan 1;108(1):104-8.
Aleksova A, Beltrami AP, Belfiore R, et al. U-shaped relationship between vitamin D levels and long-term outcome in large cohort of survivors of acute myocardial infarction. Int J Cardiol. 2016 Nov 15;223:962-966.
Grant WB. Critique of the U-shaped serum 25-hydroxyvitamin D level-disease response relation. Dermatoendocrinol. 2009 Nov;1(6):289-93.
Ames BN. Dietary carcinogens and anticarcinogens: oxygen radicals and degenerative diseases. Science 1983;221:1256–64.
 Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301:39–51
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294:56–65
Wang H, Hong J, Yang CS. δ-Tocopherol inhibits receptor tyrosine kinase-induced AKT activation in prostate cancer cells. Mol Carcinog. 2016 Nov;55(11):1728-1738.
Wang L, Sesso HD, Glynn RJ, et al. Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial. Am J Clin Nutr 2014;100:915–23.
Virtamo J, Taylor PR, Kontto J, et al. Effects of alpha-tocopherol and beta-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the alpha-tocopherol, beta-carotene Cancer Prevention Study. Int J Cancer 2014;135:178– 85.
Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Am Med Assoc 2011;306:1549–56.
Albanes D, Till C, Klein EA, et al. Plasma tocopherols and risk of prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cancer Prev Res (Phila) 2014;7:886–95.
Zhang L, Zeng H, Cheng WH. Beneficial and paradoxical roles of selenium at nutritional levels of intake in healthspan and longevity. Free Radic Biol Med. 2018 Nov 1;127:3-13.
Chen F, Du M, Blumberg JB2, et al. Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults: A Cohort Study.Ann Intern Med. 2019 Apr 9.