The Vitamin D Newsletter January 2008
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Does Vitamin D Treat Cancer?
As you may remember, the last newsletter was on preventing cancer, not treating it. Below is a small sampling of some of the questions contained in the tragic emails generated by last month's newsletter:
Dr. Cannell, I was just diagnosed with breast cancer. How much vitamin D should I take?
My mother has colon cancer, how much vitamin D should she take?
I've had prostate cancer for four years, is there any reason to think vitamin D would help?
Dr. Cannell, my son has leukemia, should I give him vitamin D?
It's not that simple...
It's one thing to talk about evidence that vitamin D may prevent cancer but something quite different to discuss evidence that vitamin D might help treat cancer. I used to think the answers to all the above questions were the same. Like anyone else, people with cancer should be screened for vitamin D deficiency and be treated if deficiency is present. Simple. However, it's not that simple. The real questions are:
- What are reasonable 25-hydroxy-vitamin D [25(OH)D] levels for someone with a life-threatening cancer?
- How much vitamin D do they need to take to obtain such levels?
- Is there any evidence, of any kind, that vitamin D will help treat cancer?
The risk/benefit analysis of taking vitamin D is quite different if you are in perfect health than if your life, or your child's life, is on the line.
Remember, unlike cancer prevention, not one human randomized controlled trial exists showing vitamin D has a treatment effect on cancer. By treatment effect, I mean prolongs the lives of cancer patients. However, as I cited in my last newsletter, Dr. Philippe Autier of the International Agency for Research on Cancer, and Dr. Sara Gandini of the European Institute of Oncology, performed a meta-analysis of 14 randomized controlled trials showing even low doses of vitamin D extend life but they looked at all-cause mortality, not just cancer. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(16):1730–1737.
Summer diagnosis prolongs life. Why?
However, some epidemiological studies indirectly address the treatment issue and are quite remarkable. The first are a series of discoveries by Professor Johan Moan, Department of Physics at the University of Oslo, with Dr. Alina Porojnicu as the lead author on most of the papers. Moan J, et al. Colon cancer: Prognosis for different latitudes, age groups and seasons in Norway. J Photochem Photobiol B. 2007 Sep 19. Lagunova Z, et al. Prostate cancer survival is dependent on season of diagnosis. Prostate. 2007 Sep 1;67(12):1362–70. Porojnicu AC, et al. Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway. Breast Cancer Res Treat. 2007 May;102(3):323–8. Porojnicu AC, et al. Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: a possible role of sun-induced Vitamin D. J Steroid Biochem Mol Biol. 2007 Mar;103(3–5):675–8. Porojnicu AC, et al. Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer. 2005 Sep 5;93(5):571–4. Porojnicu AC, et al. Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role? Lung Cancer. 2007 Mar;55(3):263–70.
What Professor Moan's group repeatedly discovered is quite simple—whether it be cancer of the breast, colon, prostate, lung, or a lymphoma: You live longer if your cancer is diagnosed in the summer. And it is not just Moan's group who has found this. A huge English study recently confirmed Moan's discovery. Lim HS, et al. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer. 2006 Oct 1;119(7):1530–6.
What do these studies mean? Something about summer has a treatment effect on cancer. Whatever it is, you live longer if you are diagnosed in the summer but die sooner if you are diagnosed in the winter. What could it be about summer? Exercise? Fresh air? Melatonin? Sunlight? Pretty girls? Remember, these patients already had cancer. Whatever it is about summer, it is not a preventative effect that Professor Moan discovered, it is a treatment effect. Something about summer prolongs the life of cancer patients.
Sunlight's robust treatment effect
Dr. Ying Zhou, a research fellow, working with Professor David Christiani at the Harvard School of Public Health, went one step further. The stuffy Harvard researchers assumed summer worked its magic, not by pretty girls, but by summer sunlight making vitamin D. So they looked at total vitamin D input, from both sun and diet, to see if high vitamin D intake improved the survival of cancer patients. Yes, indeed, remarkably. They found that early stage lung cancer patients with the highest vitamin D input (from summer season and high intake from diet) lived almost three times longer than patients with the lowest input (winter season and low intake from diet). Three times longer is a huge treatment effect, a treatment effect that most conventional cancer treatment methods would die for. Zhou W. Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2303–9.
And that's not all, Marianne Berwick and her colleagues, at the New Mexico Cancer Institute, found malignant melanoma patients with evidence of continued sun exposure had a 60% mortality reduction compared to patients who did not. That implies a robust treatment effect from sunlight. Berwick M, et al. Sun exposure and mortality from melanoma. J Natl Cancer Inst. 2005 Feb 2;97(3):195–9.
I will not list the thousands of animal studies that indicate vitamin D has a treatment effect on cancer as almost all of them studied activated vitamin D or its analogs—drugs that bypass normal regulatory mechanisms, cannot get autocrine quantities of the hormone into the cell, and that often cause hypercalcemia. However, Michael Holick's group found that simple vitamin D deficiency made cancers grow faster in mice. That is, vitamin D has a cancer treatment effect in vitamin D-deficient mice. Professor Gary Schwartz, at Wake Forest, recently reviewed the reasons to think that vitamin D may have a treatment effect in cancer. Tangpricha V, et al. Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr. 2005 Oct;135(10):2350–4. Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):6–11.
Finally, one human interventional study exists. In 2005, in an open trial, Professor Reinhold Vieth and his colleagues found just 2,000 IU of vitamin D per day had a positive effect on PSA levels in men with prostate cancer. Woo TC, et al. Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer. 2005;51(1):32–6.
So, how much vitamin D does one need?
So we come back to the crucial question. If you have cancer, how much vitamin D should you take, or, more precisely, what 25(OH)D level should you maintain? We don't know. You can correctly say that definitive studies have not been done and incorrectly conclude physicians treating cancer patients should do nothing. I say incorrectly because standards of medical practice have always demanded that doctors make reasonable decisions as to what is best for their patients based on what is currently known—what is called a risk/benefit analysis. If a patient has a potentially fatal cancer, the doctor cannot dismiss a relatively benign potential treatment modality just because definitive studies have not been done, passively watching his or her patient die. Standards of care require doctors perform a risk/benefit analysis and then act in the best interest of their patient.
Luckily, such doctors recently obtained some guidance. In the first study of its kind, Professor Bruce Hollis of the Medical University of South Carolina gave all of us something to think about. He asked and answered a simple question: How much vitamin D do you have to take to normalize the metabolism of vitamin D?
Vitamin D's unique behavior
Remember, unlike other steroid hormones, vitamin D has very unusual metabolism in most modern humans, called first-order, mass-action kinetics. What this means is that the more vitamin D you take, the higher the 25(OH)D level in your blood and the higher the 25(OH)D level in your blood, the higher the levels of activated vitamin D in your tissues. No other steroid hormone in the body behaves like this. Think about it, would you like your estrogen level to be dependent on how much cholesterol you ate? Or your cortisol level? (I'd ask the same about testosterone levels but I know men well enough not to ask.) No, the body must tightly regulate powerful steroid hormones through substrate inhibition, that is, if an enzyme turns A into B, when the body has enough B, B inhibits the enzyme and so limits its own production.
Not so with vitamin D, at least at modern, human vitamin D levels. Professor Reinhold Vieth was the first to write about this and Vieth's Chapter 61 in Feldman, Pike, and Glorieux's wonderful textbook, entitled Vitamin D (Elsevier, 2005, second edition), is a great reason to buy the textbook or have your library do so. I'm glad to see Amazon is out of stock of the new ones—someone must be reading about vitamin D!—but you can still buy used editions.
Why would the kinetics of vitamin D be different from all other steroids? Maybe they are not, Hollis reasoned like Vieth before him. Maybe vitamin D levels are so low in modern humans that its metabolic system is on full blast all the time in an attempt to give the body all the vitamin D metabolites it craves. So Hollis asked, Is vitamin D's metabolism different in populations in the upper end of 25(OH)D levels (a population of sun-exposed people and a group of women prescribed 7,000 IU per day)? Note: the entire Hollis study is free to download on Medline. Hollis BW, et al. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007 Mar;103(3–5):631–4.
If you look at the two graphs (Figures 1 and 2) of Hollis' paper, you find vitamin D's kinetics can be normalized, made just like all other steroid hormones in the body, but you have to get enough sunshine or take enough vitamin D to get your 25(OH)D level above 50 ng/mL—60 ng/mL would be even better. Then your body would start to store cholecalciferol without much further increase in 25(OH)D levels. The reaction becomes saturable. This is a remarkable discovery and it implies levels of 30 and 40 ng/mL are usually not sufficient. It also implies actual vitamin D levels (cholecalciferol levels), not just 25(OH)D levels, may be useful in diagnosing and treating deficiency. Note, that not all of the sun-exposed individuals or women prescribed 7,000 IU/day achieved such levels. That's because the sun-exposed individuals were tested after an Hawaiian winter and because prescribing and taking are two different things.
25(OH)D level should be greater than 60 ng/mL
So my answer to "How much should I take if I have cancer?" is "Take enough to get your 25(OH)D level above 60 ng/mL, summer and winter." In doing so, you will have normalized the kinetics of vitamin D and stored the parent compound, cholecalciferol, in your tissues. In the absence of sunshine, you need to take at least 5,000 IU/day to do this. And this may not be enough; cancer patients may use it up faster (increased metabolic clearance) and children may do the same due to their young and vital enzymes. Or you may need less, because you get more sun than you think, more from your diet, or because you are taking a modern medicine that interferes with the metabolism of vitamin D. An even easier way to do it is go to a sun tanning booth every day and obtain and keep a dark, full-body, tan. Then you don't have to worry about blood levels but I'd get one anyway, just to be sure it was above 60 ng/mL.
Given what Hollis discovered, given the well-known potent anti-cancer properties of activated vitamin D, given epidemiological evidence that summer extends the life of cancer patients, given a meta-analysis of randomized controlled trials showed that vitamin D prolongs life, given animal data that simple vitamin D has a treatment effect on cancer, and given a patient with a life-threatening cancer, what would a reasonable physician do? Simply let their patient die while muttering something about the lack of randomized controlled trials?
No, they would simply check 25(OH)D levels every month and advise cancer patients to take enough vitamin D or to frequent sun tanning parlors enough to keep their level above 60 ng/mL. Toxicity does not start until levels reach 200 ng/mL but if you take more than 5,000 IU per day have your doctor order a blood calcium every month or two, along with the 25(OH)D. Both you and he will feel better and because, if you have cancer, you are probably taking lots of other drugs and little is known about how modern drugs interact with vitamin D metabolism. By getting your level above 60 ng/mL, all you are doing is getting your level to where most lifeguards' levels are at the end of summer, to levels our ancestors had when they lived in the sun, to levels regular users of sun-tan parlors levels achieve, and most importantly, to levels where vitamin D's pharmacokinetics are normalized.
Little to no risk
In the end, if you have cancer and your physician won't do a risk/benefit analysis, do it yourself. The risk side of that equation is easy. Both Quest Diagnostics and Lab-Corp, the two largest reference labs in the United States, report the upper limit of 25(OH)D normal is 100 ng/mL and toxic is above 150 ng/mL, so 60 ng/mL is well below both. The reason levels up to 100 ng/mL are published normals is because there is no credible evidence in the literature that levels of 100 ng/mL do any harm and because sun worshipers often have such levels. (If you don't believe me, go to the beach in the summer for one month, sunbath every day for 30 minutes on each side in your bathing suit, and go home and have a 25(OH)D level.) By getting your level above 60 ng/mL, all you are doing is getting your levels into the mid to upper range of laboratory reference normals. Little or no risk.
What are the potential benefits? It probably depends on a number of things. Did your cancer cells retain the enzyme that activates vitamin D? Many do. Did your cancer cells retain the vitamin D receptor? Many do. If your cancer cells get more substrate [25(OH)D], will that substrate induce the cancer cells to make more vitamin D receptors or more of the activating enzyme? Some cancer cells do both. In practical terms, vitamin D is theoretically more likely to help your cancer the earlier you start taking it. However, no one knows. Certainly there is no reason, other than bad medicine, for cancer patients to die vitamin D deficient. Unfortunately, most do. Tangpricha V, et al. Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston. Endocr Pract. 2004 May–Jun;10(3):292–3. Plant AS, Tisman G. Frequency of combined deficiencies of vitamin D and holotranscobalamin in cancer patients. Nutr Cancer. 2006;56(2):143–8.
It is very important that readers understand I am not suggesting vitamin D cures cancer or that it should replace standard cancer treatment. Oncologists perform miracles every day so one should do what they say. The only exception is vitamin D. If your oncologist tells you not to take vitamin D, ask him three questions.
- How do you convert ng/mL to nmol/L?
- How many IU in a nanogram (ng)?
- How do you spell "cholecalciferol?"
If he doesn't know how to measure it, weigh it, or spell it, chances are he doesn't know much about it.
The real risk: waiting for further studies
All of the epidemiological and animal studies in the literature suggest cancer patients will prolong their lives if they take vitamin D. I can't find any studies that indicate otherwise. However, none of the suggestive studies are randomized controlled interventional trials; they are all epidemiological or animal studies, or, in the case of Vieth's, an open human study. However, if you have cancer, or your child does, do you want to wait the decades it will take for the American Cancer Society to fund randomized controlled trials using the proper dose of vitamin D? Chances are you, or your child, will not be around to see the results.
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John Jacob Cannell MD Executive Director updated 2010.06.25