Monday, January 11, 2010

Vitamin D and cancer, particularly CLL

When I started my series on vitamins I intended to deal with the question of vitamin D and CLL, but I got sidetracked. I have seen a number of comments on various sites about using vitamin D3 to slow down CLL so I guess I should write about it now.

Vitamin D is a precursor to a hormone that controls calcium metabolism. There are two major forms: vitamin D2, or ergocalciferol, and vitamin D3, or cholecalciferol. Vitamin D2 is made naturally by plants, and vitamin D3 is made in animals. In humans D3 is made in the skin when it is exposed to UVB irradiation. Both can also be synthesized.

The active form is 1,25-dihydroxyvitamin D, or calcitriol, which can be made in the body from either vitamin D2 or vitamin D3. the functions of vitamin D are:
To help improve muscle strength and immune function.
To reduce inflammation.
To promote the absorption of calcium from the small intestine.
To helps maintain adequate blood levels of the calcium and phosphate needed for bone formation, mineralization, growth and repair.

Most people get the vitamin D they need through sunlight exposure. It is also present in the diet. Foods containing Vitamin D include fatty fish, fish liver oil, and eggs, with smaller amounts in meat and cheese. Most dietary vitamin D comes from fortified foods, such as milk, juices, yogurt, bread, and breakfast cereals. A serum level of calcitriol lower than 15 ng/ml (37.5 nmol/L) is generally considered inadequate for a healthy person to maintain bone health and normal calcium metabolism, but some experts suggest that the optimal level may be as high as 80 nmol/L. The Institute of Medicine of the National Academies has developed the following recommended daily intakes of vitamin D: Birth to age 50 - 5 µg (200 iu); 51-70 - 10 µg (400 iu); 71+ 15 µg (600 iu). The 2005 Dietary Guidelines for Americans recommends that older adults, people with dark skin, and people exposed to insufficient sunlight should consume extra vitamin D (25 µg, or 1,000 iu) from vitamin D-fortified foods and/or supplements.

The proven problems of insufficient vitamin D are rickets in children and osteomalacia in adults. Excessive vitamin D intake increases calcium levels which can lead to the deposit of calcium salts in soft tissues of the body, such as the kidneys, heart, and lungs and high blood levels of calcium. Patients with high calcium levels can get heart rhythm abnormalities, changes in mental status, pain, conjunctivitis, loss of appetite, fever, chills, thirst, vomiting, weight loss and if unchecked they can lead to coma and death.

Is there any evidence that vitamin D prevents cancer? Well yes, there is some, though it is far from conclusive. First, there are epidemiologic studies which show an inverse relationship between sunlight exposure and the rates of incidence and death for certain cancers. There may be many reasons for this, but one possibility is that more sunlight leads to more D3 being produced.

When cancer cells are cultured in the laboratory vitamin D promotes their differentiation and apoptosis and it slows their proliferation.

Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have also provided evidence that higher vitamin D intakes may reduce the risk of cancer. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium and vitamin D (28 μg vitamin D, or 1,100 iu) or a placebo for 4 years. The women who took the supplements had a 60 percent lower overall incidence of cancer). This was an incidental finding since the principle end point was fracture incidence; it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake on cancer incidence.

Observational studies to determine whether vitamin D reduces the risk of particular cancers, have been carried out but they have yielded inconsistent results. Information about dietary intakes was obtained from the participants through questionnaires, diet records, or interviews. Such information is not very reliable. Of course it is possible to measure blood levels of vitamin D to avoid reliance on individuals' memories but vitamin D levels in the blood can vary seasonally and with the laboratory technique used to measure them so if only a single measurement of vitamin D is made (as was the case in most studies) interpretation is difficult.

To fully understand the effect of vitamin D on cancer, new randomized trials will need to be carried out, but there is disagreement on what dose of vitamin D to use.

Let's look at individual cancers. Although the studies are inconsistent, epidemiologic studies of the association between vitamin D and the risk of colorectal cancer have provided some suggestion of protection.

In the American Cancer Society's Cancer Prevention Study II Nutrition Cohort, the diet, medical history, and lifestyle of more than 120,000 men and women were analyzed. Men with the highest intakes of vitamin D had a slightly lower risk of colorectal cancer than those with lowest intakes, but among women there was no difference. When this study was pooled with 9 other studies there was still a difference between men with the highest and lowest intakes, but it was no longer statistically significant.

In the Women's Health Initiative randomized trial, vitamin D supplementation did not reduce the incidence of colorectal cancer, though this study has been criticized by enthusiasts because of too low a dose and too short of duration.

Among the 16,818 participants in the Third National Health and Nutrition Examination Survey, those with higher vitamin D blood levels (≥ 80 nmol/L) had a 72 percent lower risk of colorectal cancer death than those with lower vitamin D blood levels (< 50 nmol/L).

Since most colorectal cancers develop from pre-existing adenomas, any interventions that reduce the risk of adenoma development or recurrence are likely to reduce the risk of colorectal cancer. Several large studies have investigated the association of vitamin D intake or serum status with adenoma risk.

A cohort from the National Cancer Institute (NCI)-sponsored Polyp Prevention Trial (PPT) was evaluated for the association of vitamin D intake with recurrence of colorectal adenomas in individuals who previously had one or more adenomas removed during a qualifying colonoscopy. PPT was a multicenter randomized clinical trial to determine the effects of a diet high in fiber, fruits, and vegetables and low in fat on adenoma recurrence. The detailed dietary information obtained during the trial allowed the researchers to investigate the association between additional dietary factors and adenoma recurrence. Total vitamin D intake (that is, from dietary sources and supplements combined) was not associated with a reduced risk of adenoma recurrence. However, individuals who used any amount of vitamin D supplements had a lower risk of adenoma recurrence.

In another study, the vitamin D intakes of 3,000 people from several Veterans Affairs medical centers were examined to determine whether there was an association between intake and advanced colorectal neoplasia (an outcome that included high-risk adenomas as well as colon cancer). Individuals with the highest vitamin D intakes (more than 16 μg, or 645 iu, per day) had a lower risk of developing advanced neoplasia than those with lower intakes.

A pooled analysis of data from these and a number of other observational studies found that higher circulating levels of vitamin D and higher vitamin D intakes were associated with lower risks of colorectal adenoma. Inverse associations were seen with both dietary and total vitamin D intake but not with supplemental vitamin D intake. However, the associations with dietary intake were not statistically significant.

Another large, NCI-sponsored randomized, placebo-controlled trial explored the effects of calcium supplementation and blood levels of vitamin D on adenoma recurrence. Calcium supplementation reduced the risk of adenoma recurrence only in individuals with vitamin D blood levels above 73 nmol/L. Among individuals with vitamin D levels at or below this level, calcium supplementation was not associated with a reduced risk.

14 comments:

Brian Koffman said...

Terry,
Thanks for the literature review. I am vegan (mostly raw veggies) and must take 15,000 u of Vit D3 a day just to keep my level in the upper half of normal. Maybe my absorption is poor. I am NOT recommending this dose to others.
I wish CLL could be whisked away with a vitamin or a change in diet, but that doesn't seem to be the case.
Be well
Brian
PS As a strict vegan, I also must take B12.

Mike said...

this is a very poor review and does not reflect the latest data or the opinions of experts on vitamin D. I would suggest you visit www.vitaminDcouncil.org or www.vitaminD3world.com for a more comprehensive review

Terry Hamblin said...

Mike
A review isn't necessary bad because it doesn't agree with you. My major source of information was teh National Cancer Institute, and the review reflects their conclusion, that although an effect of vitamin D on cancer is biologically plausible, there is not enough convincing evidence to recommend its use. I have been to the sites you suggest and even these do not suggest that the evidence is convincing. here is a quote from one of them from a 2009 publication: When one looks at the association of vitamin D with cancer, the evidence is intriguing. For breast cancer, the strongest evidence is obtained from ecological studies that concluded that higher cancer rates in northern (v southern) latitudes were due to vitamin D deficiency. Observational studies examining the association between vitamin D intake or blood levels in relation to cancer risk in general, and breast cancer risk in particular, have yielded inconsistent results. Evidence of an adverse effect of vitamin D deficiency in colorectal cancer has been most consistent. Randomized trials, designed primarily for bone end points, have also yielded inconsistent results. Lappe et al reported a reduction of overall cancer risk (a secondary end point) in postmenopausal women randomly assigned to receive calcium alone or calcium plus vitamin D (1,100 IU/d) versus placebo; there was no vitamin D–only arm and cancer risk did not differ between the two calcium-containing arms. In contrast, a recent report from the Women's Health Initiative1 failed to identify a beneficial effect of vitamin D supplementation (at a lower dose of 400 IU/d) on breast cancer risk compared with placebo. A note of caution is injected by reports that higher blood levels of vitamin D (well below the range considered toxic) may be associated with increased esophageal and prostate cancer risk or with more aggressive prostate cancer. Taken together, the available information is inadequate to conclude whether vitamin D influences cancer risk or mortality; furthermore, in individual studies in which vitamin D has been associated with cancer, it is not clear whether it is vitamin D or the company that it keeps (eg, diet, outdoor activity, healthy weight, higher socioeconomic class) that is the potentially responsible agent. The issue of causality is of particular concern given previous failed attempts to confirm the potential cancer-lowering effects of micronutrients such as β-carotene in cancer in randomized trials, even though observational studies suggested important effects. .

Terry Hamblin said...

Continued:
Notwithstanding lack of high-level evidence, an effect of vitamin D on cancer risk or outcome is biologically plausible. Recent research has demonstrated that many tissues express 1,25-vitamin D hydroxylase, and are thus able to convert the predominant circulating form of vitamin D (inactive 25-OHD) to active 1,25-dihydroxyvitamin D. This 1,25-dihydroxyvitamin D can bind to vitamin D receptors, which are present on the nuclei of most cells. These vitamin D receptors are nuclear transcription factors that regulate the expression of more than 200 genes responsible for cell differentiation, proliferation, and apoptosis. The potential for major biologic effects underscores the critical importance of understanding the clinical impact of vitamin D on cancer risk and outcome, and should serve as stimulus for a targeted, adequately funded program of research in this area.

While awaiting results of this future research, as oncologists, we are being asked to advise our patients about whether they should take vitamin D supplements and, if so, what dose they should take. The unpredictable relationship between vitamin D intake and blood levels (likely reflecting individual variability in diet, absorption, metabolism, and adiposity, and in sun exposure as an alternate source of vitamin D) makes it difficult to recommend a standard supplement dose and supports incorporating measurement of blood levels into recommendations. Although there is some minor disagreement about specific cut points, most authorities suggest that a blood level of 25-OHD (the best marker of vitamin D status) of approximately 75 nmol/L (30 ng/mL) is required for vitamin D sufficiency, and levels above 375 nmol/L (150 ng/mL) are potentially toxic (associated with increased risk of hypercalcemia. One recent review suggests that there may be a "most advantageous" range of 25-OHD that starts at 75 nmol/L (30 ng/mL) and is ideally 90 to 100 nmol/L (36 to 40 ng/mL) that is associated with optimal musculoskeletal, neuromuscular, and cardiovascular health and immune function. Evidence regarding the safety of higher blood levels of vitamin D or supplementation with large doses of vitamin D focuses almost exclusively on short-term (up to 6 months) effects on calcium metabolism. Hypervitaminosis D (25-OHD > 375 nmol/L or > 150 ng/mL) is associated with hypercalcemia and resulting complications, including renal stones and bone demineralization. Information regarding effects of high levels of vitamin D on cell proliferation, differentiation, and apoptosis (of great relevance to cancer) or on other non–calcium-related health outcomes is lacking and is urgently needed

Terry Hamblin said...

The other site has this disclaimer: The products and the claims made about specific products on this site have not been evaluated by the United States Food and Drug Administration and are not intended to diagnose, treat, cure or prevent disease. The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem.

TedHutchinson said...

Here are some free full text online papers that provide a critical response to "official" received medical opinion.
A critical review of Vitamin D and Cancer: A report of the IARC Working Group.

How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer?: An examination using Hill's criteria for causality.

Shining light on the vitamin D: Cancer connection IARC report.

In many ways the Cancer Institute response is much like that of the Diabetics Association refusal to acknowledge that refined carbohydrates like fructose cause insulin to rise and underlie the rise in diabetes, or the Heart Associations denial of the role of omega 6 in heart disease. Because all these organizations have been in part responsible for the increase in Cancer, Diabetes, Heart disease, they are of course reluctant to acknowledge any research that shows logically the advice they have been providing to date had been to some extent contributing to the incidence of the condition.
The overwhelming weight of evidence supports the idea that those with higher levels of vitamin D have less cancer incidence and if you have a high level of vitamin D at diagnosis and treatment you generally have a better prognosis.
The cancer societies have been urging people to stay out of the sun and encourage the use of sunscreen, so are responsible partly for the ever declining rates of 25(OH)D3. They will therefore deny the association for as long as possible.

Terry Hamblin said...

These links all refer to a single issue of a new journal called Dermoendocrinology. It does not enjoy high status.

Terry Hamblin said...

Sorry, that should be Dermatoendocrinology. It is still a low status journal.

Anonymous said...

A review that disagrees with a zealot is automatically considered rubbish, even if their zealotry is over rubbish.

The questions about vitamin D3 are relevant and I thought that your review was fair and balanced.

If you really want to crank some people up, discuss gerson therapy.

TedHutchinson said...

So I presume you think journals that depend on pharmaceutical companies for advertising don't suffer from publication bias when it comes to publishing information that will be detrimental to the best financial interests of their main source of income?

What matters is the quality of the arguments and the evidence Grant and Holick present.

Look where following the information published in the top journals has got us when it comes to heart disease, cancer and diabetes. The incidence rates are rising year on year because the bias in the publication system is letting everyone down.

I suggest you invest some time reading Taubes Good Calories Bad Calories to better understand the folly the major nutritional publications have got us into.
There is a good summary of his book here
Gary Taubes Dartmouth Lecture But the book itself details and explains the way the science and the interpretation of that science in the journals has led us astray. There are thousands of references to the best journals together with a detailed analysis of the way the evidence was misrepresented.

Probably the best low carbohydrate diet research is free online at
Nutrition and Metabolism

Now we have the internet we don't need to be led by the nose by the journals into falling for the most expensive medical solutions.

Preferential publication of editorial board members in medical specialty journals
Clearly it's not necessarily or just the quality of the research that gets you published.

Terry Hamblin said...

Ted, You are clearly a vitamin D3 zealot. As a matter of fact, I am the editor of a major scientific journal that doesn't take drug company advertising. My interest is in CLL and cancer generally, not in vitamins or other forms of nutritional therapy. I need to be as convinced about vitamin D as I need to be about fludarabine and rituximab. Megadoses of vitamins are produced by the same Big Pharma companies that produce these other drugs. While there are some biological reasons why vitamin D might be beneficial and some epidemiological evidence that is suggestive, only reproducible randomized controlled trials cut the mustard as far as cancer treatments are concerned. There are currently 107 agents undergoing clinical trials for CLL, many of them with biological and epidemiological support for their working. It is a high hurdle to scale, but for drugs to be accepted they need to be unchallengable. This is not yet the case for vitamin D3 in CLL. As I said in the article, I conducted a clinical trial of vitain D in myelodysplastic syndrome on the basis that in the test tube the MDS cells could be differentiated away from leukemia by the vitamin. The clinical effect was negligible.
Although the controlled trial comparing vitamin D + calcium did show a survival advantage over the placebo arm, if you look at the graph for those receiving calcium alone without the vitamin D, the two curves practically overlap.

Anonymous said...

When I was hospitalized at Thornton Hosptial in San Diego, the TV was on the fritz and the only channel available was UCSD-TV.

That was a lucky thing. They had a very interesting discussion by a gentleman whom I believe held a PhD. He looked at studies that you have looked at, and he come to some conclusions that I think would really bother you, since you don't believe in supplementation (and I don't, either, in general).

You can watch it yourself. It's at http://www.ucsd.tv/search-details.aspx?showID=16941

I know you hold such presentations in scant regard, but I'd be interested in how you tear this poor PhD/MD apart!

Anonymous said...

Oops! My mistake. The gentleman I referred to in my previous post was a doctor of public health, obviously a suspect degree if I've ever heard one.

This following is actually the one I saw at UC San Diego:

http://www.ucsd.tv/search-details.aspx?showID=15767

lorna vanderhaeghe said...

Thanks a lot for that info. Vitamin D is one of the important vitamins. We should always be sure that we're sufficient in it.