"Ruh roh" -Scooby Doo
Am J Epidemiol. 2010 Jun 18. [Epub ahead of print]
Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.
Helzlsouer KJ; for the VDPP Steering Committee.
Abstract
The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) brought together 10 cohorts to conduct a prospective study of the association between vitamin D status, measured as serum concentrations of 25-hydroxyvitamin D (25(OH)D), and the development of 7 rarer cancer sites: endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, ovarian, and pancreatic cancers. The cohorts come from 3 continents, with participants from a wide range of latitude who are racially diverse. Across each cancer site, there was no evidence of a protective association between higher concentrations of 25-hydroxyvitamin D (>75 nmol/L) and cancer outcome. An increased risk at very high levels (>/=100 nmol/L) was noted for pancreatic cancer, confirming previous reports. The articles included in this issue detail the overall design and governance of the project, correlates of vitamin D status, and results from the cancer site-specific investigations. The Vitamin D Pooling Project realizes a major goal of consortium efforts, namely, to rigorously test hypotheses for rarer cancer outcomes that may not be adequately addressed in any one prospective cohort study. The results of this study have application for the planning and conduct of intervention trials, especially in determining potential risks.
PMID: 20562193
To rain on the high dose Vitamin D parade even more:
Tim Byers
Anticancer Vitamins du Jour-The ABCED's So Far
American Journal of Epidemiology Advance Access published on June 18, 2010
Am. J. Epidemiol. 2010 172: 1-3; doi:10.1093/aje/kwq112 [Extract] [FREE Full
Text]
It started 30 years ago with vitamin A: the idea that some cancers might be
caused by vitamin deficiencies. Animal experimental models led us to the
notion that cancer risk might be "materially" reduced by supplementation
with beta-carotene, a retinol precursor (1). Although that idea was
seductive, we were all disappointed when 2 large randomized controlled
trials that began in 1985 in Finland and the United States reported an 18%
increased risk of lung cancer caused by high-dose beta-carotene
supplementation and a 28% increased lung cancer risk caused by a combination
of beta-carotene and retinol (2, 3). The vitamin A era was over.
Next came the B vitamins. Again, based on animal experimental evidence and
supported by epidemiologic evidence of connections between diets low in B
vitamins and increased cancer risk, a large randomized controlled trial was
begun in 1985 in central China, where micronutrient deficiency was common
and where rates of cancers of the stomach and esophagus were extraordinarily
high. Nonetheless, several years of supplementation with a combination of
riboflavin (vitamin B2) and niacin (vitamin B3) had no effect on incidence
of upper gastrointestinal cancers (4). Interest in folic acid (vitamin B9)
persisted, though, in part because of its striking effect on neural tube
birth defects, coupled with speculation about possible benefits of food
fortification for diseases such as colorectal cancer that were inversely
associated with diets rich in folate-containing foods and supplements.
However, a 7-year randomized controlled trial found that high-dose folic
acid supplements actually increased risk of colorectal adenomas (5). The
vitamin B era was over.
Next came vitamin C, a popular charge led by none other than Linus Pauling,
the brilliant and charismatic 2-time Nobel laureate. Of all the cancers
thought to be related to vitamin C deficiency, gastric cancer led the way,
and of all the places on Earth where a vitamin C deficiency correction trial
might yield benefits for gastric cancer, Linxian, China, would be the best.
Indeed, vitamin C was tested in the Linxian trial, but just as for the B
vitamins, vitamin C produced no change in gastric cancer rates (6).
Next, slightly out of alphabetical order, came vitamin E. In 1993, we
launched headlong into a love affair with vitamin E fueled by compelling
observations that those who chose to take vitamin E supplements were at
lower risk of heart disease (7, 8). Vitamin E supplementation became the
rage as several large, randomized controlled trials were mounted. When those
results finally came in, the findings were again disappointing: vitamin E
supplementation offered no benefit for heart disease, and it slightly
increased overall mortality (9, 10). In the meantime, though, because of a
secondary observation that prostate cancer incidence was lower in the
vitamin E arm of the same Finnish trial that tested beta-carotene (vitamin E
had also been included as a factor) (11), a large factorial trial of vitamin
E (and selenium) was carried out for reducing prostate cancer incidence.
Disappointment again: there was no effect of either selenium or vitamin E on
incidence of prostate cancer (12). The vitamin E era ended in a whimper.
Over 2 decades of searching for an anticancer vitamin, we had seemed to skip
over vitamin D in its proper alphabetical sequence. In my role as a member
of the World Cancer Research Fund Expert Panel that considered the evidence
from commissioned meta-analyses of the world's literature on nutritional
epidemiology, I remember feeling concern as we finished our work that we
might have underestimated the importance of vitamin D because the bulk of
the evidence available at that time was derived from ecologic studies (13).
Subsequently, the International Agency for Research on Cancer conducted a
comprehensive review of the evidence for vitamin D and cancer prevention,
concluding that vitamin D may play a protective role in colorectal cancer,
but not for prostate cancer, and that the evidence is weak for breast cancer
(14). The conclusion by the International Agency for Research on Cancer
about the weakness of the evidence for breast cancer has been a source of
controversy among vitamin D protagonists (15, 16), but subsequent nested
cohort studies have found no relation between breast cancer risk and
circulating levels of vitamin D (17, 18).
Nonetheless, vitamin D remains the cancer-preventing vitamin du jour. Just
search the phrase "vitamin D and cancer" on the Internet to see what sorts
of information and products are now being marketed to the public. Vitamin D
is the new vitamin A, the new folic acid, the new vitamin C, the new vitamin
E.
An outstanding set of papers in this issue of the American Journal of
Epidemiology reports on findings about the relation between circulating
levels of vitamin D and subsequent cancer risk in a set of pooled cohort
studies conducted in the United States, Europe, and Asia. These studies
found no suggestion of an inverse association between vitamin D levels in
the circulation and later incidence of 6 types of cancers (upper
gastrointestinal, ovary, endometrial, pancreatic, kidney, and non-Hodgkin
lymphoma). Although these cancers are characterized as "rarer," this set of
sites collectively accounts for about a quarter of all deaths from cancer in
the United States. These studies offer compelling evidence against the
hypothesis that circulating levels of vitamin D are relevant to risk of
these cancers. This new information is important because an International
Agency for Research on Cancer review had decided that evidence was
previously insufficient to draw conclusions about these 6 cancer sites (14).
Whenever null findings are found, it is important to consider the usual
suspect reasons, and the authors of these papers have done an outstanding
job of that. The size of this pooled analysis is large enough to discount
concerns about low statistical power; there is a good level of internal
consistency in the previously documented associations between vitamin D
levels and factors such as seasonality, race, gender, diet, physical
activity, and body mass index; there was substantial interindividual
variation in these cohorts; and there did not seem to be confusion between
confounding factors or factors potentially in the causal pathway. The
question as to whether the time interval studied was the correct one remains
unanswered, however. If the geographic ecologic associations between sun
exposure and cancer risk are, in fact, due to long-term cumulative effects
of lifelong vitamin D exposures, then cohort studies in adulthood will not
be fully informative. However, it is important to note that this longer-term
ecologic possibility is not consistent with the other ecologic observation
of seasonal variation in cancer incidence that is often also attributed to
vitamin D levels in the circulation (19).
The only association observed in this set of 6 analyses was a troubling one:
that risk of pancreatic cancer was doubled for those in the highest quintile
of circulating vitamin D levels. This observation is disconcerting both
because pancreatic cancer is now the fourth leading cause of cancer death in
the United States and because the proponents of the vitamin D hypothesis are
now arguing that substantially elevating circulating blood concentrations
into that range should be a nutritional policy objective for the general
population (15, 16). As pointed out by Dr. Helzlsouer (20) in this issue of
the Journal, many ongoing randomized controlled trials are now using quite
high doses of vitamin D. As we await clearer evidence of benefits from those
trials, we will also need to be prepared to be vigilant about their
individual and collective power to assess any potential harms (21, 22).
It is timely for us to now reflect on the history of the past 25 years of
our alphabetical approach to studying single vitamin deficiency states as
causal factors for cancer. We have learned some hard lessons along the
alphabetical way. We now know that supernutritional levels of vitamins taken
as supplements do not emulate the apparent benefits of diets high in foods
that contain those vitamins (13), and we now know that taking vitamins in
supernutritional doses can cause serious harm. In short, we have found that
the reality of human biology is far more complex than is suggested by our
simple ideas.
Finally, it is important to recognize the efforts of the many Vitamin D
Pooling Project of Rarer Cancers collaborators who carried out such a
remarkable set of studies. As pointed out by the Institute of Medicine, we
are now in an era of "big science," in which definitive answers to big
questions will increasingly require massive efforts and large-scale
collaborations (23). Carrying out these types of collaborations requires
foresight, skill, and patience. Large-scale collaborations are critically
important, though, for our improved understanding of the true nature of the
determinants of human health. The dual problems of type 1 and type 2 errors
have best been exemplified in genetic epidemiology, but false discovery has
been a problem in nutritional epidemiology as well. Even though there was
consistency in the overall null observations across most of the cohorts in
this pooled analysis, there was some variation. It is easy to imagine that,
without this collaborative analysis, we might have been led down several
blind alleys derived from analyses of various subgroups and interactions. We
all should be grateful to the Vitamin D Pooling Project of Rarer Cancers
investigators for having saved us from years of false leads, as well as for
their vision and skill in carrying out this outstanding collaborative
project.
By the way, 100nmol/L = 40ng/mL, above which they describe as "very high levels" of Vitamin D.
Edited by FunkOdyssey, 26 June 2010 - 09:39 PM.