I found this article to be interesting--- having my own little thread day.
OncologyStat® One Source, Many Resources.®
Vitamins, Micronutrients, and Cancer Prevention: Where Do We Stand?
2008 Nov 18, Lee Schwartzberg, MD, Editor-in-Chief
Abundant preclinical evidence supports the use of antioxidants to reduce the incidence of cancer. Antioxidants interact with free radicals generated by a variety of environmental toxins, including tobacco and radiation. Excessive free radical accumulation leads to damaged DNA, which can cause oncogene activation and other processes that result in cancer.
Many antioxidants exist in nature. Some of the most potent are common micronutrients, such as vitamins A, C, and E and betacarotene.
Studies showing the linkage of antioxidants to cancer initiation and the ability to terminate tumor progression in vitro ultimately led to several large-scale cancer prevention trials designed to reduce the burden of cancer.
Cancer prevention trial results
The first large randomized cancer prevention trial, published in 1993, was conducted in a relatively poor Chinese province. This trial, which examined the effect of a combination of beta-carotene, vitamin E, and selenium in healthy individuals at risk for gastric cancer, showed a reduction in the incidence of both gastric cancer and all cancers.
However, the next large trial, the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study, targeting Finnish smokers as the at-risk population, demonstrated an increase in lung cancer rates with beta-carotene supplementation and no effect of alpha-tocopherol (vitamin E) supplements.
Concerns that vitamins could actually increase cancer incidence were heightened by results of the Beta-Carotene and Retinol
Efficacy Trial (CARET), also published in the early 1990s, which suggested that beta-carotene and vitamin A supplementation may
increase lung cancer rates
Two more recent, large, prospective, US trials in healthy individuals—the Physicians’ Health Study and the Women’s Health Study
—showed, respectively, that beta-carotene did not reduce lung cancer in male physicians and that neither beta-carotene nor
vitamin E offered cancer-preventive benefits in healthy women.
One of the largest cancer prevention trials investigating vitamins and antioxidants to date was the Selenium and Vitamin E Cancer
Prevention Trial (SELECT) funded by the National Cancer Institute and conducted in 35,000 men at risk for prostate cancer. This
study, which started in 2001, assessed whether selenium, vitamin E, or the combination would reduce this heightened risk.
The results of this trial, revealed publicly in November 2008, showed that neither selenium nor vitamin E lowered the risk of prostate
cancer. The Data Safety Monitoring Committee concluded that it was extremely unlikely that the trial would ever meet its goal of a
25% reduction in prostate cancer incidence. The interim results further revealed a nonsignificant trend toward more prostate cancer
in men taking vitamin E and a slightly higher likelihood of diabetes mellitus in men taking selenium. Based on these results, the
study was halted, and men enrolled in the study were instructed to stop taking the supplements.
Why was SELECT negative?
So why was this trial negative? Was it worth spending $120 million to obtain these results?
SELECT was based on solid, preclinical evidence supporting the use of the antioxidants studied. Selenium, a mineral that is an
integral component of several enzymes that control antioxidant processes, demonstrates cancer-preventive activity in preclinical
systems. The clinical rationale for SELECT was based on observations made in other trials of antioxidants for cancer prevention.
A 50% reduction in prostate cancer incidence was detected in a skin cancer prevention trial testing selenium. As a secondary
endpoint in the ATBC study, significantly less prostate cancer was seen in men who took beta-carotene and vitamin E. Based on
these data, it was reasonable for SELECT to proceed.
Furthermore, a previous cancer prevention trial testing finasteride had been carried out successfully, so the infrastructure to conduct SELECT largely existed before the start of the trial.
SELECT proves once again that hypotheses generated from well-conducted, well-designed cohort studies or as secondary
endpoints from randomized trials cannot be accepted as fact until they have been formally tested in a prospective trial that includes
a control group.
It may be inappropriate to extrapolate results, such as the putative reduction in prostate cancer seen in Finnish smokers, to another group, such as American males over age 55 at risk for prostate cancer. The lack of benefit for selenium and vitamin E observed in SELECT could reflect a random result in the other trials.
Alternatively, perhaps endogenous levels and consumption of these micronutrients may have differed between the population study and the previous trials.
The SELECT population may well have had higher baseline nutritional status and fewer deficiencies in these vitamins than either of the groups
previously determined to have lower prostate cancer risks. Further reports from SELECT should answer this question by examining
stored blood samples for baseline micronutrient levels.
In a recent editorial published in the Journal of Clinical Oncology before the SELECT results were released, Goodman, Alberts, and
Meyskens, the pioneering group in this field, reviewed 25 years’ worth of vitamin chemopreventive research. They presciently
stated that “taking super physiologic doses [of micronutrients] for a prolonged time may also affect many organ systems. Our
understanding of the pharmacology and physiologic effects at these high doses is incomplete.”
Indeed, a recent meta-analysis of antioxidant supplements for cancer prevention assessing 67 randomized trials actually demonstrated a net increase in mortality in the treatment arms.What are the lessons for oncologists?
What lessons do these results offer for oncologists, their patients, and their patients’ families? First, we should not be so arrogant
as to believe we know the answers before doing the studies.
Second, while vitamins and other micronutrients are critically
important for maintaining good health, it does not necessarily follow that use of supplements by nutritionally repleted individuals has
beneficial effects on either cancer or cardiovascular disease.
Third, despite compelling in vitro evidence, an intervention may simply
not work in vivo.
Fourth, in view of our admittedly incomplete knowledge at this point, the best advice may be what we learned at our mother’s knee: Eat your fruits and vegetables! This may be the most effective way to derive benefit from antioxidants.
It is entirely plausible that nature developed combinations of micronutrients to be ingested in a way that provides maximum
preventive benefit as well as nutrition. Perhaps the next wave of chemoprevention trials will evaluate that hypothesis rather than the
approach used up to now, namely, supplementation with higher doses of individual micronutrient and antioxidants.
In an era of harsh economic realities, the time for large-scale expensive chemoprevention trials may have passed. Biomarkers as endpoints
and targeted at-risk populations are likely to be the focus of future prevention trials.