Re: Vitamins, Micronutrients, and Cancer Prevention: Where Do We Stand?

[Guest guest]

Disappointing news, but well-researched and well-presented.

I'm one of those who believed himself ahead of the curve, and took

many vitamins and minerals in the belief that it would lead to better

health. Given the evidence that it may have been counterproductive,

perhaps I put myself at a disadvantage by trying to be a forward thinker.

Sometimes, maybe, it pays not to read in an attempt to be well-informed.

>

> 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 beta-carotene. 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.1

>

> 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,2 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.3 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.4

>

> 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.5,6

>

> 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.7 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.8 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.9

>

> 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.

>

> References

>

> 1. National Cancer Institute. Antioxidants and Cancer Prevention: Fact

> Sheet. Accessed November 17, 2008.

> 2. Blot WJ, Li JY, PR, et al. Nutrition intervention trials in

> Linxian, China: supplementation with specific vitamin/mineral

combinations,

> cancer incidence, and disease-specific mortality in the general

population.

> J Natl Cancer Inst. 1993 Sep 15;85(18):1483-1492.

> 3. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study

Group. The

> effect of vitamin E and beta carotene on the incidence of lung

cancer and

> other cancers in male smokers. N Engl J Med. 1994 Apr

14;330(15):1029-1035.

> 4. Omenn GS, Goodman G, Thornquist M, et al. The beta-carotene and

retinol

> efficacy trial (CARET) for chemoprevention of lung cancer in high risk

> populations: smokers and asbestos-exposed workers. Cancer Res. 1994 Apr

> 1;54(7 suppl):2038s-2043s.

> 5. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of

long-term

> supplementation with beta carotene on the incidence of malignant

neoplasms

> and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-1149.

> 6. Lee IM, Cook NR, Manson JE, et al. Beta-carotene supplementation and

> incidence of cancer and cardiovascular disease: the Women's Health

Study. J

> Natl Cancer Inst. 1999 Dec 15;91(24):2102-2106.

> 7. LC, Combs GF Jr, Turnbull BW, et al, for the Nutritional

Prevention

> of Cancer Study Group. Effects of selenium supplementation for cancer

> prevention in patients with carcinoma of the skin. A randomized

controlled

> trial. JAMA. 1996 Dec 25;276(24):1957-1963.

> 8. Goodman EG, Alberts DS, Meyskens FL. Retinol, vitamins, and cancer

> prevention: 25 years of learning and relearning. J Clin Oncol. 2008

Nov 3.

> [Epub ahead of print]

> 9. Bjelakovic G, Nikolova D, Gluud LL, et al. Antioxidant

supplements for

> prevention of mortality in healthy participants and patients with

various

> diseases. Cochrane Database Systemic Reviews. 2008 Apr 16. Issue 2.

Art.

> No.: CD007176. DOI: 10.1002/14651858.CD007176.

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