No Benefit from Low-Dose Aspirin or Vitamin E in the Primary Prevention of Cancer
Jul 11, 2005 - 12:06:00 AM
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The Women's Health Study (WHS) was a randomized, double-blind, placebo-controlled trial, conducted between September 1992 and March 2004, evaluating the balance of benefits and risks of 100 mg of aspirin every other day, and 600 IU of vitamin E every other day on the primary prevention of cardiovascular disease and cancer in a cohort of 39,876 healthy female health care professionals over an average duration of 10.1 years.
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By JAMA,
[RxPG] A major study that includes nearly 40,000 healthy women found no benefit on preventing cancer from taking low-dose aspirin, or benefit on preventing cancer or cardiovascular disease from taking vitamin E, according to two articles in the July 6 issue of JAMA.
A growing body of literature has supported a protective effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of cancer, according to background information in the first article. Observational epidemiological investigations suggest a strong inverse association, with risk reductions as high as 20 percent to 50 percent for various cancer sites. In contrast with the observational evidence on cancer incidence, data from randomized trials, which provide more definitive results due to their ability to minimize bias and confounding, have been far more limited. The Physicians' Health Study (PHS) found no effect on colorectal cancer of 325 mg aspirin administered every other day over a 5-year randomized period or in post trial follow-up. In addition, no randomized trial has yet assessed the impact of aspirin on the development of breast cancer.
The Women's Health Study (WHS) was a randomized, double-blind, placebo-controlled trial, conducted between September 1992 and March 2004, evaluating the balance of benefits and risks of 100 mg of aspirin every other day, and 600 IU of vitamin E every other day on the primary prevention of cardiovascular disease and cancer in a cohort of 39,876 healthy female health care professionals over an average duration of 10.1 years.
In the first article, Nancy R. Cook, Sc.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues evaluated the findings for the aspirin component of the WHS with regard to cancer risk. In this part of the study, 19,934 women received a dose of 100 mg of aspirin every other day and 19,942 women received placebo.
The researchers found that aspirin had no observed effect on total cancer, breast cancer, colorectal cancer, or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (22 percent reduced risk). There was also no reduction in cancer death either overall or by site, except for lung cancer death (30 percent reduced risk). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found.
"The findings from the WHS suggest that aspirin at a dose of 100 mg every other day is not effective in reducing risk of cancer in healthy women, although a beneficial effect on lung cancer cannot be ruled out. This large study of almost 40,000 women had a duration of 10 years of treatment and follow-up, which was the longest of any trial completed to date, and should be sufficient to detect long-term effects. To determine whether higher doses of aspirin taken daily would be effective in cancer prevention requires direct randomized trial data. Such data would need to be considered in the context of risk of gastrointestinal adverse effects before recommending higher-dose aspirin for cancer chemoprevention among low-risk individuals," the authors conclude.
In an accompanying editorial, Eric J. Jacobs, Ph.D., and Michael J. Thun, M.D., of the American Cancer Society, Atlanta, comment on the findings by Cook et al.
"Should the null results with respect to cancer from this large, well-conducted, long-term randomized trial, or from other chemoprevention trials, be considered discouraging news for cancer chemoprevention in general? There have been some successes in cancer chemoprevention, such as the use of tamoxifen to prevent breast cancer in high-risk women. However, currently, no agent has been shown to do for cancer what statins do for cardiovascular disease, namely substantially and relatively safely reduce disease occurrence in individuals not at especially high risk."
"Pharmacological primary prevention of diseases as heterogeneous as cancer is inherently difficult. Randomized trials of cancer chemoprevention will undoubtedly produce many null results. Nevertheless, continued systematic research on cancer chemoprevention, including long-term randomized trials of carefully chosen agents, is essential given the large potential benefits. At the same time, it is unrealistic to expect the discovery of an agent that will produce substantial reductions in overall cancer rates in the immediate future," authors write.
JAMA. 2005;294:105-106.
In an accompanying article in this week's JAMA, I-Min Lee, M.B.B.S., Sc.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues analyzed data from the vitamin E component of the Women's Health Study, which tested whether vitamin E supplementation decreases the risk of cardiovascular disease and cancer among healthy women.
According to background information in the article, previous observational studies have indicated that vitamin E may be beneficial in lowering the risk for some cardiovascular diseases; and high antioxidant intake has been linked to reduced cancer rates. For small to moderate effects, however, the amount of uncontrolled and uncontrollable confounding inherent in observational studies can be as large as the postulated benefit, so randomized clinical trials represent the most reliable study design strategy. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. By 1997, despite a lack of randomized trials, 44 percent of U.S. cardiologists reported routine use of antioxidant supplements, primarily vitamin E, compared with 42 percent who routinely used aspirin for the primary prevention of CVD.
In this component of the Women's Health Study, 39,876 apparently healthy U.S. women aged at least 45 years were randomly assigned to receive 600 IU of natural-source vitamin E on alternate days or placebo, and were followed up for an average of 10.1 years.
The researchers found with the vitamin E group, there was no significant effect on major cardiovascular events, on the incidences of heart attack or stroke, as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a 24 percent reduction. There was no significant effect on the incidences of total cancer or breast, lung, or colon cancers. Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total death.
"In conclusion, the WHS does not support recommending vitamin E supplementation for CVD or cancer prevention among healthy women. This large trial supports current guidelines stating that use of antioxidant vitamins is not justified for CVD risk reduction. ...The WHS findings should be viewed in the context of the available randomized evidence, as well as data that should be available over the next several years from ongoing trials, including the Physicians' Health Study, which will provide data on primary prevention in men. At present, in the primary prevention of CVD and cancer, therapeutic lifestyle changes including a healthy diet and control of major risk factors remain important clinical and public health strategies," the authors conclude.
JAMA. 2005;294:56-65.
In an accompanying editorial, Rita F. Redberg, M.D., M.Sc., of the University of California, San Francisco, discusses the study by Lee et al.
"Perhaps it is time to consider devoting some of the limited resources necessary to perform randomized controlled trials to other pressing, unanswered questions in the field of cardiovascular disease prevention in women. With the publication of the WHS vitamin E results, it is time to redirect attention to interventions that have been shown to or could provide significant benefit."
" ...vitamin E enters the category of therapies that were promising in epidemiologic and observational studies but failed to deliver in adequately powered randomized controlled trials. As in other studies, the 'healthy user' bias must be considered, i.e., the healthy lifestyle behaviors that characterize individuals who care enough about their health to take various supplements are actually responsible for the better health, but this is minimized with the rigorous trial design. It is estimated that almost 1 million preventable deaths per year are due to smoking, poor diet, and physical inactivity. Perhaps the most important outcome of the WHS reports will be greater recognition that it is time to concentrate on teaching nutrition, promoting regular physical activity, and strongly encouraging smoking cessation and particularly increasing outreach to women of racial and ethnic minorities," Dr. Redberg writes. "[These] are underused but proven prevention strategies for heart disease. Interestingly, these positive lifestyle changes are also associated with the prevention of cancer and Alzheimer disease."
JAMA. 2005;294:107-109.
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