From: Subject: JAMA -- Low-Dose Aspirin and Vitamin E: Challenges and Opportunities in Cancer Prevention, July 6, 2005, Jacobs and Thun 294 (1): 105 Date: Thu, 20 Jul 2006 17:16:28 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_00E7_01C6AC20.3CE242F0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_00E7_01C6AC20.3CE242F0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://jama.ama-assn.org/cgi/content/full/294/1/105 JAMA -- Low-Dose Aspirin and Vitamin E: Challenges = and Opportunities in Cancer Prevention, July 6, 2005, Jacobs and Thun = 294 (1): 105

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Low-Dose Aspirin and = Vitamin E=20

Challenges and Opportunities in Cancer = Prevention=20

Eric=20 J. Jacobs, PhD; Michael J. Thun, MD=20

JAMA. 2005;294:105-106.

This = issue of=20 JAMA includes 2 articles from the Women=92s = Health=20 Study (WHS).1-2=20 This 10-year long, placebo-controlled, randomized = trial=20 of low-dose aspirin and vitamin E included nearly = 40 000 predominantly middle-aged women with no = history=20 of cancer or cardiovascular disease.3=20 The WHS used a 2 x 2 factorial = design to=20 evaluate the effects of low-dose aspirin (100 mg) = taken=20 every other day and 600 IU of vitamin E (in the = form of=20 natural-source 3D{alpha}=20-tocopherol),=20 also taken every other day. Neither = alternate-day,=20 low-dose aspirin nor vitamin E showed any = evidence of=20 efficacy in reducing overall cancer incidence or=20 mortality.1-2=20 With respect to noncancer outcomes, notable = findings for=20 low-dose aspirin included a reduction in stroke = risk, no=20 apparent effect on myocardial infarction, and an = increased=20 risk of gastrointestinal bleeding requiring=20 transfusion.4=20 Vitamin E had no apparent effect on either = cardiovascular=20 disease incidence or on gastrointestinal = bleeding.2=20

In considering the meaning of the WHS results with = respect=20 to cancer prevention, it is important to note 2 = strengths=20 of the study. First, because of its relatively = large size=20 and substantial number of outcome events (2865 = cases of=20 cancer overall, including 1230 breast cancer = cases, 269=20 colorectal cancer cases, and 583 cancer deaths), = the WHS=20 is unlikely to have missed true important effects = on=20 overall cancer incidence, breast cancer incidence,=20 colorectal cancer incidence, or overall cancer = mortality.=20 Second, because the intervention period lasted 10 = years,=20 an unusually long time for a randomized trial, = the=20 effects of relatively long-term low-dose aspirin=20 treatment and vitamin E supplementation could be=20 evaluated. This is important given that short-term=20 effects on cancer would not necessarily be = expected.=20

Could long-term, low-dose aspirin treatment (3D≤=20150 = mg/d)=20 produce any important reduction in risk of = cancer? The=20 WHS provides strong evidence that alternate-day, = low-dose=20 aspirin treatment does not, or at least not for = women=20 within the first 10 years of treatment. There was = no=20 suggestion of reduced risk for overall cancer = incidence,=20 breast cancer incidence, colorectal cancer = incidence, or=20 cancer mortality. This remained true even in analyses=20 restricted to the second 5 years of follow-up, when=20 participants in the intervention group had = already=20 accrued a minimum of 5 years of aspirin exposure. = To our=20 knowledge, no other studies, either randomized = trials or=20 observational studies, have evaluated the effect = of=20 alternate-day, low-dose aspirin on cancer risk. A = previous, considerably smaller, randomized trial = examined=20 alternate-day use of 325 mg of aspirin and found no=20 association with colorectal cancer = incidence.5=20 However, the 5-year intervention period of this = trial may=20 have been too short to produce clear effects. = Results=20 from the WHS do not entirely rule out the possibility=20 that taking low-dose aspirin every day, rather than = every=20 other day, could have some cancer prevention = benefits.=20 Evidence about the potential effects of daily = low-dose=20 aspirin on cancer risk is limited and includes = some=20 inconsistent findings. For example, a randomized = trial=20 found a dose of 81 mg/d reduced risk of colorectal = polyp=20 recurrence.6=20 However, analyses of pharmacy databases in the = United=20 Kingdom and Denmark found no association between = low-dose=20 aspirin use and colorectal cancer incidence.7-8=20

The null results from WHS with respect to alternate-day,=20 low-dose aspirin do not refute previous evidence = that=20 moderate or high doses of aspirin (3D≥=20325 = mg/d) may=20 reduce the risk of certain cancers. In numerous=20 observational studies, regular use of aspirin has=20 consistently been associated with reduced risk of = colon or=20 colorectal cancer, with most studies reporting = 30% to 50%=20 reductions in incidence.9=20 Two randomized trials have shown that aspirin treatment = reduces the recurrence of colorectal adenomatous = polyps in=20 patients with previous polyps6=20 or colorectal cancer.10=20 Aspirin use has also been consistently associated = with=20 reduced risk of esophageal and stomach cancer, = although=20 there are fewer studies of these cancers than of=20 colorectal cancer.9,=20 11=20 The totality of the evidence from laboratory = studies,=20 observational epidemiology, and randomized trials = of=20 colorectal polyp recurrence continues to support = the=20 hypothesis that moderate or high doses of aspirin = may=20 reduce the risk of colorectal cancer, and possibly the = risk=20 of certain other cancers as well.

The null results for vitamin E (in the form of 3D{alpha}=20-tocopherol) and cancer from the WHS = add to the=20 evidence from 2 previous trials12-13=20 that even relatively long-term 3D{alpha}=20-tocopherol=20 supplementation is unlikely to have any = substantial=20 effect on cancer risk, at least in women. An = unexpected=20 reduction in prostate cancer incidence was = observed among=20 men randomized to 3D{alpha}=20-tocopherol=20 in the Alpha-Tocopherol Beta Carotene (ATBC) = trial, a=20 study that included only male smokers.12=20 However, this association was not observed in the = Heart=20 Outcomes Prevention Evaluation=96The Ongoing Outcomes=20 (HOPE-TOO) trial,13=20 in postintervention follow-up of the ATBC = trial,14=20 or in 2 large prospective observational studies,15-16=20 and may have been a result of chance. Although ongoing = randomized trials17-18=20 will eventually provide further information, the = promise=20 of 3D{alpha}-tocopherol as a cancer prevention agent = appears=20 to be dimming.

Should the null results with respect to cancer from this=20 large, well-conducted, long-term randomized = trial, or=20 from other chemoprevention trials, be considered=20 discouraging news for cancer chemoprevention in = general?=20 There have been some successes in cancer = chemoprevention,=20 such as the use of tamoxifen to prevent breast cancer = in=20 high-risk women.19=20 However, currently, no agent has been shown to do for=20 cancer what statins do for cardiovascular disease, = namely=20 substantially and relatively safely reduce = disease=20 occurrence in individuals not at especially high = risk.=20 Pharmacological primary prevention of diseases as = heterogeneous as cancer is inherently difficult.=20 Randomized trials of cancer chemoprevention will=20 undoubtedly produce many null results. = Nevertheless,=20 continued systematic research on cancer = chemoprevention,=20 including long-term randomized trials of = carefully chosen=20 agents, is essential given the large potential = benefits.=20 At the same time, it is unrealistic to expect the = discovery of an agent that will produce substantial = reductions=20 in overall cancer rates in the immediate future. =

With this in mind, it is important to remember that=20 effective methods for reducing cancer incidence = and=20 mortality have already been discovered, but are=20 underapplied. For instance, colorectal cancer = screening=20 is greatly underused,20=20 providing an important cancer prevention = opportunity for=20 physicians and other health care professionals. = Reducing=20 tobacco use is essential for cancer prevention, = and=20 strong evidence indicates that policy measures, = such as=20 increases in tobacco excise taxes and clean indoor air=20 regulations, are effective in reducing tobacco = use.21=20 In addition, clinicians can play an invaluable = role in=20 cancer prevention by asking patients about = tobacco use=20 and ensuring that patients who use tobacco = receive=20 appropriate counseling and treatment.21=20


AUTHOR INFORMATION=20
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Corresponding = Author:=20 Eric J. Jacobs, PhD, Epidemiology and = Surveillance=20 Research, American Cancer Society, National Home = Office,=20 1599 Clifton Road NE, Atlanta, GA 30329 (eric.jacobs{at}cancer.org ).

Financial Disclosures: None reported.

Editorials represent the opinions of the authors and = JAMA=20 and not those of the American Medical = Association.=20

Author=20 Affiliations: Epidemiology and Surveillance Research, = American=20 Cancer Society, Atlanta, Ga.


REFERENCES=20
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1.=20 Cook NR, Lee I-M, Gaziano JM, et al. Low-dose aspirin in the = primary=20 prevention of cancer: the Women's Health Study: a randomized = controlled trial. JAMA. 2005;294:47-55. FREE FULL TEXT
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2.=20 Lee I-M, Cook NR, Gaziano JM, et al. Vitamin E in the = primary=20 prevention of cardiovascular disease and cancer: the Women's = Health=20 Study: a randomized controlled trial. JAMA. = 2005;294:56-65. FREE FULL TEXT
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3.=20 Rexrode KM, Lee I-M, Cook NR, Hennekens CH, Buring JE. = Baseline=20 characteristics of participants in the Women's Health Study. = J=20 Womens Health Gend Based Med. 2000;9:19-26. FULL = TEXT | ISI |=20 PUBMED
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4.=20 Ridker PM, Cook NR, Lee I, et al. A randomized trial of = low-dose=20 aspirin in the primary prevention of cardiovascular disease = in=20 women. N Engl J Med. 2005;352:1293-1304. FREE FULL TEXT
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5.=20 Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. = Low-dose=20 aspirin and incidence of colorectal tumors in a randomized = trial.=20 J Natl Cancer Inst. 1993;85:1220-1224. ABSTRACT
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6.=20 Baron JA, Cole BF, Sandler RS, et al. A randomized trial of = aspirin=20 to prevent colorectal adenomas. N Engl J Med.=20 2003;348:891-899. FREE FULL TEXT
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7.=20 Garcia Rodriguez L, Huerta-Alvarez C. Reduced risk of = colorectal=20 cancer among long-term users of aspirin and non-aspirin = nonsteroidal=20 anti-inflammatory drugs. Epidemiology. = 2001;12:88-93. FULL = TEXT | ISI |=20 PUBMED
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8.=20 Friis S, Sorensen HT, McLaughlin JK, Johnsen SP, Blot WJ, = Olsen JH.=20 A population-based cohort study of the risk of colorectal = and other=20 cancers among users of low-dose aspirin. Br J Cancer. = 2003;88:684-688. FULL = TEXT | ISI |=20 PUBMED
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9.=20 Harris RE, Beebe-Donk J, Doss H, Doss DB. Aspirin, = ibuprofen, and=20 other non-steroidal anti-inflammatory drugs in cancer = prevention: a=20 critical review of non-selective COX-2 blockade [review]. = Oncol=20 Rep. 2005;13:559-583. ISI |=20 PUBMED
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10.=20 Sandler RS, Halabi S, Baron JA, et al. A randomized trial of = aspirin=20 to prevent colorectal adenomas in patients with previous = colorectal=20 cancer. N Engl J Med. 2003;348:883-890. FREE FULL TEXT
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11.=20 Thun MJ, Henley SJ. Nonsteroidal anti-inflammatory drugs as=20 anticancer agents. In: DeVita VT, Hellman S, Rosenberg SA, = eds.=20 Cancer: Principles and Practice of Oncology. 7th ed.=20 Philadelphia, Pa: Lippincott Williams & Wilkins; = 2004:541-549.
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12.=20 Alpha-Tocopherol Beta Carotene Cancer Prevention Study = Group. The=20 effect of vitamin E and beta carotene on the incidence of = lung=20 cancer and other cancers in male smokers. N Engl J = Med.=20 1994;330:1029-1035. FREE FULL TEXT
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13.=20 Lonn E, Bosch J, Yusuf S, et al. Effects of long-term = vitamin E=20 supplementation on cardiovascular events and cancer: a = randomized=20 controlled trial. JAMA. 2005;293:1338-1347. FREE FULL TEXT
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14.=20 Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of = cancer and=20 mortality following 3D{alpha}=20-tocopherol=20 and beta-carotene supplementation: a postintervention = follow-up.=20 JAMA. 2003;290:476-485. FREE FULL TEXT
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15.=20 Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci = EL.=20 Supplemental vitamin E intake and prostate cancer risk in a = large=20 cohort of men in the United States. Cancer Epidemiol = Biomarkers=20 Prev. 1999;8:893-899. FREE FULL TEXT
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16.=20 Rodriguez C, Jacobs EJ, Mondul AM, Calle EE, McCullough ML, = Thun MJ.=20 Vitamin E supplements and risk of prostate cancer in U.S. = men.=20 Cancer Epidemiol Biomarkers Prev. = 2004;13:378-382. FREE FULL TEXT
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17.=20 Christen WG, Gaziano JM, Hennekens CH. Design of Physicians' = Health=20 Study II: a randomized trial of beta-carotene, vitamins E = and C, and=20 multivitamins, in prevention of cancer, cardiovascular = disease, and=20 eye disease, and review of results of completed trials. = Ann=20 Epidemiol. 2000;10:125-134.=20 FULL = TEXT | ISI |=20 PUBMED
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18.=20 Klein EA. Selenium and vitamin E cancer prevention trial. = Ann N Y=20 Acad Sci. 2004;1031:234-241.=20 FREE FULL TEXT
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19.=20 Fisher B, Costantino JP, Wickerham LD, et al. Tamoxifen for=20 prevention of breast cancer: report of the National Surgical = Adjuvant Breast and Bowel Project P-1 Study. J Natl = Cancer=20 Inst. 1998;90:1371-1388. FREE FULL TEXT
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20.=20 Seeff LC, Nadel MR, Klabunde CN, et al. Patterns and = predictors of=20 colorectal cancer test use in the adult U.S. population.=20 Cancer. 2004;100:2093-2103. FULL = TEXT | ISI |=20 PUBMED
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21.=20 US Department of Health and Human Services. Reducing = Tobacco Use:=20 A Report of the Surgeon General. Atlanta, Ga: US Dept of = Health=20 and Human Services, Centers for Disease Control and = Prevention,=20 National Center for Chronic Disease Prevention and Health = Promotion,=20 Office on Smoking and Health; 2000.
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RELATED=20 ARTICLES=20
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Low-Dose Aspirin in the Primary Prevention of = Cancer: The=20 Women=92s Health Study: A Randomized Controlled=20 Trial
Nancy R. Cook, I-Min Lee, J. Michael = Gaziano,=20 David Gordon, Paul M Ridker, JoAnn E. Manson, Charles H. = Hennekens,=20 and Julie E. Buring
JAMA. 2005;294:47-55. =
ABSTRACT<= /A>=20 | FULL=20 TEXT  =20

Vitamin E in the Primary Prevention of = Cardiovascular=20 Disease and Cancer: The Women=92s Health Study: A Randomized = Controlled Trial
I-Min Lee, Nancy R. Cook, J. = Michael=20 Gaziano, David Gordon, Paul M Ridker, JoAnn E. Manson, = Charles H.=20 Hennekens, and Julie E. Buring
JAMA. = 2005;294:56-65.=20
ABSTRACT<= /A>=20 | FULL=20 TEXT  =20

This Week in = JAMA
JAMA.=20 2005;294:9.
FULL=20 TEXT  =20


THIS ARTICLE HAS BEEN CITED BY OTHER = ARTICLES=20
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New=20 Women's Health Study Data on Vitamin E and=20 Aspirin
Journal Watch Cardiology=20 2005;2005:1-1.
FULL=20 TEXT  =20



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