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"Scientific Controversies" Forum on Vitamin D: A Lot of Discussion, Little Agreement

Thursday, March 31, 2011 0 comments

As is clear from a number of our recent posts, there's some long-brewing controversy in academic and public health circles about the potential benefits and risks of raising the recommended daily amounts of vitamin D. One main camp believes that there is pretty solid evidence that daily vitamin D intakes of 1000 - 2000 IU could have significant health benefits - lowering the risk of osteoporosis, heart disease, cancer, even early death. The other main camp believes that the current evidence only backs bone-health benefits, which come at lower daily amounts of vitamin D, and that other benefits have yet to be demonstrated.

Both of these camps, and a couple ancillary ones, are captured in this video forum hosted by our colleagues at the Harvard School of Public Health, featuring among others, Dr. JoAnn Manson and Dr. Walter Willett.

For anyone interested in the topic, and scientific argument, it's worth a viewing: Boosting Vitamin D: Not enough or too much?

Related CNiC Posts

Our Perspective: Another Missed Opportunity for Vitamin D?

Are the New Recommendations on Vitamin D a Missed Opportunity?
Vitamin D and cancer - update

With Spring in the Air, New Sun-Safe, UV-Safe Recommendations from the American Academy of Pediatrics

Tuesday, March 29, 2011 0 comments

With spring in the air and the long sunny days of summer not too far off, the American Academy of Pediatrics has released a new policy statement on the hazards of UV radiation exposure in children and adolescents. The statement, published in the journal Pediatrics (link), refreshes and reinforces what many of us know - that unprotected sun exposure and tanning bed use are unhealthy activities for everyone, but particularly so for youth. UV radiation exposure raises the risk of skin cancer, including deadly melanoma, rates of which keep climbing higher and higher.

As we've chronicled in a number of previous blog posts (UV, tanning beds), a lot of us fall short when it comes to protecting ourselves against UV exposure. About a third of people in the US report at least one sunburn a year, with about 20 percent reporting four or more. The high rates of tanning bed use by teenagers, particularly girls, is particularly concerning, given the high concentration of UV radiation delivered by tanning beds and that the exposure occurs in a time of life that seems most important for later melanoma risk.

Taking steps to lower exposure to natural and artificial sources of UV in youth and young adults could have huge health benefits. Among a number of items, the AAP policy statement recommends that:

Pediatricians -

Incorporate advice about UV exposure in their practices
Use visits for sunburns as "teachable moments" about UV protection
Continue to encourage outdoor physical activity but in a sun-safe manner
Talk jointly with parents and children about sun-safe practices when kids get older and more independent, around ages 9 - 10
Advocate for safe-sun practices at school - earlier outdoor time, loosening of restrictions against hats, and shaded play areas

Governments -

Develop communication campaigns that raise awareness of the dangers of indoor tanning
Support broad use of successful safe-sun programs, such as the EPA's SunWise
Work toward laws/policies that ban minors' use of indoor tanning

Wholesale changes in sun exposure policies and behaviors aren't required to see positive results. Like most public health efforts, small changes can lead to significant health benefits and, even more importantly, can get the ball rolling toward bigger changes in policies and behaviors.

Coming out of a long winter, it's that time of year when the sun is at its most inviting. It also makes it a great time to lay the foundation for the sun-protection practices that we, and our kids, will carry throughout the summer and, hopefully, the rest of life.

Related CNiC Posts

Mother/Daughter Tanning and the Dual Nature of Family History

Video: No Such Thing as Safe Tanning

More Blistering Truths About Tanning Bed Use By Youth

Tanning Beds, Addiction, and Taxes

New Findings on UV in Winter: Keep That Sunscreen Handy

References Cited

Policy Statement: Ultraviolet Radiation - A Hazard to Children and Adolescents. Pediatrics. 2011 Mar;127(3):588-97.

Our Perspective: Another Missed Opportunity for Vitamin D?

Thursday, March 24, 2011 0 comments

Despite all its good press of late, vitamin D's health benefits have been challenged recently, most notably in an Institute of Medicine (IOM) report at the tail end of 2010 and in a Perspective piece in the New England Journal of Medicine yesterday (link). That the two papers have similar conclusions - vitamin D has bone health benefits but no demonstrated benefits for chronic diseases like heart disease and cancer - isn't too surprising. The latest Perspective paper was written by three of the committee members on the earlier IOM report.

In our response to that IOM paper we wrote that:

The IOM report takes a typically conservative approach to assessing studies of potential benefits and potential risks related to vitamin D intake, as well as to the blood levels of vitamin D that qualify as “sufficient.” Such an approach often minimizes potential benefits while highlighting potential risks. This can help safeguard the nation’s health from the zeitgeist of diet crazes, but when it comes to vitamin D it seems more like a missed opportunity. (Are the New Recommendations on Vitamin D a Missed Opportunity?)

In a nutshell, this captures our thoughts on the Perspective paper as well, which focuses on the potential links between vitamin D and cancer risk.

Looking at colon cancer alone, there is good evidence that people with higher circulating vitamin D levels can have as little as half the risk of developing colon cancer as those with lower vitamin D levels (International Agency for Research on Cancer 2008).

For a supplement that has a lot of potential benefit and little risk at levels that could bring this benefit, do we really need to wait 5 or more years until more definitive data might be available?

Related CNiC Posts
Are the New Recommendations on Vitamin D a Missed Opportunity?

Vitamin D and cancer - update

References Cited
International Agency for Research on Cancer (2008). Vitamin D and Cancer. Lyon, International Agency for Research on Cancer.

(Video) "8 Ways" Campaign Kickoff: Is It Possible to Prevent Cancer?

Wednesday, March 16, 2011 0 comments

After toiling for a number of years as a companion piece to our popular Your Disease Risk website, our 8 Ways to Stay Healthy and Prevent Cancer is finally breaking out and into its own spotlight (link; PDF). For the next ten months, the 8 Ways will be the cornerstone of a health promotion campaign in a partnership with KSDK TV in St. Louis.

Needless to say, the CNiC team is very excited to play an integral role in the campaign. A good proportion of the US population still questions the power of healthy behaviors to lower the risk of cancer. Through this campaign, we hope to make a real difference by changing some minds and helping people move toward healthier lifestyles.

The brief video below gives a nice overview of the campaign and features CNiC's Graham Colditz. (Cick here or the image below to see video.)

Related Links
8 Ways to Stay Healthy and Prevent Disease. A review of the 8 key things people can do to lower the risk of heart disease, stroke, diabetes, osteoporosis, and cancer.
Cancer Survivors' 8 Ways to Stay Healthy After Cancer. Eight tips that help lay the foundation for the many health-filled years that most survivors enjoy.

Related CNiC Posts

7-Minute Abs: The Science and Sense Behind Our "8 Ways to Stay Healthy and Prevent Cancer"

Priorities for prevention: breast cancer survivors

Finding the key to health as a cancer survivor: a new 8 ways

Physical activity prevents colon cancer

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In a detailed review of evidence from 20 studies one of us, Kathleen Wolin, reports that higher levels of physical activity protect against colon cancer (see study) and now the precursor lesions, colon polyps (see study) . The evidence is consistent across study design, approaches to assessment of physical activity, and the populations studied. Key features of this extensive review include the thorough search of the literature and use of state of the art statistical approaches to combine the evidence on activity and colon cancer risk.

By evaluating both colon polyps, the precursor lesion from which the majority if colon cancers develop, as well as colon cancer, Wolin is able to show that sustaining activity over the lifetime will lead to the greatest reduction in colon cancer. The parallel evidence from our previous work estimating the overall benefit of activity against colon cancer, sustained activity at the level of one hour of walking per day from age 30 to age 70 will reduce colon cancer by half compared to those who do not exercise at all (see table of results). This significant 50 percent reduction in new cases of colon cancer is a benefit that most of us can achieve. In addition, exercise reduces risk of heart disease and diabetes as well as other major chronic conditions.

Colon cancer is largely preventable. In addition to a healthy diet, maintaining a healthy weight and being physically active, screening significantly reduces the risk of both the diagnosis of colon cancer and death from colon cancer. See our related post,

New Results Further Confirm that Screening Prevents Death from Colon Cancer

Folate protects against colon cancer

Thursday, March 10, 2011 0 comments

The potential for folate to protect against colon cancer remains a question debated in the scientific literature. In part this is fed by short term studies of supplementation and the potential for an adverse effect in this setting where folate may promote the final development of colon cancer. ¹ However, across a larger number of studies evidence is confirming that higher folate levels lower long term risk of colon cancer. Let us look at that evidence.

Lee and colleagues recently reviewed the evidence for folate intake and colon cancer development by studying the time course of exposure and risk. ² This is essential when addressing the potential for prevention . ³ We note that they see a significant reduction in risk of colorectal cancer when they evaluated intake 12 to 16 years before diagnosis. Risk was reduced by 30 percent comparing those who consumed 800 micrograms per day or more against those who consumed less than 250 micrograms per day. Recent intake was not related to risk. To further refine understanding of this association the authors assessed intake in relation to the development of colon polyps, the precursor lesions from which the majority of colon cancers develop. They saw that both long and short term intake of folate were related to significantly lower risk of colon adenomatous polyps. ²

Current use of a multivitamin for 15 or more years reduced risk of colon cancer, but shorter use did not. These results are further supported by the combine data from 13 prospective cohort studies. With over 725,000 participants, these studies included over 5700 cases of colon cancer. ⁴ Dietary folate was associated with a significant reduction in risk of colon cancer. Further more the risk of colon cancer was reduced in a linear relation with higher intake of folate. A systematic review including 27 studies also showed a significant reduction in risk of colorectal caner. ⁵ Plasma folate levels also show this protective relation. ⁶

Across these studies the evidence strongly supports protection against colon cancer. While some studies have not found an effect, this may in large part be attributed to looking too close to the diagnosis of colon cancer – a time when the premalignant lesion ahs already formed. The new evidence on duration emphasizes the importance of long-term exposure to protect against cancer and the need to better focus epidemiologic studies on the appropriate time course of cancer development to improve understanding of the potential for prevention. ^7-8

Literature cited

1. Drake BF, Colditz GA. Assessing cancer prevention studies--a matter of time. JAMA : the journal of the American Medical Association. Nov 18 2009;302(19):2152-2153.

2. Lee JE, Willett WC, Fuchs CS, et al. Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr. Jan 26 2011.

3. Colditz GA, Taylor PR. Prevention trials: their place in how we understand the value of prevention strategies. Annu Rev Public Health. Apr 21 2010;31:105-120.

4. Kim DH, Smith-Warner SA, Spiegelman D, et al. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. Nov 2010;21(11):1919-1930.

5. Kennedy DA, Stern SJ, Moretti M, et al. Folate intake and the risk of colorectal cancer: A systematic review and meta-analysis. Cancer Epidemiol. Feb 2011;35(1):2-10.

6. Wei EK, Giovannucci E, Selhub J, Fuchs CS, Hankinson SE, Ma J. Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst. May 4 2005;97(9):684-692.

7. Colditz GA, Beers C. Active Cancer Prevention. In: Elwood M, Sutcliffe S, eds. Cancer Control. Oxford: Oxford University Press; 2010.

8. Colditz GA. Ensuring long-term sustainability of existing cohorts remains the highest priority to inform cancer prevention and control. Cancer causes & control : CCC. May 2010;21(5):649-656.

Taking a Step Back to Find Prevention's Place

Monday, March 7, 2011 0 comments

As a spin-off of our recent 7-Minute Abs post, I've spent part of the past week working on a journal article about the evidence and rationale behind our 8 Ways to Stay Healthy and Prevent Cancer (8 Ways link). And one of the things that the process of reviewing the science and writing the paper reminded me of what just how straightforward the major cancer prevention recommendations are, especially given the huge benefits they can hold. Things like maintaining a healthy weight, not smoking, and getting regular excercise and screening tests could eliminate half of all cancers and three quarters of some specific ones.

Public health has always had this type of focus, choosing the straightforward, broad-based approach with proven benefits whenever possible. Yet, as Sean Palfrey writes in a new Perspective piece in the New England Journal of Medicine this approach towards health is becoming more and more endangered in the high-tech era where more medical tests and more health care are generally equated with better health care.

He argues that medical education and medical care in general needs to take a step back and rely more on good clinical decision-making, rather than knee-jerk testing that may result in more test data but not necessarily any better outcomes. "Our time and attention," he writes, "have been diverted to the the task of sorting out data instead of sorting out what is important to our patients, their families, and the community at large."

An extension of this, which Palfrey hints at but doesn't explicitly state, is to broaden the clinical reach to include whole-hearted efforts at prevention. This will take a big reordering of priorities, given that prevention is often relegated to a lower rung on the medical education ladder, but it is far from hopeless. The new health care reform bill has a number of prevention-related provisions that should, if not spotlight prevention, make it an important behind-the-scenes player in the nation's health.

Time will tell where things fall. But with the science of prevention showing the large health benefits possible with behaviors we can all do, it makes little sense to not take a hard look at the current paradigm and try to get back in touch with the basics of clinical care. And what could be more basic than a healthy lifetyle?

Primary prevention of colon cancer, time to act is now!

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In this short update we draw attention to the strength of evidence that colon cancer is largely preventable with what we already know. While we have provided more extensive summaries of the overall evidence in the past ¹, and have reported in detail on specific lifestyle habits and colon cancer ^2,3, our goal here is to provide a quick update to help readers see just how strong the evidence is. For each lifestyle factor we provide a short summary of the evidence.

Data from US based cohorts show that more than 90% of adults have one or more lifestyle factors that they could change to reduce their risk of colon cancer ⁴ and other chronic diseases like diabetes ⁵ and heart disease.⁶ We conclude that if Americans modify the behavioral factors that we summarize here, with changes at an early enough age to reverse risk, then more than 80% of colon cancers could be prevented in the long term ⁴. While risk reduction strategies can be evaluated either individually or in combination showing substantial benefits for the population ⁷, we do not yet have community wide studies showing this benefit in real time – some of the challenge is the time lag from change in a health behavior to subsequent development of genetic changes, growth of tumor, and diagnosis of cancer.⁸

Table Summary of relative risk, as well as the prevalence, of each of the modifiable and no-modifiable factors related to colon cancer.

*Lifestyle factor*	*Relative risk*	*Reference*	*Population percentage who can change behavior*
Modifiable			Women	Men
Physical activity (>3 hours per week)	0.75	Wolin ²	80%	80%
Meat >7 servings per week	1.5	WCRF ⁹	25%	25%
Obesity Per 5kg/m2	1.24	Renehan ¹⁰	40%	35%
Alcohol >4 drinks per day vs. never	1.5	Fedirko ¹¹	5%	10%
Cigarette smoking	1.4	Tsoi ¹² Liang ¹³	20%	20%
Aspirin use Daily for 5 years	0.5	Flossmann ¹⁴ Rothwell ¹⁵	80%	70%
Calcium 1200 mg/day	0.80	Baron ¹⁶ Cho ¹⁷	20%	25%
Estrogen use	0.80	Grodstein ¹⁸	~	n/a
Oral contraceptive use	0.80	Martinez ¹⁹ Bosetti ²⁰	~	n/a
Non modifiable
Family history Parent or sibling	1.8	Fuchs ²¹	5%	5%
Height Per 6 inches	1.2	Wei ⁷	~	~
Screening
Colonoscopy	0.5	Frazier ²²	Approx 50% total population up to date & screened
Sigmoidoscopy	0.5	Atkin ²³	Approx 50% total population up to date & screened

The factors are listed based on the strength of the scientific evidence that a particular factor affects colon cancer risk. We also note that the majority of modifiable risk factors also contribute to other health benefits if changes are made to reduce colon cancer risk.

For example, the observational data on physical activity and colon cancer are very consistent ², the benefits of physical activity for cardiovascular and bone health are well-established ²⁴, and the adverse consequences of physical activity are minimal if it is done sensibly. Furthermore the level of inactivity in the population suggests that the vast majority of Americans could gain health benefits form increasing their level of activity.

Notably, the majority of the population is not engaging in the behaviors known to be most protective against colon cancer: 80% of adults are active less than 3 hours a week ²⁵ and 25% consume more than 7 servings of meat a week. The observational data on red meat consumption and colon cancer are only a little less consistent ⁹, there may be cardiovascular benefits to restricting red meat consumption, and the adverse consequences are almost entirely cultural and economic.

The data on obesity and colon cancer are rigorously combined by Renehan and show consistent direct relation between increasing Body Mass Index (BMI) and risk of colon cancer. ¹⁰

Calcium supplementation reduces risk of colorectal polyps and colon cancer. A randomized trial shows the does of 1200 mg per day reduces risk of polyps by 20% ¹⁶ and that this benefit persists for many years after stopping therapy. ²⁶ In addition, combined data from prospective cohort studies shows this level of calcium intake (1200mg per day) is sufficient for protection against colon cancer and that there is little added benefit from higher intakes. ¹⁷ Importantly, the lack of benefit in the randomized trial component of the Women’s Health Initiative that evaluated calcium and vitamin D in relation to colon cancer risk had the mean intake at randomization already at the 1200 mg per day for women in the trial. Thus there was likely little room for benefit in terms of reduction in risk with even high intakes during the trial. ²⁷

Alcohol is a known carcinogen causing cancer of the mouth and throat as well as breast and colon. Data on colon cancer have been combined from 27 cohort studies and 34 case-control studies.¹¹ In the combined analysis risk for colorectal cancer increased with the amount of alcohol consumed. Compared to non-drinkers, those consuming 50 grams per day (4 drinks) had a relative risk of 1.38 (95% confidence interval 1.28 to 1.50). ¹¹ Risk was present in men and women.

For aspirin, it is now clear that eicosanoids and the COX pathway play a role in neoplasia. However, there is no certain knowledge about dose and regimen, and the side effects of gastrointestinal and cerebral bleeding are well known. Evidence from several randomized trials suggests that a daily does of 75 mg is sufficient to obtain the benefit of reduce colon cancer with no added benefit form higher doses. ¹⁵ Importantly, data show that the benefit accrues some years after starting daily aspirin. ¹⁵ Furthermore, when dose and duration are taken into account the data from randomized trials and the prospective cohort studies show equivalent benefits from use of aspirin. ¹⁴ In sum, the data from randomized trials for prevention of cardiovascular disease agree with observational data when dose and duration are considered together ^14,15,28. Five years of use gives approximately 50 percent reduction in risk of death from colon cancer through 20 years of follow-up.

Cigarette smoking is a cause of many cancers. Colon cancer has been added to the list of sites where smoking now is directly related to increased risk of cancer. Combining data from 28 prospective cohort studies Tsoi and colleagues reported that current smokers had an increased risk of colorectal cancer (RR 1.20) and that the risk was stronger among men (RR=1.38). Longer duration of smoking and number of cigarettes smoked per day also increased risk of colorectal cancer. ¹²

Among women use of oral contraceptives is related to reduced risk of colorectal cancer. ^19,20 In addition, among postmenopausal women, those who currently use hormone therapy have reduced risk of colon cancer. ¹⁸

Family History

Strong evidence shows that this common malignancy has an inherited component. Those with family history gain added benefit from changing lifestyle factors and from screening. Recommendations for screening now indicate that hose with a family history should begin screening at a younger age. Obviously you need to let your health care providers know about your family history if they are to order screening tests at the appropriate age.

Given that most Americans are not engaging in behaviors known to prevent development of malignancy, early detection of polyps and colon cancer must become routine and commonplace.

Screening

For most diseases, screening is considered ‘secondary prevention’ because it detects early forms of cancer, but does not prevent the actual development of disease.

However, colon cancer screening can be considered either primary prevention or secondary prevention because the tests have the ability to detect, and often remove, both precancerous polyps and carcinomas. Approaches to colon cancer screening are cost-effective²² and are now widely integrated into primary care. Primary prevention via screening involves the removal of precancerous polyps that may have progressed to carcinoma if left undetected. Evidence suggests that removal of polyps in a population does lead to a significant reduction in the incidence of colon cancer. ²³ A randomized trial of flexible sigmoidoscopy included 113,195 people assigned to the control group and 57,237 assigned to flexible sigmoidoscopy. ²³ During follow-up of 11 years colon cancer incidence was significantly reduced in the screened group (23 percent reduction compared to that in the unscreened group). Mortality from colon cancer was reduced by 31 percent. Both reductions were statistically significant providing further support for recommendations that screening reduced incidence and mortality form this cancer.

Related CNiC posts

Colon Cancer Screening - Just a (great) first step

Literature cited

1. Tomeo C, Colditz G, Willett W, et al. Harvard report on cancer prevention Volume 3: Prevention of colon cancer in the United States. Cancer Causes and Control. 1999;10:167-180.

2. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer. Feb 24 2009;100(4):611-616.

3. Colditz G, Cannuscio C, Frazier A. Physical activity and colon cancer. Cancer Causes Control. 1997;8.

4. Platz E, Willett W, Colditz G, Rimm E, Spiegelman D, Giovannucci E. Proportion of colon cancer risk that might be preventable in a cohort of middle-aged US men. Cancer Causes Control. 2000;11:579-588.

5. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifetsyle, and risk of type 2 diabetes mellitus in women. N Eng J Med. 2001;345:790-797.

6. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary Prevention of Coronary Heart Disease in Women through Diet and Lifestyle. N Engl J Med. July 6, 2000 2000;343(1):16-22.

7. Wei EK, Colditz GA, Giovannucci EL, Fuchs CS, Rosner BA. Cumulative Risk of Colon Cancer up to Age 70 Years by Risk Factor Status Using Data From the Nurses' Health Study. Am J Epidemiol. Sep 1 2009.

8. Wei EK, Wolin KY, Colditz GA. Time course of risk factors in cancer etiology and progression. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Sep 10 2010;28(26):4052-4057.

9. World Cancer Research Fund. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington, DC: AICR; 2007.

10. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. Feb 16 2008;371(9612):569-578.

11. Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Feb 9 2011.

12. Tsoi KK, Pau CY, Wu WK, Chan FK, Griffiths S, Sung JJ. Cigarette smoking and the risk of colorectal cancer: a meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol. Jun 2009;7(6):682-688 e681-685.

13. Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer. May 15 2009;124(10):2406-2415.

14. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. May 12 2007;369(9573):1603-1613.

15. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. Nov 20 2010;376(9754):1741-1750.

16. Baron J, Beach M, Mandel J, et al. Calcium supplements for the prevention of colorectal adenomas.

Calcium Polyp Prevention Study Group. N Engl J Med. 1999;340:101-107.

17. Cho E, Smith-Warner SA, Spiegelman D, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. Jul 7 2004;96(13):1015-1022.

18. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med. May 1999;106(5):574-582.

19. Martinez M, Grodstein F, Giovannucci E, et al. A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer. Cancer Epidemiol Biomarker Prev. 1997;6:1-5.

20. Bosetti C, Bravi F, Negri E, La Vecchia C. Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis. Hum Reprod Update. Sep-Oct 2009;15(5):489-498.

21. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer. N Engl J Med. 1994;331:1669-1674.

22. Frazier AL, Colditz GA, Fuchs CS, Kuntz KM. Cost-effectiveness of screening for colorectal cancer in the general population. JAMA. Oct 18 2000;284(15):1954-1961.

23. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. May 8 2010;375(9726):1624-1633.

24. U.S. Department of Health and Human Services. Physical activity and health: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion.; 1996 1996.

25. U. S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, The President's Council on Physical Fitness and Sports. Physical Activity and Health: A Report of the Surgeon General. Washington, DC: Office of the Surgeon General;1996.

26. Grau MV, Baron JA, Sandler RS, et al. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst. Jan 17 2007;99(2):129-136.

27. Martinez ME, Marshall JR, Giovannucci E. Diet and cancer prevention: the roles of observation and experimentation. Nat Rev Cancer. Aug 7 2008.

28. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. Jan 1 2011;377(9759):31-41.

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