About the PDQ Cancer Prevention Summaries
Carcinogenesis
Risk Factors
        Risk factors causally associated with cancer
        Risk/protective factors with uncertain associations with cancer
Interventions with Proven Benefits
        Chemoprevention
Interventions with no Proven Benefit
        Vitamin and dietary supplement use
Summary

Prevention is defined as the reduction of cancer mortality via reduction in the incidence of cancer. This can be accomplished by avoiding a carcinogen or altering its metabolism; pursuing lifestyle or dietary practices that modify cancer-causing factors or genetic predispositions; medical intervention (e.g., chemoprevention); or early detection strategies that can result in removal of precancerous lesions, such as colonoscopy for colorectal polyps.

The PDQ cancer prevention summaries are primarily organized by specific anatomic cancer site to facilitate consideration of the unique characteristics of specific malignancies. In this section, an overview of cancer prevention strategies is provided, including a summary of evidence for selected preventive strategies used in the prevention of a broad spectrum of malignancies. The strength of evidence and magnitude of effects of these strategies, however, may vary by cancer site. Other PDQ cancer prevention summaries address the prevention of specific types of cancer and provide more detailed descriptions of the evidence.

Carcinogenesis refers to an underlying etiologic pathway that leads to cancer. Several models of carcinogenesis have been proposed. Two widely cited models of carcinogenesis are those of Vogelstein and Kinzler [1] and Hanahan and Weinberg.[2] The model of Vogelstein and Kinzler emphasizes that cancer is ultimately a disease of damaged DNA, comprised of a sequence of genetic mutations that can transform normal cells to cancerous cells. The genetic mutations include inactivation of tumor suppressor genes and activation of oncogenes. Compared with cancers arising in the general population, individuals with a major inherited predisposition to cancer are born with inherited (i.e., germline) mutations in genes involved in cancer causation, giving them a head start on the pathway to cancer. Similar mutations would be expected to result in cancer progression among all individuals; however, in those without a major inherited cancer predisposition, the mutation would occur as a somatic mutation later during their lifetime.

The model of Hanahan and Weinberg focuses on the hallmark events at the cellular level that lead to a malignant tumor. In this model, the hallmarks of cancer include sustained angiogenesis, limitless replicative potential, evading apoptosis, self-sufficiency in growth signals, and insensitivity to antigrowth signals, leading to the defining characteristics of malignant tumors by giving them the ability to invade and metastasize. This model highlights the fact that malignant tumors arise and flourish within the environment of a whole organism. The tissue organizational field theory,[3] posits that carcinogenesis is better conceptualized at the level of tissues rather than cells. This theory is based on the dual premise that carcinogenesis is driven by defects in tissue organization and that all cells are inherently in a proliferative state.

Models of carcinogenesis such as these are purposefully simplistic but nevertheless illustrate that carcinogenesis requires a constellation of steps that often take place over decades.

The complexity of carcinogenesis is magnified when one considers that the specific details of the carcinogenic pathway described by these models would be expected to have unique characteristics for each anatomic site. Under these circumstances, the risk factors and clinical characteristics of malignancies exhibit considerable variation by anatomic site and by different tumor types within the same anatomic site. For these reasons, human cancer is really not a single disease but is a family of different diseases.

The promise for cancer prevention is derived from observational epidemiologic studies that show associations between modifiable lifestyle factors or environmental exposures and specific cancers. For a few exposures, randomized controlled trials have tested whether interventions suggested by epidemiologic studies and leads based on laboratory research result in reduced cancer incidence and mortality.

Decades of research have consistently established the strong association between tobacco use and cancers of many sites. Specifically, cigarette smoking has been established as a cause of cancers of the lung, oral cavity, esophagus, bladder, kidney, pancreas, stomach, cervix, and acute myelogenous leukemia. The body of epidemiologic evidence confirming these associations is substantial. Further support is demonstrated by the lung cancer death rates in the United States, which have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men. As a single exposure that is relatively easy to measure accurately, this extensive body of evidence has led to the estimation that cigarette smoking causes 30% of all cancer deaths in the United States. Smoking avoidance and smoking cessation results in decreased incidence and mortality from cancer. (Refer to the PDQ summaries on Lung Cancer Prevention; Lung Cancer Screening; and Prevention and Cessation of Cigarette Smoking: Control of Tobacco Use for more information.)

Globally, infectious agents have been estimated to cause 18% of all cancer cases.[4] The burden of cancers caused by infections is much greater in developing nations (26%) than in developed nations (8%). Infection with an oncogenic strain of human papillomavirus (HPV) is considered a necessary event for subsequent cervix cancer, and vaccine-conferred immunity results in a marked decrease in precancerous lesions. Oncogenic strains of HPV are also linked with cancers of the penis, vagina, anus, and oropharynx. Other examples of infectious agents that cause cancer are hepatitis B and hepatitis C viruses (liver cancer), Epstein-Barr virus (Burkitt lymphoma), and Helicobacter pylori (gastric cancer). If an infectious agent is truly a cause of cancer, then efficacious anti-infective interventions would be expected in most instances to be effective cancer prevention interventions. This is the expectation with vaccines that protect against infection with oncogenic strains of HPV. An example in which this principle would not hold true is that use of antibiotics may not prevent carcinogenesis from a cancer-causing bacteria in the setting of antibiotic resistance. (Refer to the PDQ summaries on Cervical Cancer Prevention; Cervical Cancer Screening; Liver (Hepatocellular) Cancer Prevention; and Liver (Hepatocellular) Cancer Screening for more information.)

Radiation is energy in the form of high-speed particles or electromagnetic waves. Exposure to radiation, primarily ultraviolet radiation and ionizing radiation, is a clearly established cause of cancer. Exposure to solar ultraviolet radiation is the major cause of nonmelanoma skin cancers, which are by far the most common malignancies in human populations.[5]

Ionizing radiation is radiation with enough energy to remove tightly bound electrons from their orbits, causing atoms to become charged or ionized. Ions formed by ionizations in the molecules of living cells can go on to react with and potentially damage other atoms in the cell. At low doses (e.g., those associated with background radiation), the cells repair the damage rapidly. At moderate doses, the cells may be changed permanently or die from their inability to repair the damage. Cells changed permanently may go on to produce abnormal cells when they divide, and in some circumstances, these altered cells may become cancerous or lead to other abnormalities (e.g., birth defects). There is extensive epidemiologic and biologic evidence that links exposure to ionizing radiation with the development of lethal cancer, and in particular, cancer that involves the hematological system, breast, and thyroid. The National Research Council of the National Academies, Committee to Assess the Health Risks from Exposure to Low Levels of Ionizing Radiation, the Biologic Effects of Ionizing Radiation VII report,[6] the most widely cited source on the topic, concluded after a comprehensive review of the medical literature that no dose of radiation should be considered completely safe, and attempts should be made to keep radiation doses as low as possible. They primarily cited three lines of evidence documenting the association between ionizing radiation exposure and cancer. The first line of evidence comes from studies of the development of cancer among Japanese atomic-bomb survivors. Even at low doses of radiation, atomic-bomb survivors were at a significantly increased risk of developing cancer. The second line of evidence comes from epidemiological studies of medically irradiated populations who were irradiated for both malignant and benign diseases. Following high-dose radiation therapy for malignant disease, the risk of secondary malignancy is high. The relatively common use of radiation for benign disease between 1940 and 1960 resulted in a substantial relative risk of developing cancer. The third line of evidence comes from an increased risk of cancer-specific mortality associated with the occupational exposure to medical ionizing radiation.

The major sources of population exposure to ionizing radiation are medical radiation (including x-rays, computer tomography [CT], fluoroscopy, and nuclear medicine) and naturally occurring radon gas in the basements of homes. Exposure to ionizing radiation has increased over the last 2 decades as a result of the dramatic increase in the use of CT. Exposure to ionizing radiation associated with CT is in the range where carcinogenesis has been demonstrated.[7,8] (Refer to the PDQ summaries on Breast Cancer Prevention; Breast Cancer Screening; Skin Cancer Prevention; and Lung Cancer Prevention for more information.)

Estimates concerning the potential contribution of diet to the population burden of cancer have varied widely. In contrast to the epidemiologic evidence on cigarette smoking and cancer, evidence for the influence of dietary factors and cancer is uncertain. An assessment of the potential role of diet entails measuring the net contribution of diets, comprising factors that may protect against cancer and other factors that may increase cancer risk. Measuring an individual’s usual diet and its direct relevance to cancer risk also poses challenges.

An assessment of the overall evidence of diet in relation to cancer prevention published by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) [9] was based on systematic reviews of the epidemiologic evidence. With respect to dietary factors that may protect against cancer, the greatest consistency was seen for fruits and nonstarchy vegetables. In the WCRF/AICR report, conclusions were reached that both fruits and nonstarchy vegetables were associated with “probable decreased risk” for cancers of the mouth, esophagus, and stomach. Fruits, but not nonstarchy vegetables, were also judged to be associated with “probable decreased risk” of lung cancer. Thus, even for the two dietary exposure classes that the current evidence suggests may have the greatest cancer prevention potential, the evidence was judged to be less than convincing and was applicable to only a few malignancies.

Examples in which the type of study design led to substantively different results further illustrate the complexities of the relationship between food and nutrient intake and human cancer risk. Observational epidemiologic studies (case-control and cohort studies) have suggested associations between diet and cancer development, but randomized trials of interventions provided little or no support. For example, on the basis of population-based epidemiologic data, high-fiber diets were recommended to prevent colon neoplasms. However, a randomized controlled trial of supplemental wheat bran fiber did not reduce the risk of subsequent adenomatous polyps in individuals with previously resected polyps. Ecologic, cohort, and case-control studies found an association between fat and red meat intake and colon cancer risk, but a randomized controlled trial of a low-fat diet in postmenopausal women showed no reduction in colon cancer. The low-fat diet did not affect all-cancer mortality, overall mortality, or cardiovascular disease.

With respect to dietary factors that may increase cancer risk, the strongest evidence in the WCRF/AICR report was for drinking alcohol. The evidence was judged to be “convincing” that drinking alcohol increased the risk of cancers of the mouth, esophagus, breast, and colorectum (the latter in men). Further, the evidence was judged to be “probable” that drinking alcohol increased the risk of liver cancer and colorectal cancer (the latter in women).

In relation to human cancer, diets reflect the sum total of a complex mixture of exposures, as demonstrated by the examples of fruit/vegetable intake and alcohol consumption. No dietary factors appear to be uniformly relevant to all forms of cancer. (Refer to the PDQ summaries on Breast Cancer Prevention; Breast Cancer Screening; Colorectal Cancer Prevention; and Lung Cancer Prevention for more information.)

A growing body of epidemiologic evidence suggests that people who are more physically active have a lower risk of certain malignancies than those who are more sedentary. In the WCRF/AICR report, the evidence was judged to be “convincing” that increased physical activity protects against colorectal cancer. The evidence was also judged to be “probable” that physical activity was associated with lower risk of postmenopausal breast cancer and endometrial cancer. As with the dietary factors described above, physical activity seems to play a more prominent role in selected malignancies. The inverse associations observed for selected malignancies make this a promising area for cancer prevention research, particularly since causal associations have not been established. The excess risk of many cancers seen with obesity, in combination with evidence to suggest that physical activity is inversely associated with at least a few cancers, raises the hypothesis that energy balance may influence cancer risk. (Refer to the PDQ summaries on Breast Cancer Prevention; Colorectal Cancer Prevention; and Endometrial Cancer Prevention for more information.)

Obesity is being increasingly recognized as an important cancer risk factor. The WCRF/AICR report concluded that body fatness is convincingly linked to postmenopausal breast cancer and cancers of the esophagus, pancreas, colorectum, endometrium, and kidney. Furthermore, the WCRF/AICR report judged body fatness to be a probable risk factor for cancer of the gallbladder. A prospective study of nationally representative cohorts that examined obesity in relation to cancer mortality emphasizes the point that factors associated with cancer do not uniformly apply to all human malignancies. The study results revealed that obesity was associated with an increased risk of dying from obesity-associated malignancies, but obesity was not associated with overall cancer mortality.[10] If the associations between obesity and the cancers mentioned above are causal, which has yet to be established, the current increase in the prevalence of obesity in the United States and elsewhere poses a severe challenge to cancer prevention efforts. Furthermore, weight loss has yet to be shown to reduce risk of obesity-associated malignancies.[11] (Refer to the PDQ summaries on Breast Cancer Prevention; Colorectal Cancer Prevention; Endometrial Cancer Prevention; and Lung Cancer Prevention for more information.)

Chemoprevention refers to the use of natural or synthetic compounds to interfere with early stages of carcinogenesis, before invasive cancer appears.[12] Chemoprevention trials have had some positive results. Daily use of selective estrogen receptor modulators (tamoxifen or raloxifene) for up to 5 years reduces the incidence of breast cancer by about 50% in high-risk women. Finasteride (an alpha-reductase inhibitor) lowers the incidence of prostate cancer; this finding was complicated by a greater cumulative incidence of high-grade cancers in the finasteride-versus-placebo-group. Further analysis suggest this was due to finasteride's shrinking the prostate but not the cancer, thereby increasing the ability to diagnose high grade cancer without contributing to progression of prostate carcinogenesis. Other chemoprevention candidates include COX-2 inhibitors (which inhibit the cyclooxygenase enzymes involved in the synthesis of proinflammatory prostaglandins) to prevent colon and breast cancer, although the possibility of increased cardiovascular events may preclude their usefulness. (Refer to the PDQ summaries on Breast Cancer Prevention; Colorectal Cancer Prevention; and Prostate Cancer Prevention for more information.)

Some have advocated vitamin and mineral supplements for cancer prevention. Many different mechanistic pathways for anticancer effects have been invoked. A commonly tested hypothesis is that antioxidant vitamins may protect against cancer, based on the premise that oxidative damage to DNA leads to cancer progression. Hence preventing oxidative DNA damage would prevent progression to cancer. However, the evidence is insufficient to support the use of multivitamin and mineral supplements or single vitamins or minerals to prevent cancer.[13] Beta carotene is an antioxidant that was thought to prevent or reverse smoking-related changes leading to lung cancer, based on the results of several observational epidemiologic studies; however, two prospective placebo-controlled trials found that smokers and former smokers who received beta carotene supplements had increased lung cancer incidence and mortality.[14]

Research into the potential anticancer properties of vitamin and mineral supplements is ongoing, and the results continue to reinforce the lack of efficacy of vitamin supplements in preventing cancer. Results from several large-scale randomized trials were published in early 2009. The results of the Selenium and Vitamin E Cancer Prevention Trial indicated that taking daily selenium or vitamin E or both did not reduce the incidence of prostate cancer compared with placebo.[15]

The results of the Physicians’ Health Study II demonstrated that supplementation with vitamin E and/or vitamin C had no benefit compared with placebo in preventing either prostate cancer incidence or total cancer incidence.[16]

The results of the Women’s Antioxidant Cardiovascular Study indicated that, compared with placebo, supplementation with vitamin C, vitamin E, or beta carotene was not efficacious in reducing total cancer incidence.[17] In this same study, daily supplements containing folic acid, vitamin B6, and vitamin B12 were compared with placebo; this intervention was not efficacious in reducing the overall risk of developing cancer.[18] (Refer to the PDQ summaries on Breast Cancer Prevention; Colorectal Cancer Prevention; Lung Cancer Prevention; Prostate Cancer Prevention; and Prostate Cancer Screening for more information.)

The list of topics considered above is not exhaustive. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexual and reproductive practices, the use of exogenous estrogens, and certain occupational and chemical exposures.

In this summary, factors were selected that appear to impact the risk of several types of cancer and that have been identified as being potentially modifiable. These include cigarette smoking, which has been conclusively linked with a wide range of malignancies; avoidance of cigarette smoking has been shown to reduce cancer incidence. Other potential modifiable cancer risk factors include alcohol consumption and obesity; physical activity is inversely associated with the risk of certain cancers. More research is needed to determine whether these associations are causal and whether avoiding risk behaviors or increasing protective behaviors would actually reduce cancer incidence.

References

1. Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 10 (8): 789-99, 2004.  [PUBMED Abstract]
   
   
2. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100 (1): 57-70, 2000.  [PUBMED Abstract]
   
   
3. Sonnenschein C, Soto AM: Theories of carcinogenesis: an emerging perspective. Semin Cancer Biol 18 (5): 372-7, 2008.  [PUBMED Abstract]
   
   
4. Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118 (12): 3030-44, 2006.  [PUBMED Abstract]
   
   
5. Scotto J, Fears TR, Fraumeni JF Jr: Solar radiation. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 2nd ed. New York, NY: Oxford University Press, 1996, pp 355-72. 
   
   
6. National Research Council (U.S.), Committee to Assess Health Risks from Exposure to Low Level of Ionizing Radiation.: Health Risks From Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: National Academies Press, 2006. Also available online. Last accessed June 9, 2009. 
   
   
7. National Council on Radiation Protection and Measurements.: Ionizing Radiation Exposure of the Population of the United States. Bethesda, Md: National Council on Radiation Protection and Measurements, 2009 Also available online. Last accessed June 9, 2009. 
   
   
8. Mettler FA Jr, Thomadsen BR, Bhargavan M, et al.: Medical radiation exposure in the U.S. in 2006: preliminary results. Health Phys 95 (5): 502-7, 2008.  [PUBMED Abstract]
   
   
9. Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective . Washington, DC: World Cancer Research Fund International, American Institute for Cancer Research, 2007. Also available online. Last accessed May 5, 2009. 
   
   
10. Flegal KM, Graubard BI, Williamson DF, et al.: Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 298 (17): 2028-37, 2007.  [PUBMED Abstract]
    
    
11. Wolin KY, Colditz GA: Can weight loss prevent cancer? Br J Cancer 99 (7): 995-9, 2008.  [PUBMED Abstract]
    
    
12. William WN Jr, Heymach JV, Kim ES, et al.: Molecular targets for cancer chemoprevention. Nat Rev Drug Discov 8 (3): 213-25, 2009.  [PUBMED Abstract]
    
    
13. Huang HY, Caballero B, Chang S, et al.: The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Ann Intern Med 145 (5): 372-85, 2006.  [PUBMED Abstract]
    
    
14. Gallicchio L, Boyd K, Matanoski G, et al.: Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin Nutr 88 (2): 372-83, 2008.  [PUBMED Abstract]
    
    
15. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009.  [PUBMED Abstract]
    
    
16. Gaziano JM, Glynn RJ, Christen WG, et al.: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301 (1): 52-62, 2009.  [PUBMED Abstract]
    
    
17. Lin J, Cook NR, Albert C, et al.: Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 101 (1): 14-23, 2009.  [PUBMED Abstract]
    
    
18. Zhang SM, Cook NR, Albert CM, et al.: Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 300 (17): 2012-21, 2008.  [PUBMED Abstract]
    
    

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