Cancer prevention

INTRODUCTION  Cancer deaths exceed seven million worldwide each year, despite overwhelming evidence that many malignancies are preventable Survival rates are improving, but nearly half a million people die from cancer each year in the United States (US) alone. Cancer outranks cardiovascular disease as the number one cause of death in the US for those under the age of 85

Both screening and prevention can reduce mortality from cancer. Screening detects abnormalities before they are clinically apparent, allowing for intervention either before cancer develops or at an early stage, when treatment is most often effective. Prevention strategies focus on modifying environmental and lifestyle risk factors which promote cancer. It is estimated that 50 percent of cancer is preventable

Multiple cancer risk factors have been identified; tobacco use, excess weight, poor diet, and inactivity account for two-thirds of all cancers in the US. In one study, nine modifiable risks were identified as the cause of 35 percent of cancer deaths worldwide: smoking, alcohol use, diet low in fruit and vegetables, excess weight, inactivity, unsafe sex, urban air pollution, use of solid fuels, and contaminated injections in health-care settings. Lifestyle factors have been linked to a variety of malignancies, including the most common in the developed world: lung, colorectal, prostate, and breast cancer

This topic reviews the major modifiable cancer risk factors and briefly addresses chemoprevention. Lifestyle issues which promote cancer are also risk factors for other diseases, such as stroke, heart disease, and diabetes.

TOBACCO USE  Tobacco use kills approximately 5 million people each year, mostly through malignancy, cardiovascular, and respiratory disease. Approximately one-half of all smokers die of a tobacco-related disease, and adult smokers lose an average of 13 years of life due to this addiction

Smoking is responsible for approximately 30 percent of all cancer-related deaths in the US. It is the strongest risk factor for lung cancer, increasing risk 10 to 20-fold. Smoking is also implicated as a causative factor for leukemia as well as cancers of the oral cavity, nasal cavity, paranasal sinuses, nasopharynx, larynx, esophagus, pancreas, liver, stomach, cervix, kidney, large bowel, and bladder Some evidence also ties smoking to more aggressive prostate cancers, while the relationship of smoking and breast cancer risk is controversial. (See relevant topic reviews on the risk factors for all of these cancers).

Tobacco acts on multiple stages of carcinogenesis: it delivers carcinogens directly to tissues, causes irritation and inflammation, and interferes with the body's natural protective barriers. The dangers of tobacco are most commonly associated with cigarette smoking, but also occur with cigar, pipe, smokeless tobacco, and exposure to environmental (second-hand) tobacco smoke.

Significant health benefits accompany quitting, even for longtime tobacco users. Smoking cessation leads to reduced risk of most tobacco-related diseases and a decrease in all cause mortality. The health benefits of quitting can be seen at all ages and can be measured almost immediately after cessation

Tobacco prevention and cessation  It is crucial to both prevent initiation and promote cessation of tobacco use, given the tremendous harm of tobacco dependency. Programs and policies that reduce youth initiation and facilitate smoking cessation must be implemented in both clinical and community settings. Responsibilities for health care providers include advice and counseling, referrals to behavioral therapy and support groups, and prescriptions for nicotine replacement and other medications

DIET  A variety of dietary factors have been studied in relation to cancer. Some (dietary fat, fruits, vegetables, fiber) have not consistently been shown to affect cancer risk. Intake of other nutrients, particularly certain micronutrients, may offer a degree of protection against malignancy.

Dietary fat  Dietary fat has been extensively studied as a possible explanation for variations in international cancer rates. No clear link has been found between total fat intake and colon or breast cancer but the data are more convincing for prostate cancer and endometrial cancer

  • Epidemiologic studies of colon cancer, when adequately controlled for caloric intake, have shown no consistent association between total fat intake and cancer risk. In the prospective Women's Health Initiative Dietary Modification Trial, 48,835 women aged 50 to 79 years were randomly assigned to a behavioral modification program to decrease dietary fat or a usual diet control group. The intervention group, compared to the control group, did reduce the percentage of calories consumed as fat (by 10.7 percent in year one, 8 percent at year six). There was no difference in incidence of colorectal cancer during 8.1 years of follow-up.
  • Animal and ecologic (international) studies have shown a positive correlation between fat consumption and increased breast cancer risk, but the results of prospective case-control and cohort studies have been mixed, possibly because of the limited range of dietary fat that is typical in the American diet, and an interaction between menopausal status and fat intake. As an example, in the same cohort from the Women's Health Initiative cited above, the incidence of breast cancer in 8.1 years of follow-up was not statistically different between low dietary fat and control groups; however, there was a trend to breast cancer reduction in the low fat intervention group, especially for women with high baseline fat intake who were adherent to the diet modification
  • A diet high in animal fat may be an important factor in the development of prostate cancer. In particular, intake of large amounts of alpha-linoleic acid and low amounts of linoleic acid appear to increase risk; this combination is common in red meat and some dairy products. The mechanism of this association may be that serum levels of testosterone are lower in men who decrease their fat intake

While total fat does not appear to impact cancer risk, questions remain as to whether particular types of fat (saturated, unsaturated, or trans fats) affect risk differently, and whether fat intake in childhood or adolescence carries greater risk than intake during adulthood. One consistent finding is that excess calories from any source lead to weight gain and an increase in the risk of multiple cancers

Red meat  High intake of red meat including beef, pork, veal, and lamb, is associated with an elevated risk of colorectal cancer in both men and women. One large study (n = 148,610) concluded that the risk of colon cancer was increased in those with a long-term high intake of processed meat (relative risk [RR] 1.5, 95% CI 1.04-2.17) and with a high ratio of red meat to poultry and fish (RR 1.53, 95% CI 1.08-2.18) High intake of red meat was also associated with an increased risk of rectal cancer. The mechanisms for this increased risk have not been determined but several factors have been suggested including heme content in the meat, animal fat, and carcinogens produced when the meat is cooked at high temperatures.

Fruits and vegetables  Prospective cohort studies have demonstrated only a weak association between fruit and vegetable intake and cancer risk. In a large cohort study (n = 136,089) with 937 incident cases of colon cancer, no association was seen between either total or specific category of fruit and vegetable intake and colon cancer risk

Evidence is stronger for a link between prostate cancer and tomato products. Several cohort studies have demonstrated a significant reduction of prostate cancer risk in men with the highest intake of tomatoes and tomato products. Lycopene, a carotenoid found in tomatoes, has been postulated to be responsible for this benefit but there are no data from well-designed clinical trials to support this hypothesis

Dairy  A meta-analysis of 21 studies evaluating the relationship of dairy food intake and ovarian cancer found no evidence of association in case control studies (RR 0.96) but three prospective cohort studies did demonstrate increased risk of ovarian cancer with high intake of dairy foods (RR 1.13, 95% CI 1.05-1.22). Inaccuracy of retrospective diet reports in the case control studies may have been a factor affecting their reliability. However, a subsequent cohort study found no increase in risk of ovarian cancer with dietary dairy or lactose intake. Thus, the relationship of dairy intake to ovarian cancer is uncertain.

Fiber  Fiber intake has been shown to reduce the risk of heart disease] and diabetes, but its effect on cancer risk reduction is less certain. Large cohort studies in the US did not show an association between cancer risk and either fiber intake in general or cereal fiber in particular . A large European study (n = 519,978), however, found that dietary fiber was inversely related to colon cancer incidence (adjusted RR 0.58, 95% CI 0.41-0.85), comparing the highest to lowest quintile of dietary fiber intake. These results may have been confounded by lack of control for folate intake, and fiber may have served as a proxy for this micronutrient

A case control study demonstrated a 27 percent reduction in adenomas of the distal colon with higher fiber intake from grain, cereal, and fruit sources. Randomized controlled trials found fiber supplementation did not have a significant impact on recurrence of colorectal adenomas. A meta-analysis of five studies similarly concluded that fiber did not affect the incidence or recurrence of adenomatous polyps within a two to four year follow-up period. Similarly, a pooled analysis of 13 prospective cohort studies (involving 725,628 men and women followed for 6 to 20 years) found that dietary fiber intake was inversely associated with the risk of colorectal cancer but the association was no longer apparent after accounting for other dietary risk factors

Glycemic load  Insulin and insulin-like growth factors promote cell proliferation, and it is hypothesized that hyperinsulinemia may promote certain cancers. Foods with a high glycemic index have been evaluated for association with risk of cancer. Glycemic load is a function of a food's glycemic index (a measure of how rapidly and to what extent the blood glucose level rises), carbohydrate content per serving, and frequency of intake. These studies have yielded equivocal results.

  • One case control study of breast cancer reported an association with high glycemic load, but large cohort studies have not confirmed this finding
  • Studies of colorectal cancer and glycemic load have shown inconsistent results. Data from the Women's Health Study, evaluating dietary habits of 174 incident colon cancer patients in a cohort of 38,451 women, showed that dietary glycemic load was significantly associated with an increased risk of colorectal cancer (adjusted RR 2.85, 95% CI 1.4 to 5.8), comparing highest to lowest quintiles of glycemic load Similar positive associations were reported in several case control studies  but one large study of Canadian women found no increase in risk  Evaluation of data from the Nurse's Health Study and from the Health Professionals Follow Up Study found a small increase in risk among men with high dietary glycemic load (RR 1.32, 95% CI 0.98-1.79) and no association among women

Omega-3 fatty acids  A systematic review of prospective studies evaluating the effect of omega-3 fatty acid consumption on tumor incidence concluded that there is no association between omega-3 fatty acids and cancer risk for 11 different types of cancer Ten studies evaluated in this review reported significant findings, but individual studies indicated both increased and decreased risk with no consistent pattern.

VITAMINS AND NUTRIENTS  Several nutritional components have been shown to affect cancer risk, but the role of vitamins is less certain. A systematic review of 38 studies found that neither vitamin C nor vitamin E supplementation was beneficial for prevention of the cancers evaluated. A 2006 National Institutes of Health (NIH) consensus conference panel concluded that "present evidence is insufficient to recommend either for or against the use of multivitamin supplements by the American public to prevent chronic disease"

It has not been proven that multivitamin and mineral supplements provide added benefit to a balanced, healthful diet. Randomized trials for dietary supplementation have been hampered by the long latency in development of cancer following nutritional intervention, and by use of multivitamins by participants in control groups.

Vitamin D  Vitamin D may reduce the risk of colon cancer but the data do not show a consistent relationship. A pooled analysis of 10 cohort studies found a trend towards reduction of colorectal cancer with increasing vitamin D intake, only statistically significant among those individuals with the highest vitamin D intake. Direct effects of vitamin D on colonic epithelial cells have been described. Vitamin D may also decrease cancer risk through improved calcium absorption.

One study did not demonstrate a relationship between vitamin D levels and incidence of prostate cancer, although further studies are ongoing and there is a theoretical basis to predict an effect of vitamin D on prostate cancer. Animal models also suggest that vitamin D may have a protective effect against breast cancer, but the results from one large epidemiologic study was equivocal

A reduction in total cancer incidence (RR 0.83, 95% CI 0.41-0.74) and in gastrointestinal cancer mortality (RR 0.55, 95% CI 0.41-0.74) in men was seen with an increment of 25 nmol/L in predicted 25(OH)D level in data derived from the US Health Professionals Follow-Up Study. This incremental level of serum 25(OH)D is not readily achieved with diet (one glass of milk would be predicted to increase the plasma level only by 2 to 3 nmol/L), and would require supplementation with at least 1500 IU vitamin daily. The authors raise a question whether limiting sun exposure, to decrease skin cancer risk, might increase the mortality risk for other cancers.

Calcium  Increased calcium intake has been linked to reduced risk of colorectal cancer but increased risk of prostate cancer. There may be a minimum level of calcium intake, around 700 mg/day, that confers protection against colorectal cancer without significantly increasing prostate cancer risk.

Colorectal cancer  Multiple observational studies have demonstrated that higher calcium intake (either dietary or supplements) reduces the risk of colorectal cancer:

  • A randomized controlled trial (n = 930) showed a decreased risk of recurrent colorectal adenomas in patients assigned to take 1200 mg elemental calcium daily compared to placebo (RR .85, 95% CI 0.74-0.98)
  • Two epidemiologic studies, with 8 and 19 year follow-up, have shown an inverse relationship between calcium intake, as reported in food diaries, and incidence of colorectal cancer. In the large cohort from the Health Professionals Follow-up Study and Nurse's Health Study, the risk of distal, but not proximal, colon cancer was reduced in both men and women who took up to 1250 mg/day elemental calcium versus <500 mg/day (RR 0.58, 95% CI 0.32-1.05)]. The data suggest a threshold effect, with no incremental improvement beyond 700 mg/day of elemental calcium.

These results were not confirmed in the Women's Health Initiative (n = 36,282), which found no significant decrease in incidence or stage of colorectal cancer in the group who had been randomly assigned to receive calcium 500 mg and vitamin D 200 IU twice daily, compared to placebo. The average age of women at the start of randomization was 62 years, and follow-up was seven years. Given the known slow progression rate for colorectal cancer, seven years may be too short an interval to find an effect on cancer incidence, and longer-term follow-up for this study population is planned.

Calcium may offer protection by reducing epithelial cell proliferation in the colon, either directly or indirectly by binding secondary bile acids and ionized fatty acids

Prostate cancer  Case-control and prospective studies of calcium and prostate cancer have reported inconsistent results  Three large cohort studies found an increased risk of prostate cancer with different measures of calcium intake. Two other prospective studies found no association

Suggesting the risk of prostate cancer may be increased with high, but not moderate, calcium intake, one study of 3811 incident cases of prostate cancer found that total calcium over 2000 mg/day from both diet and supplementation was linked to a 20 percent increase in prostate cancer risk (RR 1.2, 95% CI 1.0-1.6). High dietary calcium (greater than or equal to2000 mg/d) was associated with an even greater increased risk of prostate cancer (RR 1.6, 95% CI 1.1-2.3), but moderate dietary calcium was not. Data from another study showed stronger associations between high calcium intake (greater than or equal to2000 mg/d) and total, advanced, and metastatic disease (RR 1.71, 2.97, and 4.57, respectively)

It has been suggested that high calcium levels may increase prostate cancer risk by down-regulating the active form of vitamin D, thus interfering with vitamin D's proposed inhibition of tumor growth and metastasis.

Selenium  Animal studies suggest that a higher intake of selenium decreases the risk of a variety of tumors, and some epidemiologic studies have shown an inverse relationship between selenium and cancer. A randomized trial of selenium and skin cancer risk showed a significant mortality reduction in cancers of the lung, colon, and prostate. However, a Finnish fortification intervention did not show a large impact on cancer risk. Ongoing studies such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will provide valuable information on the overall risks and benefits of selenium

Folate  Folate is present in green, leafy vegetables, fruits, cereals and grains, nuts, and meats. Folic acid, the form of the vitamin included in supplements, has the same biologic effects as folate, but is more bioavailable. Folate is important in DNA synthesis, methylation, and repair, as well as in the regulation of gene expression.

The role of folate in cancer prevention is uncertain. Folate has been associated with a decreased risk for colon and other cancers, especially in individuals who consume alcohol, in observational studies. However, randomized trials have not confirmed these findings.

Support for folate as a factor in cancer protection is as follows:

  • Subjects with lower levels of methylenetetrahydrofolate reductase, an enzyme involved in folate metabolism, have a reduced risk of colon cancer, as well as cancers of the esophagus, stomach and pancreas
  • An inverse relationship was found between folate intake and the risk of developing adenomatous polyps in the combined analysis of data from the Nurses Health Study and Health Professionals Follow-Up Study
  • The Nurses Health Study demonstrated a decreased risk of colon cancer in women who took folic acid-containing multivitamins for at least 15 years, suggesting that folate levels may be particularly important in the early stages of colorectal cancer development.. Findings from the Women's Health Initiative data, however, showed that increased dietary folate and vitamin B6 intake lowered colorectal cancer risk, while vitamin supplementation with folic acid and B6 did not
  • Dietary folate, but not vitamin supplementation, was associated with a reduced risk for pancreatic cancer in a Swedish cohort of 82,000 men and women prospectively followed for seven years]. A meta-analysis found that dietary folate was associated with reduced risk for esophageal squamous cell cancer (RR 0.66, 95% CI 0.53-0.83), and pancreatic cancer (RR 0.49, 95% CI 0.35-0.67), comparing highest versus lowest intake categories

However, a meta-analysis of case-control studies and observational studies did not demonstrate an association between low dietary folate intake and breast cancer. The study found evidence of publication bias in previous case-control studies that had suggested an association.

In contrast to the biologic and observational evidence supporting a role for folate and folic acid supplementation in cancer prevention, randomized trials have not confirmed these benefits and have raised the possibility of harm. The largest controlled trial to evaluate folic acid supplementation in patients with known colorectal adenomas found no decrease in new adenomas at three and six year follow-up, but an increase in risk of advanced colon lesions and an increase in noncolorectal cancer in patients who received folic acid, compared to controls

Folate in alcohol users  The interaction between folate and alcohol may be important in cancer prevention  Alcohol consumption is known to both interfere with folate availability and increase the risk of colon and breast cancer. In one study, the increase in colon cancer risk associated with alcohol use was not seen in men with the highest folate intake. Similarly, the increased risk of breast cancer associated with alcohol use was most pronounced in women with the lowest folate intake]. An inverse relationship between folate intake and breast cancer was most evident among women whose alcohol consumption was greater than 15 g (about one drink) per day. Increasing levels of plasma folate correlated with decreased risk of breast cancer particularly among women who consumed alcohol

Other  Several other vitamin supplements have been evaluated, with variable findings:

Vitamin E (600 IU alpha-tocopherol every other day) did not prevent invasive cancer in a 10 year follow-up to the Women's Health Study, evaluating healthy women age 45 years and older (mean age 55 years)]. One study did find a decrease in risk for prostate cancer with vitamin E supplementation in male smokers

Beta carotene may increase the incidence of lung cancer incidence and mortality in patients with risk factors (smokers or asbestos exposure)  Beta carotene did not decrease cancer incidence in studies of American women and men

Supplementation with a combination of beta-carotene, selenium, and zinc decreased the incidence of noncardia stomach cancer, but not other intestinal malignancies, in a population in rural China with baseline deficiencies in micronutrients

ALCOHOL  Alcohol consumption increases the risk of cancers of the colon, breast], oropharynx, and esophagus. Moderate alcohol use has beneficial effects on cardiovascular health, but consumption of as little as one drink per day has been associated with an increase cancer risk

Several mechanisms have been postulated to account for the carcinogenicity of alcohol. Its solvent properties may allow carcinogens to penetrate cell membranes. Alcohol increases estrogen levels and impacts folate metabolism. Alcohol may also act as an irritant, causing increased cell production, as a transporter carrying carcinogens, or as a prometabolite for identified carcinogens

PHYSICAL INACTIVITY  Decreased physical activity appears to increase the risk for cancer, in addition to multiple other diseases.. Over 60 percent of US adults are not regularly active, including 25 percent who are almost entirely sedentary]. It is estimated that sedentary lifestyle is associated with 5 percent of cancer deaths

Physical activity is associated with a decreased risk of colon and breast cancer . One study demonstrated a negative correlation between moderate to strenuous exercise and ER-negative, but not ER-positive, breast cancer. Limited evidence suggests that activity offers some protection against endometrial and prostate cancer. As well, physical activity may reduce the risk of lung cancer but the data are inconsistent

The association between physical activity and decreased risk for breast and colon cancer has been demonstrated across levels of obesity, suggesting that the protective effect of activity goes beyond its impact on body weight

The American Cancer Society Cancer Prevention Study II Nutrition Cohort did not demonstrate overall risk reduction for prostate cancer with increased recreational activity. However, individuals with the highest recreational physical activity had a reduced risk (RR 0.69) of aggressive prostate cancer. In this same cohort, colon and rectal cancer risk was reduced with recreational physical activity in both men and women. Risk reduction for colon, but not rectal, cancer was proportional to hours of activity per week and metabolic equivalent hours

Several mechanisms have been proposed to explain the possible protective effect of physical activity including: reduction in circulating levels of insulin, hormones, and other growth factors; impact on prostaglandin levels; improved immune function, and altered bile acid metabolism . Physical activity during certain periods of life, such as adolescence, may offer additional protection against disease. The optimal duration, intensity, and frequency of physical activity that may afford cancer protection is unknown.

EXCESS WEIGHT  Almost 65 percent of US adults are overweight; over 30 percent are considered obese The obesity epidemic affects people of all ages, socioeconomic levels, geographic regions and ethnicities, and causes significant medical consequences.

Excess weight and obesity are associated with an increase in the risk of multiple cancers including colorectal, postmenopausal breast, endometrial, renal, and esophageal cancer, with a population attributable risk from 9 percent (postmenopausal breast cancer) to 39 percent (endometrial cancer). Obesity may also increase risk for cancer of the prostate, liver, gallbladder, pancreas, stomach, ovary, and cervix in addition to non-Hodgkin's lymphoma and multiple myeloma. Overall, observational studies suggest that obesity in the US may account for 14 percent of cancer deaths in men and 20 percent of cancer deaths in women

EXCESS SUN EXPOSURE  Over 1 million cases of skin cancer, including basal cell and squamous cell carcinoma, are diagnosed each year. The American Cancer Society estimates over 59,000 cases of malignant melanoma in the US in 2005 [9], and the incidence continues to rise Although most skin cancers are curable, 2005 US death rates from skin cancer are projected to be over 10,000 (7770 from melanoma, 2820 from other skin cancers)

Radiation from the sun is the primary cause of both melanomatous and non-melanomatous skin cancer. Ultraviolet radiation causes genetic mutations and interferes with the cutaneous immune system, limiting the body's ability to reject abnormal cells. Risk of squamous cell and basal cell cancer appear to correlate with total lifetime sun exposure. Cumulative sun exposure may also increase melanoma risk, but repeated intense exposures leading to blistering burns may be even more dangerous

Recommendations for sun protection  Targeting only the subset of the population with high-risk characteristics such as fair skin, large number of nevi, or positive family history, fails to identify an adequate proportion of people who develop disease]. All individuals should limit the time spent in the sun, especially between the hours of 10 am and 3 pm, wear hats, sunglasses, and other protective clothing, and use sunscreen. Because the majority of lifetime sun exposure usually occurs during childhood and adolescence, protective behaviors early in life will provide the greatest benefit. In addition, the World Health Organization recently recommended against tanning bed use by anyone under the age of 18

INFECTION  It is estimated that 17 percent of all new cancers worldwide are due to infections. Viruses may increase cancer risk through cellular transformation, disruption of cell cycle control, increased cell turnover rates, and immune suppression

Multiple links between infectious agents and cancer have been established:

  • Human papillomavirus (HPV) with cervical and other anogenital cancers
  • Hepatitis B (HBV) and C (HCV) with hepatocellular carcinoma
  • Human T-cell lymphotropic virus (HTLV-I) with adult T cell leukemia
  • Human immunodeficiency virus (HIV-I) with Kaposi sarcoma and non-Hodgkin's lymphoma
  • Human herpes virus 8 (HHV-8) with Kaposi sarcoma and primary effusion lymphoma
  • Epstein-Barr virus (EBV) with Burkitt's lymphoma
  • Helicobacter pylori (H. pylori) with gastric cancer

The majority of these viruses are spread through contact with infected blood or body fluids, thus offering opportunities for prevention.  Vaccinations for HBV and HPV are particularly promising.

Strategies to prevent transmission through infected blood and blood products must also be implemented. Examples include use of sterile disposable needles for a single patient in healthcare settings, needle exchange programs, regulation of tattooing, continued screening of blood, organ, and semen donors, and the development of artificial blood products.

For some viruses, interventions are available to prevent or delay progression to cancer after infection has occurred. In the case of HPV, use of the Papanicolaou (Pap) test has dramatically reduced the incidence of cervical cancer where screening is widely available. Testing for HPV type in conjunction with Pap testing may offer additional screening benefit. . Retroviral therapy for HIV infection has greatly altered the course of disease and associated cancers. Highly active antiretroviral therapy (HAART) has been shown to reduce the incidence of AIDS-related lymphoma

Excess alcohol use may play a role in cancer development in patients with chronic HBV and HCV infections and should be avoided. Preliminary data suggest that antiviral therapy may reduce the risk of cancer in these individuals. The use of medications such as interferon in patients with chronic HBV and HCV infections has led to loss of HBeAg, decrease in HBV DNA levels and reduction of HCV RNA, but the long-term effect of antiviral therapy on cancer risk is not known

CHEMOPREVENTION  For several cancers, prophylactic medication can reduce cancer risk for high risk individuals. The risk/benefit ratio for chemoprevention must be evaluated for individual cases.

Selective estrogen receptor modulators and breast cancer

Tamoxifen  Tamoxifen is an estrogen receptor antagonist with both estrogen agonist and antagonist properties. It is approved in the US for both primary and secondary prevention in high-risk women

Benefit from tamoxifen was most convincingly shown in the Breast Cancer Prevention Trial (NSABP P-I), a double-blind randomized trial of 13,388 women at increased risk for breast cancer (age >60, history LCIS, or calculated five year risk >1.66 percent according to the Gail model, The study showed an approximate 50 percent reduction in the relative risk of both invasive and noninvasive (ie, ductal and lobular carcinomas in situ) breast cancer with tamoxifen. Risk was reduced only for estrogen receptor positive tumors. Women in the tamoxifen arm had an approximately two-fold increased incidence in endometrial tumors (cancers and uterine sarcomas), pulmonary embolism, deep vein thrombosis (DVT), and stroke

Benefit was also shown in the International Breast Cancer Intervention Study (IBIS-I) that randomly assigned high risk women to tamoxifen or placebo and found a lower risk of breast cancer with tamoxifen compared to placebo (RR .32, 95% CI 8-59). However, all-cause mortality was higher in the tamoxifen group (OR 2.5, 95% CI 1.5-4.4) with an increase in thromboembolic events, especially in women who had surgery

Two other smaller placebo-controlled trials failed to show benefit, while an overview analysis that considered all four trials concluded that there was an approximately 38 percent reduction in the risk of breast cancer with tamoxifen and a two-fold increase in the risk of thromboembolic events and endometrial tumors; no impact on either breast cancer-specific or overall mortality could be shown

Because of the potential for serious side effects, the US Preventive Services Task Force (USPSTF) has recommended against routine use of tamoxifen for breast cancer prevention in women of average risk. The current recommendation is that health care providers discuss the risks and benefits of chemoprevention with women at high risk of breast cancer and low risk of adverse effects from the medication.

Raloxifene  Raloxifene is a selective estrogen receptor modulator (SERM) that is currently approved for the prevention of osteoporosis, but not for the prevention of breast cancer. Newly published data from the STAR trial suggest that raloxifene is as effective as tamoxifen in reducing the incidence of invasive breast cancers in high-risk women, but with fewer of the most serious side effects associated with tamoxifen

In the STAR trial, compared to tamoxifen, raloxifene was associated with a significantly lower risk of DVT, pulmonary embolus, and cataracts, but a nonsignificantly higher risk of noninvasive breast cancers]. The risk of other cancers, fractures, ischemic heart disease, and stroke was similar for both drugs. In a companion quality of life study, sexual function was slightly better with tamoxifen, while gynecologic problems, need for hysterectomy for noncancerous conditions, vasomotor symptoms, leg cramps, and bladder control symptoms were all significantly more common with tamoxifen]. Musculoskeletal problems, dyspareunia, and weight gain were more common with raloxifene.

Raloxifene is a reasonable alternative to tamoxifen for postmenopausal women who meet high-risk criteria as set forth in the STAR trial: over the age of 60, or with a history of LCIS, or with a five-year estimated risk for breast cancer of at least 1.66 percent as determined by the Gail model]. Raloxifen was approved by the US FDA in September 2007 for postmenopausal women at high risk for invasive breast cancer. There are no data on the use of raloxifene in premenopausal women, and it should not be used in this group.

Aspirin and other anti-inflammatory drugs   Several theories have been proposed for why aspirin and other NSAIDs are effective in reducing colorectal cancer risk, and possibly effective for other cancers. These medications may cause cell cycle arrest or apoptosis (programmed cell death) of abnormal cells. Reduced risk may also relate to irreversible inhibition of cyclooxygenase-2. Inhibition of this enzyme decreases the synthesis of prostaglandins, which may inhibit tumor growth. Finally, aspirin may influence intracellular signaling through inhibition of phospholipase activity.

Colorectal cancer  Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to decrease the risk of adenomatous polyps and colorectal cancer. The optimal dose of aspirin, however has not been established . Low dose aspirin (100 mg every other day) did not prevent total cancer death, or incidence of breast, colorectal, or lung cancer, when compared with placebo, at 10 year follow-up in the Women's Health Study of healthy women over age 45 years]. Full dose aspirin (greater than or equal to325 mg) taken daily for a minimum of five years, compared with no aspirin, did decrease the incidence of colorectal cancer in the Cancer Prevention Study II Nutrition Cohort (RR 0.68, 95% CI 0.52-0.90)

The dosage and duration of use for NSAIDs in colorectal cancer prevention has not been well defined. The Nurses' Health Study data showed that long term use was necessary, suggesting action early in the pathway to carcinogenesis

In addition, celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to decrease the number of polyps in patients with familial adenomatous polyposis (FAP). The adverse effect of COX-2 inhibitors on cardiovascular disease highlights the challenge of balancing risks and benefits in chemoprevention for cancer.

The United States Preventive Services Task Force (USPSTF) has found the evidence to be of poor quality that links use of aspirin or NSAID to decreased colorectal cancer mortality in average risk families. There is good evidence that chronic use of aspirin, at doses suggested to decrease the incidence of colorectal cancer, increases the risk for gastrointestinal bleeding and hemorrhagic stroke. In addition to GI complications, chronic NSAID also increases risk for renal failure and hypertension. Both the USPSTF and the American Cancer Society do not recommend aspirin or NSAID use to prevent colorectal cancer for average risk patients

Other cancers  Data from the Cancer Prevention Study II Nutrition Cohort (n=146,000), with 18,000 cancers diagnosed during a ten year follow-up period, found that the overall cancer incidence in men was lower for those who took greater than or equal to325 mg aspirin daily for at least five years compared to no aspirin use; cancer incidence in women was lower, but the difference was not statistically significant]. In addition to colorectal cancer, longterm aspirin use was associated with a lower incidence of prostate cancer (RR 0.81, 95% CI 0.7-0.94) and a trend to lower incidence in breast cancer (RR 0.83, 0.63-1.10).

Finasteride and prostate cancer   The randomized Prostate Cancer Prevention Trial (PCPT) evaluated the use of finasteride, an aza-steroid inhibitor, as a chemopreventive agent in 19,000 men who were at increased risk for prostate cancer. Compared to men in the placebo group, the incidence of prostate cancer was decreased in the finasteride group (18.4 percent versus 24.4 percent) but there was an increase in the absolute number and proportion of high grade tumors. Concerns about increased risk for high grade prostate cancer dampened enthusiasm for the use of finasteride as a chemopreventive agent.

Subsequent analysis of the trial results suggests that detection bias accounted for the apparent increase of high-grade disease with finasteride: finasteride improved operating characteristics of the PSA test for cancer detection by decreasing the rate of false positive results in men with benign prostatic hypertrophy (BPH). It is premature to recommend the use of finasteride as a chemopreventive agent in men at high risk for prostate cancer, but clinicians should feel comfortable about using finasteride in men with large-gland BPH.

SUMMARY AND RECOMMENDATIONS  Many cancers are preventable. Basic lifestyle changes can have a tremendous impact on the rates of cancer. The fact that such changes also protect against other chronic diseases (cardiovascular disease, stroke, and diabetes) makes the case for prevention even more compelling.

General lifestyle recommendations include:

  • Avoid tobacco
  • Be physically active
  • Maintain a healthy weight
  • Eat a diet rich in fruits, vegetables, and whole grains, and low in saturated/trans fat
  • Limit alcohol
  • Protect against sexually transmitted infections
  • Avoid excess sun
  • Get regular screening

Specific factors associated with cancer risk include the following:

  • Tobacco use is responsible for 90 percent of all lung cancer deaths, and is tied to multiple other cancers.
  • The association of dietary fat, fruits, vegetables, and fiber with cancer risk is largely unconfirmed. Red meat consumption may promote colorectal cancer and a high intake of tomatoes probably decreases prostate cancer risk.
  • Vitamin D may reduce the risk of colorectal and prostate cancer. Calcium intake, at a minimum of 700 mg/day, may protect against colorectal cancer but high calcium intake (>2000 mg/day) increases risk for prostate cancer. Folate in diet has been associated with a decreased risk of colon and breast cancer, especially in women who drink alcohol; data on folic acid or multivitamin supplementation are inconsistent.
  • Alcohol intake, even in moderate quantities, increases the risk for colon, breast, esophageal and oropharyngeal cancer.
  • Physical activity is inversely related to risk for colon and breast cancer. Excess weight increases the risk of multiple cancers.
  • Skin cancer is directly related to sun exposure, and melanoma rates are increasing. A history of blistering sunburns are of particular risk for melanoma; cumulative sun exposure has more impact on non-melanoma cancers.
  • HPV, HCV, HTLV1, HIV, EBV, and H pylori have been linked to human cancers. Exposure prevention, screening, and early treatment for abnormal Pap smears and HIV infection can prevent cancer.
  • Chemoprevention may be helpful in high risk patients but risks and benefits should be weighed carefully. Aspirin and NSAIDs offer protection against adenomatous polyps and colorectal cancer, but are not recommended for routine use in average risk patients.

Tamoxifen decreases incidence of breast cancer in high risk women, but increases the risk for thromboembolic disease and early stage endometrial cancer. Raloxifene is a reasonable alternative, but has not been evaluated in premenopausal women.

The use of finasteride as a chemopreventive agent should be discussed with men who are interested in preventing prostate cancer.