Author: Graham A Colditz, MD, DrPH

Section Editors: David Seres, MD, Paul J Hesketh, MD

Deputy Editor: Jane Givens, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2021. | This topic last updated: Feb 05, 2021.

INTRODUCTION

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 that promote cancer. It is estimated
that 50 percent of cancer is preventable [1], although proof of efficacy from trial data is lacking.
Despite a robust knowledge of what factors decrease cancer risk, implementation of cancer
prevention lags [2,3].

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, red
meat, and processed meat
● Limit alcohol (zero is best)
● Protect against sexually transmitted infections; vaccinate girls and boys against human
papillomavirus (HPV)
● Avoid excess sun and tanning beds
● Get regular screening for breast, cervical, colorectal, and lung cancer (if heavy smoking
history)

This topic reviews the major modifiable cancer risk factors and briefly addresses cancer
chemoprevention. More detailed discussion of risk factors and chemoprevention strategies for
specific cancers can be found elsewhere:

● (See "Risk factors for prostate cancer".)

● (See "Chemoprevention strategies in prostate cancer".)
 ● (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and
diagnosis".)
● (See "Clinical manifestations of lung cancer".)
● (See "Factors that modify breast cancer risk in women".)
● (See "Menopausal hormone therapy and the risk of breast cancer".)
● (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer
prevention".)
● (See "Colorectal cancer: Epidemiology, risk factors, and protective factors".)
● (See "Clinical manifestations of lung cancer".)

In addition, lifestyle issues which are associated with an increased risk of cancer and are also
risk factors for other diseases, such as stroke, heart disease, and diabetes, are discussed
elsewhere. (See "Overview of primary prevention of cardiovascular disease" and "Risk factors
for type 2 diabetes mellitus".)

The roles of physical activity, dietary patterns, and weight in cancer survivors are discussed
separately. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

EPIDEMIOLOGY

Estimates show that annually there are 18 million cancer cases and over 9 million cancer deaths
worldwide, despite overwhelming evidence that many malignancies are preventable [4,5].
Survival rates are improving, but cancer remains a leading cause of death in the United States,
with approximately 600,000 people dying from the disease each year [6].

Multiple cancer risk factors have been identified [7,8]. Tobacco use, excess weight, poor diet,
and inactivity account for two-thirds of cancer deaths in the United States [7]. 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 [9]. The
International Agency for Research on Cancer (IARC) has identified and tabulated over 100
human carcinogens [10].

Lifestyle factors have been linked to a variety of malignancies, including the most common in the
developed world: lung, colorectal, prostate, and breast cancer [11]. In a longitudinal study,
participants with four positive lifestyle factors (never smoking, body mass index [BMI] <30 kg/m2,
physical activity >3.5 hours weekly, healthy diet) had approximately one-third the risk of cancer
compared with those who had none of these factors [12]. A comprehensive systematic review
with a global focus conducted by the World Cancer Research Fund came to similar conclusions
regarding dietary, weight, and activity factors [13]. In a study based upon recommendations from
the World Cancer Research Fund and the American Institute of Cancer Research related to
weight management, physical activity, plant and animal food consumption, breastfeeding (in
women), and alcohol intake, there was an association between higher scores (better
compliance) and risk reduction for total cancer as well as specific cancers (eg, colorectal,
stomach, breast, endometrium, lung, kidney, liver, esophagus, but not for prostate, ovarian,
pancreatic, or bladder) [14].

A study in the Nurses’ Health Study and Health Professional Follow-Up Study populations (n =
111,562) found substantial longevity benefits in those adopting an overall healthy lifestyle [15]. In
women, having four or five healthy behaviors (never smoking, physical activity, healthy weight,
healthy diet, moderate alcohol) was linked to 8.3 years’ longer life expectancy without cancer
compared with those without any of the behaviors. Men experienced 6.0 additional years without
cancer.

TOBACCO USE

Tobacco use is the most preventable cause of cancer and accounts for 21 percent of total cancer
deaths worldwide [4]. 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 tobacco use [16-18]. (See
"Cigarette smoking and other possible risk factors for lung cancer".)

Smoking is responsible for approximately 30 percent of all cancer-related deaths in the United
States [18]. It is the strongest risk factor for lung cancer, increasing risk 10- to 20-fold [19,20].
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 [21,22]. Studies also suggest that smoking is
associated with increased incidence of breast cancer as well as prostate cancer, particularly in
African American individuals [23-27]. Refer to the relevant UpToDate topic reviews for full
discussion of the risk factors for each 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 [28].
The dangers of tobacco are most commonly associated with cigarette smoking but also occur
with cigars, pipes, smokeless tobacco, and exposure to environmental (secondhand) tobacco
smoke. (See "Secondhand smoke exposure: Effects in adults".)

Tobacco cessation and prevention — Significant health benefits accompany quitting, even for
longtime tobacco users. The health benefits of quitting can be seen at all ages and can be
measured almost immediately after cessation [29]. Smoking cessation leads to reduced risk of
most tobacco-related diseases and a decrease in all-cause mortality.
 Tobacco cessation is associated with a reduction in cancer risk, and among smokers with a
smoking-related cancer, smoking cessation decreases the risk of developing a second
smoking-related malignancy and may improve the outcomes of cancer treatment [27,30].
(See "Benefits and consequences of smoking cessation", section on 'Benefits of smoking
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 [31]. Responsibilities for health care providers include advice and counseling,
referrals to behavioral therapy and support groups, and prescriptions for nicotine
replacement and other medications [32,33]. (See "Pharmacotherapy for smoking cessation
in adults" and "Behavioral approaches to smoking cessation" and "Overview of smoking
cessation management in adults".)

Many of these same efforts should also be extended to the prevention of youth initiation and
use of e-cigarettes, which, along with other possible harms, may increase the risk of
combustible tobacco use. (See "Vaping and e-cigarettes".)

ENVIRONMENTAL EXPOSURES

Potentially modifiable or avoidable environmental contributors to increased cancer incidence

include exposure to excessive solar radiation or to artificial ultraviolet radiation, air pollution,
radon gas in enclosed environments, and arsenic in drinking water.

Excess sun exposure, artificial ultraviolet radiation — Over one million cases of skin cancer,
including basal cell and squamous cell carcinoma, are diagnosed each year. The American
Cancer Society estimates that there will be approximately 100,000 cases of malignant
melanoma in the United States in 2021 [6]. Due to improvements in treatment, the death rate for
melanoma decreased by 5.7 percent annually from 2014 to 2018 [6]. 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, particularly in
childhood and adolescence, may be even more dangerous [34].

Ultraviolet exposure from tanning beds has been classified as a human carcinogen, with a 75
percent increase in risk for melanoma in patients who utilized tanning booths before age 35 [35].
(See "Risk factors for the development of melanoma".)
 Recommendations for sun/ultraviolet protection — Interventions limited to people with
high-risk characteristics such as fair skin, large number of nevi, or positive family history, fail to
target an adequate proportion of people who develop disease [36].

All individuals should limit the time spent in the sun, especially between the hours of 10 AM and
4 PM; wear hats, sunglasses, and other protective clothing; and use sunscreen with sun
protection factor (SPF) 30 or higher. Because the majority of lifetime sun exposure usually
occurs during childhood and adolescence, protective behaviors early in life will provide the
greatest benefit. The Environmental Protection Agency (EPA) offers simple action steps for sun
protection. In addition, WHO has recommended that tanning bed use should be avoided entirely
[37]. (See "Primary prevention of melanoma" and "Sunburn".)

Air pollution — Diesel exhaust and particulate matter air pollution have been associated with
increased risk of lung cancer. These are discussed elsewhere. (See "Cigarette smoking and
other possible risk factors for lung cancer", section on 'Air pollution and diesel exhaust'.)

Radon — The small increase in lung cancer risk associated with increased indoor radon levels
is described separately. (See "Cigarette smoking and other possible risk factors for lung cancer",
section on 'Radon'.)

Arsenic — Long-term exposure to elevated arsenic levels in drinking water is associated with an
increase in the risk of certain cancers, with strong evidence supporting a dose-response
relationship for bladder cancer [38,39]. Most municipal water supplies are tested regularly for
arsenic to ensure safe levels. Private drinking wells are more likely to have elevated levels and
should be professionally tested regularly. (See "Arsenic exposure and poisoning", section on
'Drinking water'.)

PHYSICAL ACTIVITY

Decreased physical activity appears to be associated with an increased risk for cancer [40,41],
and it is estimated that a sedentary lifestyle is associated with 5 percent of cancer deaths [42].
However, these data are observational, and a causal relationship has not established from
randomized trials. For people who do not smoke, exercise is one of the most important
modifiable risk factors (along with weight control and dietary choices) and may partially attenuate
the adverse effects of certain other risk factors [43]. (See "The benefits and risks of aerobic
exercise".)

Physical activity is associated with a decreased risk for many different types of cancers [44], but
the most compelling data are in the reduction in colon and breast cancer risk [45-48]:

● In one prospective study, there was a negative correlation between moderate to strenuous
exercise and estrogen-receptor (ER)-negative, although not ER-positive, breast cancer [47].
 ● In a meta-analysis of 52 studies, there was a 24 percent reduced risk of colon cancer when
comparing the most versus the least active individuals (relative risk [RR] 0.76, 95% CI 0.72-
0.81) [45]. In a subsequent meta-analysis including 21 studies, there were similar findings;
the risk reduction was the same for both proximal and distal colon cancers [49]. In another
meta-analysis, increased physical activity was associated with a 16 percent reduction in the
risk of developing adenomatous colon polyps (RR 0.84, 95% CI 0.77-0.92) [50].

● 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 [44,51-53].

Limited evidence also suggests that activity offers some protection against endometrial and
prostate cancer [45,54,55].

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 [56-
58]. Physical activity during certain periods of life, such as adolescence, may offer additional
protection against disease, particularly for breast cancer [59,60]. The optimal duration, intensity,
and frequency of physical activity that may afford cancer protection is unknown.

OBESITY

Excess weight is associated with an increased risk of many types of cancer. Obesity has been
estimated to cause 20 percent of all cancers [1]. A working group convened by the International
Agency for Research on Cancer (IARC) concluded that the strength of the available evidence
was sufficient to establish that absence of excess body fatness had a cancer preventive effect in
many malignancies, including esophageal adenocarcinoma, gastric cardia, colorectal,
hepatocellular, endometrial, ovarian, gallbladder, pancreatic, renal cell, thyroid, and
postmenopausal breast cancers, multiple myeloma, and meningioma [61].

Weight loss methods including bariatric surgery have been associated with decreased cancer
mortality. In one retrospective cohort study, bariatric surgery was associated with a 60 percent
reduction in cancer mortality (5.5 versus 13.3 per 10,000 person-years) over seven-year follow-
up [62]. In another retrospective cohort study, bariatric surgery was associated with a 33 percent
reduction in overall cancer risk, with greater reductions of 40 to 55 percent in specific weight-
related cancers: colon cancer, postmenopausal breast cancer, endometrial cancer, and
pancreatic cancer [63]. The IARC analysis also found that bariatric surgery was associated with
a reduced risk of endometrial and breast cancers [61]; in the Nurses’ Health Study, sustained
weight loss of 22 pounds or more in women who had not used menopausal hormone therapy
lowered breast cancer risk [64].
The relationship between obesity and cancer risk is discussed in detail separately, and
associations between obesity and specific cancer types are discussed in the individual topics
that cover the specific cancer type. (See "Overweight and obesity in adults: Health
consequences", section on 'Cancer'.)

DIET

Specific components of diet as well as overall dietary patterns have been studied in relation to
the risk of cancer. Overall, dietary fat, fruits, and vegetables have not consistently been shown to
affect cancer risk [65]. However, certain dietary patterns, as well as intake of other nutrients,
particularly certain micronutrients, may offer a degree of protection against certain malignancies.
(See "Healthy diet in adults" and "Colorectal cancer: Epidemiology, risk factors, and protective
factors" and "Risk factors for prostate cancer".)

Dietary components — Inconsistent results of nutritional (diet or supplement) studies can be

attributed to multiple factors [66]. Observational studies are subject to imprecision in diet recall,
and confounding factors that influence the risk of cancer and occur disproportionately among
individuals exposed and not exposed to the nutrient of interest. Randomized controlled trials may
yield inaccurate results because of poor adherence to the dietary intervention, insufficient follow-
up time, wrong dose or form of the nutrient, or a study population that is replete in the nutrient
studied. Additionally, studies tend to focus on one nutrient in isolation, when whole foods or the
full composition of a diet may correlate better with cancer risk than any single component.

Dietary fat — Dietary fat has been extensively studied as a possible factor explaining the
variation in international cancer rates. No clear link has been found between total fat intake and
colon or breast cancer; the data are somewhat more convincing for prostate cancer [67]. (See
"Dietary fat".)

● While some reports suggest that a diet low in animal fat and/or cholesterol may be
protective against colorectal cancer, epidemiologic studies of colon cancer, controlled for
caloric intake, have shown no consistent association between total fat intake and cancer
risk. In the largest trial to examine this issue, the prospective Women's Health Initiative
Dietary Modification Trial, 48,835 women were randomly assigned to a behavioral
modification program to decrease dietary fat or a usual diet control group [68]. The
intervention group, compared with controls, reduced the percentage of calories consumed
as fat (by 10.7 percent in year 1, 8 percent at year 6). There was no difference in incidence
of colorectal cancer during 8.1 years of follow-up. (See "Colorectal cancer: Epidemiology,
risk factors, and protective factors", section on 'Diet'.)

● Animal and ecologic (international) studies show a positive correlation between fat
consumption and increased breast cancer risk. Results of case-control and cohort studies
 have been mixed, however. 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; 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 [69]. (See "Factors that modify breast
cancer risk in women".)

● 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
[70]. The mechanism of this association may be that serum levels of testosterone are lower
in men who decrease their fat intake. (See "Risk factors for prostate cancer", section on
'Animal fat'.)

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 a greater risk than intake during adulthood. One consistent
finding is that excess calories from any source leads to weight gain and an increase in the risk of
multiple cancers [71]. (See 'Obesity' above.)

Red meat — Consumption of red and processed meat is consistently associated with an
increased risk of numerous chronic diseases, including colorectal cancer and advanced prostate
cancer [72-74]. Overall, these risks are small to moderate but are nevertheless important given
the high level of consumption in the United States and growing level of consumption worldwide.
(See "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Other risk
factors'.)

The International Agency for Research on Cancer classifies processed meat as a Group 1
human carcinogen [75]. (See "Colorectal cancer: Epidemiology, risk factors, and protective
factors", section on 'Red and processed meat'.)

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. It isn't known if risk varies with different animal
raising strategies (eg, grass-fed beef).

The 2020 American Cancer Society guideline on diet and physical activity for cancer prevention
recommends a healthy diet, defined as having a variety of vegetables (dark green, red and
orange, fiber-rich legumes and others), fruits, and whole grains, and limiting or not including red
and processed meats, sugar-sweetened beverages, or highly processed foods and refined grain
products [76].
For a broader discussion of evidence and dietary recommendations regarding red and
processed meat, see elsewhere. (See "Healthy diet in adults".)

Fruits and vegetables — Despite suggestions from case-control studies that high intake of
fruit and vegetables is associated with a significant reduction in cancer, prospective studies have
found less consistent results [77-80]. Data from the European Prospective Investigation into
Cancer and Nutrition (EPIC) study, a cohort study of nearly 500,000 European men and women
followed for nine years, found only a weak association between increased intake of fruits and
vegetables and overall risk of cancer (hazard ratio [HR] 0.97, 95% CI 0.96-0.99) [81].

Many epidemiologic studies [82,83], though not all [84], suggest a weak association between the
intake of a diet high in fruits and vegetables and protection from colorectal cancer. A pooled
analysis of 14 cohort studies (n >750,000), including the previous study [84], concluded that
eating more than 800 g/day of fruit and vegetables, compared with less than 200 g/day,
decreased risk for distal colon cancer (relative risk [RR] 0.74) but not for proximal cancer [85]. A
subsequent meta-analysis of 19 cohort studies concluded a weaker protective effect, with most
of the risk reduction attributable identified at a far lower threshold (100 g/day) of fruit and
vegetable intake [86]. A meta-analysis of the relationship between fiber and colorectal cancer
found no significant association between fruit, vegetable, or legume fiber and the incidence of
colorectal cancer [87].

Evidence is somewhat stronger for a possible protective link between prostate cancer and
consumption of tomato products. Initial studies provided conflicting results, and a systematic
review performed by the US Food and Drug Administration (FDA) found "very limited evidence"
to support an association between tomato consumption and reduced risk of prostate or other
(ovarian, gastric, and pancreatic) cancers [88]. An analysis of a prospective cohort of 51,529
men from the Health Professionals Follow-up Study has suggested that dietary intake of
lycopene is associated with a lower incidence of prostate cancer and a decreased risk of lethal
prostate cancer [89]. Analysis of tumor biomarkers was consistent with a possible role of
inhibition of tumor neoangiogenesis as the mechanism underlying these observations. (See
"Risk factors for prostate cancer", section on 'Lycopene and tomato based products'.)

In an analysis of the Pooling Project of Prospective Studies of Diet and Cancer, total fruit and
vegetable intake was inversely related to the incidence of estrogen-receptor (ER)-negative
breast cancer, with vegetable intake alone associated with an 18 percent risk reduction
comparing the highest quintile of intake with the lowest [90].

A meta-analysis found that intake of high amounts of soy (20 mg/day of isoflavone) in Asian
women was associated with a decreased risk for breast cancer compared with Asian women
consuming lower amounts (5 mg/day) [91]. However, even the lowest intake of soy isoflavones in
the Asian population was more than fivefold the "high" intake (0.8 mg/day) of women in Western
countries, where studies have not shown a protective effect for soy. In another meta-analysis,
Chinese women who were in the highest quintile of soy intake had a decreased risk of lung
cancer compared with those in the lowest quintile [92]. Increased flavonoids found in tomatoes,
green peppers, berries, and citrus fruits have been associated with a modest decrease in breast
cancer risk in Western populations [93].

Dairy — The relationship between dairy intake and ovarian cancer is uncertain. Two meta-
analyses evaluating the relationship of dairy food intake and ovarian cancer found no evidence
of a significant association [94,95], while a third meta-analysis of 21 studies found no 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) [96].
Inaccuracy of retrospective diet reports in the case-control studies may affect their reliability [97].
However, a subsequent cohort study found no increase in risk of ovarian cancer with dietary
dairy or lactose intake [98]. Thus, the relationship of dairy intake to ovarian cancer is uncertain.

Several studies suggest that intake of low-fat dairy products may protect against breast cancer,
mainly in premenopausal women [99-102]. In the largest prospective cohort study of over 88,000
women in the Nurses' Health Study, there was an inverse association between breast cancer risk
and the intake of low-fat dairy products, calcium (mainly dairy intake), and vitamin D (mainly non-
dairy intake) in premenopausal but not postmenopausal women [99]. By contrast, a large pooled
analysis of eight prospective studies mainly comprising postmenopausal women did not find a
strong association between dairy intake and breast cancer risk [103].

Calcium intake, as determined by a food frequency questionnaire, was associated with

decreased total cancer risk over seven years in women, but not in men, in a large United States
cohort of 567,000 participants aged 50 to 71 years [104]. A decrease in cancers of the digestive
tract (particularly colon cancer) with higher dairy food and calcium intake was noted in both men
and women, however (for highest versus lowest quintile, RR 0.84 in men and 0.77 in women).

The association between calcium intake and colorectal cancer risk is discussed below. (See
'Calcium' below.)

Fiber — Fiber intake is associated with a reduction in the risk of heart disease [105,106] and
diabetes [107,108], and colorectal cancer [109]. Though there has been some variance in results
of individual observational studies, a World Cancer Research Fund Continuous Update Project
dose response meta-analysis has found a decrease in risk of colorectal cancer with increasing
intake of fiber. This analysis, including 15 studies with a total of 14,876 cases, showed a 9
percent lower risk of disease for every 10 g/day intake of foods containing fiber (RR 0.91, 95%
CI 0.88-0.94). Similar inverse associations were found in North American (RR 0.92, 95% CI
0.88-0.96) and European (RR 0.90, 95% CI 0.85-0.96) populations [110]. (See "Colorectal
cancer: Epidemiology, risk factors, and protective factors", section on 'Fiber'.)
 Glycemic load — Insulin and insulin-like growth factors promote cell proliferation, and it is
hypothesized that hyperinsulinemia may promote certain cancers [111]. An increased risk for
certain cancers has been associated with diabetes (primarily type 2) [112]. Patients with diabetes
have a twofold or greater risk of cancers of the liver, pancreas, and endometrium and a slightly
lower but increased risk for cancers of the colon, breast and bladder; the risk of prostate cancer
is decreased in patients with diabetes [113].

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.
Intake of foods with a high glycemic index has been evaluated for association with risk of cancer.
These studies have yielded equivocal results. (See "Dietary carbohydrates".)

● A large study involving participants in the National Institutes of Health (NIH)-American

Association of Retired Persons (AARP) Diet and Health Study found no significant
association between glycemic index or glycemic load (calculated from food questionnaires)
with 15,000 cases of cancer in women or 33,000 cases of cancer in men identified over nine
years [114].

● One case-control study of breast cancer reported an association with high glycemic load
[115], but large cohort studies have not confirmed this finding [116-120]. A meta-analysis of
prospective cohort studies found no significant association between glycemic load and
breast cancer risk but noted that a diet with a high glycemic index was positively associated
with increased breast cancer risk [121].

● Glycemic load was not associated with prostate cancer risk in a large cohort study [122].

● Studies of colorectal cancer and glycemic load have also shown inconsistent results
[70,123-126]. 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 with lowest quintiles of glycemic load [123]. On the other
hand, a large study of Canadian women found no increase in risk [125]. 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) but no association among women [126]. A meta-analysis found no association of
glycemic load or glycemic index with colorectal cancer risk [127].

Omega-3 fatty acids and dietary fish — 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
[128]. Ten studies evaluated in this review reported significant findings, but individual studies
indicated both increased and decreased risk with no consistent pattern. A subsequent
randomized trial found an increase in cancer risk for women treated with omega-3 fatty acids,
but not for men [129].

While an association has not been found for dietary supplementation with omega-3 fatty acids
and cancer incidence, an association was found in a systematic review of 41 observational
studies for fish consumption and a decreased incidence of colorectal cancer [130]. In that
analysis, including case-control and cohort studies, an inverse relationship between fish intake
and rectal cancer was demonstrated (odds ratio [OR] 0.79, 95% CI 0.65-0.97), while an inverse
trend was suggested for colon cancer (OR 0.96, 95% CI 0.81-1.14).

Coffee — Coffee intake has been associated with a lower risk of certain cancers, including
endometrial and liver cancer [131,132]. World Cancer Research Fund Continuous Update
Project dose response meta-analyses found a significant 7 percent lower risk of endometrial
cancer (RR 0.93, 95% CI 0.91-0.96) and 14 percent lower risk of liver cancer (RR 0.86, 95% CI
0.81-0.90) for every one cup of coffee/day. For endometrial cancer, the results were similar for
decaffeinated coffee, a significant 8 percent lower risk (RR 0.92, 95% CI 0.87-0.97) per one
cup/day.

Caffeine — The effects of caffeine on several types of cancer are described separately. (See
"Benefits and risks of caffeine and caffeinated beverages", section on 'Cancer'.)

Dietary patterns — Adherence to certain dietary patterns has been associated with impacts on
cancer incidence and overall mortality. A meta-analysis of prospective studies of “healthy” and
“unhealthy” dietary patterns found favorable associations between a healthy diet and lower risks
of certain types of cancers [133]. In a large cohort study of the Mediterranean diet (ie, high intake
of fruits, vegetables, nuts, legumes, whole wheat bread, fish, and olive oil), a two-point increase
in dietary compliance (on a 10-point scale) was associated with a 4 to 12 percent lower risk of
cancer [134,135]. In a study of cancer risk and mortality [136], all-cause mortality was 17 percent
lower with a vegetarian diet than for non-vegetarians.

By contrast, studies of a "Western" diet have found an association with increased risk of some
cancers compared with adherence to a "prudent" diet, although the components of a "Western"
diet vary from study to study [137]. In another cohort study, diets high in ultra-processed foods
were associated with greater than 10 percent increases in the risk of all-cancer and breast
cancer [138]. Ultra-processed foods included mass-produced packaged breads, packaged
snacks, sodas, reconstituted meat products with nitrite preservatives, instant soups, frozen
meals, and others.

Specific dietary patterns may affect the incidence and mortality rate of certain types of cancer.
See appropriate topic reviews. (See "Colorectal cancer: Epidemiology, risk factors, and
protective factors", section on 'Diet' and "Colorectal cancer: Epidemiology, risk factors, and
protective factors", section on 'Red and processed meat' and "Risk factors for prostate cancer",
section on 'Diet' and "Cigarette smoking and other possible risk factors for lung cancer", section
on 'Dietary factors' and "Factors that modify breast cancer risk in women", section on 'Low-fat
dietary pattern in postmenopausal women'.)

VITAMINS AND MICRONUTRIENTS

Multiple observational and prospective studies of the use of supplemental vitamins and minerals
to prevent cancer have been disappointing [139]. A systematic review of 38 studies found that
neither vitamin C nor vitamin E supplementation was beneficial for prevention of the cancers
evaluated [140]. 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" [141]. A
subsequent long-term randomized trial (mean 9.4 years treatment) in 8000 women found no
evidence that supplementation with vitamin C, E, or beta-carotene (singly or in combination)
decreased cancer incidence or cancer mortality [142]. Additionally, two long-term observational
studies, one including over 160,000 women with follow-up of approximately eight years [143] and
another including over 180,000 multiethnic participants with 11-year follow-up [144], found no
association between multivitamin use and risk of cancer. (See "Vitamin supplementation in
disease prevention".)

However, the large (n = 14,641) randomized Physicians' Health Study II found that
supplementation with a multivitamin resulted in a small reduction in total cancer that narrowly
reached statistical significance (hazard ratio [HR] 0.92, 95% CI 0.86-0.998) [145]. The study
population was male clinicians 50 years and older at recruitment, and thus generally well-
nourished and highly educated. With a mean follow-up of 11.2 years, there was a reduction in
total cancer from 18.3 to 17.0 events per 1000 person-years, comparing groups assigned to
multivitamins and placebo, respectively. No difference was found in the secondary outcome of
decreased incidence of specific cancers, and there was no impact on cancer mortality. For men
with a baseline history of cancer, multivitamin use was associated with a reduction in total cancer
(HR 0.73, 95% CI 0.56-0.96).

Given the variability of study findings, with only marginal benefit in some and no benefit in
others, meta-analysis incorporating the prior studies would be helpful. Pending such analysis, it
has not been established that multivitamin and mineral supplements provide added benefit to a
balanced, healthful diet for most individuals [146,147]. The only prospective trial of vitamin
supplementation (selenium plus vitamin E and beta-carotene) to show a durable finding of fewer
deaths in the treated group was conducted in remote Linxian Province, China, a region where
the population consumes a poor diet, and enrollees likely suffered deficiencies of the nutrients
tested [148]. The US Preventive Services Task Force (USPSTF) recommends against
supplementation with beta-carotene due to an increased risk for lung cancer and against
supplementation with vitamin E due to lack of benefit for reduction in cancer risk [147,149].

Vitamin D — Studies of the relationship between vitamin D intake or serum levels of 25(OH)D
and cancer risk have been inconsistent [150]. Studies vary in regard to participants (sex,
baseline serum levels), types of cancer evaluated, and dose of vitamin D. Overall, it does not
appear that vitamin D supplements should be prescribed to decrease cancer risk [151]. (See
"Vitamin D and extraskeletal health", section on 'Cancer' and "Risk factors for prostate cancer",
section on 'Calcium and vitamin D' and "Factors that modify breast cancer risk in women",
section on 'Calcium/vitamin D' and "Chemoprevention strategies in prostate cancer", section on
'Vitamin D analogs'.)

Calcium — Increased calcium intake has been linked to reduced risk of colorectal cancer but
may be associated with an 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 supplemental) is associated with a reduced risk of colorectal cancer
[152,153]. As an example, in a combined 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 subjects who more than 1250 mg/day elemental calcium versus ≤500 mg/day
(relative risk [RR] 0.58, 95% CI 0.32-1.05) [154].

Calcium supplementation appears to prevent the recurrence of colorectal adenomas. Meta-

analyses have found a 12 to 13 percent lower risk of recurrence of adenomas in patients
randomized to calcium supplementation [155,156]. (See "Overview of colon polyps".)

Despite these benefits in adenoma prevention trials, whether calcium supplementation

reduces the risk of colorectal cancer is unproven.

A protective effect of calcium supplementation could not be shown by 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 international units twice/day compared with placebo [157]. 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. However, it has been noted that the baseline mean calcium intake in
the Women's Health Initiative participants (1151 mg/day) was above the threshold for effect
indicated by previous studies and thus increasing intake would be expected to show no
effect [158].
 ● Prostate cancer – Case-control and prospective studies of calcium and prostate cancer
have reported inconsistent results [159]. Three large cohort studies found an increased risk
of prostate cancer with different measures of calcium intake [160-162]. Two other
prospective studies found no association [163,164]. (See "Risk factors for prostate cancer",
section on 'Calcium and vitamin D'.)

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) [162]. High dietary calcium (≥2000 mg/day) 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 (≥2000 mg/day) and total, advanced, and
metastatic disease (RR 1.71, 2.97, and 4.57, respectively) [161].

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 — Although human epidemiologic studies and animal studies have suggested a
potential protective effect of selenium on cancer incidence, randomized controlled human trials
have not found a beneficial effect of selenium on overall cancer mortality or incidence [165-169].

Vitamin E — Evidence does not support a role for vitamin E supplementation in the prevention
of cancer, and some evidence suggests that vitamin E may be harmful. In 2014, the USPSTF
made a recommendation against use of vitamin E for cancer prevention, citing adequate
evidence of lack of benefit, but also noted adequate evidence that vitamin E has few or no
substantial harms [149]. (See "Vitamin supplementation in disease prevention", section on
'Cancer' and "Overview of vitamin E", section on 'Potential benefits'.)

Folate and other B vitamins — Folate is present in green, leafy vegetables, fruits, cereals and
grains, nuts, and meats. Folic acid, a synthetic form included in supplements, has many of 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 or folic acid 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, some randomized trials have suggested the possibility that folic
acid may increase risk for cancer.

Support from observational studies 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 [170] as well as cancers of the
esophagus, stomach and pancreas [171].

● 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 [172].

● The Nurses' Health Study demonstrated a decreased risk of colon cancer (RR 0.25, CI
0.13-0.51) 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 [173]. 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 [174].

● 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 [175]. 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
[171].

However, a meta-analysis of case-control studies and observational studies did not demonstrate
an association between low dietary folate intake and breast cancer [176]. The study found
evidence of publication bias in previous studies that had suggested an association.

In contrast to biologic and observational evidence supporting a role for folate in cancer
prevention, randomized trials of folic acid supplementation have not shown benefit and some
trials have raised the possibility of harm. Concern for a possible increase in cancer risk had been
initially raised by findings from several individual trials, including the following:

● The largest controlled trial to evaluate folic acid supplementation in patients with 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 in noncolorectal cancer in patients who
received folic acid compared with controls [177].

● Combined analysis of two trials evaluating vitamin supplementation in patients with ischemic
heart disease found an increased risk for cancer incidence (primarily lung cancer; HR 1.21,
95% CI 1.03-1.41) and cancer mortality (HR 1.38, CI 1.07-1.79) at three-year follow-up in
participants who received folic acid plus vitamin B12 supplementation for three years [178].

● The incidence of prostate cancer was increased in the group of men randomly assigned to
receive folic acid (1 mg/day) in a placebo-controlled trial of chemoprevention for colorectal
 polyps [179].

Two meta-analyses, however, have not found an increase in the risk of cancer [180,181].

● In the largest meta-analysis of individual patient data from randomized trials of folic acid for
the prevention of cardiovascular disease (10 trials, n = 49,969) and colorectal adenoma
(three trials, n = 2652), during an average of 5.2 years of treatment, there was no significant
difference in overall cancer incidence for patients assigned to folic acid or placebo (RR 1.06,
95% CI 0.99-1.13) [181]. There was also no significant effect on the incidence of specific
cancers, including cancers of the large intestine, prostate, lung, or breast.

● Similarly, a meta-analysis based on individual patient data from eight randomized trials of
patients with increased cardiovascular risk (n = 37,485) found no significant effect of folic
acid supplementation in varying doses (0.8 to 40 mg/day) on cancer incidence (RR 1.05,
95% CI 0.98-1.13) or cancer mortality (1.00, 0.85-1.18) with a median follow-up of five years
[180]; findings were similar in a subsequent trial in patients with cardiovascular disease
[129].

Serum levels of other B vitamins have been associated with reduced cancer risk in observational
studies:

● A meta-analysis of prospective studies found an inverse association for risk of colorectal

cancer with vitamin B6 intake and blood levels of pyridoxal 5'-phosphate, the active form of
vitamin B6 [182]. However, it is not known whether supplementation with vitamin B6 will
decrease cancer risk.

● In a prospective study over eight years, involving more than 500,000 participants, having a
serum level above median for B6 and methionine was associated with a lower risk of lung
cancer in both never and current smokers [183]. In this cohort, a lower risk of lung cancer
was also seen in smokers (past or current) with higher levels of folate but not in those who
never smoked.

Folate in alcohol users — The interaction between folate and alcohol may be important in
cancer prevention (see 'Alcohol' below). 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
[184].

Iron — Observational studies suggest that increased iron stores or dietary iron may be
associated with increased risk for cancer [185,186]. A randomized trial conducted to evaluate the
benefits of phlebotomy in patients with peripheral artery disease found a significant reduction in
cancer incidence at six months (HR 0.65, 95% CI 0.43-0.97) in patients assigned to the
phlebotomy group compared with controls [187]. This finding warrants confirmation.
Other — Other vitamin supplements have been evaluated, with variable findings:

● High doses of beta-carotene have been associated with an increased incidence of lung
cancer [188-190]. Beta-carotene doses used in some of these trials may also be found in
multivitamin formulations used to promote visual health. Beta-carotene did not decrease
cancer incidence in studies of American women [191] and men [192]. (See "Cigarette
smoking and other possible risk factors for lung cancer", section on 'Beta-carotene
supplementation'.)

● In the Nurses’ Health Study (n = 75,170) and Health Professionals Follow-up Study
populations (n = 48,400) a lower risk of squamous cell carcinoma was found with increased
intake of total vitamin A as well as retinol and select carotenoids [193].

● Supplementation with a combination of beta-carotene, selenium, and zinc decreased the

incidence of noncardiac stomach cancer, but not other intestinal malignancies, in a
population in rural China with baseline deficiencies in micronutrients [194].

ALCOHOL

Alcohol consumption increases the risk of multiple cancers. The 2020 American Cancer Society
guideline on diet and physical activity for cancer prevention recommends not drinking alcohol.
People who do choose to drink alcohol should limit consumption to no more than one drink/day
for women and two drinks/day for men [76]. (See "Overview of the risks and benefits of alcohol
consumption", section on 'Alcohol effect on specific conditions'.)

Findings from other studies include:

● A prospective study of over one million women (average age 56 years) found that, at an
average follow-up of 7.5 years, 10 g/day of alcohol (one drink) increased the risk for cancers
of the oropharynx, esophagus, larynx, rectum, liver, and breast [195]. The overall risk for
cancer was increased 6 percent (95% CI 4-7) for each 10 g/day of alcohol (of any type)
consumed. The increased risk for cancers involving the upper respiratory and digestive tract
was seen only in current smokers.

● Increased risk for breast cancer with low to moderate alcohol consumption was found in the
Women's Health Study [196] as well as in the Nurse's Health Study [197].

● The European Prospective Investigation into Cancer and Nutrition (EPIC) study in eight
European countries found alcohol consumption could account for 10 percent of the
attributable risk for any cancer in men and 3 percent in women [198]. The risk was greatest
for consumption of more than recommended upper limits of alcohol, and it was greatest for
upper gastrointestinal and hepatocellular cancer.
 ● It has been estimated that, worldwide, 3.6 percent of cancers are associated with chronic
alcohol drinking [199]. In 2016, in those aged 50 and over, 18.9 percent of alcohol-related
deaths in men and 27.1 percent of alcohol-related deaths in women were due to cancer
[200].

Moderate alcohol use can have beneficial effects on cardiovascular health in older adults, but
the increased risks of cancer and other harms likely offset such benefits [200,201]. Even light
alcohol consumption of three to six drinks/week has been associated with a small increased risk
for breast cancer in women, as well as increased risk for oropharyngeal and esophageal cancer
[202]. A Global Burden of Disease Study analysis found that cancer risk increased monotonically
with increasing alcohol intake [200]. (See "Overview of the risks and benefits of alcohol
consumption", section on 'Cardiovascular disease'.)

Several mechanisms have been postulated to account for the carcinogenicity of alcohol [199]. 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; as an inhibitor of DNA
methylation; or as a prometabolite for identified carcinogens such as acetaldehyde
[199,203,204].

For unclear reasons, moderate consumption of alcohol has been associated with a decreased
risk of renal cell carcinoma. (See "Epidemiology, pathology, and pathogenesis of renal cell
carcinoma", section on 'Alcohol'.)

INFECTIONS

It is estimated that 17 percent of all new cancers worldwide are due to infections [205]. Viruses
may increase cancer risk through cellular transformation, disruption of cell cycle control,
increased cell turnover rates, and immune suppression [206].

Multiple links between infectious agents and cancer have been established:

● Human papillomavirus (HPV) with cervical and other anogenital cancers as well as
squamous cell cancers of the head and neck [207] (see "Virology of human papillomavirus
infections and the link to cancer" and "Epidemiology, staging, and clinical presentation of
human papillomavirus-associated head and neck cancer")

● Hepatitis B (HBV) and C (HCV) with hepatocellular carcinoma [208] (see "Epidemiology and
risk factors for hepatocellular carcinoma")

● Human T-cell lymphotropic virus type 1 (HTLV-1) with adult T-cell leukemia [209] (see
"Treatment of large granular lymphocyte leukemia")
 ● Human immunodeficiency virus (HIV) with Kaposi sarcoma as well as with non-Hodgkin
lymphoma [205] and with multiple non-acquired immunodeficiency syndrome (AIDS)-
defining malignancies [210] (see "HIV infection and malignancy: Epidemiology and
pathogenesis")

● Human herpes virus 8 (HHV-8) with Kaposi sarcoma and primary effusion lymphoma
[211,212] (see "Virology, epidemiology, and transmission of human herpesvirus 8 infection")

● Epstein-Barr virus (EBV) with Burkitt lymphoma [211] (see "Pathobiology of Burkitt
lymphoma")

● The bacterium Helicobacter pylori with gastrointestinal malignancies including gastric cancer
[213] and mucosa-associated lymphoid tissue (MALT) lymphomas

● Liver flukes with cholangiocarcinoma and hepatocellular carcinoma [214] (see "Liver flukes:
Clonorchis, Opisthorchis, and Metorchis")

The majority of these are viruses that are spread through contact with infected blood or body
fluids, thus offering opportunities for prevention. Vaccinations for HBV and HPV are clearly
beneficial. (See "Prevention of sexually transmitted infections" and "Hepatitis B virus
immunization in adults" and "Adolescent sexuality", section on 'STIs and HIV'.)

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 health
care 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:

● HPV vaccination is recommended for both girls and boys, as well as for young women and
young men who were not vaccinated during childhood. Additionally, cervical cancer
screening has dramatically reduced the incidence of cervical cancer where screening is
widely available [215]. (See "Human papillomavirus vaccination" and "Screening for cervical
cancer in resource-rich settings".)

● Pre-exposure prophylaxis (PrEP) can significantly lower the risk of HIV infection in high-risk
groups, and retroviral therapy for HIV infection has greatly altered the course of disease and
associated cancers. Antiretroviral therapy (ART) has been shown to reduce the incidence of
AIDS-related lymphoma [216]. (See "Selecting antiretroviral regimens for treatment-naïve
persons with HIV-1: General approach".)

● Decreasing the hepatitis B viral load by treatment with interferon or nucleoside/tide

analogues in patients with chronic hepatitis B infection was associated with a decreased risk
 for hepatoma [217,218]. (See "Hepatitis B virus: Overview of management".)

● 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 patients with chronic HCV infections, with reduction of HCV
RNA, but the long-term effect of antiviral therapy on cancer risk is not known [219].

CHEMOPREVENTION

For breast cancer, prophylactic medication can reduce cancer risk for high-risk individuals. The
risk/benefit ratio for chemoprevention must be evaluated for individual patients. This, and
chemoprevention for prostate cancer, are discussed in detail in the relevant UpToDate topics.
(See "Chemoprevention strategies in prostate cancer" and "Selective estrogen receptor
modulators and aromatase inhibitors for breast cancer prevention" and "Cancer risks and
management of BRCA1/2 carriers without cancer".)

Aspirin and other antiinflammatory drugs — Several theories have been proposed for why
aspirin and other nonsteroidal antiinflammatory drugs (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 (COX-). 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 NSAIDs has been shown to decrease
the risk of adenomatous polyps and colorectal cancer [220-223]. In high-risk patients with Lynch
syndrome, a randomized controlled trial found 600 mg/day of aspirin decreased the risk of
colorectal cancer by 60 percent [224]. The optimal dose of aspirin for patients at lower risk,
however, has not been established [225]. (See "NSAIDs (including aspirin): Role in prevention of
colorectal cancer".)

Accumulated evidence indicates that aspirin needs to be taken long-term and at a daily dosing of
a minimum of 75 mg to reduce risk [222,223,226-229]. The US Preventive Services Task Force
(USPSTF) recommends long-term daily low-dose aspirin for the primary prevention of colorectal
cancer and cardiovascular disease for people aged 50 to 59 years who have a 10-year risk of
cardiovascular disease of 10 percent or higher and who do not have an increased bleeding risk
[230]. For those aged 60 to 69 years with a 10-year risk of cardiovascular disease of 10 percent
or higher, aspirin use may be appropriate, but the decision should be individualized. (See
"Aspirin in the primary prevention of cardiovascular disease and cancer".)
 Other cancers — Data regarding aspirin in the prevention of cancers other than colorectal
are less consistent but seem to suggest that daily (but not alternate-day) dosing of aspirin
decreases the risk of cancer but with a long latency, requiring long-term follow-up of individual
patient data to assess the impact of aspirin on cancer prevention [222,226,229,231-235]. Aspirin
and NSAIDS in the prevention of breast cancer is discussed elsewhere. (See "Factors that
modify breast cancer risk in women", section on 'Nonsteroidal anti-inflammatory drugs'.)

Other drugs — Although evidence is not compelling enough to suggest initiation of other drugs
for cancer prevention, observational studies and limited experimental evidence suggest a
possible future role for other drugs [236-247].

Metformin — The anti-diabetic drug metformin has been associated with reduced incidence
of several types of cancer in patients with type 2 diabetes.

● A systematic review and meta-analysis included 11 independent studies contributing 4042

cases of cancer and 529 deaths in patients with diabetes [239]. Both cancer incidence and
cancer mortality were reduced by 30 percent among users of metformin. Reductions in the
incidence of pancreatic and liver cancer as well as nonsignificant reductions for breast,
colon, and prostate were observed. There was a trend toward a dose-response relationship.
In two subsequent meta-analyses in patients with diabetes, there was an association
between metformin use and a decrease in colorectal cancer risk [240] and a decrease in
risk of colorectal, liver, and lung cancers [241].

● In an observational study of 4085 patients in the United Kingdom who used metformin for
type 2 diabetes from 1994 to 2003, cancer incidence was 40 percent lower than among
diabetic patients who did not take metformin (7.3 versus 11.6 percent, hazard ratio [HR]
0.46, 95% CI 0.40-0.53) [237].

● In a prospective study of 1353 patients with type 2 diabetes in the Netherlands, during 9.6
years of follow-up, cancer mortality was reduced in those who used metformin (HR 0.43, CI
0.23-0.80) [238].

● In a registry-based case control study in the United Kingdom, metformin use was associated
with a 60 percent decrease in pancreatic cancer risk among women but had no effect on
cancer risk among men [242].

Among postulated mechanisms for such a benefit are the inhibition of cancer cell growth and
suppression of HER2 overexpression and inhibition of mTOR [243-245]. Alternatively, these
results may reflect increased risk due to use of other regimens for diabetes rather than
decreased risk due to use of metformin.

Warfarin — Studies show mixed results regarding the association between warfarin use and
cancer risk [247,248]. In a population-based cohort study of over one million people in Norway,
warfarin users (for at least six months) had a lower incidence of all cancer diagnosed at least two
years after initiating warfarin (incidence rate ratio [IRR] 0.84; 95% CI, 0.82-0.86) [247]. Warfarin
users also had lower incidence of lung, prostate, and breast cancer. Warfarin is known to block
murine tumorigenesis, and it is postulated that its biochemical actions enhance antitumor
immune surveillance [247].

Statins — Studies of statins show mixed results; there is no convincing evidence that statins
influence the risk of cancer. An association between statin use and decreased risk of a variety of
cancers (particularly gastrointestinal and breast cancers) has been suggested in multiple
observational studies; however, such data are subject to confounding by risk factors and
comorbidities [236]. By contrast, a meta-analysis of 27 randomized trials of statins (in which
cancer prevention was not a primary outcome) did not find that statins reduced the incidence of
any cancer [246].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short,
easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Medications for the prevention of breast
cancer (Beyond the Basics)")

SUMMARY

● Many cancers are preventable. Basic lifestyle changes can have a tremendous impact on
the rates of cancer. General lifestyle recommendations include avoiding tobacco, being
physically active, maintaining a healthy weight, eating a healthy diet, limiting or eliminating
alcohol, protecting against sexually transmitted infections, avoiding sun exposure, and
obtaining appropriate cancer screening. (See 'Introduction' above.)
● Tobacco use is the most preventable cause of cancer, responsible for 90 percent of all lung
cancer deaths. Significant health benefits accompany quitting, even for longtime tobacco
users. The health benefits of quitting can be seen at all ages and can be measured almost
immediately after cessation. (See 'Tobacco use' above.)

● Potentially modifiable or avoidable environmental contributors to cancer incidence include

exposure to excessive solar radiation or to artificial ultraviolet radiation, air pollution, radon
gas in enclosed environments, and arsenic in drinking water. (See 'Environmental
exposures' above.)

● Decreased physical activity appears to increase the risk for cancer [11,40], and it is
estimated that a sedentary lifestyle is associated with 5 percent of cancer deaths. Physical
activity is associated with a decreased risk for many different types of cancers [44], but the
most compelling data are in the reduction in colon and breast cancer risk. (See 'Physical
activity' above.)

● Obesity has been found to increase the risk of many types of cancers, with an estimated 4.5
million deaths worldwide annually caused by excess weight. (See 'Obesity' above.)

● The association of dietary fat, fruits, and vegetables with cancer risk is largely unconfirmed.
Red meat and processed meat consumption may promote colorectal cancer and a high
intake of tomatoes probably decreases prostate cancer risk. (See 'Diet' above.)

● High calcium intake (>2000 mg/day) increases risk for prostate cancer. Folate in diet has
been associated with a decreased risk of colon cancer, especially in women who drink
alcohol; data on folic acid or multivitamin supplementation are inconsistent. (See 'Vitamins
and micronutrients' above.)

● Alcohol intake, even in light to moderate quantities, increases the risk for colon, breast,
esophageal, and oropharyngeal cancer. (See 'Alcohol' above.)

● Skin cancer is directly related to natural and artificial ultraviolet exposure. A history of
blistering sunburns and indoor tanning, especially in youth and young adults, is of particular
risk for melanoma; cumulative sun exposure has more impact on non-melanoma cancers.
(See 'Excess sun exposure, artificial ultraviolet radiation' above.)

● Human papillomavirus (HPV), hepatitis C virus (HCV), human T-lymphotropic virus type 1
(HTLV-1), human immunodeficiency virus (HIV), hepatitis B (HBV), Epstein–Barr virus
(EBV), and Helicobacter pylori have been linked to human cancers. Exposure prevention,
pre-exposure prophylaxis (PrEP), screening, vaccination, and early treatment can help
prevent infection-associated cancers. (See 'Infections' above.)
 ● Chemoprevention may be helpful in high-risk patients, but risks and benefits should be
weighed carefully. Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) offer protection
against adenomatous polyps and colorectal cancer, and long-term use in low doses likely
decreases cancer-related mortality risk from other solid tumors. (See 'Chemoprevention'
above.)

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