Nutrition and Cancer Prevention

Nicole Stendell-Hollis, MS, RD INTRODUCTION

Throughout history, changes and trends in food and beverage intake, physical activity habits, and body composition have accompanied the increases in industrialization and urbanization throughout the world. In general, diets have become more energy dense, while levels of physical activity have decreased as the population has become increasingly sedentary, resulting in increased rates of overweight and obesity worldwide. These changes correlate with shifts in cancer incidence throughout the world, with a doubling of global cancer rates projected to occur by 2030.1

Approximately one-third of the cancer deaths that occur yearly in the United States are estimated to be due to nutrition and physical activity factors, as well as weight status.2 Cancer is caused by both internal factors (e.g., inherited mutations, hormones, immune conditions, and metabolic mutations) and external factors (e.g., tobacco, chemicals, radiation, and infectious organisms); these factors may work either collectively or in sequence to initiate or promote carcinogenesis. Although all cancers involve the malfunction of genes that control cell growth and division, only approximately 5% of cancers are attributed to hereditary factors. Hence, for those individuals who do not use tobacco, choices associated with diet, physical activity, and weight control are the most significant modifiable aspects of cancer risk.

Recent cancer prevention recommendations by organizations focused on chronic diseases, such as the American Cancer Society (ACS) and the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), focus on healthy diet choices, increased physical activity, and achievement and/or maintenance of a healthy weight. Specifically, the ACS’s 2006 Recommendations for Nutrition and Physical Activity for Cancer Prevention3 emphasize the following ways to decrease one’s risk for developing cancer:

Maintain a healthy body weight throughout life.

Adopt a physically active lifestyle.

Consume a healthy diet with an emphasis on plant food sources.

If you drink alcoholic beverages, limit consumption.

In concurrence with these recommendations, the WCRF/AICR’s 2007 Guidelines for Cancer Prevention include the following points:1

Be as lean as possible within the normal range of body weight.

Be physically active as part of everyday life.

Limit consumption of energy-dense foods and avoid sugary drinks.

Eat mostly foods of plant origin.

Limit intake of red meat and avoid processed meat.

Limit alcoholic drinks.

Limit consumption of salt and avoid moldy grains or legumes.

Aim to meet nutritional needs through diet alone.

Mothers should breastfeed if possible; children should be breastfed if possible.

Cancer survivors: Follow the recommendations for cancer prevention.

Throughout this chapter, recommendations are made based on the evidence and defined as convincing, probable, or limited/suggestive. Table 6.1 provides definitions and criteria for these terms based on the review and strength of the evidence. This chapter summarizes the AICR’s recent recommendations related to diet (Table 6.2), physical activity, and weight control for the prevention of cancer.1

Table 6.1 Criteria for Judging the Evidence

Convincing

Strong, high-quality evidence from numerous combinations of scientific studies, including epidemiological and experimental research, as well as proof of plausible biological mechanisms

Probable

Evidence is slightly less robust, but still generally justifies goals and recommendations

Limited/suggestive

Evidence is too limited to permit a probable judgment, but there is a suggestive direction of effect

Source: Adapted from World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC:

Author; 2007.

Decreases Risk

Increases Risk

Meat, poultry, Fish (limited)

Red meat (convincing)

fish, and eggs Foods containing vitamin D

Processed meat (convincing)

(limited)

Cantonese-style salted fish

(probable)

Foods containing iron (limited)

Smoked foods (limited)

Grilled (broiled) or barbequed

(charbroiled) animal products

(limited)

Plant foods Non-starchy vegetables

Chili pepper (limited)

(probable and limited)

Allium vegetables (probable)

Garlic (probable)

Fruits (probable and limited)

Foods containing folate and

selenium (probable and limited)

Foods containing carotenoids

and vitamin C (probable)

Carrots (limited)

Legumes (limited)

Foods containing pyridoxine,

vitamin E, and quercetin

(limited)

Grains, roots, Foods containing fiber

Aflatoxins (convincing)

tubers, and (probable and limited)

plantains

Milk and Milk (probable and limited)

Diets high in calcium (probable)

dairy

Milk, dairy products, and cheese

products

(limited)

Fats and oils

Total fat (limited)

Foods containing animal fats

(limited)

Butter (limited)

Sugars and

Salt (probable)

salt

Salted and salty foods (probable)

Foods containing sugar (limited)

Water, fruit

Arsenic in drinking water

juices, soft

(convincing, probable, and

drinks, and

limited)

hot drinks

Mate (probable and limited)

High-temperature drinks (limited)

(continues)

Decreases Risk

Increases Risk

Alcohol

Alcoholic drinks (convincing and probable)

Dietary supplements

Calcium (probable)

Selenium (probable and limited)

Retinol and alpha-tocopherol (limited)

Beta-carotene supplements (convincing)

Retinol and selenium supplements (limited)

Source: Adapted from World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: Author; 2007.

The Role of Diet

Food and nutrients have the ability to modify cancer risk at a large number of sites by a variety of factors that influence cellular processes associated with carcinogenesis. DNA repair; cellular proliferation, differentiation, and apoptosis; hormonal regulation; inflammation and immunity; the cell cycle; and carcinogen metabolism have all been identified as processes that may be altered by diet, nutrients, or bioactive food compounds, thereby affecting cancer risk.1

Substantial changes have transpired in the patterns of foods and beverages available and consumed throughout the world. These trends have resulted in a reduction in some dietary deficiencies and improvements in overall nutrition, but also in unfavorable shifts in the composition of diets. The increased proportions of energy-dense foods now consumed by much of the world’s population contain large amounts of fats, oils, and sugars—all of which contribute to an increased risk of some types of cancer. There are several plausible theories for this increase in cancer risk due to dietary choices, such as an excess intake of energy, increased exposure to red meat, insufficient intake of fruits and vegetables, and/or an imbalance of omega-3 and omega-6 fatty acids. All of these factors may further contribute to risk both alone and through an undesirable increase in body weight. These factors and others are discussed in more detail in this chapter.

Meat, Poultry, Fish, and Eggs

One notable change in dietary patterns is the increased accessibility of animal products, which traditionally have provided only a small percentage of the overall food availability. Meat consumption has tended to increase with economic development, with the ultimate result of worldwide meat consumption per person approximately doubling between 1961 and 2002. In general, animal products provide relatively high amounts of fat and energy, both of which contribute to the increased risk of some cancers.

Evidence from epidemiological studies illustrate a dose-response relationship between red meat consumption and colorectal cancer, and suggest red meat intake is a causative factor in esophageal, lung, pancreas, and endometrial cancers.4 Several conceivable mechanisms for an underlying causative association between red meat intake and cancer have been proposed: the generation of potentially carcinogenic and mutagenic ^-nitroso compounds by gastrointestinal bacteria5; the production of carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons due to cooking at high temper-atures6; and possible excess iron exposure leading to excess generation of free radicals, oxidative stress, inflammation, and hypoxia.7

The term “processed meat” is defined inconsistently in the literature. For the purpose of this review, processed meat is defined as any meat that has been preserved by smoking, curing, salting, or addition of preservatives. Examples include ham, bacon, pastrami, salami, sausages, bratwursts, frankfurters, hotdogs, and sometimes minced meats. A considerable body of strong evidence from cohort studies indicates that processed meat is a con-tributary factor in colorectal cancer, and limited evidence suggests that processed meat is a contributory factor in esophageal, lung, stomach, and prostate cancers.8 Several plausible mechanisms for explaining the carcinogenic capacity of these foods exist:

Nitrates are commonly used as preservatives for meats, which may contribute to the production and exposure of ^-nitroso compounds, thereby increasing the risk of cancer.

Many processed meats contain high levels of salt and nitrites, which may negatively influence cancer risk.9

Processed meats generally contain high amounts of fat and iron, which may increase the production of free radicals, thereby increasing cancer risk.

Processed meats are likely to be cooked at high temperatures, increasing the production of heterocyclic amines and polycyclic aromatic hydrocarbons.

Probable evidence exists that Cantonese-style salted fish is associated with increased risk of nasopharyngeal cancer because of the high levels of the known carcinogens ^-nitrosamines found in this product. Cantonese-style salted fish refers to the traditional method of preserving raw fish through drying and salting of fish, thereby contributing to fermentation and/or insect infestation of the fish and increasing the risk of cancer.

There is limited evidence that smoked, grilled (broiled), and barbequed (charbroiled) foods are causative factors in stomach cancer, as meats cooked at a high temperature, over an open flame, or charred or “well done” may lead to the development of heterocyclic amines or polycyclic aromatic hydrocarbons.

The evidence regarding poultry and eggs is too limited in amount, consistency, and/or quality to draw any conclusions. There are also limited data suggesting that eating fish and foods containing vitamin D may be protective against colorectal cancer owing to their involvement in inflammation, and cellular proliferation and differentiation, respectively.10

In conclusion, it is recommended to limit intake of red meat to no more than three (3-4 oz/serving) servings per week, and to avoid processed meats altogether.1

Plant Foods

Despite the numerous benefits of eating a plant-based diet, consumption of plant foods around the world varies and is generally lower than what is commonly recommended. Historically, diets have combined grains and legumes, thereby ensuring adequate protein consumption, while providing only small amounts of animal products. Nutrient-dense plant sources such as vegetables and fruits are rich sources of a variety of vitamins, minerals, phytochemicals, and fiber, but provide only a limited amount of energy. Nuts and seeds provide concentrated sources of micronutrients and essential fatty acids, and many herbs and spices have known beneficial pharmacological properties. Therefore, it is recommended to eat mostly foods of plant origin, with an average daily consumption of 21 oz of non-starchy vegetables and fruits and 25 g of unprocessed cereal grains and legumes.1

Non-starchy vegetables can be defined as green, leafy vegetables including broccoli, okra, eggplant, and bok choy, as well as roots and tubers such as carrots, artichokes, celery root, rutabaga, and turnips. A substantial amount of probable—although not convincing—evidence exists that nonstarchy vegetables protect against mouth, pharynx, larynx, esophageal, and stomach cancers, and limited evidence suggests that non-starchy vegetables may protect against nasopharyngeal, lung, colorectal, ovarian, and endometrial cancers. Several hypotheses have been put forth to explain these protective effects. Non-starchy vegetables contain an abundance of potentially anticarcinogenic substances, including antioxidants such as carotenoids and vitamin C, dietary fiber, and numerous phytochemicals (glucosinolates, dithiolthiones, indoles, chlorophyll, flavonoids, allyl sulfides, and phytoestrogens). Bioactive food components (BAFC) may alter cancer risk through their antioxidant properties, modulation of detoxification enzymes, stimulation of the immune system, antiproliferative activities, and modulation of hormone concentrations and metabolism.11 Non-starchy vegetables also contain substantial amounts of folate, which plays an important role in the synthesis and methylation of DNA, and which may prevent expression of the aberrant gene linked to several types of cancer.12 Additionally, probable data exist that the allium vegetables (onions, garlic, leeks, chives, and shallots) lower the risk of stomach and colorectal cancers; limited evidence suggests carrots are protective against cervical cancer.

Cruciferous vegetables are increasingly receiving attention as potential anticarcinogenic agents because of their high concentrations of glucosino-lates, which are metabolized to isothiocyanates (ITCs) and indoles in the digestion process. These metabolic products lessen the effects of polycyclic aromatic hydrocarbons and nitrosamines via the activation of glutathione-S-transferases (GSTs) and inhibition of cytochrome P450 isoenzymes. Additionally, ITCs have been shown to modify meat-derived urinary mutagens as well as mutations formed by tobacco carcinogens.13 Despite this promising preliminary evidence, research has shown inconsistent results regarding cruciferous vegetables’ potential to act as anticarcinogenic agents. Of course, it is difficult to pinpoint the specific anticarcinogenic effect of the various nutrients in foods in general, as most likely this effect arises through the additive and synergistic actions of the many nutrients present in whole fruits and vegetables.

Consistent, plausible evidence indicates that fruits probably protect against mouth, pharynx, larynx, esophageal, lung, and stomach cancers, with limited evidence for protection against nasopharyngeal, liver, and colorectal cancers.14- 16 Fruits are a rich source of vitamin C, phenols, and flavonoids, as well as other potentially bioactive phytochemicals; this nutritional content may explain fruits’ shielding effect against certain types of cancer. Vitamin C is especially protective against cancer, as it readily traps free radicals and reactive oxygen species, thereby protecting against oxidative damage; it also regenerates other antioxidants such as vitamin E and inhibits the formation of carcinogens.17 Some fruits contain high concentrations of the antioxidantacting flavonoids, which have the ability to inhibit carcinogen-activating enzymes and DNA damage.18 Finally, the antioxidant phytochemicals commonly found in fruits may diminish the free-radical damage generated by inflammation.

The evidence regarding specific carotenoids and other nutrients found within fruits and vegetables is summarized in Table 6.3, and the general mechanisms involved are discussed later in this section. Many of the protective effects of the carotenoids result from their antioxidant properties, which can prevent lipid oxidation and free-radical-induced oxidative stress.17 Additionally, several of the carotenoids function as pro-vitamin A

Probable Evidence

Limited Evidence

Carotenoids

Mouth

(pro-vitamin A,

Pharynx

a-carotene,

Larynx

p-carotene,

Lung

lycopene, and

Esophageal

p-cryptoxanthin)

Prostate

Folate-containing

Pancreas

foods

Esophageal

Colorectal

Pyridoxine (vitamin B6)-containing foods

Esophageal

Vitamin C— containing foods

Esophageal

Vitamin E—

Esophageal

containing foods

Prostate

Selenium—

Prostate

Lung

containing foods

Stomach

Colorectal

Quercetin— containing foods

Lung

Source: Adapted from World Cancer Research Fund/American Institute for Cancer Research. Food,

Nutrition, Physical Activity, and the Prevention of Cancer.

A Global Perspective. Washington, DC:

Author; 2007.

precursors, which, once converted to retinol, play a role in cellular differentiation, immuno-enhancement, and activation of carcinogenic-metabolizing enzymes.17 Finally, lycopene—the most potent of the carotenoid antioxidants—demonstrates an antiproliferative effect, reduces plasma low-density lipoprotein cholesterol, improves immune function, and reduces inflammation.19- 20

The benefits of folate in relation to the prevention of cancer have previously been discussed. At the same time, it is important to note that in animal studies, high doses of folate have been shown to promote carcinogenesis. Thus dose is an important factor to consider when determining folate’s effect on cancer prevention.

Pyridoxine (vitamin B6) is involved in one-carbon metabolism and thus plays a role in the synthesis, repair, and methylation of DNA, as demonstrated in animal studies.21 Vitamin E is another antioxidant that has been reported to enhance DNA repair and to prevent DNA damage, lipid peroxidation, and the activation of carcinogens such as nitrosamines.17 Vitamin E has also been reported to enhance the immune system, which may play a role in the body’s ability to shield against cancer.17

Selenoproteins, which are commonly found in foods containing selenium, have been shown to demonstrate anti-inflammatory and antioxidant properties primarily due to the activity of the glutathione peroxidases, which protect against oxidative damage, and the thioredoxin reductases, which regenerate oxidized ascorbic acid to its reduced antioxidant form.22

Lastly, the flavonoid quercetin has antioxidant properties as well as the ability to inhibit the expression of CYP1A1 (a cytochrome P450 enzyme that helps to metabolize toxins23), resulting in decreased formation of DNA adducts.24 Elevated CYP1A1 activity has been correlated with an increased risk of lung cancer.25

While the evidence is inconsistent, limited data suggest that legumes and soy products may exhibit a protective effect against stomach and prostate cancers.26 Ecological studies support a potential inverse dose-response relationship between soy intake and stomach and prostate cancer risk, perhaps due to soy’s numerous BAFCs. Legumes and other soy foods are rich in BAFCs that exhibit anticarcinogenic effects, such as protease inhibitors, saponins, and phytoestrogens (genistein, daidzein),27 all of which may modulate estrogen metabolism, demonstrate antioxidant properties, inhibit tumor angiogenesis, and influence apoptosis and cell growth.

The evidence for the protective effects of nuts and seeds is too limited in amount, consistency, and quality to draw any decisive conclusions. Limited evidence does suggest that chili pepper may increase the risk of stomach cancer. This increased risk is likely related to its pro-irritant effect, which may possibly increase the risk of inflammation in the stomach.28

Grains, Roots, Tubers, and Plantains

The starchy plant foods traditionally have served as the primary source of energy since societies and agriculture have evolved. Their whole, unprocessed forms represent a plentiful source of dietary fiber and other micronutrients. With the trends toward increased industrialization and urbanization, consumption of these whole foods has decreased, with more being consumed in the refined form of cereal grains. These processed foodstuffs are more energy dense and generally contain added fat, sugar, or salt, thereby lowering the overall nutrient value of the food. Roots and tubers, when eaten with their skins on, provide a rich source of fiber and micronutrients as well; however, most urbanized populations tend to eat them in a more processed form.

In general, the evidence that grains, roots, tubers, or plantains are able to modify cancer risk is not convincing. Probable data do suggest that foods containing fiber likely have a protective effect against colorectal cancer, with limited data suggesting that such fiber-containing foods may lower the risk of esophageal cancer. Rich sources of fiber include unprocessed grains, roots, tubers, and plantains, as well as fruits, vegetables, and legumes. Fiber’s protective effect is thought to be due to its bulky, satiating effect and the fact that fiber-containing foods are also low in energy. Additionally, fiber dilutes fecal contents, increases stool weight, and decreases transit time, effectively removing potentially carcinogenic compounds within the intestinal tract, as well as fermentation by-products produced by the gut flora from various dietary carbohydrates.

Aflatoxins, which are naturally occurring mycotoxins produced by certain molds or fungi, are classified as human carcinogens.29 Although most molds are destroyed by the cooking process, the toxins they produce may persist in the cooked foods. The main foods prone to contamination by aflatoxins are cereal grains and legumes, and this issue is considered to be the most problematic in countries with hot, humid climates and poor storage facilities. Aflatoxins become a worldwide problem when these contaminated foods are exported to other countries. Cohort and case-control studies have shown a convincing association between aflatoxin biomarkers and hepatocellular carcinoma, possibly due to its interaction with the GST genotype. Evidence shows that the positive GSTM1/GSTT1 genotypes are protective against liver cancer from hepatitis infection combined with aflatoxin exposure, while the negative GSTM1/GSTT1 genotypes increase risk.30 Other conceivable mechanisms include the production of epoxide products of aflatoxin, which are commonly found in the liver and known to be genotoxic to the p53 gene, leading to the increased proliferation of abnormal cells and causing the progression of cancer.31 Additionally, the synergistic effect of hepatitis infection and aflatoxin exposure may be explained by the increased production of the enzyme CYP1A2, which is responsible for the increased production of the genotoxic metabolites of aflatoxin. Likewise, the hepatitis virus may increase gene transversion, inhibit nucleotide repair, or act as a tumor promoter.32 In any event, strong evidence supports the existence of a dose-response relationship between aflatoxin-contaminated foods and liver cancer.

In conclusion, it is recommended to consume unprocessed grains and/or legumes with every meal while limiting the intake of processed starchy foods.

Milk and Dairy Products

Until the late nineteenth century, cow’s milk was primarily used as an artificial substitute for breast milk to feed infants, with adults consuming very little,

if any, of this product. With the industrialization of cattle farming in the twentieth century, cow’s milk became a staple food in the United States and other European countries, representing a major source of calcium as well as other vitamins, minerals, and protein.

Data from cohort studies suggest that milk is probably protective against colorectal cancer, with limited evidence suggesting it is protective against bladder cancer and a causative factor in prostate cancer. Interestingly, limited data suggest that cheese consumption may be a causative factor in colorectal cancer, despite milk and dairy products’ protective effects against colorectal cancer. The ability of milk to decrease colorectal cancer risk likely results in part from its calcium content, which decreases cell proliferation and/or promotes cell differentiation; calcium also protects the gastrointestinal lining by binding to potentially damaging bile and fatty acids.33

Alternatively, calcium may actually increase prostate cancer risk by reducing circulating 1,25-dihydroxyvitamin D, which is thought to inhibit development of prostate cancer through its ability to regulate prostate growth and differentiation.34 Other hypotheses seeking to explain the association between dairy products and prostate cancer point to the effects of the increased concentrations of insulin-like growth factors35 or estrogens36 found in these foods.

Finally, while no specific mechanism has been identified, cheese could plausibly cause colorectal cancer through an indirect mechanism related to its saturated fat content. Saturated fat may increase insulin production and expression in colorectal cells as well as stimulate the production of inflammatory mediators associated with carcinogenesis.37

Fats and Oils

Similar to meat and dairy consumption, fat and oil intake tends to increase with greater industrialization and urbanization. Specifically, commercially bred animals have a higher fat content than wild animals. On a global scale, production and consumption of animal fats and plant oils continues to increase. Contradicting previous reports, only limited evidence now suggests that diets high in fats and oils might be causative of some types of cancer.

Fats can be classified as either saturated or unsaturated, depending on their chemical structure. Liquid oils in general have higher concentrations of unsaturated fatty acids, whereas solid fats have higher concentrations of saturated fatty acids. The two essential polyunsaturated fatty acids, linoleic acid (Q-6) and linolenic acid (Q-3), are important lipid constituents whose amounts in the diet were once thought to be roughly equal. More recently, trends toward greater urbanization have caused vegetable oils, which are predominantly composed of Q-6 fatty acids, to become more widely available. Thus the ratio of Q-6 to Q-3 fatty acids has gradually increased to between 10:1 and 20:1 in most high-income countries.38 This imbalance in fatty acids is concerning because the Q-3 fatty acids have a known immune-enhancing effect, whereas the Q-6 fatty acids may have a suppressing effect on the immune system, thereby increasing cancer risk.39

Trans-fatty acids are unsaturated fatty acids that have been partially converted to saturated fatty acids by the hydrogenation process, resulting in chemically unsaturated fatty acids that behave like saturated fatty acids. This process alone has greatly increased the production and consumption of total fat and saturated fat throughout the world, thereby contributing to the steady increase in consumption of energy-dense foods and, indirectly, obesity.

Limited evidence suggests that consumption of total fat is a contributing factor in the progression of lung cancer, although no evidence for a plausible mechanism has been identified.40 Of course, the primary modifiable cause of lung cancer remains the smoking of tobacco products.

Select, speculative data suggest that total fat intake is also causative of postmenopausal breast cancer, possibly due to the increased production of endogenous estrogen derived from dietary fat intake.41 The recent results of the prospective low-fat dietary modification trial of the Women’s Health Initiative (WHI), however, did not demonstrate a reduction in breast cancer risk among postmenopausal women consuming a low-fat (20-25% total energy intake) diet for more than 7 years,42 perhaps due to poor adherence to the diet plan. Nevertheless, a small reduction in risk was observed among the subset of women entering the trial who had the highest dietary fat eating pattern at baseline. Further, an analysis of cancer incidence related to fat intake undertaken in 2007 from the WHI study showed that ovarian cancer risk is reduced in women who adhere to a low-fat eating pattern post menopause.43 Additionally, low-fat diets are generally associated with higher fiber intake, which may assist in reducing total estrogen concentration in the body by decreasing intestinal reabsorption. Other likely mechanisms include a decrease in the sex hormone-binding globulin associated with increased body mass, leading to elevated concentrations of free estradiol,44 or early menarche related to energy-dense diets, which is an established risk factor for breast cancer.45

Limited but consistent evidence suggests that consumption of animal fats is a contributing factor in colorectal cancer. However, in terms of cholesterol and trans-fatty acids, there is insufficient corroborative evidence specifically linking these lipids to cancer risk. The low-fat diet intervention studied in the WHI dietary modification trial participants, for example, showed no association between adoption of a low-fat diet post menopause and colorectal cancer risk.43

Sugars and Salts

Sugars and salts are most commonly consumed as ingredients in processed foods. Consumption of these foods is increasing globally. Specifically, intake of added sugars is rising with the trend toward increased ingestion of sugary beverages, such that sugars now account for a substantial quantity of total energy intake. The consumption of salt, though variable worldwide, has also generally risen with increasing availability. Excess sugar and salt intake has been associated with obesity and cardiovascular disease, respectively, in addition to certain cancers.46, 47

It is difficult to assess the overall effect of sugar as a modifier of cancer risk because of the inconsistencies in the classification of sugars. Sugars may, for example, be categorized as sucrose, maltose, lactose, glucose, fructose, refined sugars, high-fructose corn syrup, chemical sweeteners, or naturally occurring intrinsic sugars. Further, the United States Department of Agriculture (USDA) database for quantifying sugar in foods is relatively incomplete, making the use of this variable by epidemiological studies difficult at best. Additionally, sugar’s contribution to body weight may influence cancer risk. While the data are hard to interpret, there is limited evidence that sugar intake is a contributory factor in the development of colorectal cancer.

Despite the World Health Organization’s (WHO) recommendation of restricting salt consumption to less than 5 g per day, worldwide the consumption of salt has been estimated to vary from between 6 g and 18 g per day. A substantial body of probable evidence related to total salt intake, added table salt, and sodium intake supports salt’s role as a mechanistic cause of stomach cancer, possibly related to damage to the stomach lining by excess salt intake.48 Further, elevated salt intake has been shown to increase the formation of endogenous A-nitroso compounds,49 demonstrate a synergistic effect with gastric carcinogenesis,49 and contribute to gastric cancer in subjects with Helicobacter pylori infections who have also been exposed to a carcinogen.50

Beverages

When referring to beverages and cancer risk, this section focuses on water, fruit juices, soft drinks, and hot drinks; alcohol is considered separately later in the chapter.

Water quality and sufficiency is a worldwide public health issue, as water may be easily compromised by chemicals or microbiological contamination. Water is also an essential nutrient; without it, people die within a matter of days. Fruit juices are frequently diluted with water and contain added sugar, while soft drinks are made almost entirely from water, sugar, coloring, flavoring,

and combinations of herbs and other ingredients to enhance taste. The primary hot drinks consumed worldwide are coffee and tea, both of which contain stimulants and other bioactive ingredients that are generally consumed with the addition of milk and sugar. A variety of herbal mixtures are also consumed, including mate, a South American tea-like beverage.

Overall, the evidence related to non-alcoholic drinks and cancer risk focuses on water supply contamination with arsenic or irritation to the oral cavity by the very-high-temperature consumption of mate or other hot beverages. Arsenic residues can result from agricultural, mining, and industrial processes, or from naturally occurring volcanic activity. Arsenic is a known human carcinogen.51 WHO guidelines recommend that arsenic levels in drinking water not exceed 10 mcg/L, although in affected areas these levels may range from tens to thousands of micrograms per liter.52 Other factors in the water supply that are known to increase cancer risk include contamination by H. pylori (associated with stomach cancer)50 and infestation by schistosomes (parasitic worms found in the blood of humans and other mammals that are associated with bladder and liver cancer).53

Convincing data exist that arsenic in drinking water is causative of lung cancer, probable data demonstrate that arsenic in drinking water causes skin cancer, and limited data show that it causes kidney and bladder cancer. Several mechanisms have been proposed to explain how arsenic may be associated with increased cancer risk. Arsenic is known to cause changes in the methylation of oncogenes or tumor-suppressor genes; increase the generation of free radicals; and cause the depletion of reduced glutathione, leading to a chronic state of oxidative stress that can damage DNA and induce cell proliferation.54

Constant irritation to the epithelial surface by very hot beverages may increase cancer risk due to chronic inflammation. Evidence suggests that chemically irritating components within beverages may be a causative factor in cancer progression, although few data exist to confirm this relationship. It is generally believed that the increased risk derives from the extremely hot temperature or, more likely, from a combination of the high temperature and chemical irritants in the beverage.

The evidence is too limited in amount, consistency, and quality to draw any conclusions about the consumption of soft drinks and fruit juices and modulation of cancer risk. By contrast, tea—especially black and green tea—is known to contain various antioxidants and phenolic compounds that exhibit promising anticarcinogenic effects. However, the evidence has been inconsistent in suggesting regular tea consumption may be protective against certain types of cancer. Perhaps the inconsistencies in the data are related to the different cultures within which these teas are consumed. For example, the ways in which teas are prepared and drunk vary significantly between cultures in regard to how strong the tea is and whether it is consumed with or without milk and sugar; both of these factors may influence its anticarcinogenic potential.

Mate, which is prepared by steeping the dried leaves of yerba mate, is typically drunk scalding hot through a metal straw. This practice generates repetitive damage and inflammation to the mouth, pharynx, larynx, and esophagus, resulting in increased cancer risk. Although evidence on this issue is limited, it suggests that mate and other hot beverages may be a contributing factor in the progression of mouth, pharynx, larynx, and esophageal cancers.

Alcohol

Alcoholic drinks can be produced from the fermentation of many plants and some animal foods, with the alcohol content of the different beverages varying greatly. The main alcoholic drinks consumed include beers, ciders, wines, and liquors. These libations have been popular in most populations ever since alcohol’s effects on mood were identified, although the level of intake varies widely depending on availability, price, culture or religion, and dependency. The active ingredient present in alcohol, ethanol, has been labeled a human carcinogen.55

Convincing evidence suggests that alcoholic drinks are causative of mouth, pharynx, larynx, and esophageal cancers, as well as breast cancer in women and colorectal cancer in men. Alcohol is a probable cause of liver cancer in men and women, and colorectal cancer in women. The reactive metabolites of alcohol, such as acetaldehyde, are likely to be carcinogenic.56 Further, alcohol may modulate the production of prostaglandins, lipid peroxidation, and free radicals; enhance the penetration of carcinogens into cells through its solvency actions; and alter retinoid status effecting cellular growth, cellular differentiation, and apoptosis.56

Epidemiological studies suggest that in assessing alcohol’s contribution to cancer risk, using breast cancer as an example, folate intake/status may be of particular importance. Women with low folate intake are especially vulnerable in terms of the cancer-promoting effects of alcohol intake.57 Heavy alcohol consumers are also more likely to have nutrient deficiencies, which together with the previously mentioned factors may increase the risk of cancer development.

If alcoholic drinks are consumed, they should be limited to no more than two drinks per day for men and one drink per day for women. Sufficient folate intake should be promoted in those wishing to consume alcohol in any amount. Table 6.4 provides recommended portion sizes for various types of alcoholic beverages.

Table 6.4 Recommended Serving Sizes for Alcoholic Beverages*

Beer: 12 ounces Wine: 5 ounces Distilled spirits: 1.5 ounces Wine cooler: 10 ounces

*One drink is defined as having 1/2 ounce (approximately 14 g) of pure ethanol.

Dietary Supplements

In this section, dietary supplements such as vitamins, minerals, and phytochemicals are considered separately from whole foods and their subsequent effects on cancer risk. The manufacturing and marketing of dietary supplements has escalated ever since claims regarding their health-promoting benefits in the prevention of disease were postulated. The effect of these bioactive substances differs depending on the quantity consumed. Consequently, evidence from clinical studies is difficult to interpret because different combinations and concentrations are used in the various investigations. Moreover, while nutrients at lower doses may be protective against cancer risk, higher doses may actually be toxic or pathogenic, further complicating the interpretation of the evidence.

BAFCs are bioactive constituents of plant foods that are not considered to be essential, but whose consumption has been shown to have beneficial effects on health and in the prevention of diseases due to the substances’ antioxidant, anticarcinogenic, anti-inflammatory, antimicrobial, and immunomodulatory effects.11 Phytochemicals are classified as flavonoids, isoflavones, glucosino-lates, terpenes, organosulfur compounds, saponins, capsaicinoids, or phytosterols; they are found in many vegetables, fruits, legumes, herbs, and teas.

Retinoids demonstrate antitumor actions, although their mechanisms of action are not well understood. Retinol is known to bind to cell receptors and promote cellular differentiation, alteration of membranes, and induction of immunological adjuvant effects,58 suggesting that retinol supplements might be protective against squamous cell skin cancer. Conversely, limited data suggest that high-dose intake of retinol supplements is a causative agent for lung cancer in smokers. Convincing evidence also demonstrates a causative effect for high-dose beta-carotene supplements in lung cancer in smokers. Perhaps the protective association of carotenoid intake against cancer risk is lost or reversed at very high doses, or the protective effect of naturally occurring carotenoids is not due to the individual carotenoids but rather to the synergistic effect of all the carotenoids together, or in combination with other dietary constituents.

Alpha-tocopherol is thought to be the most biologically active of the eight different isomers that exist for vitamin E. This substance is known to inhibit cellular proliferation, directly activate certain enzymes, and demonstrate transcriptional control over several genes.59 Alpha-tocopherol has also demonstrated the ability to inhibit the propagation of prostate tumors in animal models.60 The research on this topic is sparse, but suggests that alpha-tocopherol supplementation might have a protective effect against prostate cancer.

1-25-dihydroxyvitamin D, a vitamin D metabolite, has antiproliferative, pro-differentiation, and apoptotic effects in some cells that are mediated by the vitamin D receptor. Additionally, a high level of sunlight exposure, which can convert 7-dehydrocholesterol into vitamin D3 in the skin, has been correlated with lower breast cancer incidence and mortality in ecological stud-ies.61 These observations, together with experimental evidence, have inspired the hypothesis that high levels of vitamin D might reduce the risk of breast cancer. Notably, however, the effects of vitamin D are strongly correlated with its interactions with calcium, as both of these substances are growthrestraining and able to induce cell differentiation and apoptosis. Further complicating the interpretation of the data is the fact that the biologically active form of vitamin D is dependent on diet, supplements, and UV exposure to the skin. Inconsistent evidence from cohort and ecological studies implies that consumption of foods containing vitamin D and improvement in vitamin D status may be protective against colorectal and breast cancer, respectively.

Calcium plays an important role as a second messenger affecting numerous cellular functions throughout the body. Consistent evidence exist that calcium probably protects against colorectal cancer, possibly through its direct growth-restricting, differentiation, and apoptosis-inducing actions toward normal and tumor colorectal cells. Additionally, calcium may bind to bile and fatty acids, thereby decreasing injury to the intestinal lining. Evidence of varying quality has demonstrated a dose-response relationship between calcium intake and colorectal cancer; importantly, however, elevated levels of calcium intake have also been correlated with increased risk for prostate cancer.

An insufficient intake of selenium has been noted to cause a lack of selenoprotein expression; these proteins have numerous anti-inflammatory and antioxidant functions, as previously discussed. Selenoproteins appear to reach their maximal levels easily with normal dietary selenium intake and do not increase with supplementation. Nevertheless, it is postulated that supra-physiological concentrations might influence programmed cell death, DNA repair, carcinogen metabolism, the immune system, and antiangiogenic properties.62 Strong, probable evidence suggests that selenium protects against prostate cancer; limited evidence indicates that it is protective against lung cancer. Conversely, some data suggest that selenium supplements may be causative of skin cancer.

A review completed by U.S. Preventive Services Task Force concluded that the evidence is either too limited or too inconsistent to make a recommendation in support of or against any type of supplement use for the prevention of cancer.63 It is recommended that the general population achieve nutritional adequacy without the addition of dietary supplements. Supplements should be prescribed when dietary approaches are inadequate in achieving average daily intake goals.

Food Production, Preservation, Processing, and Preparation

The various methods of food preparation and preservation employed may also modify cancer risk. Nearly all foods and beverages are altered in some manner before they are consumed. Thus it is plausible that the various methods of processing and/or preservation might have protective, causative, or neutral effects on the risk of cancer.

The use of synthetic pesticides and herbicides has greatly increased since the middle of the twentieth century, with an estimated 2,500 tons of these chemicals being used worldwide in 2001. In many countries, the use of pesticides and herbicides is regulated to minimize the buildup of residues in foods and drinks. Although no epidemiological data exist that show current levels are carcinogenic, theoretical grounds for concern remain.

Another cause for concern is the use of veterinary drugs to treat and prevent infectious diseases and/or promote growth in industrial animal production. If any of these medications are found to be carcinogenic, they are removed from the market, of course. Nevertheless, the toxicity of such drugs remains constantly under review.

The use of genetic modification techniques for the production of foods for human and animal consumption is regulated in most, but not all, countries. Currently, the effect of gene modification on cancer risk is unknown because there are too few data available from which to draw any decisive conclusions.

The many methods for preserving foods include drying, fermenting, canning and bottling, pasteurizing, chemical preservation, and irradiation. The safety of such methods is continually reviewed, and to date no consistent associations between preservation and cancer risk have been identified.

Many processed foods contain additives that may be either synthetic or naturally occurring, such as bulking aids, colors, flavors, and solvents. Although these additives may serve useful functions, they may also be toxic, mutagenic,

and/or carcinogenic. For that reason, these additives face constant scrutiny regarding their safety.

The naturally occurring aflatoxins, which are known carcinogens, are produced by certain molds or fungi in cereal grains and legumes. Although they are usually destroyed by the cooking process, the toxins they generate may remain if the grains or legumes are kept in hot, humid climates and poor storage facilities.

Lastly, preparation methods such as industrial cooking, steaming, boiling, stewing, baking, roasting, microwaving, frying, broiling, and barbequing may alter cancer risk, but currently the evidence is too limited in amount to draw any conclusions. It is recommended to avoid salted foods and moldy grains or legumes.

The Role of Physical Activity

Physical activity can be classified as occupational, household, transportation, or recreational, and can be further identified as vigorous, moderate, light, or sedentary, with a combination of frequency, intensity, and duration determining total physical activity levels. General levels of physical activity have declined in recent decades, with more machines performing the work that was previously done by hand, and transportation, which was once accomplished by walking or cycling, being carried out by automobiles. In most industrialized countries, people engage in some form of recreation, although in general they remain largely inactive, performing mostly sedentary activities.

Studies have found that physical inactivity is related to a higher overall cancer incidence and mortality.64 Hypothesized mechanisms for the protective association of increased amounts of physical activity include the promotion of healthy levels of circulating hormones and the ability to consume more foods without accompanying weight gain. Additionally, the evidence indicates that the more people are physically active, the better their potential for lowering their cancer risk. No threshold level in regard to physical activity and cancer risk has been identified.

A number of mechanisms have been recognized as potential ways in which physical activity may protect against colorectal cancer, including reduction in insulin resistance, beneficial effects on body fat levels, beneficial effects on steroid hormones, and reduction of gastrointestinal transit time.65 An abundant and convincing body of evidence demonstrates that higher levels of physical activity are associated with lower risk of colorectal cancer. Limited data suggest that physical activity is protective against premenopausal breast cancer and probably protective against postmenopausal breast cancer. The proposed protective mechanisms in these types of cancer are the beneficial effect on body fat levels, the reduction of circulating estrogen and androgens, and possible enhancement of the immune system.65 Furthermore, studies consistently find that physical activity may lower the risk of endometrial cancer through mechanisms similar to those proposed for breast cancer.

The evidence regarding the protective effects of physical activity on lung and pancreatic cancers is limited but suggest that exercise may lower the risk of developing both types of cancer. No specific mechanisms for the reduction of lung cancer risk have been identified, and the association is complex, possibly reflecting reverse causation due to chronic lung disease. The mechanisms by which physical activity may lower pancreatic cancer risk include a reduction in insulin resistance and gastrointestinal transit time, with the latter factor having beneficial effects on the content and secretion of bile and affecting general pancreatic activity.

It is recommended that individuals be moderately physically active for at least 30 minutes or more every day and to limit their sedentary habits as much as possible.

The Role of Body Weight

The degree of body fatness, rates of growth and their outcome, and lactation all affect cancer risk throughout the lifespan. The rates of overweight and obesity doubled in many high-income countries between 1990 and 2005. Being overweight or obese increases the risk for a number of diseases, including dyslipidemia, hypertension and stroke, type II diabetes, coronary heart disease, and selected cancers, and shortens life expectancy.66

The distribution of body fat varies from person to person and is primarily determined by genetics. Body fat may accumulate subcutaneously or viscerally, as well as peripherally or abdominally. Estimates of body fat levels can be made by measuring waist-to-hip circumference or body mass index (BMI; see Table 6.5), with waist-to-hip circumference (or abdominal fatness) generally considered to be a better predictor of chronic diseases such as cardiovascular or metabolic disease. The WHO reference values for waist measurements are 37 inches for men and 31.5 inches for women, roughly correlating to a BMI of 25 kg/m2.1 Adult weight gain generally occurs as a result of accumulation of fat rather than lean tissue, and it Table 6.5 Body Mass Index Classification Classification BMI (kg/m2)

Underweight: BMI < 18.5 Normal weight: BMI = 18.5-24.9 Overweight: BMI = 25.0-29.9 Obese: BMI > 30.0 Morbidly obese: BMI > 40.0

may more accurately reflect body fatness than just an increase in body mass alone. The recommended median adult BMI is in the range of 21 to 23 kg/m2. Ideally, the proportion of the population that is overweight or obese will not exceed the current level, or preferably be lower, in 10 years.

Body fatness has been acknowledged as a probable cause of esophageal, pancreatic, colorectal, postmenopausal breast (probable for premenopausal breast cancer), endometrial, and kidney cancers, and limited evidence indicates that it may cause liver and lung cancers. Evidence for a relationship between excess abdominal fat and increased cancer risk is convincing in regard to colorectal cancer, and excess abdominal fat is considered a probable cause of pancreatic, postmenopausal breast, and endometrial cancer. Lastly, adult weight gain has been identified as a probable cause of postmenopausal breast cancer.

There are several plausible mechanisms by which excess body and abdominal fat might modify cancer risk. First, elevated body fat levels increase the inflammatory response. Second, increased body fat levels increase the concentration of circulating estrogen. Third, excess body fat decreases insulin sensitivity.67 Further, the elevated levels of insulin-like growth factor 1 (IGF-1), insulin, and leptin found in obese individuals can promote the growth of cancer cells.68

Growth during childhood is a predictor of age at sexual maturity as well as eventual attainment of adult height, and the rate of growth has metabolic and hormonal effects that can influence cancer risk throughout the lifespan. Based on the evidence, greater adult attained height appears unlikely to modify cancer risk directly, but it is a marker for genetic, environmental, hormonal, and nutritional factors affecting growth from preconception to the completion of linear growth. For every tissue or organ, unfavorable environmental influences—such as inadequate nutrients or energy obtained—during critical periods of development can restrict growth and impair future functioning, with the timing, severity, and duration determining the extent of the potentially negative impact.

Growth can be divided into three phases: fetal-infant, childhood, and puberty. Growth during the fetal-infant period is considered the most vulnerable to the availability of nutrients and energy. When nutrient intake is suboptimal, brain growth is protected relative to stature growth, which in turn is less affected than increases in body weight. Negative influences on growth during this period tend to affect a person’s future adult height and body shape. For example, any nutrient deficiency during this critical period may result in a person’s predisposition to excess body fatness because his or her energy intake exceeds the available nutrients’ ability to lay down lean tissue mass; as a consequence, any excess of energy is stored as fat. In general, individuals characterized by a lower birth weight have a greater tendency to store fat, resulting in an increased risk of overweight and obesity. Speculative evidence has also led to the hypothesis that a greater birth weight is a probable cause of premenopausal breast cancer. The effects of lactation during the infant period on body weight and cancer risk will be considered separately.

Growth hormones, insulin-like growth factors, and sex hormone-binding proteins all affect height, growth, sexual maturity, fat storage, and other various processes that may be relevant to cancer development. For this reason, nutritional factors that alter height might also potentially influence cancer risk. Convincing evidence suggests that various factors influencing attainment of a greater adult height are causative agents for colorectal cancer and postmenopausal breast cancer. Of course, this risk is unlikely to be due to height alone, but instead probably reflects a combination of factors promoting linear growth in childhood. The data imply that a greater adult height is a probable cause of premenopausal breast, pancreatic, and ovary cancers, and limited data support the supposition that it is a cause of endometrial cancer.

Human milk is the natural, complete food for infants until six months of age, with no truly equivalent substitute. Not only does breast milk provide a complete source of nutrition, but it also provides immunologically active components. However, the hormones associated with amenorrhea and infertility are actually believed to be substances that modify cancer risk, probably due to the decreased lifetime exposure to menstrual cycles. Decreased exposure to certain hormones, such as androgen, can also influence cancer risk.69 Abundant and consistent data demonstrate that lactation has a convincing protective effect against premenopausal and postmenopausal breast cancer, with limited evidence suggesting that it is protective against ovarian cancer. It is recommended that women exclusively breastfeed infants for the first six months of life and continue with complementary feeding thereafter.

Cancer Survivorship

The total number of cancer survivors worldwide continues to grow. In tandem, awareness of their unique needs has increased. In particular, lifestyle modifications’ potential to prevent cancer recurrence and the need for improved quality of life both during and after cancer treatment have generated significant interest in recent decades. As yet, research into the effects of food, nutrition, physical activity, and body weight on cancer survivorship remains in the early stages. For that reason, recommendations regarding the prevention of future cancer events cannot not be made with certainty. Despite the lack of data on this issue, when possible and appropriate, the same recommendations made for primary cancer prevention should also be applied to cancer survivors to prevent future recurrence as well as to improve general quality of life. Specifically, it is recommended that all cancer survivors receive nutritional care from an appropriately trained professional and, if able, aim to follow the recommendations for diet, healthy weight, and physical activity.

SUMMARY The role of diet, physical activity, and body composition in cancer prevention and recurrence is a subject of active research, as reflected by current cancer prevention recommendations by organizations focused on chronic diseases. The worldwide prevention of cancer remains a vital, and largely unsolved, challenge. Currently, the evidence suggests that appropriate modifications of food intake, physical activity levels, and body composition are effective ways of addressing this need. For that reason, clinicians should encourage their patients to consume an increased plant-based, low-fat, complex-carbohydrate-rich diet; to engage in increased physical activity; and to maintain a healthy body weight through small, attainable, lifelong behavior change. A summary of the recommendations is provided in Table 6.6.

Meat, poultry, fish, and eggs

Limit intake of red meat to no more than three 3- to 4-oz servings per week, and avoid processed meats altogether.

Plant foods

Eat mostly foods of plant origin, with an average daily consumption of 21 oz of non-starchy vegetables and fruits and 25 g of unprocessed cereal grains and legumes.

Grains, roots, tubers, and plantains

Consume unprocessed grains and/or legumes with every meal, and limit the intake of starchy foods.

Alcohol

If alcoholic drinks are consumed, limit to no more than two drinks per day for men and one drink per day for women. Sufficient folate intake should be promoted in those wishing to consume alcohol in any amount.

Dietary supplements

The general population should strive to achieve nutritional adequacy without the addition of dietary supplements. Supplements should be prescribed when dietary approaches are inadequate in achieving average daily intake goals.

Food production, preservation, processing, and preparation

Avoid salted foods and moldy grains or legumes.

Physical activity

Be moderately physically active for at least 30 minutes or more every day, and limit sedentary habits as much as possible.

Body weight

Strive to maintain a median adult BMI between 21 and 23 kg/m2.

Lactation

Exclusively breastfeed infants for the first six months of life, and continue with complementary feeding thereafter.

Survivorship

All cancer survivors should receive nutritional care from an appropriately trained professional and, if able, aim to follow the recommendations for diet, healthy weight, and physical activity.

Source: Adapted from World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: Author; 2007.

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