COMPLEMENTARY FEEDING OF THE BREASTFED CHILD The risk of carcinogenic effect. Max Mantik

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1 COMPLEMENTARY FEEDING OF THE BREASTFED CHILD The risk of carcinogenic effect Max Mantik

2 Objectives To discuss complimentary breast feeding To address the links between childhood environments and risk onset of cancer To present current knowledge of causation and environmental risk factors To biological efects development on cancer 2

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5 Energy required(top line and the amount from breast milk) WHO/UNICEF,

6 DURATION OF EXCLUSIVE BREASTFEEDING AND AGE OF INTRODUCTION OF COMPLEMENTARY FOODS Exclusive breastfeeding from birth to 6 months of age Complementary foods at 6 months of age (180 days) while continuing to breastfeed. Continue frequent, on-demand breastfeeding until 2 years of age or beyond WHO, guiding principles for complementary feeding of the breastfed child,

7 Responsive feeding Principles of psycho-social care Sensitive Patiently, and encourage Combinations, tastes, textures Minimize distractions Periods of learning and love 7

8 SAFE PREPARATION AND STORAGE OF COMPLEMENTARY FOODS The peak incidence of diarrheal disease is during the second half year of infancy, as The intake of complementary foods increases Difficult to keep clean Feeding bottles are a particularly important route of transmission of pathogens 8

9 SAFE PREPARATION AND STORAGE OF COMPLEMENTARY FOODS Practice good hygiene and proper food handling Hand hygiene Storing foods safely and serving foods immediately Clean utensils to prepare and serve food Clean cups and bowls Avoiding the use of feeding bottles, which are difficult to keep clean. 9

10 Breastfed children at months In developing countries about 550 g/d Receive 35-40% of total energy needs from breast milk 10

11 FOOD CONSISTENCY Gradually increase food consistency and variety as the infant gets older Pureed, mashed and semi-solid foods beginning at six months By 8 months "finger foods" (snacks) By 12 months, the same types of foods as consumed by the rest of the family 11

12 NUTRIENT CONTENT OF COMPLEMENTARY FOODS Variety of foods to ensure that nutrient needs are met Meat, poultry, fish or eggs should be eaten daily, or as often as possible Vitamin A-rich fruits and vegetables should be eaten daily Adequate fat content Avoid giving drinks with low nutrient value, such as tea, coffee and sugary drinks such as soda Limit the amount of juice offered so as to avoid displacing more nutrient-rich foods 12

13 USE OF VITAMIN-MINERAL SUPPLEMENTS OR FORTIFIED PRODUCTS FOR INFANT AND MOTHER Fortified complementary foods or vitamin-mineral supplements for the infant, as needed 13

14 FEEDING DURING AND AFTER ILLNESS Increase fluid intake during illness, including more frequent breastfeeding, and encourage the child to eat soft, varied, appetizing, favorite foods After illness, give food more often than usual and encourage the child to eat more 14

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17 Cancers that develop in children Leukemia 30% Brain and spinal cord tumors 26% Neuroblastoma 6% Wilms tumor 5% Lymphoma Hodgkin 3% Non Hodgkin 5% Rhabdomyosarcoma 3% Retinoblastoma 2% Bone cancer (including osteosarcoma and Ewing sarcoma) 3% 17

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21 Risk Factors and Causes of Childhood Cancer Different cancers have different risk factors In adults, lifestyle-related risk factors, such as being overweight, eating an unhealthy diet, not getting enough exercise, and habits like smoking and drinking alcohol Many years to influence cancer risk, and they are not thought to play much of a role in childhood cancers Radiation exposure, link with some types of childhood cancers DNA changes that turn on oncogenes or turn off tumor suppressor genes. 21

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24 Inherited versus acquired gene mutations Most childhood cancers are not caused by inherited DNA changes. They are the result of DNA changes that happen early in the child s life, sometimes even before birth à acquired mutation Some children inherit DNA changes (mutations) from a parent that increase their risk of certain types of cancer 24

25 Compared with adults, infants and young children Eat relatively more food per unit of body weight than do adults. Eat large quantities of single foods. Playing on the floor and placing hands and objects in their mouths, may increase exposures to pesticides. Developing organ systems susceptible to the effects of pesticides or less able to clear the metabolites. Unique exposure pathways such as through the placenta and through breast milk. 25

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30 Artificial Sweetener Cyclamate banned as food additive in US in 1969 and saccharine in 1977 after being associated with bladder cancer in mice Under public pressure, saccharine returned to the market; it was reviewed and taken off the list of potential carcinogens in 2000 Aspartame: no evidence implicating it in increased cancer risk 30

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32 Inconsistencies in results of nutritional Can be attributed to multiple factors Observational studies à imprecision in diet recall 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 à inaccurate results poor adherence to the dietary intervention, insufficient follow-up time, wrong dose or form of the nutrient. 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. 32

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37 Objectives To discuss complimentary breast feeding To address the links between childhood environments and risk onset of cancer To present current knowledge of causation and environmental risk factors To biological efects development on cancer 37

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40 Cancer in children Childhood cancers make up less than 1% of all cancers diagnosed each year. About 10,380 children in the United States under the age of 15 will be diagnosed with cancer in Childhood cancer rates have been rising slightly for the past few decades. Because of major treatment advances in recent decades, more than 80% of children with cancer now survive 5 years or more. Overall, this is a huge increase since the mid-1970s, when the 5-year survival rate was about 58%. Still, survival rates vary depending on the type of cancer and other factors. The survival rates for a specific type of childhood cancer can be found in our information for that cancer type. After accidents, cancer is the second leading cause of death in children ages 1 to 14. About 1,250 children younger than 15 years old are expected to die from cancer in

41 HRs (95% CIs) for total cancer and specific cancer types associated with a 1-point increment in WCRF/AICR score (range: 0 6 in men, 0 7 in women). Dora Romaguera et al. Am J Clin Nutr 2012;96: by American Society for Nutrition 41

42 Childhood exposure Children, in general, are more susceptible to toxicants, such as arsenic, for a variety of reasons including: more opportunities for exposure from increased hand-to-mouth behavior and breathing closer to the ground, differences in metabolism, and greater sensitivity of the developing nervous system to toxic insults [101,102]. Children are less able than adults to internally detoxify inorganic arsenic through methylation [101]. Children can become poisoned with arsenic through accidental ingestion, as in the case of two siblings who drank outdated arsenic-containing pesticide stored in a water bottle [45]. Children can also develop arsenic poisoning from playing on soil contaminated with arsenic from nearby mining or smelting or in hazardous waste sites. Another potential source of exposure is through contact with "pressure treated wood" through playing on it, chewing it, or being in the vicinity when it is burned 42

43 Cancer prevention In 2008, there were an estimated 12.7 million cancer cases and 7.6 million cancer deaths worldwide, despite overwhelming evidence that many malignancies are preventable [1,2]. Survival rates are improving, but over half a million people die from cancer each year in the United States alone. Cancer outranks cardiovascular disease as the number one cause of death in the United States for those under the age of 85 [3]. 43

44 The International Agency for Research on Cancer (IARC) has identified and tabulated over 100 human carcinogens [7]. 44

45 Aflatoxins Liver (hepatocellular carcinoma) Suppl 7 (1987); 56 (1993); 82 (2002) Salted fish, Chinese style Nasopharynx Stomach 56 (19 Tobacco smoking Bone marrow (myeloid leukemia) * ; cervix * ; oropharynx, hypopharynx); stomach * ; ureter * ; urinary bladder; in smokers children: hepatoblastoma * Breast; in smokers children: childhood leukemia (particularly acute lymphocytic) 38 (1986); 83 (2004) Benzene Leukemia (acute nonlymphocytic) Leukemia (acute lymphocytic, chronic lymphocytic, multiple myeloma, non-hodgkin lymphoma) 7 (1974); 29 (1982) 45

46 Lifestyle factors have been linked to a variety of malignancies 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 [10]. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective. Washington, DC: AICR,

47 Can Childhood Cancers Be Prevented? 47

48 Screening for cancer in children 48

49 selenium Cancer Epidemiologic studies support a possible relationship between Se and cancer mortality [149,150]. As a result, a number of studies have investigated the role of selenium supplementation for prevention of cancer. (See "Cancer prevention", section on 'Selenium' and "Risk factors for prostate cancer".) 49

50 Dietary selenium Dietary reference intake is available from seafoods, organ meats, and plant foods. Plant Se content depends upon soil Se concentrations. The RDA for selenium is 20 mcg daily for young children, rising to 55 mcg daily for adults (table 2) [23]. 50

51 Possible signs and symptoms of cancer in children An unusual lump or swelling Unexplained paleness and loss of energy Easy bruising An ongoing pain in one area of the body Limping Unexplained fever or illness that doesn t go away Frequent headaches, often with vomiting Sudden eye or vision changes Sudden unexplained weight loss 51

52 References: Cancer in Children American Cancer Society. Cancer Facts & Figures Atlanta, Ga: American Cancer Society; American Cancer Society. Cancer Facts & Figures Atlanta, Ga: American Cancer Society; American Cancer Society. Cancer site detailed guides. Accessed at on November 7, Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. J Natl Cancer Inst. 2011;103: National Cancer Institute. A Snapshot of Pediatric Cancers Accessed at on November 7, Ross JA, Severson RK, Pollock BH, Robison LL. Childhood cancer in the United States. A geographical analysis of cases from the Pediatric Cooperative Clinical Trials groups. Cancer. 1996;77:

53 Risk Factors and Causes of Childhood Cancer 53

54 Organically grown foods are foods that are grown or processed without the use of synthetic fertilizers or pesticides [1-5]. Organic farmers attempt to protect the environment by using natural matter (eg, aged manure, humus, and compost) for fertilizer and biological methods of pest control (eg, crop rotation and natural insect predators like lady bugs) [2,4,6]. Livestock and poultry used for egg, dairy, and meat production are raised on organically grown feed, without antibiotics or hormones, and provided with access to the outdoors [6] 54

55 The standards for growing and labeling organic food may vary depending upon the certifying organization or agency. The World Health Organization (WHO) and the Food and Agriculture Organization [7], as well as the Environmental Protection Agency (EPA) of the United States have adopted or proposed guidelines for the production, processing, labeling, and marketing of organic foods in an attempt to ensure that all foods that are labeled organic meet the same minimum standards. 55

56 Labeling requirements As of April, 2008, food that is labeled "100 percent organic" or "organic" in the United States must meet the standards of the United States Department of Agriculture (USDA), with the following labeling requirements [8]: To be labeled as "100 percent organic," all ingredients must be certified as organically produced and processed (excluding water and salt). To be labeled "organic," foods must consist of at least 95 percent certified organically processed ingredients (excluding water and salt); the remaining 5 percent of ingredients may be non-organically produced but must be on the USDA's National List. Products at least 70 percent certified organic ingredients (excluding water and salt) can use the claim "made with organic ingredients" and may list up to three individual organically produced ingredients on the side panel, but may not claim to be organic on the front of the package. 56

57 Exposure in childhood Most evidence indicates that traces of pesticide residues in foods are not a problem for most people [83]. However, data are limited regarding the toxicologic consequences of exposure to pesticide residue during infancy and early childhood [84]. 57

58 The FDA monitors nutritional concerns, including pesticide exposure, through the Total Diet Study. This study examines 234 foods selected to typify the American diet. Between 1985 and 1991, analysis of these foods revealed: No residues were found in infant formulas No residues over the EPA tolerance or FDA action level were found in any of the "market basket" foods Low levels of malathion were found in some cereals Low levels of thiabendazole, a post-harvest fungicide, were found on some fruits and fruit products 58

59 Factors to consider when deciding whether to use organic products include: Organic foods are not free of synthetic pesticide residues, but typically contain smaller amounts than are present on conventionally grown foods. Thus, organically grown foods provide an alternative source of fruits and vegetables for individuals who are concerned about synthetic pesticides. (See 'Reduction of exposure' above.) Infants and children may be more susceptible to the adverse effects of pesticides than are adults. (See 'Exposure in utero' above and 'Exposure in childhood' above.) In general, the traces of pesticide residue that are found in food pose little threat to human health. Potential adverse effects of pesticide exposure on special populations include neurologic, developmental, and reproductive disorders. (See 'Exposure in utero' above and 'Adverse effects' above.) Populations involved in agricultural work have higher levels of pesticide exposure, but evidence of adverse effects of such exposure levels is limited. (See 'Exposure in utero' above and 'Exposure in childhood' above.) Pesticides help to maintain an abundant and varied food supply. Pesticide use is regulated by the EPA and enforced by the USDA and the FDA. Efforts are being made to ensure that these regulations are appropriate for infants and children. (See 'Pesticide regulation' above.) Exposure to pesticide residue in either organic or conventionally grown food can be reduced through washing, peeling, cooking, or processing of foods. (See 'Reduction of exposure' above.) Organic food production does not eliminate the risk of foodborne illness, and "organic" should not be interpreted as meaning "safe". (See 'Microbial infection' above.) Organic farming is typically performed by smaller, family-owned farms and may be more environmentally friendly [5]. Because organic farming prohibits nontherapeutic antibiotics, it may reduce the risk of disease attributed to organisms that are resistant to multiple antibiotics. (See 'Hormone, sex-steroid, and antibiotic treatment of livestock' above.) It has been postulated that ingested estrogen in food derived from sex-hormone-treated animals may lead to earlier development of puberty, but limited studies have not supported this hypothesis in humans. (See 'Hormone, sex-steroid, and antibiotic treatment of livestock' above.) 59

60 reduce exposure to foodborne pathogens and pesticides: Buy the freshest foods available. They will have the best taste and highest nutrient (ie, vitamin) content. Consider using frozen or canned fruits and vegetables as an alternative or supplement to fresh produce. These foods maintain most of their nutritional value and may also reduce pesticide exposure as compared to fresh produce. Eat a variety of foods to ensure a balanced nutritional intake and to lessen contamination from any one source. Select produce that is free of dirt, insect holes, mold, or decay. (See 'Natural toxins' above.) Always wash fruits and vegetables thoroughly with a dish brush, but do not use soap or other detergents. Peel fruits and vegetables before eating and throw away the outer leaves of leafy vegetables. Some nutrients and fiber may be lost when produce is peeled. Trim fat from meat and skin from poultry and fish because some pesticide residues are concentrated in fat. Make sure that apple juice and cider are pasteurized, to reduce the risk of food-borne illness such as E.Coli O157. (See 'Microbial infection' above.) 60

61 Arsenic exposure is associated with cancers Skin cancer Ingestion of inorganic arsenic increases the risk of developing skin cancers (picture 1) [69]. Lesions commonly described are multiple squamous cell carcinomas, arising from the arsenic hyperkeratotic warts, as well as basal cell carcinomas arising from cells not associated with hyperkeratinization. Bladder cancer There has also been considerable epidemiologic evidence to support the association between exposure to inorganic arsenic and bladder cancer [67]. A cohort study from Taiwan found that, compared with people drinking water with an arsenic concentration of 10 mcg/l, the adjusted relative risks of bladder cancer in people exposed to well water containing arsenic in concentrations of 10.1 to 50, 50.1 to 100, and >100 mcg/l were 1.9, 8.2, and 15.3, respectively [70]. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Drinking water'.) Lung cancer There is evidence to support an association between arsenic exposure and lung cancer [67,71-73]. Observational studies from Chile have found a dose-response relationship, with evidence that the risk for lung cancer may begin to increase when arsenic concentrations in drinking water reach approximately 60 mcg/l [71,72]. The adjusted relative risk for lung cancer was 8.9 for drinking water with arsenic concentrations of 200 to 400 mcg/l [72]. In another study, mortality rates from lung cancer declined following the elimination of arsenic from drinking water [74]. There is also evidence of synergy between arsenic and smoking on the risk of lung cancer [72,73]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Occupational and environmental carcinogens'.) Liver Arsenic exposure is believed to increase the risk of hepatic angiosarcomas, but it does not appear to be associated with hepatocellular carcinoma [75]. 61

62 N-nitroso compounds N-nitroso compounds are potent neurocarcinogens in animal models [59]. Human exposure to these agents occurs from both endogenous and exogenous sources. 62

63 N-nitroso compounds Exogenous The major exogenous sources of population exposures to N- nitroso compounds include tobacco smoke, cosmetics, automobile interiors, and cured meats [11]. Other sources include rubber products (baby pacifiers, bottle nipples) and certain drugs including antihistamines, diuretics, oral hypoglycemic agents, antibiotics, tranquilizers, and opiates. N-nitrodiethanolamine, a carcinogen in animal models, occurs mainly as a contaminant in cosmetic products, soaps, shampoos, and hand lotions. Endogenous Endogenous formation of N-nitroso compounds is a complex process that occurs in the stomach, and is dependent upon the presence of NOC precursors, gastric ph, the presence of bacteria, and other physiologic parameters [3]. Thus, measurement of exposure to endogenous NOCs is extremely difficult. 63

64 In the four largest case-control studies, all of which included over 200 patients diagnosed with glioma and appropriate controls, and some assessment of meat intake [60-63], two reported a significant two- to threefold increased risk of glioma for high consumers of cured meat or bacon, as compared with those with a low intake [61,62]. However, excess risks were only observed among men and, in one, the relative risks were for high intake of cured meat in combination with low fruit and vegetable intake [61]. A meta-analysis that included nine observational studies (primarily case-control studies) reported a relative risk of 1.48 (95% CI ) for adult glioma among individuals with a high intake of cured meat [64]. 64

65 Two more recent publications using data from prospective cohort studies found no associations with meat intake or dietary N-nitroso compounds [65,66]. Both studies had over 300 glioma cases and detailed dietary assessment to examine these exposures and their potential relation to glioma risk. The lack of association in these two large prospective studies cast doubt on the N-nitroso compound hypothesis, at least in relation to adult glioma risk. 65

66 Antioxidants, fruits, and vegetables Indirect support for the NOC hypothesis includes the observation that certain inhibitors of the nitrosation process, vitamins C and E, appear to reduce brain tumor risk in adults and children [11,46,67]. Dietary studies have demonstrated a reduced risk of brain tumors in children who consume increased amounts of fruits and fruit juices [11]. Prenatal vitamin supplementation (including vitamins A and C and folate) and increased maternal intake of vegetables have been associated with a lowered brain tumor risk in the offspring [67-69]. 66

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69 dietary trace minerals Cancer Epidemiologic studies support a possible relationship between Se and cancer mortality [149,150]. As a result, a number of studies have investigated the role of selenium supplementation for prevention of cancer. (See "Cancer prevention", section on 'Selenium' and "Risk factors for prostate cancer".) 69

70 Selenium Animal studies suggest that selenium decreases the risk of a variety of tumors, and some epidemiologic studies have shown an inverse relationship between selenium and cancer [ ]. One study using NHANES III data from 14,000 adults found an inverse association between selenium levels and cancer mortality at levels of selenium up to 130 ng/ml but an increase in mortality at levels >150 ng/ml [151]. A placebo-controlled randomized trial of selenium for prevention of nonmelanoma skin cancer showed a significant mortality reduction in cancers of the lung, colon, and prostate [152]. A systematic review of the effects of antioxidant supplements on cancer included four randomized trials of selenium alone or in combination with other supplements and found that selenium reduced the overall risk of cancer in men (RR 0.77, 95% CI ) but not in women [153]. However, a later meta-analysis of randomized trials of antioxidant therapy included five trials of selenium and found no significant cancer risk reduction (RR 0.62, ) [154]. 70

71 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 71

72 Red meat High intake of red meat has been associated with increased risk of colon cancer. A working group of the International Agency for Research on Cancer (IARC) reviewed observational studies evaluating the association of cancer with red meat or processed meat consumption, giving the highest weight to prospective cohort studies and population-based case-control studies [63]. The largest body of evidence related to associations with colorectal cancer, with 7 of 14 cohort studies and 7 of 15 case control studies finding positive associations for red meat and colorectal cancer, and 12 of 18 cohort studies and 6 of 9 casecontrol studies finding an association for processed meat and colorectal cancer. A meta-analysis found a dose-response relationship based on 10 cohort studies, with risk increased by 17 percent (CI ) per 100 g/day of red meat and increased by 18 percent (95% CI ) per 50 g/day of processed meat. The working group concluded that evidence was sufficient to identify carcinogenicity for processed meat but limited for the association of red meat consumption and cancer 72

73 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 [66-69]. 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 with overall risk of cancer (HR 0.97, 95% CI ) [70]. 73

74 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) [79]. 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 [80]. 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 [81]. 74

75 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 [82,83], 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 ) [84]. Inaccuracy of retrospective diet reports in the case-control studies may affect their reliability [85]. However, a subsequent cohort study found no increase in risk of ovarian cancer with dietary dairy or lactose intake [86]. Thus, the relationship of dairy intake to ovarian cancer is uncertain 75

76 Fiber Fiber intake is associated with a reduction in the risk of heart disease [93,94] and diabetes [95,96], but its effect on cancer risk reduction is less certain. Results have been variable among large epidemiologic studies and meta-analyses, and the degree of protection from dietary fiber, if any, will remain unsettled until prospective intervention studies are done. In the absence of randomized trials, observational data may be confounded by the relationship of fiber intake with other micronutrients and with other choices related to lifestyle and diet. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Fiber'.) 76

77 Fiber Several large epidemiologic studies have reported a significant inverse associated between fiber intake and colorectal cancer risk. As an example, a large European study involving 519,978 patients found that intake of dietary fiber was inversely related to colon cancer incidence (adjusted RR 0.58, 95% CI ), comparing the highest to lowest quintiles of fiber intake [97]. However, the results may have been confounded by lack of control for folate intake, and fiber may have served as a proxy for this micronutrient. (See 'Folate and other B vitamins' below.) 77

78 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 [119]. 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 [120]. 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 [121]. In that analysis, including casecontrol and cohort studies, an inverse relationship between fish intake and rectal cancer was demonstrated (odds ratio [OR] 0.79, 95% CI ), while an inverse trend was suggested for colon cancer (OR 0.96, 95% CI ). 78

79 VITAMINS AND MICRONUTRIENTS Multiple observational and prospective studies of the use of supplemental vitamins and minerals to prevent cancer have been disappointing [122]. A systematic review of 38 studies found that neither vitamin C nor vitamin E supplementation was beneficial for prevention of the cancers evaluated [123]. 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" [124]. A subsequent long-term randomized trial (mean 9.4 years treatment) in 8000 women found no evidence that supplementation with vitamin C, E, or betacarotene (singly or in combination) decreased cancer incidence or cancer mortality [125]. Additionally, two long-term observational studies, one including over 160,000 women with follow-up of approximately eight years [126] and another including over 180,000 multiethnic participants with 11-year follow-up [127], found no association between multivitamin use and risk of cancer. (See "Vitamin supplementation in disease prevention".) 79

80 Selenium and Vit E Based on preliminary evidence from earlier smaller trials, the role of selenium in decreasing the incidence of prostate cancer was evaluated in the much larger Selenium and Vitamin E Cancer Prevention Trial (SELECT), which included over 35,000 men [155]. The trial was stopped prematurely for futility as neither vitamin E nor selenium protected participants from prostate cancer and there was a nonsignificant trend toward increased risk for diabetes in the selenium group [156]. (See "Chemoprevention strategies in prostate cancer", section on 'Selenium' and "Risk factors for type 2 diabetes mellitus", section on 'Selenium'.) 80

81 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 [132]. 81

82 In long-term follow-up (7 up to 12 years) of the SELECT trial, the risk of prostate cancer was higher in the men who were assigned to take vitamin E alone compared with placebo (HR 1.17, 99%CI ) [157]. Vitamin E (600 international units of alpha-tocopherol every other day) did not prevent invasive cancer in a 10-year follow-up to the Women's Health Study, evaluating healthy women age 45 years and older (mean age 55 years) [158]. Neither vitamin E nor vitamin C decreased risk for prostate or total cancer in a Physicians' Health Study randomized trial of 14,641 men aged 50 and older followed for eight years [159]. In a meta-analysis of six randomized trials, vitamin E supplementation had no effect on cancer incidence or cancer mortality [153]. 82

83 DIET PATTERNS Dietary patterns, instead of components of the diet in isolation, have been the focus of an expanding body of literature. The Mediterranean diet is characterized by a high intake of fruits, vegetables, nuts, legumes, whole wheat bread, fish, and olive oil. A large cohort study in Greece found that, when compliance with the Mediterranean diet was scored on a 10-point scale, a two-point increase in adherence to the traditional Greek Mediterranean diet was associated with a 12 percent lower risk of cancer [186]. In a larger analysis of the EPIC cohort, greater adherence to the Mediterranean diet also was associated with a decreased risk of cancer (for every two-point increase in diet score, cancer risk decreased 4 percent), with a suggestion of a stronger association with smoking-related cancers [187]. The Mediterranean diet has not consistently been associated with decreased risk of any specific tumor. A decreased risk of colorectal cancer was identified in one large cohort study in Europe [188], but not in a large United States cohort [189]. Data for breast cancer is similarly mixed with no association found among Swedish and British cohorts [190,191], while data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort identified an association for overall breast cancer risk and risk of postmenopausal tumors [192]. The association was more pronounced for estrogen-receptor-negative/progesterone-receptor-negative (ER-/PR-) tumors. 83

84 DIET A variety of dietary factors have been studied in relation to cancer. Overall, dietary fat, fruits, vegetables, and fiber have not consistently been shown to affect cancer risk [56]. Intake of other nutrients, particularly certain micronutrients, may offer a degree of protection against certain malignancies 84

85 Fruit and vegetables and cancer risk Current advice in relation to diet and cancer should include the recommendation to consume adequate amounts of fruit and vegetables, but should put most emphasis on the well-established adverse effects of obesity and high alcohol intakes Key TJ, Br J Cancer

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