14 Primary Dietary Prevention: Is the Fiber Story Over?

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Abstract

Colorectal cancer is a major cause of morbid- ity in developed countries, and epidemiological and experimental research suggests that environmental factors, particularly diet, may play a key etiologic role. Among the various dietary factors that have been proposed to affect the risk and progression of colon cancer, dietary fiber has been of greatest interest, due to the effects of fiber on the function of the large bowel.

Dietary fiber is a heterogeneous group of compounds, consisting of the remnants of plant cells resistant to hydrolysis by human alimentary enzymes. Several case–control studies and a few cohort studies have linked higher fiber intake to reduced risk for colorectal cancer, although the results of these observational studies have been inconsistent. In the large European Prospective Investigation into Cancer and Nutrition observational study, higher dietary fiber from foods was associated with an estimated 25% reduc- tion in risk for large bowel cancer. However, no significant relationship between fiber intake (or major food sources of fiber) and risk for colorectal cancer was observed in a recently reported large pooled analysis of several cohort studies.

Well-known limitations of observational studies, particularly relating to the collection and interpretation of dietary data, constrain conclusions from these studies. To date, intervention studies testing the relationship between dietary fiber and colon cancer have focused on whether fiber supplementation or diet modification can affect the risk for adenoma recurrence and growth in individuals with a history of adenomatous polyps. In four of these intervention studies, subjects in the intervention arm were prescribed dietary fiber

supplements, and beneficial effects on adenoma recurrence were not observed over 3–5 years of follow-up. In a large randomized U.S. study, the Polyp Prevention Trial, the effect of prescribing diet modification (increased fiber and reduced fat intakes) was tested, and no effects on adenoma recurrence were observed, although dietary biomarker data suggest that the change in dietary intakes in the intervention arm was not substantial. The effect of increased dietary fiber intake on risk for colorectal cancer has not been adequately addressed in studies conducted to date. Longer-term trials and higher levels of fiber intake are strategies that have been suggested to increase knowledge in this area. Also, labora- tory and clinical studies that continue to provide insight into biological mechanisms may help to better target intervention efforts.

Introduction

On a worldwide basis, cancer of the colon is the fourth most commonly diagnosed cancer, and incidence rates have been steadily increasing, especially in developed countries (WCRF/AICR 1997). In the U.S. alone, over 145,000 cases of colon and rectal cancer are currently diagnosed each year (Jemal et al. 2005). Results from eco- logic and migrant studies have long suggested that diet is an important environmental factor that influences the risk and progression of colon cancer. Food provides nutrients and numerous other bioactive compounds, many of which have been specifically shown to have effects on cellu- lar and molecular events and activities that have been identified in the development and progression of colon cancer (Milner 2004; Kris-Etherton

14 Primary Dietary Prevention:

Is the Fiber Story Over?

Cheryl L. Rock

Recent Results in Cancer Research, Vol. 174

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et al. 2002; Rock 1998). As summarized in several reviews (Willett 1999, 2000; WCRF/AICR 1997), the continued accumulation of data on diet and cancer over the past several decades supports the concept that diet can affect risk and progression of colon cancer, although disentangling the effects of various foods, specific dietary constituents, and related lifestyle factors and characteristics (e.g., physical activity, obesity) that influence risk for colon cancer has proven to be very chal- lenging.

Among the various dietary factors that have been proposed to affect the risk and progression of colon cancer, dietary fiber has probably been of greatest interest, due to the observed effects of fiber on the function of the large bowel. Dietary fiber reduces transit time, dilutes potential carcino- gens, binds carcinogenic substances, stimulates bacterial anaerobic fermentation, and leads to the production of short-chain fatty acids that have fa- vorable effects on cell growth regulation (Slavin 2003; Marlett et al. 2002). By definition, dietary fiber is a heterogeneous group of compounds, consisting of the remnants of plant cells resistant to hydrolysis by human alimentary enzymes:

structural and storage polysaccharides and lignin (Marlett et al. 2002). Major sources of fiber in the diet include vegetables and fruit, whole grains, legumes, and nuts. All of these foods are complex, consisting of numerous bioactive constituents in addition to fiber, which can confound the interpretation of epidemiological studies. The interpretation of intervention studies testing whether fiber may have an effect on selected colon cancer-related outcomes also is complicated by the nature of the intervention, the time interval, the stage in the colon cancer continuum under study, and the magnitude and nature of change in fiber intake that is achieved. At this point, addressing whether or not the fiber story is over first requires a critical evaluation of problems and issues with the currently available data.

Key Issues

A major challenge in epidemiological research examining the link between nutritional factors, such as dietary fiber, and cancer risk are the well- known limitations in dietary assessment meth-

odologies, as recently summarized (Prentice et al. 2004). Accurate assessment of diet has recognized limitations and constraints, even when the most well-developed and established dietary assessment methods are used. Improvements in food and dietary supplement databases used to assess status also are sorely needed to more ac- curately characterize actual intakes (Dwyer et al.

2003).

Most epidemiological observational studies relating dietary factors to cancer risk are conducted within a defined, specific population, using rather crude dietary assessment method- ologies. As summarized by Prentice (2000), recent nutrient intakes may differ from those over the years or decades during the long process of the development of cancer, and nutrients (such as fiber) in the population under study may not be highly variable, which precludes identifying associations with cancer risk across a range of intakes. The diet is a complex mixture of foods and nutrients that are typically highly correlated, so estimating the relationship between cancer risk and a specific nutrient (such as fiber), while accommodating other dietary factors, is a chal- lenging task even with the best analytical approaches (Prentice 2000). Most epidemiological studies involve collecting and reporting data on quantified nutrient intakes, but the nutrient or dietary factor in the analysis may be a surrogate or even simply an indicator of foods or a general dietary pattern. Assumptions regarding cause and effect also are not necessarily true. Whole grains, although a major source of dietary fiber, are also rich sources of compounds that exhibit hormonal and antioxidant activities (Slavin 2003): whole grains are not synonymous with fiber and may not even be the main source of fiber in an individual diet. Similarly, vegetables and fruit contribute a number of biologically active compounds to the diet, in addition to fiber. Evalu- ating and interpreting dietary data, whether ex- pressed as intakes of specific foods or estimated nutrient intakes, cannot be approached simplis- tically. Also, the dietary pattern, or specifically, a high-fiber diet, is usually associated with lower level of red meat consumption, reduced likelihood of obesity, and greater likelihood of higher level of physical activity (Willett 1999), and evidence suggests that all of these factors may inde-

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pendently modify risk for colon cancer (WCRF/

AICR 1997).

The identification of dietary biomarkers is currently considered an important research goal for nutritional epidemiology and cancer research (Prentice et al. 2004; Prentice 2003). In addition to being recognized as important to assess true exposure in observational epidemiological studies, dietary biomarkers are particularly mean- ingful in intervention studies. A specific dietary biomarker for fiber intake, which would verify and better characterize intake, has not been identified or established. As a marker of intake of vegetables and fruit (among the major sources of fiber in most diets), plasma or serum carotenoid concentrations have some utility in verifying intake of those dietary fiber sources. Plasma or serum carotenoid concentrations have been con- sistently shown to be a marker of vegetable and fruit intakes in observational studies, and tissue concentrations increase in response to feeding or prescribing these foods and in diet intervention studies that successfully promote increased vegetable and fruit intake (Rock et al. 2001; Polsinelli et al. 1998). Serum beta-sitosterol concentration is currently under study as a potential biomarker of intake of seeds, nuts, cereal, and legumes, which are other major sources of fiber (Muti et al. 2003). In the absence of a biomarker for fiber intake, estimated fiber intake in a free-living population should be assumed to be a crude es- timate, which likely explains a great deal of the inconsistencies in the scientific literature.

To date, intervention studies testing the relationship between dietary fiber and colon cancer have focused on only one stage in the development and progression of colon cancer: whether fiber supplementation or diet modification can affect the risk for adenoma recurrence and growth in individuals with a history of adenomatous polyps, over a 2- to 5-year period of time (Asano and McLeod 2005). A finding of no effect in a study of this type does not address the possibility that a lifetime of high or low fiber intake, or differential fiber intake at another point in the cancer continuum, might affect risk for colon cancer.

Another issue with the relevant intervention studies to date relates to adherence with the prescribed regimen, and whether the degree of change in dietary intake (if that is the focus of

the intervention) was sufficient to promote biological changes relevant to colon cancer risk or progression. For example, in one study involving wheat bran supplementation, the median increase in fiber intake over baseline achieved in the intervention group was 7 g/day (MacLennan et al. 1995). In the large U.S. Polyp Prevention Trial (PPT), which aimed to promote an increase in fiber, fruit, and vegetable intakes, the absolute difference in daily fiber intake between the intervention and control groups over the 4-year period of the study was 6.9 g/1,000 kcal (Schatzkin et al. 2000), promoted in part by an increase in self-reported vegetable and fruit intake (Lanza et al. 2001). However, a worrisome finding that af- fects the interpretation of the results of this study is that the increase in serum carotenoid concentration (a biomarker of vegetable and fruit intake) in the intervention group was minimal, as discussed below.

Thus, several basic issues and considerations affect the interpretation of currently available data from studies to date that have addressed the question of whether dietary fiber plays a role in the risk and progression of colon cancer.

Recent Evidence from Epidemiological Observational Studies

As previously reviewed (WCRF/AICR 1997) reduced risk for colon cancer in association with higher fiber intake has been observed in most case–control studies. However, results from prospective cohort studies, in which dietary data are collected before the diagnosis of disease, are more inconsistent and generally do not identify a protective effect of dietary fiber (Willett 1999).

Two notably large prospective epidemiological observational studies that have examined the relationship between risk for colorectal cancer and fiber intake reported results within the past few years, with opposite results and conclusions.

In the multi-center European Prospective Investigation into Cancer and Nutrition (EPIC) Study, data from 519,978 individuals, in whom 1,065 cases of colorectal cancer were identified during an average follow-up period of 4.5 years, were the focus of the analysis (Bingham et al.

2003). In that study, dietary fiber in foods was

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found to be inversely related to incidence of colorectal cancer (adjusted relative risk [RR]

0.75, 95% confidence interval [CI] 0.59–0.95, for highest vs lowest quintile), adjusted for age, weight, height, sex, non-fat energy intake, and energy from fat, and stratified by center. Analysis of relationships between colorectal cancer risk and intakes of specific foods did not reveal significant associations, although a protective effect from cereal fiber intake was marginally signifi- cant (p=0.06). The EPIC Study involves a very di- verse study population recruited from ten Euro- pean countries, so the range of consumption and heterogeneity of dietary intakes of food sources of fiber are notable. Country-specific questionnaires were used to assess dietary intakes, and 24-h dietary recalls were collected from 8% of the sample as an approach to calibrating the dietary questionnaires.

In a pooled analysis based on data from 13 prospective cohort studies, involving data collected from 725,628 men and women followed for 6–20 years across the studies, 8,081 colorectal cancer cases were identified, and the relationship between dietary fiber intake and colorectal cancer was examined (Park et al. 2005). In that study, a significant inverse association was found in the age-adjusted model (pooled RR, 0.84;

95%CI, 0.77–0.92, for highest vs lowest quintile).

Adjusting for other risk factors (including age, body mass index, nondietary risk factors, mul- tiple vitamin use, and energy intake) attenuated the association, although it remained significant.

Adjustment for folate intake further attenuated the association, so that the relationship became nonsignificant, and further adjustment for red meat, milk, and alcohol intakes further weak- ened the association (RR, 0.94; 95%CI, 0.86–

1.03, for highest vs lowest quintile). When risk was examined in relation to major food sources of fiber (whole grains and vegetables and fruit), significant associations were not identified. The dietary data used in this study were obtained via study-specific questionnaires with different levels of detail in queries for food choices relevant to fiber intake.

It would appear unlikely that epidemiological observational studies will find resolution on the issue of whether dietary fiber intake plays a role in the primary prevention of colorectal can-

cer, which may be attributable, at least in part, to the general constraints and limitations of this approach. Across these studies, differences in the populations under study, approaches used to col- lect and analyze the data (including the selection of covariates to include in multivariate analysis), and other study characteristics likely explain the divergent results.

Results from Intervention Studies and Clinical Trials

As noted above, intervention studies testing the relationship between dietary fiber and the risk and progression of colon cancer have focused on whether fiber supplementation or diet modification can affect adenoma recurrence and growth.

The rationale for using recurrence of colorectal adenomas as the primary end point is that adenomatous polyps are considered precursors of most cancers of the large bowel (Einspahr et al.

1997), and a clinical trial testing the effect of fiber intake on incident colon cancer would require a large sample, a very long follow-up period, and considerable resources and support. However, it must be recognized that without specific knowledge of the critical points at which diet may affect the development of colon cancer, the focus of intervention studies to date may not appro- priately test for effects of dietary fiber on risk for colon cancer.

As summarized in two recent comprehen- sive reviews (Asano and McLeod 2005; Faivre and Bonithon-Kopp 2002), four studies have tested the effect of fiber supplementation (wheat bran or ispaghula husk) on polyp recurrence, although one of these studies (DeCosse et al.

1989) was excluded from the Cochrane Review because it did not meet the requirement for predefined outcomes. Another notable char- acteristic of that study is that while subjects in only one treatment arm were prescribed supplemental wheat bran, subjects in both arms were prescribed supplemental vitamin C and alpha- tocopherol. In three of the studies, the subjects were individuals who had a previous adenoma;

in the study by DeCosse et al. (1989), the subjects had been diagnosed with familial polyposis.

In these studies, the amount of wheat bran pre-

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scribed ranged from 11 to 22.5 g/day, and in the study involving supplementation with ispaghula husk (Bonithon-Kopp et al. 2000), the amount prescribed was 3.5 g/day. The length of follow-up ranged from 3 to 5 years. No effect on adenoma recurrence was observed in the studies involving wheat bran supplementation (Alberts et al. 2000;

MacLennan et al. 1995; DeCosse et al. 1989), and a significant increase in adenoma recurrence was observed in association with ispaghula husk supplementation in the study that tested that intervention (Bonithon-Kopp et al. 2000).

The effect of diet modification to promote increased fiber intake on adenoma recurrence has been examined in two studies reported to date.

In one of these studies (McKeown-Eyssen et al.

1994), the goal for subjects in the intervention arm was to achieve 50 g/day fiber intake and less than 20% energy from fat. After 12 months of dietary counseling, the intervention group reported an average of 35 g/day fiber intake and 25% energy from fat, while the control group reported an average of 16 g/day fiber intake and 35% energy from fat. In the total study sample of 201 subjects, no significant effect on adenoma recurrence was observed at the 2-year follow-up time point, although nonsignificant differential effects were suggested in the analysis of gender subgroups.

The effect of increasing intakes of fiber (with the goal of 18 g/1,000 kcal) and vegetables and fruit (aiming for five to eight servings/day), concurrent with reduced fat intake (20% energy from fat), on adenoma recurrence at 4 years fol- lowing randomization was the focus of the PPT (Schatzkin et al. 2000). The PPT was a large randomized trial involving 2,079 study participants, and those assigned to the intervention group received over 50 h of dietary counseling. The absolute difference between the self-reported daily intakes of the intervention and control groups over the 4-year period was 9.7% energy from fat, 6.9 g/1,000 kcal dietary fiber, and 1.1 servings/1,000 kcal vegetables and fruit (Lanza et al. 2001). As noted above, however, the intervention group exhibited only a minimal increase in total serum carotenoid concentration (ap- proximately 5%), despite reporting substantially increased carotenoid intake in association with reported increased intake of vegetables and fruit.

The difference between the control and intervention groups for this dietary biomarker was sta- tistically significant, but the minimal change that was observed is not consistent with the dietary intakes that were reported.

Do the intervention studies conducted to date resolve the question of whether dietary fiber intake plays a role in primary prevention? Issues such as the timing in the cancer continuum, the length of follow-up in the studies, the nature of the intervention, and the degree of change in intake that was actually achieved all affect how confidently one can answer that question. The need for longer-term trials and higher levels of dietary fiber intake in the intervention has been suggested (Asano and McLeod 2005). Also, labo- ratory and clinical studies that continue to provide insight about biological mechanisms may help to better target intervention efforts, if future studies are to be conducted with a more in-depth knowledge base.

Conclusions

At this point, reviews of the scientific literature on the health benefits of fiber intake have uniformly agreed on the general recommendation that increased fiber intake, relative to current average intakes in developed countries, is well founded (Food and Nutrition Board 2002; Marlett et al.

2002). Current dietary recommendations in the U.S. advise fiber intakes of 38 and 25 g/day for men and women, respectively, aged 19–50 years, and 30 and 21 g/day for men and women aged 51 years and older, based on thorough review of evidence relating fiber to optimal health and disease prevention (Food and Nutrition Board 2002). Nutritional surveys conducted over the past decade suggest that median fiber intake ranges from 16.5 to 17.9 g/day for men and 12.1 to 13.8 g/day for women in the U.S., so the levels of intake that are currently recommended repre- sent a considerable increase for most individuals.

The rationale for this recommendation is based on the consistent evidence relating increased fiber intake to lower risk for common gastrointes- tinal problems (e.g., constipation, diverticulosis, diverticulitis) and cardiovascular disease, recog- nizing that the specific link between fiber intake

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and risk for colon cancer has not been as established as with these other conditions.

Another relevant benefit of dietary fiber that has been observed in both epidemiological and experimental studies is that this dietary constitu- ent is a key feature of a diet that is low in energy density. Current evidence strongly supports the concept that a low-energy density diet, which is characterized by high dietary fiber intake, may play a critical role in promoting weight control and in preventing adult weight gain (Liu et al.

2003; Burton-Freeman 2000). Obesity is a nutritional factor that appears to promote a considerable increase in risk for several types of cancer, including colon cancer (Calle et al. 2003).

Finally, fiber-rich foods, such as vegetables and fruits, whole grains, legumes and nuts, are all good sources of essential nutrients and other bioactive compounds that exhibit numerous biological activities that promote normal cell growth regulation and function (Slavin 2003; Marlett et al. 2002).

On the basis of current evidence, the defini- tive relationship between dietary fiber intake and risk and progression of colon cancer cannot be resolved at this time. However, increased fiber intake remains a dietary strategy that may contribute (indirectly, if not directly) to reduced risk and progression of cancer.

References

Alberts DS, Martinez ME, Roe DJ, Guillen-Rodriguez JM, Marshall JR, van Leeuwen JB et al (2000) Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. N Engl J Med 342:1156–1162

Asano TK, McLeod RS (2005) Dietary fibre and the prevention of colorectal adenomas and carcinomas (Cochrane Review), The Cochrane Library, Issue 4, Wiley, Chichester

Bingham SA, Day NE, Luben R, Ferrari P, Silmani N, Norat T et al (2003) Dietary fibre in food and protection against colorectal cancer in the Euro- pean Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet 361:1496–1501

Bonithon-Kopp C, Kronborg O, Glacosa A, Rath U, Faivre J, the European Cancer Prevention Organi- sation Study Group (2000) Calcium and fiber supplementation in prevention of colorectal adenoma recurrence: a randomized intervention trial. Lancet 356:1300–1336

Burton-Freeman B (2000) Dietary fiber and energy regulation. J Nutr 130 [Suppl]:272S–275S

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity and mortality from cancer in a prospectively studied cohort of U.S.

adults. N Engl J Med 348:1625–1638

DeCosse JJ, Miller HH, Lesser ML (1989) Effect of wheat fiber and vitamin C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81:1290–1297

Dwyer J, Picciano MF, Raiten DJ, Members of the Steering Committee (2003) Food and dietary supplement databases for what we eat in America- NHANES. J Nutr 133 [Suppl]:624S–634S

Einspahr JG, Alberts DS, Gapstur SM, Bostick RM, Emerson SSD, Gerner EW (1997) Surrogate end- point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials.

Cancer Epidemiol Biomarkers Prev 6:37–48 Faivre J, Bonithon-Kopp C (2002) Effect of fiber and

calcium supplementation on adenoma recurrence and growth. IARC Sci Publ 156:457–461

Food and Nutrition Board, Institute of Medicine (2002) Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. National Academy, Washington, DC Jemal A, Murray T, Ward E, Samuels A, Tiwari RC,

Ghafoor A et al (2005) CA Cancer J Clin 55:10–30 Kris-Etherton PM, Hecker KD, Bonanome A, Coval

SM, Binkoski AE, Hilpert KF et al (2002) Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 113 [Suppl]:71S–88S

Lanza E, Schatzkin A, Daston C, Corle D, Freedman L, Ballard-Barbash R et al (2001) Implementation of a 4-y, high-fiber, high-fruit-and-vegetable, low- fat dietary intervention: results of dietary changes in the Polyp Prevention Trial. Am J Clin Nutr 74:387–401

Liu S, Willett WC, Manson JE, Hu FB, Rosner B, Cold- itz G (2003) Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle- aged women. Am J Clin Nutr 78:920–927

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MacLennan R, Macrae FA, Bain C, Battistutta D, Chapuis P, Gratten H (1995) Randomized trial of intake of fat, fiber and beta carotene to pre- vent colorectal adenomas. J Natl Cancer Inst 87:1760–1766

Marlett JA, McBurney MI, Slavin JL (2002) Posi- tion of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc 102:993–1000

McKeown-Eyssen G, Brigh-See E, Dion P, Bruce WR, Jazmajl V (1994) A randomized trial of a low-fat high-fibre diet in the recurrence of colorectal polyps. J Clin Epidemiol 47:525–536

Milner JA (2004) Molecular targets for bioactive food components. J Nutr 134 [Suppl]:2492S–2498S Muti P, Awad AB, Schunemann H, Fink CS, Hovey K,

Freudenheim JL et al (2003) A plant-food-based diet modifies the serum beta-sitosterol concentration of hyperandrogenic postmenopausal women. J Nutr 133:4252–4255

Park V, Hunter DJ, Spiegelman D, Bergkvist L, Ber- rino F, van den Brandt PA et al (2005) Dietary fiber intake and risk of colorectal cancer. JAMA 294:2849–2857

Polsinelli ML, Rock CL, Henderson SA, Drewnowski A (1998) Plasma carotenoids as biomarkers of fruit and vegetable servings in women. J Am Diet Assoc 98:194–196

Prentice RL (2000) Future possibilities in the prevention of breast cancer. Fat and fiber and breast cancer research. Breast Cancer Res 2:268–276

Prentice RL (2003) Dietary assessment and the reli- ability of nutritional epidemiology reports. Lancet 362:182–183

Prentice RL, Willett WC, Greenwald P, Alberts D, Bernstein L, Boyd NF et al (2004) Nutrition and physical activity and chronic disease prevention:

research strategies and recommendations. J Natl Cancer Inst 96:1276–1287

Rock CL (1998) Nutritional factors in cancer prevention. Hematol Oncol Clin N Am 12:975–991 Rock CL, Moskowitz A, Huizar B, Saenz CC, Clark

JT, Daly TL et al (2001) High vegetable and fruit diet intervention in premenopausal women with cervical intraepithelial neoplasia. J Am Diet Assoc 101:1167–1174

Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B et al (2000) Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N Engl J Med 342:1149–1155

Slavin J (2003) Why whole grains are protective: biological mechanisms. Proc Nutr Soc 62:129–134 Willett WC (1999) Goals for nutrition in the year 2000.

CA Cancer J Clin 49:331–352

Willett WC (2000) Diet and cancer. Oncologist 5:393–404

World Cancer Research Fund in Association with American Institute for Cancer Research (WCRF/

AICR) (1997) Food, nutrition and the prevention of cancer: a global perspective. American Institute for Cancer Research, Washington, DC