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Primary Dietary Prevention:
Is the Fiber Story Over?
Cheryl L. Rock
Recent Results in Cancer Research, Vol. 174
© Springer-Verlag Berlin Heidelberg 2007
Abstract
Colorectal cancer is a major cause of morbidity 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% reduction 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, laboratory 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 ecologic 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 cellular and molecular events and activities that have
been identified in the development and progression of colon cancer (Milner 2004; Kris-Etherton
172
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 challenging.
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 carcinogens, binds carcinogenic substances, stimulates
bacterial anaerobic fermentation, and leads to the
production of short-chain fatty acids that have favorable 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 wellknown limitations in dietary assessment meth-
Cheryl L. Rock
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 accurately 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 methodologies. 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 challenging 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. Evaluating and interpreting dietary data, whether expressed as intakes of specific foods or estimated
nutrient intakes, cannot be approached simplistically. 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-
14 Primary Dietary Prevention: Is the Fiber Story Over?
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 meaningful 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 consistently 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 estimate, 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
173
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 affects 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
174
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 significant (p=0.06). The EPIC Study involves a very diverse study population recruited from ten European 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, multiple 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 weakened 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-
Cheryl L. Rock
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 collect 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 appropriately test for effects of dietary fiber on risk for
colon cancer.
As summarized in two recent comprehensive 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 characteristic 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 alphatocopherol. 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-
14 Primary Dietary Prevention: Is the Fiber Story Over?
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 following 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 (approximately 5%), despite reporting substantially
increased carotenoid intake in association with
reported increased intake of vegetables and fruit.
175
The difference between the control and intervention groups for this dietary biomarker was statistically 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, laboratory 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 represent 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 gastrointestinal problems (e.g., constipation, diverticulosis,
diverticulitis) and cardiovascular disease, recognizing that the specific link between fiber intake
176
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 constituent 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 definitive 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.
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