Diet, Colorectal Cancer REED 2005

1130-0108/2005/97/6/432-448
REVISTA ESPAOLA DE ENFERMEDADES DIGESTIVAS

Copyright 2005 ARN EDICIONES, S. L.
REV ESP ENFERM DIG (Madrid)

Vol. 97. N. 6, pp. 432-448, 2005
POINT OF VIEW
Colorectal cancer: influence of diet and lifestyle factors

A. Franco1,2, A. K. Sikalidis1 and J. A. Sols Herruzo3
Department of Nutritional Sciences. University of California. Berkeley, USA. 2Division of Gastroenterology. University
of California. San Francisco, USA. 3Division of Digestive Diseases. Hospital 12 de Octubre. Madrid, Spain
1
Franco A, Sikalidis AK, Sols Herruzo JA. Colorectal cancer:

influence of diet and lifestyle factors. Rev Esp Enferm Dig
2005; 97: 432-448.
INTRODUCTION
Colorectal cancer (CRC) is one of the most commonly
diagnosed cancers, with more than 944,000 cases and
492,000 cancer-related deaths reported worldwide in
2000 (1). Migrant and temporal studies suggest that colorectal cancer is determined largely by environmental exposures, as it is shown by large rate variations between
different countries and by dramatic increases in incidence
among populations migrating from low-risk to high-risk
areas (2). Based on such epidemiological studies, it has
been estimated that as much as 70-80% of colorectal cancer could be attributed to the contribution of environmental and lifestyle factors (3,4). These observations suggest
the importance of potentially modifiable factors that may
be largely preventable.
On the other hand, although the environment is central
to the etiology of most cases of colorectal cancer, individual, genetically-determined susceptibility is also im-
This article has been realized with the support of a grant of Universidad
Complutense, Madrid and the University of California.
Recibido: 26-04-05.
Aceptado: 29-04-05.
Correspondencia: Alejandro Franco Ugidos. Paseo de la Esperanza, 8, P3,
7D. 28005 Madrid. e-mail: afrancougidos@hotmail.com
portant and plays a decisive role through its interaction

with the other different etiologic factors, as it is shown by
the recent discoveries related to the interaction between
gene, environment and diet. At this point, the implications of environmental causes of colon cancer are evident. If we could identify and modify these relevant factors, then we might be able to prevent most colorectal
cancer incidence. The challenge is to discover the environmental factors that are responsible for this disease and
then change them.
DIET
Diet is one of the most important lifestyle factors and
has been studied widely. The first major report was a review of the available evidence on diet and cancer published by the USA National Academy of Science in 1982
(5). This report found convincing evidence that diet
played an important role in human cancer and included a
series of recommendations that at that time emphasized a
reduction in total fat intake (6,7). Since the early 1980s
many different investigations (animal experiments, retrospective and prospective epidemiological studies, clinical
trials) have addressed the potential effects of diet on cancer incidence. Later on, in 1997, a comprehensive review
of diet and cancer was published (8), and even since that
time new major results have been reported.
Although much has been learned, progress has been
slower and more difficult than it was anticipated. For instance, different trials with a variety of nutritional modifications (e.g., increases in fiber, fruits, and vegetables,
lower fat intake, or supplementation with various whole
foods or with one or more vitamins or minerals) have
shown limited effects in colorectal neoplasia prevention
(9). Nonetheless, several lines of evidence support a role
for dietary modifications in the prevention of colorectal
neoplasia. A large number of observational studies sug-
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LIFESTYLE FACTORS
gest that vegetables, fruits, a high-fiber diet, and certain

micronutrients might be protective against CRC; while
heavy alcohol intake, and red meat (and the way it is
cooked and prepared) might increase CRC risk (9-11). At
the same time, several animal studies confirmed that dietary changes might reduce cancer risk (12-14). The following sections describe these data.
Dietary fat and meat intake
Previous old studies suggested a positive correlation
between dietary fat and CCR risk (6,7,15), which resulted
in dietary recommendations based on a reduction in total
fat intake. The mechanism postulated for the possible relation between a high-fat diet and colonic cancer resides
on the association between fat intake and the production
of bile acids. Primary bile acids, also called conjugated
bile salts, are produced by the liver to participate in the
absorption of fat from the small intestine. Although primary bile acids are very efficiently reabsorbed and redirected to the liver at the ileum, a small percentage, approximately 1-2%, is not absorbed but rather escapes into
the colon, where it becomes metabolized by the colonic
microflora into secondary bile acids, which are known to
be mutagenic (18).
However, several recent studies (16-21) indicate that
there is essentially no association of fat intake with risk
of colorectal cancer, independently of the kind of fat (total, saturated, monounsaturated or polyunsaturated), and
it seems that at least part of the high colon cancer rates in
Western countries previously attributed to fat intake are
probably due to a sedentary lifestyle with high energy intakes (22,23). Another concern is the possible association
between trans-fatty acids (found in soft margarine and
baked goods) with colorectal neoplasia; although there is
some preliminary evidence available (24,25), the data are
not yet conclusive.
Only one study (26) has found an increased risk with
fat intake, and it was attributable to animal fat intake, and
not to vegetable one. Other further analyses in this last
study indicated that red meat intake, a major source of
animal fat, was the fact associated with the increased risk
of colon cancer. Nowadays, it appears that the association
of fat intake with colorectal cancer is specific to fat from
animal sources and may be attributed to red meat intake,
rather than fat per se (27,28).
Related to meat intake, the majority of studies have
shown an increased risk of colorectal cancer with high intakes of red meat, with a relative risk of 1.35 (95% CI:
1.21-1.51) (21,26,28,29,31,32), sometimes even stronger
with processed meat (20,29-31), especially when longterm consumption was examined. Red meat refers to
beef, pork and lamb as main meals, and processed meat
includes sausages, hamburgers, smoked, cured, salted,
and canned meat. The fact, previously discussed, that fat
intake does not seem to be associated with colon cancer,
REV ESP ENFERM DIG 2005; 97(6): 432-448
433
suggests that the findings related to meat intake could be

explained by the non-fat components of meat. It has been
suggested that cooking methods at high temperature may
influence the production of carcinogenic components
(heterocyclic amines, polyaromatic hydrocarbons) on the
surface of meats cooked during long periods of time or in
direct contact with fire (28-30,34). At the same time, humans have different enzymes involved in the metabolism
of these compounds, and individuals whose phenotypes
provide a higher predisposition to transform them into
more active molecules, as the fast acetylator phenotype, could be at increased risk of developing polyps and
large bowel cancer (35). Furthermore, processed meat
may also increase the presence of possible carcinogenic
factors as nitrosamine precursors (30,33,34). Finally,
there have also been some suggestions that an excessive
iron intake, especially in the heme form found in red
meat, may also be associated with an increased risk of
colorectal cancer (29,33). As proposed mechanisms,
heme has been shown to produce cytotoxic effects over
colonocytes (36,37), and an increase in the fecal concentrations of N-nitrous compounds (36).
Non-red meat sources of animal protein, including
low-fat dairy products, fish, and poultry, either have not
been associated with a higher risk of colon cancer or even
have been related to a lower risk (16,20,21,32).
To summarize this part: recent data suggest that dietary fat does not seem to be a major risk factor for CRC.
On the other hand, red meat intake, and in particular
processed meat, seems to be associated with a higher risk
of colon cancer, so it has been strongly suggested that it
should be eaten less frequently, and maybe avoiding its
preparation at high temperatures, in direct contact with
fire, or in a very-well cooked way (as it occurs when it is
grilled) in order to minimize CCR risk (8,33,38,40).
Fiber
The hypothesis that fiber (mainly found in fruits, vegetables and cereals) reduces the risk of colon cancer has
been popular since the 1970s, when Denis Burkitt observed that African natives that consumed a high-fiber
diet exhibited low rates of colorectal cancer (39). Many
potential mechanisms of action have been proposed (4144): diluting and binding potential carcinogens and
speeding their transit through the colon; affecting different mechanisms of carcinogen activation after altering
the colonic flora and reducing the pH; or even serving as
the substrate for the generation of short-chain fatty acids
(especially butyrate), which may be protective through
their ability to modulate gene expression, inhibit the
growth of tumorogenic cell lines, induce apoptosis and
promote differentiation.
The strongest evidence supporting the fiber hypothesis
is the remarkable consistency of the protective effect on
epidemiological observations in populations with a high
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A. FRANCO ET AL.
intake of fiber-rich foods (44), strengthened by a metaanalysis of case-control studies that shows a dose-dependent protective effect (45). However, recent studies have
cast doubt on the cancer-preventing effects of fiber: some
large prospective studies conducted in specific populations do not support this protective effect (21,26,40,4648). Furthermore, even no randomized interventional
studies have assessed the effect of high-fiber intakes in
CRC prevention, most of the trials studying the prevented
effect of high fiber diets in the growth of adenomas have
shown a lack of effect (49,50) or a very modest protective
effect (16,51). However, a recent cohort study conducted
in ten European countries has shown a clear protective
effect of fiber with a dose-response relationship (52).
Why the results differ is not clear (58). As in the studies about fruit and vegetables, this could be due to some
kind of bias, for example: in the duration of studies, in
the selection process, secondary to some uncontrolled
confounding factors, and so on. Many questions yet remain unsolved in regards to the relation between dietary
fiber and the development of CRC: its real effect, its
mechanism, how to differentiate it from other potential
anticarcinogens present in fiber-rich foods. And if finally
it is a protective agent: the exact type and source of fiber,
the way to administer it, the amount required, when and
during what period of time and in what target group (e.g.
those without prior adenomas, or even for everybody). In
the near future, results from some trials with different approaches (different type of fiber administered in a different way to specific groups or using other efficacy measures of the intervention) may also enhance the
understanding of fibers chemopreventive potential.
Nevertheless, despite a lack of complete scientific evidence and regardless of a few publications that do not
consider that higher consumption of fiber foods or supplements can reduce the risk of colon cancer (53), there
are still reasons to think that consuming a high-fiber diet
may be protective against colon cancer. Furthermore, we
also have to consider its positive effects on the gastrointestinal system (as a preventive factor against constipation, hemorrhoids and diverticulosis), as well as in the
cardiovascular one. Thus, it is still reasonable to recommend a total fiber intake of at least 30-35 g/day
(8,38,40,44).
Fruits and vegetables
The role of fruits and vegetables in colorectal carcinogenesis has been controversial, especially in recent years.
Initially, the majority of case-control studies showed that
a high intake of vegetables and fruits was associated with
a lower risk of colon cancer (32,54-56). However, more
recent prospective studies have found no protective effect
(21,26). This absence of association has also been supported by randomized intervention studies with fruits and
vegetables (49), and also with dietary antioxidants (57)
(including vitamins A, C, and E, commonly found in

fruits and vegetables) that used colorectal adenomas as
their end point.
The causes of discrepancy between studies remains
unclear (58). As in the studies about fiber, it could be due
to different types of bias in the investigations, or as a result of the many different biologically active chemicals
found in fruits and vegetables that may potentially reduce
cancer incidence, for example: carotenoids, folic acid, vitamin C, flavonoids, phytoestrogens, isothiocyanates,
fiber, and so on (55); and nowadays it is unknown which
of them are responsible for these possibly reduced risk.
The identification of the specific protective constituents,
or the combination of them, as well as the types and
amounts of fruits and vegetables that may be particularly
protective could help provide better guidance.
However, despite the lack of conclusive data, it is still
believed that a higher intake of fruits and vegetables (especially vegetables) could be beneficial to prevent CRC.
And considering its other health benefits, their consumption should be encouraged (8,38,40,53,58,59).
Micronutrients
Calcium and vitamin D
There is a large body of epidemiological evidence that
supports a protective effect of calcium against colorectal
cancer. Case-control and prospective epidemiological
studies show moderate inverse association (a decrease
around 25%) between calcium intake and CRC risk
(60,61). There are also interesting data from randomized
clinical trials that show that calcium supplementation
(1,200-2,000 mg per day) produces a modest, but rapid
decrease in the incidence of recurrent colorectal adenomas (62-66), although in one of the studies (66) such an
effect was only observed in subjects with higher levels of
vitamin D, suggesting that perhaps both calcium and adequate levels of vitamin D are required for the protective
effect to be exerted.
Different mechanisms have been proposed for calciums potential to reduce the risk of colorectal cancer:
from binding secondary bile acids and fatty acids, sequestering these mutagenic substances from contact with
epithelial cells, to a direct action decreasing colonic epithelial cell proliferation and promoting its differentiation, through a calcium-sensing receptor (67-69).
Furthermore, related to the possible protective effect
of vitamin D, in vitro and in vivo studies have shown that
vitamin D and its analogs can inhibit colonic epithelial
cell proliferation, induce differentiation and promote
apoptosis, as well as their positive effects on calcium absorption and transportation (67-69). In addition, a large
epidemiological study has reported a 29% reduction in
the risk of CRC among men with the highest vitamin D
intakes from dietary or supplemental sources (70). Any-
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LIFESTYLE FACTORS
way, these are still preliminary results, and there are no

prospective studies yet (40,71).
As a summary, the most recent studies support the notion of a modest protective effect of calcium in CRC risk,
in the range of about 20 to 30%. Based on these data, on
its benefits to bone health, and on the fact that many people in western countries do not achieve the recommended
daily allowance, some experts suggest starting to consider calcium supplementation (about 1200 mg/day)
(8,38,73) at least for individuals at high risk for colon
cancer. However, there are also some data against its use,
especially in men, provided by a study where it was positively associated with a higher risk of prostate cancer
(72), and considering the fact that the protective effect
appears to depend upon other different variables as colon
subsite, gender, source (dietary or supplemental), and
lifestyle factors such as smoking or dietary intake of vitamin D, it seems reasonable to wait for future studies incorporating a thorough examination of these variables
(40,71).
Selenium
There is some evidence from epidemiological and animal studies that insufficient selenium intake is related to
an increased risk for colon and other types of cancer
(74,75). In a recent study designed to assess the use of selenium supplements in the prevention of non-melanoma
skin cancers, those receiving supplements had, in an unexpected result, a decreased risk for colon and other types
of cancer (lung, prostate), although they developed somewhat more skin cancers (76). However, in case-control
and cohort studies correlations between the levels of selenium in the blood or nails and reductions in colorectal
neoplasia have been inconsistent (9,77,78). Possible
mechanisms for these beneficial effects could include actions on DNA repair, as well as an antioxidant or apoptosis inducing role (79,80).
These results need confirmation, but the protective effect of selenium in colorectal cancer is a plausible possibility.
Iron
Some data have led to speculation that dietary iron
could increase the risk of colon cancer. Iron is a pro-oxidant that via the production of oxygen radicals -known to
damage protein, lipids, and DNA- could promote the induction of somatic mutations that may favor the development of CRC (81-83). At the same time, in animal studies
luminal iron concentrations also increase mucosal
colonic proliferation (84). Finally, a prospective study
has shown that high iron consumption could be associated with an increased risk of colorectal cancer (85). All
these data need to be confirmed.
435
On the other hand, the effect of total body iron is not

clear, and data in that regard are still contradictory
(86,87).
Antioxidant vitamins
It has been proposed that the probable protective effects of diets rich in fruits and vegetables against the development of colorectal cancer are due to their content of
vitamins with antioxidant properties, particularly
carotenoids (vitamin A precursors), retinoids (vitamin
A), ascorbic acid (vitamin C), and -tocopherol (vitamin
E) (54,56). Anti-oxidants vitamins may inhibit free-radical reactions and thereby prevent oxidative damage to
DNA, as well as be involved in cellular proliferation as
part of signaling cascades (for example vitamin E) (82).
In addition, certain studies suggest that antioxidants may
also inhibit tumorigenesis by stimulating the immune
system (88).
Prospective data, however, do not support this hypothesis. Vitamin supplementation (A, C, E or a combination
of them) has been evaluated in several large prospective
studies (89-94). All found no protective effect of vitamin
supplementation against adenoma or cancer incidence.
Additionally, there are studies which show that individuals randomized to beta-carotene may actually have higher
rates of certain tumors such as lung cancer (95,96). However, more recently another study suggested a reduction
in recurrent adenomas in subjects who neither smoked
nor drank alcohol with beta-carotene supplementation,
but an increase among participants who used tobacco or
alcohol (97).
All these contradictory results require confirmation in
other trials, but there is now little reason to recommend
anti-oxidant vitamins for the prevention of colorectal
cancer (38,40).
Folate and methionine
Lower folic acid and methionine intakes have been associated with an increased risk of colon adenoma and
colon cancer (98-100). At the same time, the long-term
use (for more than 15 years) of multivitamins containing
folic acid has been associated with a lower risk of colon
cancer (91,101), and the protective effect (91) was seen
to be primarily due to the folic acid component of multivitamins, rather than anti-oxidant vitamins.
Folate status may be also an important determinant of
neoplastic risk in persons with ulcerative colitis (UC). A
reverse association between red blood cell folate concentrations and colorectal dysplasia has been reported (102),
and also a reduced risk of colorectal dysplasia among patients who receive folate supplements (103). The relationship between inflammatory bowel disease and low
folate levels is also well known secondary to the use of
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A. FRANCO ET AL.
some drugs (e.g. azathioprine), which may enhance the

risk of cancer.
The protective mechanism is unknown, but both folic
acid (found essentially in fruit and vegetables) and methionine (found in high concentrations in red meat, chicken and fish) serve as methyl donors; methyl groups are
necessary for DNA synthesis, methylation and repair
(104); for the translation and function of proteins; and
possibly to diminish mucosal proliferation (105).
Dietary and genetic factors may modulate the proposed chemopreventive effects of folate and methionine.
Certain studies have shown that heavy alcohol consumption and polymorphisms in the enzyme methylenetetrahydrofolate reductase may reduce the availability of
methyl groups, thus altering the chemopreventive effects
of folate or methionine (58,98,99,106). It also seems that
the protective effect of folic acid comes from supplements (91) rather than higher dietary intake, maybe because of a loss of folic acid during food preparation due
to its water soluble nature, or because of its lower
bioavailability when in food (9).
Nowadays there is controversy on how to increase
folic acid levels in the general population, which are frequently diminished even in Western societies. The promotion of higher fruit and vegetables intakes (even
though folic acid from these foods has a lower bioavailability) has been considered, as well as the fortification of
some specific meals, and even a recommendation of daily
RDA level supplementation (400 mcg/day). In the
U.S.A., the enrichment act of 1998 postulated the mandatory fortification of cereals with folate, with an expectation to minimize the incidence of neural tube defects in
newborns, and to reduce the risk of cardiovascular disease (CVD) associated with high homocysteine levels,
which are lowered by folic acid. A significant reduction
in the incidence of neural tube defects was achieved, but
the success rate regarding CVD has proven difficult to assess, and there is no information available for colorectal
cancer risk (149). Whether the benefits of additional folate may be greater for some groups e. g., those who
consume alcohol on a daily basis, those taking medications reducing its levels, or those with a higher risk of
colon cancer for any reason is also debated.
In the near future, with all these data and the upcoming
results of interventional studies, recommendations about
folate and methionine as preventive factors for CRC will
be clearer.
tions. Several animal models support this hypothesis for

example, studies in mice have shown that energy
(caloric) restriction can profoundly reduce the rate of mucosal proliferation and the development of tumors, including colonic ones (107); at the same time, chemically
induced carcinogenesis experiments in rats reveal that the
risk of colon cancer varies with the type of diet (e.g. increased by 50% in rats fed with high-energy diets) (150).
However, these results are difficult to interpret because
they may be dependent on other factors such as physical
activity (which appears to be protective) or obesity
(which seems to increase the risk).
Nowadays the indicators of energy balance used in humans are growth rates and body weight. Thus, adult
height could provide an indirect indicator of pre-adult nutrition, and adult weight gain and obesity could reflect a
long-term positive energy balance later in life.
Regarding height, taller adults even after controlling
for body weight have been associated with an increased
risk of colon cancer (20,23,108), maybe reflecting the
importance of nutrition in the early stages of life, or
maybe just because of its close correlation with the total
length of the human colon.
Obesity
A significant body of epidemiological studies suggests
that obesity, defined as a high body mass index (BMI), is
a risk factor for colon cancer (8,20,23,38,108,113), while
weight loss seems to be protective (40). At the same time,
in animal models obesity has also been associated with
an increased risk of colon cancer (151). The association
is clearer for colon neoplasias, but less clear for rectal
ones, and it appears to be more consistent for men and
young women (less than 55 years), diminishing then in
aging women (114,115). This last fact is probably related
to the menopausal status and the different origin of estrogens between premenopause and postmenopause periods,
since estrogens appear to be a protective factor, as seen in
postmenopausal women using replacement estrogens
who have a lower risk (116). Some data also indicate that
a tendency for central distribution of adiposity (visceral
adiposity), as typically found in men, increases the risk
independently of BMI (23).
Physical activity
LIFESTYLE
Energy balance
It has been suggested that energy imbalance (the difference between energy consumption and energy intake)
is one of the factors involved in the increased rates of colorectal cancer among economically developed popula-
Many studies conducted in diverse populations show

that more physically active individuals, especially lifelong, are at a lower risk for colon cancer, with a reduced
incidence by up to 50% (8,22,23,38,109,110,112,113,
117,118). This effect is independent of other risk factors
such as diet and body weight, and it appears with different types of physical activity (at work or during leisure
time), although some studies also suggest that more in-
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LIFESTYLE FACTORS
tense activity may confer greater protection than less intense activity (110,117,118). But even a relatively moderate level of activity for example, walking fast for one
hour daily or moderate jogging 3-4 hours per week,
which can be achieved by many individuals even in highly industrialized countries can markedly reduce colon
cancer risk (40,112). As with BMI, the relationship between physical activity and colon cancer risk is less clear
for rectal neplasias (8).
The underlying mechanisms by which obesity increases risk and why exercise is protective are being studied.
One hypothesis is that insulin resistance and compensatory hyperinsulinemia, as components of the metabolic
syndrome (syndrome X) related to obesity and lack of
physical inactivity, may enhance the risk of colon cancer.
Some studies have found that type 2 diabetes mellitus
(119-122) and higher insulin concentrations (123) are associated with a higher risk of colon adenomas and cancer.
As potential mechanisms, insulin has growth-promoting
effects by itself, and it also promotes insulin-like growth
factor-I (IGF-I) tumorogenic actions (124). Although
obesity is probably the most important influence on this
syndrome, the degree of physical activity, genetic factors,
and selected dietary components may also influence it.
Two dietary patterns that have been related to the induction of these situations are: an abundant intake of foods
with a high dietary glycemic index (white bread, rice,
potatoes, cereals) showing fast carbohydrate absorption;
and a high sucrose intake (cakes, desserts and refined
sugar); both of them could be associated with an increased risk of colon cancer (20,125-127).
It has also been postulated that leptin, a hormone produced by fat cells and associated with colon cancer in
some experimental studies, may play a role in its pathogenesis, maybe inducing colonic cell proliferation (128130). Other potential mechanism include an increased release of cytokines from adipose tissue, which may play a
role in the inflammatory state associated with CRC (131).
Furthermore, other proposed mechanisms to explain
why physical activity may diminish colon cancer risk include a reduction in intestinal transit time, which would
limit the period of contact between the colon mucosa and
cancer promoting contents (secondary bile acids, dietary
toxics). It also may reduce body mass index and insulin
resistance (132).
With all these data, the current recommendation is to
be physically active, and to avoid overweight and obesity
in order to prevent CRC (8,38,40).
Smoking
The majority of recent studies show an association between cigarette smoking, colorectal adenomas, and cancer (20,120,133-137). This association depends on the
number of cigarettes smoked, the amount of time exposed to them, and the age when the habit started, so the
437
relation with colorectal cancer appears after a sufficiently

long and continuous period of exposure (up to 35-40
years). Despite the fact that a precise explanation for the
increased risk with cigarette smoking is unknown, cigarette smoke contains over 60 carcinogens and free radicals, which could affect the colorectal mucosa for example, altering the expression of important cancer-related
genes (137). Whether tobacco use is linked predominantly to specific subgroups of colorectal cancer, such as
those with p53 mutations (138) or those categorized by
microsatellite instability (139), requires further study to
identify susceptible individuals. These are just a few reasons added to many other public health implications regarding why people should be recommended not to
smoke cigarettes.
Alcohol
Alcohol has been consistently linked with an increased
risk for colon adenomas, and in the majority of studies
also with CRC, although the magnitude of this relationship is modest (8,27,58,62,91,98,99,109,120,140-143).
This association has been found for both colon and rectal
cancer in a dose-response relationship, starting in moderate drinkers (more than two drinks a day). Regarding
whether or not this is related to beverage-type specific effects (wine, beer, spirits), evidence is not clear (144).
Furthermore, a greater elevation in colorectal cancer or
adenoma risk is also seen among individuals with high
intakes of alcohol and low intakes of folate (91,98100,145-147). This higher risk may be related to the antagonist effect of alcohol on folate metabolism (148).
The mechanisms of alcohol as a colorectal carcinogen
include increased mucosal cell proliferation, activation of
intestinal procarcinogens, changes in bile composition,
and increased nitrosamine levels (144).
CONCLUSION
Although many mechanisms remain unclear, there is
convincing evidence from epidemiological and experimental studies that dietary, environmental, and/or
lifestyle factors are likely to have a major influence on
the risk of colorectal cancer. Data available suggest that
diets high in red meat especially if cooked at high temperatures or in processed meat (smoked, cured, salted
and canned), and perhaps in refined carbohydrates, increase this risk. Regarding fiber, fruits and vegetables,
despite previous data recent epidemiological studies have
tended not to support a strong protective effect of their intake on CRC risk; however, some micronutrients in these
foods could be beneficial and, considering other health
benefits, their consumption should be encouraged. Folic
acid is one of those micronutrients that has been shown to
be a protective factor and is being studied in randomized
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A. FRANCO ET AL.
intervention trials. There is also recent evidence supporting a protective effect of calcium and vitamin D. On the
other hand, excessive alcohol consumption, probably in
combination with a diet low in certain micronutrients
such as folate and methionine, and smoking during a long
period of time appear to increase risk. Physical inactivity
and excess body weight are also consistent risk factors
for colon cancer.
It is also important to recognize that the clear benefits of
screening for colorectal cancer make it the primary method
of prevention nowadays; and that promising chemopreventive pharmacological agents, as some nonsteroidal anti-inflammatory drugs, are also currently being evaluated.
To conclude, overwhelming evidence indicates that
primary prevention is feasible for colon cancer at least to
some extent, and it has been suggested that as many as
70% of colon cancers may be preventable by moderate
changes in diet and lifestyle. Thus, current data are sufficiently strong to justify provisional dietary and lifestyle
recommendations, which in combination with efforts at
screening, chemopreventive treatment and surveillance
will allow progress against this frequent, complex, and
also preventable disease.
Furthermore, a more effective, individualized guidance will be possible in the near future once the relationship between specific genetic patterns and individual predisposition to the effects whether protective or casual
of different environmental factors is assessed.
Obesity increases CRC risk, while physical activity

decreases it. Physical activity and avoidance of overweight and obesity are recommended in order to prevent
CRC.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
KEY POINTS AND RECOMMENDATIONS

Epidemiological evidence indicates that a high proportion of CRC is due to dietary and lifestyle factors.
Red meat intake (and especially processed meat:
smoked, cured, salted and canned) maybe related to the
way it is cooked is associated with an increased risk of
CRC, though mechanisms are unclear.
Although evidence is not clear, a high-fiber diet
may reduce CRC risk and also exert other benefits on the
gastrointestinal system and general health.
Despite a lack of clear evidence, fruits and especially vegetables may be protective against CRC.
Calcium supplements, in the presence of adequate
levels of vitamin D, may help protect against CRC.
An appropriate folate and methionine status seems
to be a protective factor for CRC. Folate supplementation, especially for some groups (heavy alcohol drinkers,
some inflammatory bowel disease patients), could help
protect them against CRC.
With the exception of calcium and folate, there is
little reason to recommend supplementation (e.g., antioxidant vitamins) with the idea of reducing CRC risk.
Smoking increases CRC risk.
Alcohol consumption, especially high intakes, increases the risk of CRC, particularly in the presence of
low folate levels.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer

burden: Globocan 2000. Int J Cancer 2001; 94: 153-6.
Parkin DM, Muir CS, Whelan SL, et al. Cancer incidence in five
continents. IARC Sci Publ 1992; (120): 45-173. Oxford: Oxford
University Press.
Doll R, Peto R. The causes of cancer. J Natl Cancer Inst 1981; 66:
1191-308.
Willett WC. Diet, nutrition and avoidable cancer. Environ Health
Perspect 1995; 103 (Supl. 8): 165-70.
Committee on Diet, Nutrition, and Cancer, Assembly of Life Sciences, National Research Council. Diet, Nutrition, and Cancer.
Washington, D.C.: National Academy Press, 1982.
Walker AR, Burkitt DP. Colonic cancer: hypotheses of causation,
dietary prophylaxis, and future research. Am J Dig Dis 1976; 21:
910-7.
PWynder EL. The epidemiology of large bowel cancer. Cancer Res
1975; 35: 3388-94.
World Cancer Research Fund in association with American Institute
for Cancer Research. Food, Nutrition and the Prevention of Cancer:
A Global Perspective. Washington, DC: eAmerican Institute for
Cancer Research, 1997.
Hawk ET, Umar A. Colorectal cancer chemoprevention: an
overview of the science. Gastroenterology 2004; 126: 1423-47.
Slattery ML. Diet, lifestyle, and colon cancer. Semin Gastrointest
Dis 2000; 11: 142-6.
Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a
review. J Am Diet Assoc 1996; 96: 1027-39.
Corpet DE, Pierre F. Point: from animal models to prevention of
colon cancer. Systematic review of chemoprevention in min mice
and choice of the model system. Cancer Epidemiol Biomarkers Prev
2003; 12: 391-400.
Lamson DW, Brignall MS. Natural agents in the prevention of cancer. Part one: human chemoprevention trials. Altern Med Rev 2001;
6: 7-19.
Lamson DW, Brignall MS. Natural agents in the prevention of cancer, part two: preclinical data and chemoprevention for common
cancers. Altern Med Rev 2001; 6: 167-87.
Boyle P, Zaridze DG, Smans M. Descriptive epidemiology of colorectal cancer. Int J Cancer 1985; 36: 9-18.
Giovannucci E, Stampfer MJ, Colditz G, et al. Relationship of diet
to risk of colorectal adenoma in men. J Natl Cancer Inst 1992; 84:
91-8.
Howe GR, Aronson KJ, Benito E, et al. The relationship between dietary fat intake and risk of colorectal cancer evidence from the combined analysis of 13 case-control studies. Cancer Causes Control
1997; 8: 215-28.
Van Munster IP, Nagengast FM. The role of carbohydrate fermentation in colon cancer prevention. Scand J Gastroenterol Suppl 1993;
200: 80-6.
Stemmermann GN, Nomura AM, Heilbrun LK. Dietary fat and the
risk of colorectal cancer. Cancer Res 1984; 44: 4633-7.
Bostick RM, Potter JD, Kushi LH, et al. Sugar, meat, and fat intake,
and non-dietary risk factors for colon cancer incidence in Iowa
women (United States). Cancer Causes Control 1994; 5: 38-52.
Giovannucci E, Rimm EB, Stampfer MJ, et al. Intake of fat, meat,
and fiber in relation to risk of colon cancer in men. Cancer Res
1994; 54: 2390-7.
Martnez ME, Giovannucci E, Spiegelman D, et al. Leisure-time
physical activity, body size, and colon cancer in women. Nurses
Health Study Research Group. J Natl Cancer Inst 1997; 89 (13):
948-55.
Vol. 97. N. 6, 2005
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.

LIFESTYLE FACTORS
Giovannucci E, Ascherio A, Rimm EB, et al. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med
1995; 122: 327-34.
Slattery ML, Benson J, et al. Trans-fatty acids and colon cancer.
Nutr Cancer 2001; 39 (2): 170-5.
McKelvey W, Greenland S, et al. A case-control study of colorectal
adenomatous polyps and consumption of foods containing partially
hydrogenated oils. Cancer Epidemiol Biomarkers Prev 1999; 8 (6):
519-24.
Willett WC, Stampfer MJ, Colditz GA, et al. Relation of meat, fat,
and fiber intake to the risk of colon cancer in a prospective study
among women. N Engl J Med 1990; 323: 1664-72.
Potter JD. Nutrition and colorectal cancer. Cancer Causes Control
1996; 7: 127-46.
Kushi L, Giovannucci E: Dietary fat and cancer. Am J Med 2002;
113 (9B): 63S-70S.
Chao A, Thun MJ, et al. Meat consumption and risk of colorectal
cancer. JAMA 2005; 293: 172-82.
Le Marchand L. Meat intake, metabolic genes and colorectal cancer.
IARC Sci Publ 2002; 156: 481-5.
Norat T, Lukanova A, et al. Meat consumption and colorectal cancer
risk. Int J Cancer 2002; 98: 241-56.
Benito E, Obrador A, Stiggelbout A, et al. A population based casecontrol study of colorectal cancer in Majorca. I. Dietary factors. Int J
Cancer 1990; 45: 69-76.
Willettt WC. Diet and cancer. JAMA 2005; 293: 233-5.
Cummings JH, Bingham SA. Diet and the prevention of cancer.
BMJ 1998; 317: 1636-40.
RobertsThompson IC, Ryan P, et al. Diet, acetylator phenotype,
and risk of colorectal neoplasia. Lancet 1996; 347: 1372-4.
Cross AJ, Pollock JRA, Bingham SA. Heme, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising
from red meat. Cancer Res 2003; 63: 2358-60.
Sesink AL, Termont DS, et al. Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme. Cancer Res
1999; 59: 5704-9.
Burt RW, Winawer SJ, Bond JH, et al. Preventing Colorectal Cancer: A Clinicians Guide. American Gastroenterological Association, 2004.
Burkitt DP. Epidemiology of cancer of the colon and rectum. Cancer
1971; 28: 3-13.
Castells A, Marzo M, Bellas B, et al. Gua de Prctica Clnica de
Prevencin del Cncer Colorrectal. Gastroenterol Hepatol 2004; 27
(10): 573-634.
Harris PJ, Ferguson LR. Dietary fibre: its composition and role in
protection against colorectal cancer. Mutat Res 1993; 290: 97-110.
Klurfeld DM. Dietary fiber-mediated mechanisms in carcinogenesis.
Cancer Res 1992; 52 (Supl.): 2055s-9s.
Kritchevsky D. Cereal fibres and colorectal cancer: a search for
mechanisms. Eur J Cancer Prev 1998; 7 (Supl. 2): 33-9.
Young-In K, et al. American Gastroenterological Association medical position statement: impact of dietary fiber on colon cancer occurrence. American College of Gastroenterology. Gastroenterology
2000; 118 (6): 1233-4.
Friedenrech CM, Brant RF, Riboli E. Influence of methodologic factors in a pooled analysis of 13 case-control studies of colorectal cancer and dietary fiber. Epidemiology 1994; 5: 66-79.
Fuchs CS, Giovannucci EL, et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 1999; 340 (3):
169-76.
Steinmetz KA, Kushi LH, et al. Vegetables, fruit, and colon cancer
in the Iowa Womens Health Study. Am J Epidemiol 1994; 139: 115.
Riboli E, Norat T. Epidemiologic evidence of the protective effect of
fruit and vegetables on cancer risk. Am J Clin Nutr 2003; 78: 559S69S.
Schatzkin A, Lanza E, et al. Lack of effect of a low-fat, high-fiber
diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 2000; 342: 1149-55.
Asano T, McLeod R. Dietary fibre for the prevention of colorectal
adenomas and carcinomas. The Cochrane Library. Chichester, UK:
John Wiley & Sons Ltd, 2003.
MacLennan R, Macrae F, Bain C, et al. Randomized trial of intake
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
439
of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl

Cancer Inst 1995; 87: 1760-6.
Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study.
Lancet 2003; 361: 1496-501.
Willett WA. Goals for Nutrition in the Year 2000. CA Cancer J Clin
1999; 49: 331-52.
Trock B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon
cancer: Critical review and metaanalyses of the epidemiologic evidence. J Natl Cancer Inst 1990; 82: 650-61.
Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I: Epidemiology. Cancer Causes Control 1991; 2: 325-57.
Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: A review of the epidemiological evidence. Nutr Cancer 1992;
18: 1-29.
Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med
1994; 331: 141-7.
Giovannucci E. Diet, body weight, and colorectal cancer: a summary of the epidemiologic evidence. J Womens Health 2003; 12 (2):
173-82.
The American Cancer Society 1996 Advisory Committee on Diet,
Nutrition, and Cancer Prevention. Guidelines on diet, nutrition, and
cancer prevention: reducing the risk of cancer with healthy food
choices and physical activity. CA Cancer J Clin 1996; 46: 325-41.
Wu K, Willett W, et al. Calcium intake and risk of colon cancer in
women and men. J Nat Cancer Inst 2002; 94: 437-46.
Norat T, Riboli E. Dairy products and colorectal cancer. A review of
possible mechanisms and epidemiological evidence. Eur J Clin Nutr
2003; 57: 1-17.
Bonithon-Kopp C, Kronborg O, et al. Calcium supplementation in
prevention of colorectal adenoma recurrence: a randomised intervention trial. Lancet 2000; 356: 1300-6.
Baron J, Beach M, Mandel J, et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999; 340: 101-7.
Bostick R, Fosdick L, Wood J, et al. Calcium and colorectal epithelial cell proliferation in sporadic adenoma patients: a randomized,
double-blinded, placebo- controlled clinical trial. J Nat Cancer Inst
1995; 87: 1307-15.
Hofstad B, Almendingen K, Vatn M, et al. Growth and recurrence of
colorectal polyps: a double-blind 3-year intervention with calcium
and antioxidants. Digestion 1998; 59: 148-56.
Grau MV, Baron JA, Sandler RS, et al. Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J
Natl Cancer Inst 2003; 95: 1765-71.
Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer
2003; 3 (8): 601-14.
Martnez ME, Willett WC. Calcium, vitamin D, and colorectal cancer: a review of the epidemiologic evidence. Cancer Epidemiol Biomarkers Prev 1998; 7: 163-8.
Garland CF, Garland FC, Gorham ED. Calcium and vitamin D.
Their potential roles in colon and breast cancer prevention. Ann N Y
Acad Sci 1999; 889: 107-19.
McCullough ML, Robertson AS, et al. Calcium, vitamin D, dairy
products, and risk of colorectal cancer in the cancer prevention study
II nutrition cohort (United States). Cancer Causes Control 2003; 14:
1-12.
Chia V, Newcomb PA. Calcium and colorectal cancer: some questions remain. Nutr Rev 2004; 62 (3): 115-20.
Giovannucci E, Rimm EB, Wolk A, et al. Calcium and fructose intake
in relation to risk of prostate cancer. Cancer Res 1998; 58: 442-7.
Bresalier RS. Calcium, chemoprevention, and cancer: a small step
forward (a long way to go). Gastroenterology 1999; 116 (5): 1261-3.
Clark LC. The epidemiology of selenium and cancer. Fed Proc
1985; 44: 2584-9.
Ip C. The chemopreventive role of selenium in carcinogenesis. Adv
Exp Med Biol 1986; 206: 431-47.
Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium
supplementation for cancer prevention in patients with carcinoma of
the skin: a randomized controlled trial: Nutritional Prevention of
Cancer Study Group. JAMA 1996; 276: 1957-63.
440
77.
A. FRANCO ET AL.
Knekt P, Aromaa A, Maatela J, et al. Serum selenium and subsequent risk of cancer among Finnish men and women. J Natl Cancer
Inst 1990; 82: 864-8.
78. Nelson RL, Davis FG, et al. Serum selenium and colonic neoplastic
risk. Dis Colon Rectum 1995; 38: 1306-10.
79. Narayanan BA, Narayanan NK, Desai D, et al. Effects of a combination of docosahexaenoic acid and 1,4-phenylene bis(methylene) selenocyanate on cyclooxygenase 2, inducible nitric oxide synthase
and beta-catenin pathways in colon cancer cells. Carcinogenesis
2004; 25 (12): 2443-9.
80. Nelson RL, Abcarian H, et al. The effect of dietary selenium deficiency on acute colorectal mucosal nucleotoxicity induced by several carcinogens in the rodent. Am J Surg 1996; 172 (1): 85-8.
81. Lund EK, S, Wharf G, et al. Oral ferrous sulfate supplements increase the free radical-generating capacity of feces from healthy volunteers. Am J Clin Nutr 1999; 69: 250-5.
82. Babbs CF. Free radicals and the etiology of colon cancer. Free Radic
Biol Med 1990; 8: 191-200.
83. Weinberg ED. The role of iron in cancer. Eur J Cancer Prev 1996; 5:
19-36.
84. Lund EK, Wharf SG, et al. Increases in the concentrations of available iron in response to dietary iron supplementation are associated
with changes in crypt cell proliferation in rat large intestine. J Nutr
1998; 128: 175-9.
85. Wurzemann JI, Silver A, et al. Iron intake and risk of colon cancer.
Cancer Epidemiol Biomarkers Prev 1996; 5: 503-7.
86. Shaheen NJ, Silverman LM, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst. 2003; 95 (2): 154-9.
87. Kato I, Dnistrian AM, et al. Iron intake, body iron stores and colorectal cancer risk in women: a nested case-control study. Int J Cancer 1999; 80 (5): 693-8.
88. Biasco G, Paganelli GM, et al. Chemoprevention of colorectal cancer: role of antioxidant vitamins. Eur J Cancer Prev 1992; 1 (Supl.
3): 87-91.
89. Malila N, Virtamo J, et al. The effect of alpha-tocopherol and beta
carotene supplementation on colorectal adenomas in middle-aged
male smokers. Cancer Epidemiol Biomarkers Prev 1999; 8: 489-93.
90. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of
longterm supplementation with beta carotene on the incidence of
malignant neoplasms and cardiovascular disease. N Engl J Med
1996; 334: 1145-9.
91. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use,
folate, and colon cancer in women in the Nurses Health Study. Ann
Intern Med 1998; 129: 517-24.
92. Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med
1994; 331: 141-7.
93. Hofstad B, Almendingen K, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998; 59: 148-56.
94. Malila N, Virtanen M, et al. A comparison of prospective and retrospective assessments of diet in a study of colorectal cancer. Nutr
Cancer 1998; 32: 146-53.
95. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of longterm supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;
334: 1145-9.
96. The Alpha-Tocopherol Beta-Carotene CancerbPrevention Study
Group. The effect of vitamin E and beta carotene on the incidence of
lung cancer and other cancers in male smokers. N Engl J Med 1994;
330: 1029-35.
97. Baron JA, Cole BF, et al. Neoplastic and antineoplastic effects of
betacarotene on colorectal adenoma recurrence: results of a randomized trial. J Natl Cancer Inst 2003; 95: 717-22.
98. Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine,
and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst
1993; 85: 875-84.
99. Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J Natl Cancer
Inst 1995; 87: 265-73.
100. Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991; 20: 368-74.
101.
White E, Shannon JS, Patterson RE. Relationship between vitamin

and calcium supplement use and colon cancer. Cancer Epidemiol
Biomarkers Prev 1997; 6: 769-74.
102. Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin
Oncol 1993; 119: 549-54.
103. Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic
acid supplementation on the risk for cancer or dysplasia in ulcerative
colitis. Gastroenterology 1997; 112: 29-32.
104. Choi SW, Mason JB. Folate and carcinogenesis: an integrated
scheme. J Nutr 2000; 130: 129-32.
105. Kim YI, Baik HW, Fawaz K, et al. Effects of folate supplementation
on two provisional molecular markers of colon cancer: a prospective, randomized trial. Am J Gastroenterol 2001; 96: 184-95.
106. Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate
reductase polymorphism, dietary interactions, and risk of colorectal
cancer. Cancer Res 1997; 57: 1098-102.
107. Weindruch R, Walford RL. Dietary restriction in mice beginning at
1 year of age: effect on life-span and spontaneous cancer incidence.
Science 1982; 215: 1415-8.
108. Chute CG, Willett WC, Colditz GA, et al. A prospective study of
body mass, height, and smoking on the risk of colorectal cancer in
women. Cancer Causes Control 1991; 2: 117-24.
109. Wu AH, Paganini-Hill A, Ross RK, et al. Alcohol, physical activity
and other risk factors for colorectal cancer: A prospective study. Br J
Cancer 1987; 55: 687-94.
110. IARC Working Group on the Evaluation of Cancer-Preventive
Agents. Weight control and physical activity. Handbooks of cancer
prevention, vol. 6. Lyon: IARC Press, 2002.
111. Le Marchand L, Wilkins LR, Mi MP. Obesity in youth and middle
age and risk of colorectal cancer in men. Cancer Causes Control
1992; 3: 349-54.
112. Martnez ME, Giovannucci E, Spiegelman, et al. Leisure-time physical activity, body size, and colon cancer in women. Nurses Health
Study Research Group. J Natl Cancer Inst 1997; 89: 948-55.
113. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001; 131: 3109-20S.
114. Terry P, Giovannucci E, Bergkvist L, et al. Body weight and colorectal cancer risk in a cohort of Swedish women: relation varies by
age and cancer site. Br J Cancer 2001; 85: 346-9.
115. Terry P, Miller AB, Rohan TE. Obesity and colorectal cancer risk in
women. Gut 2002; 51: 191-4.
116. La Vecchia C, Brinton LA, McTiernan A. Menopause, hormone replacement therapy and cancer. Maturitas 2001; 39: 87-115.
117. Colditz G, Cannuscio C, Frazier A. Physical activity and reduced
risk of colon cancer: Implications for prevention. Cancer Causes
Control 1997; 8: 649-53.
118. Oliveria SA, Christos PJ. The epidemiology of physical activity and
cancer. Ann N Y Acad Sci 1997; 833: 79-90.
119. Hu FB, Manson JE, Liu S, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J
Natl Cancer Inst 1999; 91: 542-7.
120. Le Marchand L, Wilkens LR, Kolonel LN, et al. Associations of
sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with
the risk of colorectal cancer. Cancer Res 1997; 57: 4787-94.
121. Kono S, Honjo S, Todoroki I, et al. Glucose intolerance and adenomas of the sigmoid colon in Japanese men (Japan). Cancer Causes
Control 1998; 9: 441-6.
122. Nilsen TI, Vatten LJ. Prospective study of colorectal cancer risk
and physical activity, diabetes, blood glucose and BMI: Exploring the hyperinsulinaemia hypothesis. Br J Cancer 2001; 84:
417-22.
123. Schoen RE, Tangen CM, Kuller LH, et al. Increased blood glucose
and insulin, body size, and incident colorectal cancer. J Natl Cancer
Inst 1999; 91: 1147-54.
124. Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth
factor (IGF)-I and IGF binding protein-3. J Natl Cancer Inst 1999;
91: 620-5.
125. Slattery ML, Benson J, Berry TD, et al. Dietary sugar and colon cancer. Cancer Epidemiol Biomarkers Prev 1997; 6: 677-85.
126. Franceschi S, Favero A, La Vecchia C, et al. Food groups and risk of
colorectal cancer in Italy. Int J Cancer 1997; 72: 56-61.
Vol. 97. N. 6, 2005
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.

LIFESTYLE FACTORS
Slattery ML, Boucher KM, Caan BJ, et al. Eating patterns and risk
of colon cancer. Am J Epidemiol 1998; 148: 4-16.
Hardwick JC, Van Den Brink GR, Offerhaus GJ, et al. Leptin is a
growth factor for colonic epithelial cells. Gastroenterology 2001;
121 (1): 79-90.
FitzGerald AJ, Mandir N, Goodlad RA. Leptin, cell proliferation
and crypt fission in the gastrointestinal tract of intravenously fed
rats. Cell Prolif 2005; 38 (1): 25-33.
Stattin P, Lukanova A, Biessy C, et al. Obesity and colon cancer:
does leptin provide a link? Int J Cancer 2004; 109 (1): 149-52.
Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J
Physiol Gastrointest Liver Physiol 2004; 287 (1): G7-17.
Shephard RJ, Shek PN. Associations between physical activity and
susceptibility to cancer: possible mechanisms. Sports Med 1998; 26:
293-315.
Giovannucci E, Colditz GA, Stampfer MJ, et al. A prospective study
of cigarette smoking and risk of colorectal adenoma and colorectal
cancer in U.S. women. J Natl Cancer Inst 1994; 86: 192-9.
Giovannucci E, Rimm EB, Stampfer MJ, et al. A prospective study
of cigarette smoking and risk of colorectal adenoma and colorectal
cancer in U.S. men. J Natl Cancer Inst 1994; 86: 183-91.
Kuper H, Boffetta P, Adami HO. Tobacco use and cancer causation:
association by tumour type. J Intern Med 2002; 252: 206-24.
Giovannucci E, Martnez ME. Tobacco, colorectal cancer, and adenomas: a review of the evidence. J Natl Cancer Inst 1996; 88: 171730.
Giovannucci E. An updated review of the epidemiological evidence
that cigarette smoking increases risk of colorectal cancer. Cancer
Epidemiol Biomarkers Prev 2001; 10 (7): 725-31.
Freedman AN, Michalek AM, Marshall JR, et al. The relationship
between smoking exposure and p53 overexpression in colorectal
cancer. Br J Cancer 1996; 73: 902-8.
Slattery ML, Curtin K, Anderson K, et al. Associations between cig-
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
441
arette smoking, lifestyle factors, and microsatellite instability in

colon tumors. J Natl Cancer Inst (Bethesda) 2000; 92: 1831-6.
Klatsky AL, Armstrong MA, Friedman GD, et al. The relations of
alcoholic beverage use to colon and rectal cancer. Am J Epidemiol
1988; 128: 1007-15.
Hirayama T. Association between alcohol consumption and cancer
of the sigmoid colon: Observations from a Japanese cohort study.
Lancet 1989; 2 (8665): 725-7.
Kune GA, Vitetta L. Alcohol consumption and the etiology of colorectal cancer: A review of the scientific evidence from 1957 to
1991. Nutr Cancer 1992; 18: 97-111.
Longnecker M, Orza M, Adams M, et al. A metaanalysis of alcoholic beverage in relation to risk of colorectal cancer. Cancer Causes
Control 1990; 1: 59-68.
Pedersen A, Johansen C, Gronbaek M. Relations between amount
and type of alcohol and colon and rectal cancer in a Danish population based cohort study. Gut 2003; 52(6): 861-7.
Su LJ, Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Ann Epidemiol 2001; 11: 65-72.
Kato I, Dnistrian AM, Schwartz M, et al. Serum folate, homocysteine and colorectal cancer risk in women: A nested case-control
study. Br J Cancer 1999; 79: 1917-22.
Baron JA, Sandler RS, Haile RW, et al. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl
Cancer Inst 1998; 90: 57-62.
Giovannucci E, Willett WC. Dietary factors and risk of colon cancer. Ann Med 1994; 26: 443-52.
Rader JI. Folic acid fortification, folate status and plasma homocysteine. J Nutr 2002; 132 (8 Supl.): 2466S-70S.
Kritchevsky D. Diet and cancer: what's next? J Nutr 2003; 133 (11
Supl. 1): 3827S-9S.
Weber RV, Stein DE, Scholes J, et al. Obesity potentiates AOM-induced colon cancer. Dig Dis Sci 2000; 45 (5): 890-5.
Cncer de colon: influencia de la dieta y el estilo de vida

A. Franco1,2, A. K. Sikalidis2 y J. A. Sols Herruzo3
Departamento de Nutricin. Universidad de California. Berkeley, EE.UU. 2Servicio de Gastroenterologa. Centro
Mdico de la Universidad de California. San Francisco, EE.UU. 3Servicio de Medicina de Aparato Digestivo. Hospital
12 de Octubre. Madrid
1
INTRODUCCIN
El cncer colorrectal (CCR) es uno de los tumores ms
frecuentes, con ms de 944.000 casos y 492.000 fallecimientos por causas relacionadas estimados en el ao
2000 en todo el mundo (1). Estudios temporales y en poblaciones migratorias sugieren que el CCR depende en
Trabajo realizado con el soporte de una beca de la Universidad Complutense de Madrid y de la Universidad de California.
gran medida de factores ambientales, como queda de manifiesto en las grandes variaciones en las frecuencias de
aparicin observadas entre diferentes pases y por los
acusados incrementos en el nmero de casos entre poblaciones que han emigrado desde reas de baja incidencia a
otras de mayor riesgo (2). Basndose en estos estudios
epidemiolgicos, se ha estimado que hasta un 70-80% del
cncer colorrectal podra ser atribuido a la accin de factores dietticos, ambientales y/o relacionados con el estilo de vida (3,4). Estas afirmaciones sugieren la importancia de causas potencialmente modificables que en gran
medida podran prevenirse.
442
A. FRANCO ET AL.
Por otro lado, aunque los factores ambientales pudieran ser claves en la etiologa de la mayora de los casos,
la susceptibilidad gentica individual juega tambin un
papel decisivo, a travs de su interaccin con el resto de
factores etiolgicos implicados, como ponen de manifiesto los recientes avances en el conocimiento de la relacin
entre los genes, la dieta y el ambiente. Con todo esto, parece evidente la implicacin de factores ambientales en la
etiologa del cncer colorrectal. Si pudiramos identificarlos y modificarlos, podramos prevenir un gran nmero de los casos de cncer de colon. El reto es descubrir estos factores ambientales responsables y corregirlos.
DIETA
La dieta es uno de los factores relacionados con el estilo de vida ms importantes y que ha sido ampliamente estudiado. El primer informe relevante fue una revisin de
los datos disponibles acerca de la relacin entre dieta y
cncer publicado por la Academia Nacional de Ciencia
de EE.UU. en 1982 (5). Este informe conclua que la dieta jugaba un papel importante en la gnesis del cncer e
inclua una serie de recomendaciones, que en aquellos
tiempos se basaban en la reduccin de la ingesta total de
grasas (6,7). Desde comienzos de los aos 80, muchas investigaciones de distinto tipo (experimentos en animales,
estudios epidemiolgicos retrospectivos y prospectivos,
ensayos clnicos) han revisado los efectos potenciales de
la dieta en la aparicin de tumores. En 1997 se public
una revisin muy completa (8) e incluso desde entonces,
se han conocido nuevos resultados relevantes.
Aunque se ha avanzado mucho, el proceso ha sido lento y ms difcil de lo inicialmente previsto. As, ensayos
clnicos con distinto tipo de intervenciones dietticas (por
ejemplo: incrementando el consumo de fibra, fruta y verduras, disminuyendo la ingesta de grasas o administrando
suplementos con una o varias vitaminas o minerales) han
mostrado resultados muy poco concluyentes (9). Sin embargo, varias lneas de investigacin apoyan el papel que
modificaciones en la dieta pudieran tener en la prevencin
de este tipo de tumores. Por ejemplo, un gran nmero de
estudios observacionales sugieren que las verduras, la fruta, una dieta rica en fibra, y ciertos micronutrientes podran proteger de la aparicin del CCR; mientras que el
consumo de alcohol y de carne roja (as como la forma en
la que es cocinada), podran incrementar el riesgo del mismo (9-11). Del mismo modo, varios estudios en animales
han confirmado que algunas intervenciones dietticas podran reducir el riesgo de neoplasia (12-14). Los prximos
apartados describen ms detalladamente estos datos.
Consumo de grasas y carne
Diversos estudios en los aos 70 mostraban una correlacin positiva entre la ingesta de grasa y el riesgo de
CCR (6,7,15), lo que condicion que las recomendaciones dietticas de aquel momento sugirieran reducir el
consumo de grasa. El mecanismo propuesto para explicar
la posible relacin entre una dieta rica en grasas y el cncer de colon se basa en la asociacin entre la ingesta de
grasa y la produccin de sales biliares. Los cidos biliares
primarios o conjugados son producidos por el hgado
para participar en la absorcin de lpidos procedentes de
la dieta en el intestino delgado. Aunque posteriormente
su reabsorcin en el leon terminal es muy eficiente, un
pequeo porcentaje, aproximadamente el 1-2%, no es reabsorbido, accediendo al colon, donde son convertidos
por la microflora intestinal en cidos biliares secundarios,
que presentan propiedades mutagnicas (18).
Sin embargo, estudios recientes (16-21) muestran que
esencialmente no existe asociacin entre la ingesta de
grasa y el riesgo de cncer colorrectal, independientemente del tipo de grasa consumida (total, saturada, monoinsaturada o poliinsaturada), y parece que, al menos en
parte, la elevada frecuencia de cncer de colon en pases
occidentales previamente atribuida al alto consumo de
grasas, probablemente sea secundaria a un estilo de vida
en el que prima el alto consumo energtico y el sedentarismo (22,23). Por otro lado, en lo relativo a la posible
asociacin entre el consumo de cidos grasos trans (presentes en la margarina y en la bollera industrial) y el cncer de colon, aunque hay algunos datos preliminares que
la apoyan (24,25), no son concluyentes.
Solamente un estudio (26) describe un incremento del
riesgo con el consumo de grasa, y este incremento es atribuible a la ingesta de grasa animal, no a la de grasa vegetal. Anlisis posteriores de este ltimo estudio muestran
que el consumo de carne roja, una de las fuentes principales de grasa animal, es el factor asociado con el incremento de riesgo de cncer de colon. Por lo tanto, actualmente se cree que la asociacin entre el consumo de
grasa y el cncer de colon es especfica para grasas de
origen animal y que podra ser debida al consumo de carne roja, ms que al de grasa per se (27,28).
En lo relativo a la ingesta de carne, la mayora de los
estudios muestran un incremento del riesgo con el consumo de grandes cantidades de carne roja, con un riesgo relativo de 1,35 (intervalo de confianza 95%: 1,21-1,51)
(21,26,28,29,31,32), e incluso en ocasiones, an mayor
riesgo con el de carne procesada (20,29-31), especialmente cuando se estudia su consumo a largo plazo. Se
considera carne roja a la de buey, vaca, cerdo y cordero;
y carne procesada a aquella curada, salada, adobada o
ahumada, incluyendo los embutidos, las salchichas, las
hamburguesas y la carne envasada. La idea, previamente
expuesta, de que el consumo de grasa no parece asociarse
a la aparicin de CCR, sugiere que los hallazgos relativos
al consumo de carne pudieran ser explicados por otros
factores no relacionados con su componente graso. Se ha
especulado con que los mtodos de preparacin de la carne a alta temperatura podran favorecer la aparicin de
carcingenos (aminas heterocclicas, hidrocarburos polia-
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ESTILO DE VIDA
romticos) en la superficie de las carnes cocinadas durante largos periodos de tiempo o en contacto directo con el
fuego (28-30,34). Asimismo, tambin se ha sugerido que
dado que existen diferentes variantes enzimticas implicadas en el metabolismo de estas sustancias, los individuos
con fenotipos con mayor predisposicin para transformarlas en molculas ms activas, como los llamados acetiladores rpidos, presentaran un mayor riesgo de desarrollar plipos y cncer en el intestino grueso (35). Adems,
la carne procesada podra tambin favorecer la aparicin
de otros potenciales carcingenos como las nitrosaminas
(30,33,34). Finalmente, tambin se ha propuesto que un
consumo exagerado de hierro, especialmente en la forma
de hierro heme en la que se encuentra en la carne roja, podra asociarse con un mayor riesgo de cncer colorrectal
(29,33). Como posibles mecanismos de accin, el hierro
en forma heme producira efectos citotxicos sobre los
colonocitos (36,37), e incrementara las concentraciones
fecales de sustancias nitrogenadas (36).
Otras fuentes alimentarias de protenas de origen animal distintas a la carne roja, como los derivados lcteos,
el pescado y las carnes magras (pollo, conejo, pavo), o
bien no se han asociado con un mayor riesgo de cncer de
colon, o incluso se han relacionado con una menor frecuencia de aparicin (16,20,21,32).
Como resumen de este apartado, los datos ms recientes orientan a pensar que el consumo de grasa no es un
factor de riesgo destacado para el desarrollo de CCR. Por
otro lado, el consumo de carne roja, y especialmente el de
carne procesada, parece asociarse con un mayor riesgo,
lo que ha llevado a sugerir que su consumo debera moderarse, quizs evitando tambin los mtodos de preparacin a altas temperaturas, en contacto directo con el fuego, as como la carne muy cocinada (por ejemplo a la
parrilla) (8,33,38,40).
Fibra
La hiptesis de que la fibra (presente fundamentalmente en frutas, verduras y cereales) reduce el riesgo de
cncer de colon ha tenido mucha aceptacin desde los
aos 70, cuando Denis Burkitt observ que nativos africanos que consuman una dieta rica en fibra, presentaban
una menor incidencia de CCR (39). Se han propuesto
muchos potenciales mecanismos de accin de la fibra
(41-44), por ejemplo: a travs de la dilucin y unin de
potenciales carcingenos, acelerando as su paso a travs
del colon; disminuyendo la activacin de sustancias potencialmente tumorognicas tras alterar la flora intestinal
y modificar el pH; o incluso sirviendo como sustrato para
la generacin de cidos grasos de cadena corta (especialmente butirato), que protegeran del desarrollo del cncer, ya que actan modulando la expresin gnica, inhibiendo el crecimiento de lneas celulares tumorales,
induciendo fenmenos de apoptosis y promoviendo la diferenciacin celular.
443
Los datos que ms apoyan la hiptesis de la accin

protectora de la fibra provienen de estudios epidemiolgicos en poblaciones con consumos de grandes cantidades de fibra, que consistentemente muestran un efecto
protector (44); as como de la informacin aportada por
un metanlisis de estudios tipo casos y controles que
orienta hacia un efecto protector dependiente de la cantidad de fibra consumida (45). Sin embargo, investigaciones recientes lo han puesto en duda: varios estudios prospectivos, con un gran nmero de pacientes y realizados
en poblaciones especficas, no apoyan la existencia de
este posible efecto protector (21,26,40,46-48). Por otro
lado, aunque no se han realizado ensayos intervencionales aleatorizados estudiando el efecto de dietas ricas en
fibra en la prevencin del CCR, la mayora de los ensayos clnicos aleatorizados diseados para valorar el desarrollo de adenomas de colon con el consumo de este tipo
de dietas, muestran una ausencia de efectividad (49,50) o
tan slo un leve efecto protector (16,51). Sin embargo, un
reciente estudio de cohortes llevado a cabo en diez pases
europeos observa, en cambio, un marcado efecto preventivo de la fibra con una clara relacin dosis-respuesta
(52).
Las causas para esta disparidad de resultados son inciertas (58). Como tambin ocurre en los artculos acerca
del efecto de las frutas y verduras, pudiera ser debido a la
presencia de algn tipo de sesgo en los estudios, ya fuera
en su duracin, en la seleccin de los pacientes, secundario a la implicacin de algn factor de confusin, etc.
Quedan por lo tanto muchas preguntas por resolver acerca de la relacin entre el consumo de fibra y el desarrollo
de CCR: conocer su efecto real, sus mecanismos de accin, as como diferenciar sus efectos de los de otras potenciales sustancias antitumorales presentes en los alimentos ricos en fibra. Y si finalmente presentara efectos
protectores: qu tipo de fibra, de qu origen, cmo administrarla, en qu cantidad, cundo, durante qu periodo de
tiempo y a qu grupo de individuos (p. ej. a aquellos con
una historia previa de adenomas, o bien de forma generalizada). En un futuro cercano, los resultados de diversos
ensayos con otras formas de estudiar la relacin (distintos
tipos de fibra administrados de diversos modos a grupos
de poblacin especficos, o el uso de otras variables para
determinar la eficacia de la intervencin) ayudarn a
comprender mejor el posible efecto protector de la fibra.
Sin embargo, a pesar de la ausencia de evidencia cientfica clara, y aunque algunos autores no consideran que
un consumo elevado de alimentos ricos en fibra (o de suplementos dietticos) pueda reducir el riesgo de cncer
de colon (53), todava existen razones para pensar que
una alimentacin rica en fibra pudiera ser un factor protector. Adems tambin habra que considerar sus efectos
positivos tanto a nivel gastrointestinal (en la prevencin
del estreimiento, de la patologa recto-anal benigna y de
la diverticulosis), como en el mbito cardiovascular. Por
todas estas razones, todava parece razonable recomendar
una ingesta de fibra de al menos 30-35 g/da (8,38,40,44).
444
A. FRANCO ET AL.
Frutas y verduras
El papel de las frutas y verduras en la prevencin del
desarrollo de tumores colorrectales no est completamente definido, especialmente a la luz de los nuevos datos conocidos recientemente. La mayora de los estudios previos de tipo casos y controles, mostraban que un
consumo elevado se asociaba a un menor riesgo de cncer de colon (32,54-56). Sin embargo, estudios prospectivos ms recientes no refieren un efecto protector (21,26).
Tampoco ensayos aleatorizados con administracin de
frutas y verduras (49) o de antioxidantes (incluyendo vitaminas A, C, y E, que se encuentran en cantidades significativas en frutas y verduras) (57), y que usan la aparicin de adenomas colorrectales como elemento de
anlisis, han encontrado un efecto protector.
Las causas para esta disparidad de resultados, como
tambin ocurre en los artculos acerca de la fibra, son inciertas (58). Podra ser debido a la presencia de algn tipo
de sesgo en los estudios, o al hecho de que las frutas y
verduras contienen una gran cantidad de sustancias biolgicamente activas que potencialmente podran reducir la
incidencia de tumores, por ejemplo: cido flico, carotenoides, vitamina C, flavonoides, fitoestrgenos, isotiocianatos, fibra, etc. (55); y actualmente no se conoce cules de ellas seran responsables de esta posible reduccin
del riesgo. La identificacin del componente, o de la
combinacin de componentes, as como el conocimiento
del tipo y la cantidad de frutas y verduras que pudieran
ser particularmente protectoras, ayudara en la realizacin de unas recomendaciones dietticas ms concretas.
Con todo esto, y a pesar de la falta de datos concluyentes, todava se considera que una alimentacin rica en
frutas y verduras (especialmente en verduras) podra ser
beneficiosa en la prevencin del CCR. Si adems se tienen en cuenta sus efectos positivos a otros niveles, se
debe seguir recomendando un consumo abundante de
frutas y verduras (8,38,40,53,58,59).
Micronutrientes
Calcio y vitamina D
Existen numerosos datos epidemiolgicos que sugieren un papel protector del calcio en el desarrollo del cncer colorrectal. Estudios de tipo casos y controles y estudios prospectivos muestran que existe asociacin inversa
entre el consumo de calcio y el riesgo de CCR, aunque la
reduccin sea moderada (en torno al 25%) (60,61). Tambin se han publicado varios ensayos clnicos aleatorizados en los que la administracin de suplementos de calcio
(1.200-2.000 mg/da) se asocia con una menor tasa de recurrencia de adenomas colorrectales, observado adems
el efecto en un corto periodo de tiempo, aunque su magnitud sea tambin leve (62-66). En uno de estos ltimos
ensayos (66), la asociacin slo se encontr en pacientes
con niveles altos de vitamina D, lo que pudiera sugerir

que quizs sean necesarias ambas circunstancias para
conseguir un efecto protector: tanto la administracin de
calcio, como unos niveles adecuados de vitamina D.
Se han propuesto diferentes mecanismos por los cuales
el calcio reducira el riesgo de cncer de colon: desde su
unin a sustancias con capacidad mutagnica, como los
cidos biliares secundarios y algunos cidos grasos, impidiendo as su contacto con el epitelio; hasta su accin directa, a travs de un receptor especfico, sobre la mucosa
del colon, disminuyendo su proliferacin y favoreciendo
su diferenciacin (67-69).
En lo relativo al posible efecto protector de la Vitamina D, estudios tanto in vitro como in vivo muestran, que
la vitamina D y sus anlogos inhiben la proliferacin del
epitelio del colon, inducen su diferenciacin y promueven fenmenos de apoptosis, adems de sus efectos positivos en la absorcin y transporte del calcio (67-69). Adems, un reciente estudio epidemiolgico con un gran
nmero de pacientes refiere una reduccin del 30% en el
riesgo de CCR en varones con los mayores consumos de
vitamina D, ya sea procedente de la dieta o en forma de
suplementos orales (70). De todos modos, estos resultados an son preliminares, y todava no se dispone de ningn estudio prospectivo (40,71).
Como resumen, los estudios ms recientes sugieren un
moderado efecto protector del calcio sobre la aparicin
de CCR, con una reduccin del riesgo de en torno al 2030%. Basndose en estos datos, en sus beneficios sobre la
mineralizacin sea, y en la constatacin de que muchas
personas en los pases occidentales no consumen la cantidad diaria recomendada, algunos autores recomiendan
comenzar a considerar ya la administracin de suplementos de calcio (aproximadamente 1.200 mg/da) (8,38,73),
al menos en individuos con un riesgo elevado de CCR.
Sin embargo, la existencia de algunas observaciones que
podran contraindicar su uso en varones, como la asociacin positiva con el riesgo de cncer de prstata descrita
en un estudio (72), y el hecho de que el efecto protector
parece tambin depender de otros factores como la localizacin del tumor, el sexo del paciente, la fuente de origen
del calcio (diettico o suplementos), as como de factores
relacionados con el estilo de vida como el consumo de tabaco o los niveles de vitamina D, haran ms razonable
esperar al resultado de nuevos estudios que tuvieran en
cuenta todas estas variables para delimitar sus efectos y
posibilidades reales (40,71).
Selenio
Existen datos, procedentes de estudios epidemiolgicos y en animales, que muestran que un consumo insuficiente de selenio se asocia con un riesgo elevado de cncer de colon, as como de otros tipos tumorales (74,75).
Adems, en un ensayo diseado para valorar el uso de suplementos de selenio en la prevencin de tumores de piel
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ESTILO DE VIDA
de tipo no melanoma, los sujetos que tomaban suplementos, presentaban, de forma inesperada, un menor riesgo
de diversos tumores (colon, pulmn, y prstata), aunque
desarrollaban ms frecuentemente, de forma tambin
inesperada, tumores de piel (76). Sin embargo, en estudios de tipo casos y controles, y en estudios de cohortes,
la relacin entre los niveles de selenio (en sangre o a nivel ungueal) y la frecuencia de CCR no ha sido consistente (9,77,78). Posibles mecanismos para estos efectos
beneficiosos del selenio incluyen sus acciones en la reparacin del DNA, como antioxidante y como inductor de
apoptosis (79,80).
Estos resultados positivos necesitan ser confirmados,
pero el efecto protector del selenio en el desarrollo del
cncer colorrectal es una posibilidad a tener en cuenta.
Hierro
Algunos datos han llevado a sugerir que la cantidad
de hierro de la dieta podra incrementar el riesgo de cncer de colon. Se sabe que el hierro en una molcula prooxidante implicada en la produccin de radicales de
oxgeno, que actuaran causando dao en las protenas,
los lpidos y el ADN, lo que podra favorecer la generacin de mutaciones somticas implicadas en el desarrollo de CCR (81-83). Adems, en estudios en animales,
el hierro en la luz intestinal incrementa la proliferacin
mucosa colnica (84). Finalmente, un estudio prospectivo ha mostrado que un consumo elevado de hierro podra asociarse con un incremento del riesgo de cncer
colorrectal (85). Todos estos datos necesitan ser confirmados.
En lo que respecta al efecto de los depsitos totales de
hierro en el organismo, su relacin con el riesgo de CCR
no est bien definida, y los datos son contradictorios
(86,87).
Vitaminas antioxidantes
Se ha sugerido que el posible efecto protector de las
dietas ricas en frutas y verduras en el desarrollo de cncer
colorrectal pudiera deberse a su alto contenido en vitaminas con propiedades antioxidantes, fundamentalmente:
carotenoides (precursores de la vitamina A), retinoides
(vitamina A), cido ascrbico (vitamina C), y -tocoferol
(vitamina E) (54,56). Las molculas antioxidantes prevendran el dao oxidativo al ADN, mediante la inhibicin de la accin de los radicales libres, adems de la posible implicacin de algunas de estas vitaminas (por
ejemplo la vitamina E) en los fenmenos de proliferacin
celular, como parte de los mecanismos de generacin de
seales intracelulares (82). Adems, algunos estudios sugieren tambin que las sustancias antioxidantes podran
inhibir el proceso mutagnico, a travs de la estimulacin
del sistema inmune (88).
445
Sin embargo, diversos estudios prospectivos no apoyan estas hiptesis. La administracin de vitaminas (A,
C, E, o una combinacin de las mismas) ha sido evaluada
en varios estudios con un gran nmero de pacientes (8994). Ninguno de ellos describe un efecto protector ni en
la incidencia de adenomas ni en la de cncer. Adems,
otros ensayos incluso han llegado a mostrar que, sujetos a
los que aleatorizadamente se les administraban beta-carotenos, presentaban una mayor incidencia de ciertos tumores, como por ejemplo, de cncer de pulmn (95,96). Sin
embargo, en un estudio reciente, se ha observado una reduccin de la recurrencia de adenomas con la administracin de beta-carotenos, pero slo en sujetos que no fumaban ni consuman alcohol, mientras que en pacientes
fumadores o que consuman alcohol se apreciaba un incremento del riesgo (97).
Todos estos resultados contradictorios necesitan ser
evaluados con nuevos estudios, pero no parece que actualmente existan datos para recomendar la administracin de vitaminas antioxidantes con el fin de prevenir el
desarrollo de cncer colorrectal (38,40).
cido flico y metionina
El consumo reducido de cido flico y metionina se ha
asociado con un incremento del riesgo de adenomas y de
cncer de colon (98-100). Tambin se ha observado que
la administracin de suplementos multivitamnicos con
cido flico, durante largos periodos de tiempo (ms de
15 aos), se asocia con un menor riesgo de CCR
(91,101), debindose el efecto protector a la administracin de cido flico, no a la de vitaminas (91).
Adems, los niveles de folato son un importante determinante del riesgo de neoplasia en pacientes con colitis
ulcerosa (CU). Se ha descrito una asociacin inversa entre los niveles de folato intraeritrocitario y la aparicin de
displasia colorrectal (102), y tambin un menor riesgo de
aparicin de displasia en pacientes a los que se les administran suplementos de cido flico (103). Es tambin sabido, que los pacientes con enfermedad inflamatoria intestinal pueden presentar niveles reducidos de folato en
sangre, secundariamente al uso de algunas medicaciones
(p. ej.: azatioprina, ciclosporina), lo que tambin podra
incrementar el riesgo.
Los mecanismos que median estos efectos protectores
no se conocen, pero se sabe que tanto el cido flico (que
se encuentra fundamentalmente en frutas y verduras),
como la metionina (presente en concentraciones significativas en la carne roja, el pollo y el pescado), actan
como donantes de grupos metilo, que son necesarios para
la formacin, metilacin, reparacin y traduccin del
ADN (104); as como para la formacin y funcionamiento de protenas; adems de presentar un posible efecto directo reduciendo la proliferacin mucosa (105).
Se conoce tambin la influencia que diversos componentes de la dieta, as como factores genticos, ejercen
446
A. FRANCO ET AL.
modulando los efectos preventivos del cido flico y de

la metionina. Algunos estudios muestran que un consumo
elevado de alcohol, as como algunos polimorfismos genticos en la enzima metilen-tetrahidrofolato reductasa,
podran reducir la disponibilidad de grupos metilo, alterando as los efectos preventivos del folato o de la metionina (58,98,99,106). Adems, parece que el efecto protector del cido flico se consigue fundamentalmente con
la administracin de suplementos (91), ms que con incrementos en el consumo de alimentos ricos en folato,
quizs debido a que se pierde durante la preparacin de la
comida, debido a su naturaleza hidrosoluble, o a su menor biodisponibilidad cuando procede de la dieta (9).
Actualmente se estn estudiando diversos mtodos
para incrementar los niveles de cido flico en la poblacin general, habitualmente disminuidos, incluso en las
poblaciones occidentales. Se ha valorado promocionar el
consumo de frutas y verduras (aunque este cido flico
tiene una menor biodisponibilidad), fortificar especficamente algunos alimentos, o incluso recomendar el consumo generalizado de un suplemento diario. En EE.UU.,
una ley del ao 1998 obliga a fortificar los cereales con
cido flico, con la idea de reducir la incidencia de defectos neurolgicos en recin nacidos, y de reducir el riesgo
de enfermedades cardiovasculares asociadas con la presencia de niveles elevados de homocistena, que se reducen con la administracin de cido flico. Se ha conseguido una reduccin significativa de la incidencia de
defectos neurolgicos, pero es difcil valorar su efecto en
la aparicin de enfermedades cardiovasculares y an es
pronto para valorar su influencia en la aparicin de tumores de colon (149). Tampoco est totalmente definido si
los beneficios de un consumo adicional de cido flico
podran ser mayores en algunos grupos, por ejemplo: en
los consumidores diarios de alcohol, en pacientes bajo
tratamiento con algn frmaco que disminuyera sus niveles, o en aquellos que por cualquier razn pudieran tener
un mayor riesgo tumoral.
Prximamente, con todos estos datos y los que se obtendrn de estudios intervencionales que se estn realizando, las recomendaciones acerca del cido flico y la
metionina como factores protectores del CCR, estarn
ms definidas.
ESTILO DE VIDA
Balance energtico
Se ha sugerido que el disbalance energtico (la desproporcin entre la energa consumida y la utilizada), es uno
de los factores que podran explicar el incremento del nmero de casos de cncer colorrectal que se observa en las
sociedades econmicamente desarrolladas. Diversos modelos animales apoyan esta idea, por ejemplo, estudios en
ratones muestran que la restriccin energtica (calrica)
reduce marcadamente la proliferacin mucosa y el desa-
rrollo de tumores, incluidos los de colon (107), as como

experimentos en ratas en los que el riesgo de aparicin de
neoplasias qumicamente inducidas vara con el tipo de
dieta administrada (incrementndose hasta en un 50%
con una dieta hipercalrica) (150). Sin embargo, estos resultados son difciles de interpretar porque podran ser
debidos a otros factores, como el grado de actividad fsica (factor protector) o la existencia de obesidad (que incrementa el riesgo).
Actualmente, como indicadores del balance energtico
se utilizan la altura y el peso. As, la altura alcanzada despus de la adolescencia representara, de forma indirecta,
la nutricin durante la infancia; mientras que la ganancia
de peso y la obesidad que tuvieran lugar durante la edad
adulta seran debidas a un balance energtico positivo durante esta segunda etapa.
En lo relativo a la altura, se ha descrito que la talla del
adulto, tras controlar el efecto del peso, se asocia con un
mayor riesgo de cncer de colon (20,23,108), quizs reflejando la importancia de la nutricin durante las primeras etapas de la vida, o quizs simplemente debido a su
relacin con la longitud total del intestino grueso.
Obesidad
Un gran nmero de estudios epidemiolgicos sugieren
que la obesidad, definida como una elevacin del ndice
de masa corporal (IMC), es un factor de riesgo para el
cncer de colon (8,20,23,38,108-113), mientras que la
prdida de peso se convierte en un factor protector (40).
Adems, en modelos animales, la obesidad tambin se ha
asociado con un incremento del riesgo de tumores de colon (151). La relacin es ms evidente en el caso de los
tumores de colon y menos en los rectales y parece ser
ms consistente en varones y en mujeres jvenes (menores de 55 aos), pero se atena en mujeres de mayor edad
(114,115). Esta ltima observacin probablemente dependa de factores relacionados con la menopausia, quizs
debido a que la cantidad y procedencia de los estrgenos
vara entre la etapa previa y la posterior a la menopausia,
ya que en algunos estudios, fundamentalmente en mujeres bajo tratamiento hormonal sustitutivo despus de la
menopausia, la administracin de estrgenos parece ser
un factor protector (116). Algunos trabajos sugieren tambin que la tendencia a presentar una distribucin central
de la grasa corporal (adiposidad visceral), tpicamente caracterstica de los varones, incrementa el riesgo de CCR,
independientemente del IMC (23).
Actividad fsica
Diversos estudios, realizados en diferentes poblaciones, muestran que los individuos fsicamente ms activos, especialmente si lo son durante largos periodos de
tiempo, presentan un menor riesgo de cncer de colon,
Vol. 97. N. 6, 2005

ESTILO DE VIDA
con una reduccin de la incidencia de hasta un 50%

(8,22,23,38,109,110,112,113,117,118). Este efecto es independiente de otros factores de riesgo como la dieta y el
peso, y aparece con distintos grados de actividad fsica
(ya sea durante el periodo laboral o en el tiempo libre),
aunque algunos estudios sugieren tambin que un mayor
grado de actividad fsica podra proteger en mayor medida que una actividad menos intensa (110,117,118). Pero
incluso grados de actividad moderados, como por ejemplo, caminar diariamente a un ritmo rpido durante una
hora, o realizar carrera continua a un ritmo moderado 3-4
horas a la semana, que podran ser realizados por la gran
mayora de los individuos de los pases desarrollados, reduciran significativamente el riesgo de cncer de colon
(40,112). Al igual que para el IMC, la relacin entre la
actividad fsica y el menor riesgo tumoral, no es tan evidente para los cnceres rectales (8).
Se han propuesto diversos mecanismos por los cuales
la obesidad incrementara el riesgo de CCR y el ejercicio
fsico lo atenuara. Una de las teoras ms en boga es la
basada en la aparicin de resistencia a la insulina e hiperinsulinemia compensadora, fenmenos que se asocian a
la obesidad, a la ausencia de actividad fsica, y a la diabetes mellitus tipo 2, en ocasiones dentro del llamado sndrome metablico o sndrome X. Diversos estudios han
descrito asociacin entre la diabetes mellitus tipo 2 (119122), los niveles elevados de insulina (123), y un incremento del riesgo de adenomas y cncer de colon. Como
posibles mecanismos, la insulina actuara estimulando el
crecimiento celular de forma directa, as como promoviendo la accin del factor de crecimiento IGF-1, que
presenta acciones tumorognicas (124). Aunque actualmente se considera que la obesidad es el factor ms importante en el desarrollo de este sndrome, el grado de actividad fsica, ciertos componentes de la dieta y factores
genticos tambin participaran en su modulacin. Se han
descrito dos patrones dietticos asociados a la induccin
de estos fenmenos: el consumo frecuente de alimentos
con un ndice glucmico elevado (pan blanco, arroz, patatas, cereales), que refleja una absorcin muy rpida de
los hidratos de carbono; y la ingesta habitual de alimentos ricos en sacarosa (postres, bollera industrial), y en algunos estudios ambos parecen asociarse con un mayor
riesgo de cncer de colon (20,125-127).
Tambin se ha sugerido que la leptina, una hormona
producida por el tejido adiposo, y que se ha relacionado
con el cncer de colon en algunos estudios experimentales, pudiera estar implicada en la patognesis del CCR en
sujetos obesos, quizs favoreciendo la proliferacin de la
mucosa colnica (128-130). Otro posible mecanismo sera la liberacin de citoquinas por parte de los adipocitos,
que estaran implicadas en los fenmenos inflamatorios
asociados con el CCR (131).
En lo que se refiere a la actividad fsica, se ha postulado que disminuira el tiempo de trnsito de los alimentos
a travs del intestino, limitando de este modo el tiempo
de contacto entre la mucosa del colon y sustancias poten-
447
cialmente carcingenas (cidos biliares secundarios, txicos dietticos, etc.). Tambin podra actuar a travs de la
reduccin del ndice de masa corporal, as como disminuyendo el grado de insulinorresistencia (132).
Con todos estos datos, se puede concluir que es recomendable realizar ejercicio fsico y evitar el sobrepeso y
la obesidad como medios para prevenir el CCR (8,38,40).
Tabaquismo
La mayora de los estudios recientes muestran una clara asociacin entre el tabaquismo, los adenomas colorrectales y el CCR (20,120,133-137). En general, la asociacin depende del nmero de cigarrillos consumidos, del
tiempo de exposicin al tabaco, y de la edad en la que se
empez a fumar, apareciendo la relacin con el cncer de
colon tras un largo periodo de tiempo de exposicin continuada (a partir de 35-40 aos). Los motivos por los cuales fumar incrementa el riesgo no se conocen con exactitud, pero el tabaco contiene, o produce durante su
combustin, ms de 60 carcingenos y radicales libres
que podran afectar a la mucosa del colon, por ejemplo,
alterando la expresin de diversos genes relacionados
con la aparicin de tumores (137). Otra posibilidad que
est siendo estudiada actualmente es que el uso de tabaco
produzca un mayor riesgo en algunos subgrupos especficos de pacientes, como aquellos con mutaciones del gen
p53 (138), o aquellos que presentan inestabilidad de microsatlites (139). Estas son tan slo algunas razones que
se aaden al gran nmero de efectos nocivos conocidos
del tabaco por los cuales debera recomendarse no fumar.
Alcohol
El consumo de alcohol se asocia de una forma clara
con un incremento del riesgo de adenomas colorrectales,
y en la mayora de los estudios, tambin de CCR, aunque
en este ltimo caso el grado de asociacin sea moderado
(8,27,58,62,91,98,99,109,120,140-143). La relacin se
ha descrito tanto para tumores del colon como para tumores rectales, y es funcin de la cantidad de alcohol consumida, apareciendo a partir de consumos moderados (ms
de dos bebidas al da). En lo referente a si el riesgo se
asocia con el tipo de bebida alcohlica consumido (vino,
cerveza, productos de alta graduacin), los datos no son
concluyentes (144). Se ha observado tambin, una elevacin marcada del riesgo de adenomas y cnceres colorrectales en individuos que consumen grandes cantidades
de alcohol, y que a la vez presentan un dficit de cido
flico (91,98-100,145-147). Este mayor riesgo podra ser
debido a la accin antagnica del alcohol en el metabolismo del cido flico (148).
Los mecanismos por los cuales el alcohol actuara
como carcingeno en el colon incluyen: el incremento de
la proliferacin mucosa, la activacin de sustancias pro-
448
A. FRANCO ET AL.
carcingenas en el intestino, cambios en la composicin

de la bilis y elevacin de la concentracin de nitrosaminas (144).
CONCLUSIN
Aunque muchos mecanismos an se desconocen, existen datos convincentes, procedentes de estudios epidemiolgicos y experimentales, de que factores dietticos,
ambientales y/o relacionados con el estilo de vida ejercen
una gran influencia en el desarrollo de tumores de colon.
Los datos sugieren que dietas ricas en carne roja, especialmente si es cocinada a altas temperaturas, o con grandes cantidades de carne procesada (curada, ahumada,
salada o en conserva), y quizs con un exceso de azcares
refinados, incrementan el riesgo. En lo referido a la fibra,
la fruta y las verduras, a pesar de lo sugerido por estudios
previos, las investigaciones ms recientes no han encontrado un efecto protector claro y marcado con su ingesta;
de todos modos, quizs algunos de los micronutrientes
que componen estos alimentos pudiera proteger del desarrollo del CCR, y considerando sus muchos efectos beneficiosos a otros niveles, su consumo debe recomendarse.
El cido flico es uno de los micronutrientes que ha mostrado efectos protectores y est siendo estudiado en ensayos clnicos aleatorizados. Tambin existen datos que
apoyan el efecto protector del calcio y la vitamina D. Por
otro lado, el consumo excesivo de alcohol, especialmente
cuando se asocia a una dieta pobre en determinados micronutrientes, como el cido flico y la metionina; y la
exposicin al tabaco de forma continuada durante un largo periodo de tiempo, incrementan el riesgo. La ausencia
de actividad fsica y el exceso de peso son tambin factores de riesgo para la aparicin de cncer de colon.
Es tambin necesario recalcar que los beneficios derivados de los mtodos de diagnstico precoz (screening)
lo convierten actualmente en el principal mtodo de prevencin; y que adems tambin se est estudiando la utilizacin de frmacos con accin preventiva, como por
ejemplo diversos antiinflamatorios no esteroideos, con
resultados prometedores.
Como conclusin, los estudios sugieren que la prevencin primaria del cncer de colon, al menos en cierto grado, es posible, estimndose que hasta el 70% de los casos
podran evitarse con cambios moderados en la dieta y en
el estilo de vida. Por lo tanto, los datos disponibles actualmente justificaran la realizacin de recomendaciones
provisionales en cuanto a la dieta y al estilo de vida, que
en combinacin con mtodos de diagnstico precoz, tratamiento preventivo y seguimiento, podran conseguir
grandes resultados contra esta frecuente y compleja enfermedad, pero en gran modo tambin prevenible.
Adems, en un futuro cercano ser posible realizar recomendaciones individualizadas, y por lo tanto ms efectivas, a medida que se vaya conociendo mejor la relacin
entre la presencia de patrones genticos concretos y una
mayor o menor predisposicin a la accin, sea causal o
protectora, de los diversos factores ambientales implicados.
PUNTOS CLAVE Y RECOMENDACIONES

Los datos epidemiolgicos sugieren que un gran
porcentaje de los casos de CCR son debidos a factores
dietticos y/o relacionados con el estilo de vida.
El consumo de carne roja (y especialmente de carnes procesadas: curadas, ahumadas, saladas o en conserva), quizs dependiendo del modo de cocinarla, se asocia
con un incremento del riego de CCR, aunque los mecanismos no son conocidos.
Aunque los datos no son concluyentes, una dieta
rica en fibra podra reducir el riesgo de CCR, adems de
sus otros efectos beneficiosos tanto a nivel gastrointestinal como en el resto del organismo.
Aunque los datos tampoco son concluyentes, una
dieta rica en fruta, y especialmente en verduras, podra
proteger del desarrollo de CCR.
Los suplementos de calcio, en presencia de unos niveles adecuados de vitamina D, podran ayudar en la prevencin del CCR.
La presencia de unos niveles adecuados de cido flico y metionina podra proteger del desarrollo de CCR.
Los suplementos de cido flico, especialmente en algunos grupos (consumos elevados de alcohol, algunos pacientes con enfermedad inflamatoria intestinal) podran
ayudar en este objetivo.
Con excepcin de los suplementos de calcio y cido
flico, no existen datos suficientes para recomendar la
administracin de otros suplementos (p. ej.: vitaminas
antioxidantes) con la idea de reducir la aparicin de CCR.
Fumar incrementa el riesgo de padecer CCR.
El consumo de alcohol, especialmente en grandes
cantidades, y particularmente en combinacin con niveles disminuidos de cido flico, incrementa el riesgo de
CCR.
La obesidad incrementa el riesgo de CCR, mientras
que la actividad fsica lo reduce. Es recomendable practicar ejercicio fsico, as como evitar el exceso de peso,
para prevenir el desarrollo de CCR.
All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

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1130-0108/2005/97/6/432-448

REVISTA ESPAOLA DE ENFERMEDADES DIGESTIVAS

REV ESP ENFERM DIG (Madrid)

Colorectal cancer: influence of diet and lifestyle factors

Franco A, Sikalidis AK, Sols Herruzo JA. Colorectal cancer:

portant and plays a decisive role through its interaction

Vol. 97. N. 6, 2005

COLORECTAL CANCER: INFLUENCE OF DIET AND

gest that vegetables, fruits, a high-fiber diet, and certain

REV ESP ENFERM DIG 2005; 97(6): 432-448

suggests that the findings related to meat intake could be

REV ESP ENFERM DIG (Madrid)

(including vitamins A, C, and E, commonly found in

REV ESP ENFERM DIG 2005; 97(6): 432-448

Vol. 97. N. 6, 2005

COLORECTAL CANCER: INFLUENCE OF DIET AND

way, these are still preliminary results, and there are no

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On the other hand, the effect of total body iron is not

some drugs (e.g. azathioprine), which may enhance the

REV ESP ENFERM DIG (Madrid)

tions. Several animal models support this hypothesis for

Many studies conducted in diverse populations show

REV ESP ENFERM DIG 2005; 97(6): 432-448

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COLORECTAL CANCER: INFLUENCE OF DIET AND

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relation with colorectal cancer appears after a sufficiently

Obesity increases CRC risk, while physical activity

KEY POINTS AND RECOMMENDATIONS

REV ESP ENFERM DIG (Madrid)

Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer

REV ESP ENFERM DIG 2005; 97(6): 432-448

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COLORECTAL CANCER: INFLUENCE OF DIET AND

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of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl

REV ESP ENFERM DIG (Madrid)

White E, Shannon JS, Patterson RE. Relationship between vitamin

REV ESP ENFERM DIG 2005; 97(6): 432-448

Vol. 97. N. 6, 2005

COLORECTAL CANCER: INFLUENCE OF DIET AND

arette smoking, lifestyle factors, and microsatellite instability in

Cncer de colon: influencia de la dieta y el estilo de vida

REV ESP ENFERM DIG 2005; 97(6): 432-448

REV ESP ENFERM DIG (Madrid)

REV ESP ENFERM DIG 2005; 97(6): 432-448

Vol. 97. N. 6, 2005

CNCER DE COLON: INFLUENCIA DE LA DIETA Y EL

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Los datos que ms apoyan la hiptesis de la accin

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con niveles altos de vitamina D, lo que pudiera sugerir

REV ESP ENFERM DIG 2005; 97(6): 432-448

Vol. 97. N. 6, 2005

CNCER DE COLON: INFLUENCIA DE LA DIETA Y EL

REV ESP ENFERM DIG 2005; 97(6): 432-448

modulando los efectos preventivos del cido flico y de

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rrollo de tumores, incluidos los de colon (107), as como

REV ESP ENFERM DIG 2005; 97(6): 432-448

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CNCER DE COLON: INFLUENCIA DE LA DIETA Y EL

con una reduccin de la incidencia de hasta un 50%