Diet, nutrition and the prevention of cancer
Timothy J Key1,*, Arthur Schatzkin2, Walter C Willett3, Naomi E Allen1,
Elizabeth A Spencer1and Ruth C Travis1
1Cancer Research UK Epidemiology Unit, University of Oxford, Oxford, UK:2Nutritional Epidemiology Branch,
Division of Cancer, Epidemiology and Genetics, National Cancer Institute, Bethesda, USA:3Departments of
Epidemiology and Nutrition, Harvard School of Public Health, Boston, USA
Objective: To assess the epidemiological evidence on diet and cancer and make
public health recommendations.
Design: Review of published studies, concentrating on recent systematic reviews,
meta-analyses and large prospective studies.
Conclusions and recommendations: Overweight/obesity increases the risk for
cancers of the oesophagus (adenocarcinoma), colorectum, breast (postmenopausal),
endometrium and kidney; body weight should be maintained in the body mass index
range of 18.5-25kg/m2, and weight gain in adulthood avoided. Alcohol causes
cancers of the oral cavity, pharynx, oesophagus and liver, and a small increase in the
risk for breast cancer; if consumed, alcohol intake should not exceed 2units/d.
Aflatoxin in foods causes liver cancer, although its importance in the absence of
hepatitis virus infections is not clear; exposure to aflatoxin in foods should be
minimised. Chinese-style salted fish increases the risk for nasopharyngeal cancer,
particularly if eaten during childhood, and should be eaten only in moderation. Fruits
and vegetables probably reduce the risk for cancers of the oral cavity, oesophagus,
stomach and colorectum, and diets should include at least 400g/d of total fruits and
vegetables. Preserved meat and red meat probably increase the risk for colorectal
cancer; if eaten, consumption of these foods should be moderate. Salt preserved
foods and high salt intake probably increase the risk for stomach cancer; overall
consumption of salt preserved foods and salt should be moderate. Very hot drinks and
foods probably increase the risk for cancers of the oral cavity, pharynx and
oesophagus; drinks and foods should not be consumed when they are scalding hot.
Physical activity, the main determinant of energy expenditure, reduces the risk for
colorectal cancer and probably reduces the risk for breast cancer; regular physical
activity should be taken.
Dietary factors have been thought to account for about
30% of cancers in Western countries1, making diet second
only to tobacco as a preventable cause of cancer. The
contribution of diet to cancer risk in developing countries
has been considered to be lower, perhaps around 20%2.
Unravelling the effects of diet on cancer risk is, therefore,
of great public health importance, but research to date has
uncovered few definite effects and left frustratingly large
areas of uncertainty.
In this paper, we summarise our view of the current
state of knowledge on diet and cancer. This paper is not a
systematic review of diet and cancer. Other organisations
have recently published detailed reviews of this subject, in
particular the World Cancer Research Fund/American
Institute for Cancer Research3, and the Department of
Health in the UK4. These publications provide good
reviews of research published up until the mid 1990s; we
have, therefore, based our review on the material
summarised in these reports and on more recent studies,
giving particular credence to the results of large
prospective studies and to the few results from
randomised controlled trials. We start by briefly discussing
the types of evidence available for formulating and testing
International comparisons, migrants and time
Many of the prominent hypotheses for effects of diet on
cancer risk have been derived from examination of the
associations between dietary patterns and cancer rates in
different populations around the world. It was noted in the
1970s that developed Western countries have diets high in
animal products, fat and sugar, and high rates of cancers
of the colorectum, breast and prostate. In contrast,
q The Authors 2004*Corresponding author: Email email@example.com
Public Health Nutrition: 7(1A), 187–200
developing countries typically have diets based on one or
two starchy staple foods, low intakes of animal products,
fat and sugar, low rates of these ‘Western’ cancers, and
sometimes high rates of other types of cancer such as
cancers of the oesophagus, stomach and liver5. Other
studies have shown that cancer rates often change in
populations which migrate from one country to another,
and change over time within countries. For example, the
formerly low rates of colorectal cancer among Japanese
people have increased both on migration to the USA and,
more recently, with the increasing Westernisation of the
diet in Japan6. As discussed below, some of the main
hypotheses that were derived from these ecological
observations have not been supported by the results of
detailed studies of the diets of individuals. However, the
international variations in diet and cancer rates continue to
suggest that diet is an important risk factor for many
common cancers, and therefore that cancer may be partly
preventable by dietary changes.
Figure 1 shows estimated incidence rates for the most
common cancers world-wide in 20007. Lung cancer is the
most common cancer in the world, and the most common
cancer among men in both developed and developing
countries, whereas breast cancer is the most common
cancer among women. The archetypal Western cancers
are those of the colorectum, breast and prostate.
Westernisation encompasses many changes in diet and
lifestyle, including increased consumption of meat, dairy
products, sugar and other refined carbohydrates, and
reduced intake of relatively unrefined starchy staple foods.
In terms of nutrients, Western diets are characterised by
adequate or excessive energy intake, together with high
intakes of protein and fat, whereas micronutrient
deficiency (i.e. deficiency of vitamins or trace minerals)
is much more common in developing countries. Thus, the
search for the nutritional causes of the typical Western
cancers has focussed mainly on excess consumption of
macronutrients, whereas the search for the nutritional
causes of the typical cancers of developing countries has
focussed on deficient intake of micronutrients.
During the last 30 years, hundreds of studies have been
published that have examined the association between the
diets of individuals and their risk for developing cancer.
Most of the earlier studies used a case-control design, in
which people who already have cancer are asked what
they used to eat before they were diagnosed with cancer,
and their diets are compared with those reported by
people without cancer (controls). These case-control
studies are useful for searching for possible dietary effects,
but cannot be relied on to establish moderate dietary
associations because they are susceptible to both recall
and selection biases: people with cancer may recall their
diet differently from healthy people, and healthy controls
are rarely fully representative of the base population and
mayreport a relatively ‘healthy’ diet8,9. Theimpact of these
biases varies between studies, especially in relation to the
participation rate among eligible controls, but in general
relative risks in case-control studies of up to at least 1.3
may reflect bias rather than a true association.
In prospective studies, dietary intakes are measured at
recruitment and people are followed-up for cancer
incidence, then the cancer incidence rates are compared
between groups with different diets at baseline. This
design eliminates the recall and selection biases to which
case-control studies are susceptible, but other factors such
as measurement error and confounding must be
considered when interpreting the results of prospective
studies (as well as case-control studies) of diet and cancer.
Another limitation of most prospective studies is that the
baseline dietary intake is measured at one point during
adult life, which may not be the most relevant period in
relation to the development of cancer over many years.
Interpretation of observational studies
Large prospective studies can establish whether or not
there is any association between reported diet and cancer
risk within the population studied. The main factors that
need to be considered when interpreting results from such
studies are measurement error and confounding.
Fig. 1 Age-adjusted incidence rates of common cancers among
men and women in developed and developing countries
TJ Key et al. 188
Epidemiological studies generally use a relatively short
and simple dietary questionnaire. The validity of such
questionnaires has been extensively investigated, and
while it is clear that current assessment methods are
moderately precise and can detect some associations of
diet with disease risk, it is also possible that the
measurement error is sometimes large enough to obscure
some potentiallyimportant associations of diet with cancer
risk. A further problem is that there are often strong
correlations between different foods and nutrients,
making it hard to attribute associations with risk to
particular dietary factors, especially when the precision of
the measurements is variable.
Body mass index (the weight in kilograms divided by
the square of the height in metres: kg/m2) and alcohol
present special cases. Body mass index is not diet per se,
but is determined by the balance of energy intake and
energy expenditure; body mass index therefore serves as
an indicator of chronic energy balance, and can be
measured much more accurately and precisely in
epidemiological studies than either energy intake or
energy expenditure. Alcohol is not always included under
the term diet, but alcoholic drinks do contribute a
significant supply of energy and some nutrients in many
populations. Although estimates of alcohol intake
commonly suffer from underreporting, they generally
rank individuals much more precisely than estimates of
intakes of other foods and nutrients.
Observed associations of dietary factors with cancer risk
can be confounded by other risk factors for cancer, such as
smoking and physical activity, which are associated with
dietary habits. In theory, confounding can be allowed for
by statistical adjustments, but in practice this adjustment is
never perfect because the non-dietary risk factors
themselves are measured with some error. The possibility
that apparent dietary associations with cancer risk are
confounded by other risk factors, therefore, needs to be
examined very carefully. Allowing for confounding is
smoking causes a very large increase in risk and is known
to be associated with diet. The relationship between diet
and other cancers needs to take into account potential
confounding factors, such as Helicobacter pylori for
stomach cancer, physical activity for colorectal cancer,
and humanpapillomavirusfor cervicalcancer (seebelow).
Randomised controlled trials
Randomised controlled trials eliminate both the biases and
the confounding which can affect observational studies
and the results can, therefore, be confidently interpreted in
terms of cause and effect. Within the field of diet and
cancer, however, trials are limited by the difficulty of
randomising at the level of foods, and by the constraints
that only a small number of nutritional factors can be
tested in eachtrial, usually for a short period. The results of
the few large trials that have been completed are
important, but where trials do not show an effect it
remains possible that an effect would have been seen at a
different dose, at a different time in life, or if the duration
of the trial had been longer. Another point which should
be considered when interpreting the results from
randomised controlled trials is the possibility that the
effect of a dietary component on cancer risk may differ
according to the characteristics of the population studied;
for example, the effects of a multinutrient supplement
could be more marked in a population with a low dietary
intake of micronutrients than in a population with a high
dietary intake of micronutrients.
Within the field of diet and cancer, randomised
controlled trials are most suitable for testing hypotheses
for protective effects of specific micronutrients. An
extensive review of these hypotheses and of the design
and interpretation of such trials is given in the first IARC
Handbook of Cancer Prevention10.
Review of the role of diet in the aetiology of the
Cancers of the oral cavity, pharynx and
Cancers of the oral cavity, pharynx and oesophagus were
estimated to account for 867,000 cases and 582,000 deaths
in 200011. Incidence rates of these cancers vary widely
between populations; for example, oesophageal cancer is
over a hundred times more common in parts of Central
Asia, China and Southern Africa than in most parts of
Europe, North America and West Africa7. In developed
countries, the main risk factors are alcohol and tobacco,
and up to 75% of these cancers are attributable to these
two lifestyle factors6. The mechanism of the effect of
alcohol on these cancers is not known, but may involve
direct effects on the epithelium12. Overweight/obesity is
an established risk factor specifically for adenocarcinoma
(but not squamous cell carcinoma) of the oesophagus13–
15. In developing countries, around 60% of cancers of the
oral cavity, pharynx and oesophagus are thought to be
due to micronutrient deficiencies related to a restricted
diet that is low in fruits and vegetables and animal
products3,16; it should be noted, however, that the
evidence for a protective effect of fruits and vegetables is
largely derived from case-control studies and there are few
data yet from prospective studies17. The relative roles of
various micronutrients are not yet clear, but deficiencies of
riboflavin, folate, vitamin C and zinc may all be
important3,16. There is also consistent evidence that
consuming drinks and foods at a very high temperature
increases the risk for these cancers18. The results of trials
in Linxian, China, aimed at reducing oesophageal cancer
Diet, nutrition and cancer189
rates with micronutrient supplements, have been prom-
ising but not definitive19,20.
This is particularly common in Southeast Asia7, and has
been consistently associated with a high intake of Chinese-
style salted fish, especially during early childhood21,22, as
well as with infection with the Epstein–Barr virus23.
Chinese-style salted fish is a special product which is
usually softened by partial decomposition before or
during salting; other types of salted fish have been studied
and not found to be convincingly associated with the risk
for developing nasopharyngeal cancer22.
Stomach cancer was estimated to account for 876,000
cases and 647,000 deaths in 200011. Until about 20 years
ago stomach cancer was the most common cancer in the
world, but mortality rates have been falling in all Western
countries24and stomach cancer is now much more
common in Asia than in Europe or North America7.
Infection with the bacterium H. pylori is an established
risk factor, but not a sufficient cause, for the develop-
ment of stomach cancer25. Diet is also thought to be
important in the aetiology of this disease, and dietary
changes are implicated in the recent decline in stomach
cancer incidence and mortality rates in many countries.
Substantial evidence, mainly from case-control studies,
suggests that risk is increased by high intakes of some
traditionally preserved salted foods, especially meats and
pickles, and with salt per se, and that risk is decreased by
high intakes of fruits and vegetables26, perhaps due to
their vitamin C content. However, evidence from
prospective studies does not clearly support a protective
effect for fruits and vegetables27,28. The introduction of
refrigeration has also been associated with decreased
risk, probably through reducing intakes of salted foods
and facilitating year-round fruit and vegetable availability3.
The results of micronutrient supplementation trials in
developing countries have been encouraging but not
definitive. In Linxian, China, combined supplementation
with b-carotene, selenium and a-tocopherol resulted in a
significant reduction in stomach cancer mortality, but no
significant benefit was obtained from vitamin C19. A recent
trial in Colombia showed increased regression of
precancerous gastric dysplasia both in subjects given
b-carotene and in subjects given vitamin C29.
Further prospective data are needed, in particular to
examine whether some of the dietary associations may be
partly confounded by H. pylori infection and whether
dietary factors may modify the association of H. pylori
Colorectal cancer is the third most common cancer in the
world7and was estimated to account for 945,000 cases and
10-fold higher in developed than in developing countries7.
It has been suggested that diet-related factors may account
The best established dietary-related risk factor is over-
in risk3. Adult height, which is partly determined by the
adequacy of nutrition in childhood and adolescence, is
has been consistently associated with a reduced risk15,31.
These factors together, however, do not explain the large
variation between populations, and there is almost
universal agreement that some aspects of a Western diet
are a major determinant of risk.
International correlation studies show a strong association
between per capita consumption of meat and colorectal
cancer mortality5, and several mechanisms have been
proposed through which meat may increase cancer risk.
Mutagenic heterocyclic amines and polycyclic aromatic
hydrocarbons can be formed during the cooking of meat
at high temperatures32,33, and nitrites and their related
compounds found in smoked, salted and some processed
meat products may be converted to carcinogenic N-nitroso
compounds in the colon34. In addition, high iron levels in
the colon may increase the formation of mutagenic free
radicals35. The results of observational studies of meat and
colorectal cancer have varied3; a recent systematic review
concluded that preserved meat is associated with an
increased risk for colorectal cancer but that fresh meat is
not36and most studies have not observed positive
associations with poultry or fish3. However, mortality
rates for colorectal cancer are similar in Western
vegetarians and comparable non-vegetarians37. Overall,
the evidence is not conclusive but suggests that high
consumption of preserved and red meat probably
increases the risk for colorectal cancer.
As with meat, international correlation studies show a
strong association between per capita consumption of fat
and colorectal cancer mortality5. Possible mechanisms
proposed to explain such an association are that a high fat
intake may increase the levels of cytotoxic free fatty acids
or secondary bile acids in the lumen of the large intestine.
However, the results of observational studies of fat and
colorectal cancer have, overall, not been supportive of an
association with fat intake, especially after adjusting for
total energy intake3,38.
Fruits, vegetables and fibre
Burkitt39suggested that the low rates of colorectal cancer
in Africa were due to the high consumption of dietary
fibre, and there are several plausible mechanisms for a
protective effect. Fibre increases stool bulk and speeds the
TJ Key et al. 190
transit of food through the colon, thus diluting the gut
contents and perhaps reducing the absorption of
carcinogens by the colonic mucosa40. Fermentation of
fibre (and resistant starch) in the large intestine produces
short chain fatty acids such as butyrate, which may protect
against colorectal cancer through the ability to promote
differentiation, induce apoptosis and/or inhibit the
production of secondary bile acids by reducing luminal
pH41,42. Many case-control studies of colorectal cancer
have observed moderately lower risk in association with
high consumption of dietary fibre, and/or fruits and
vegetables43,44, but the results of recent large prospective
studies have been inconsistent45–47. Furthermore, results
from randomised controlled trials have not shown that
intervention over a 3–4 year period with supplemental
fibre or a diet low in fat and high in fibre and fruits and
vegetables can reduce the recurrence of colorectal
adenomas48–50. It is possible that some of the incon-
sistencies are due to differences between studies in the
types of fibre eaten and in the methods for classifying fibre
in food tables. Other possibilities are that the association
with fruits and vegetables is principally due to an increase
in risk at very low levels of consumption51, or that high
intakes of refined flour or sugar (rather than low intakes of
fibre) increase risk through chronic hyperinsulinaemia or
other mechanisms52,53. At present, the hypothesis that
fruits, vegetables and fibre may reduce the risk for
colorectal cancer has not been firmly established.
Some recent prospective studies have suggested that a
methyl-deplete diet (i.e. a diet low in folate and
methionine and high in alcohol) is associated with an
increased risk of colon cancer54,55. Also, use of folic acid-
containing multiple vitamin supplements has been
associated with lower risk of colon cancer56. A diminished
folate status may contribute to carcinogenesis by alteration
of gene expression and increased DNA damage57,58and
chromosome breakage59. The finding that a common
polymorphism in the methylenetetrahydrofolate reductase
gene involved in folic acid metabolism may also be
associated with colorectal cancer60strengthens the
hypothesis that dietary folate may be an important factor
in colorectal carcinogenesis.
Another promising hypothesis is that relatively high
intakes of calcium may reduce the risk for colorectal
cancer, perhaps by forming complexes with secondary
bile acids in the intestinal lumen3or by inhibiting the
hyperproliferative effects of dietary haem61. Several
observational studies have supported this hypothesis3,4,
and two trials have suggested that supplemental calcium
may have a modest protective effect on the recurrence of
colorectal adenomas50,62. More data are needed to
evaluate this hypothesis.
Cancer of the liver
Liver cancer was estimated to account for 564,000 cases
and 549,000 deaths in 200011. Approximately 75% of cases
of liver cancer occur in developing countries, and liver
cancer rates vary over 20-fold between countries, being
much higher in sub-Saharan Africa and Southeast Asia
than in Europe and North America7. The major risk factor
for hepatocellular carcinoma, the main type of liver
cancer, is chronic infection with hepatitis B, and to a lesser
extent,hepatitis C virus63. Ingestion of foodscontaminated
with the mycotoxin aflatoxin22,64is an important risk factor
among people in developing countries with active
hepatitis virus infection. Excessive alcohol consumption
is the main diet-related risk factor for liver cancer in
Western countries, probably via the development of
cirrhosis and alcoholic hepatitis6. Little is known about
possible nutritional cofactors for viral carcinogenesis, but
this may be an important area for research3.
Cancer of the pancreas
Cancer of the pancreas was estimated to account for
216,000 cases and 214,000 deaths in 2000 and is more
common in Western countries than in developing
countries7,11. Time trends suggest that both incidence
and mortality for cancer of the pancreas are increasing in
most parts of the world, although some of this apparent
increase may be due to improvements in diagnostic
methods6. Overweight/obesity possibly increases the
risk3,65. Some studies have suggested that risk is increased
by high intakes of meat, and reduced by high intakes of
vegetables, but these data are not consistent and come
mostly from case-control studies3. Over the next few years
there will be substantially more prospective data on diet
and cancer of the pancreas, and it is possible that more
clear-cut associations with dietary factors will emerge.
Lung cancer is the most common cancer in the world7and
was estimated toaccount for 1,239,000cases and 1,103,000
deaths in 200011. Heavy smoking increases the risk by
around 30-fold, and smoking causes over 80% of lung
cancers in Western countries6. The possibility that diet
might also have an effect on lung cancer risk was raised in
the 1970s following the observation that, after allowing for
smoking, increased lung cancer risk was associated with a
low dietary intake of vitamin A66. Since then, numerous
observational studies have found that lung cancer patients
generally report a lower intake of fruits, vegetables and
related nutrients (such as b-carotene) than controls3,4. The
only one of these factors to have been tested in controlled
trials, namely b-carotene, has however, failed to produce
any benefit when given as a supplement for up to 12
The possible effect of diet on lung cancer risk remains
controversial. Several recent observational studies have
continued to observe an association of fruits and
Diet, nutrition and cancer191
vegetables with reduced risk, but this association has been
weak in prospective studies70,71. This apparent relation-
ship may be partly due to residual confounding by
smoking, since smokers generally consume less fruits and
vegetables than non-smokers, but there may also be some
protective effect of these foods. In public health terms,
however, the overriding priority is to reduce the
prevalence of smoking.
Breast cancer is the second most common cancer in the
world and the most common cancer among women.
Breast cancer was estimated to account for 1,105,000 cases
and 373,000 deaths in women in 200011. Incidence rates
are about five times higher in Western countries than in
less developed countries and Japan7. Much of this
international variation is due to differences in established
reproductive risk factors such as age at menarche, parity
and age at births, and breastfeeding72,73, but differences in
dietary habits and physical activity may also contribute. In
fact, age at menarche is partly determined by dietary
factors, in that restricted dietary intake during childhood
and adolescence leads to delayed menarche. Adult height,
also, is weakly positively associated with risk, and is partly
determined by dietary factors during childhood and
adolescence72. Oestradiol and perhaps other hormones
play a key role in the aetiology of breast cancer72, and it is
possible that any further dietary effects on risk are
mediated by hormonal mechanisms.
Obesity increases breast cancer risk in postmenopausal
women by around 50%, probably by increasing serum
concentrations of free oestradiol72. Obesity does not
increase risk among premenopausal women (perhaps
because it frequently leads to anovular menstrual cycles),
but obesity in premenopausal women is likely to lead to
obesity throughout life and therefore to an eventual
increase in breast cancer risk.
The only other established dietary risk factor for breast
cancer is alcohol. There is now a large amount of data
from well-designed studies which consistently shows a
small increase in risk with increasing consumption, with
about a 7% increase in risk for an average of one alcoholic
drink every day74. The mechanism for this association is
not known, but may involve increases in oestrogen
levels75; alternatively, some recent studies suggest that the
adverse effect of alcohol may be exacerbated by a low
Much research and controversy has surrounded the
hypothesis that a high fat intake increases breast cancer
risk. The best data currently available, however, do not
support this hypothesis77, and only limited data are
available to evaluate whether dietary fat alters circulating
Other dietary factors
The results of studies of other dietary factors including
meat, dairy products, fruits and vegetables, fibre and
phyto-oestrogens are inconsistent3,4,80,81.
Cancer of the endometrium
Endometrial cancer was estimated to account for 189,000
cases and 45,000 deaths in women in 2000, with the
highest incidence rates occurring in Western countries7,11.
Endometrial cancer risk is about 3-fold higher in obese
women than lean women15,82. As with breast cancer, the
effect of obesity in postmenopausal women on the risk for
endometrial cancer is probably mediated by the increase
in serum concentrations of oestradiol and the reduction in
serum concentrations of sex hormone-binding globulin; in
premenopausal women, the mechanism probably
involves the increase in anovulation and consequent
increased exposure to oestradiol unopposed by pro-
gesterone83. Some case-control studies have suggested
that diets high in fruits and vegetables may reduce risk and
that diets high in saturated or total fat may increase risk,
but the data are limited3.
Cancer of the cervix
Cancer of the cervix was estimated to account for 471,000
cases and 233,00 deaths in women in 200011. The highest
rates are in sub-Saharan Africa, Central and South America,
and south-east Asia7. The major cause of cervical cancer is
infection with certain subtypes of the human papilloma-
virus84. Fruits, vegetables and related nutrients such as
carotenoids and folate tend to be inversely related with
risk3,4, but these associations may be largely due to
confounding by papillomavirus infections, smoking and
other factors. Further research is needed, particularly on
the possible role of folate deficiency3,4.
Cancer of the ovary
Cancer of the ovary was estimated to account for 192,000
cases and 114,000 deaths in women in 200011, with the
highest incidence rates occurring in Western countries7.
Risk is reduced by high parity and by long-term use of
combined oral contraceptives85. Some studies have
suggested that risk is increased by high intakes of fat or
dairy products, and reduced by high intakes of vegetables,
but the data are not consistent and more prospective data
are required to examine these possible associations3.
Prostate cancer was estimated to account for 543,000
cases and 204,000 deaths in 200011. Prostate cancer
incidence rates are strongly affected by diagnostic
practices and, therefore, difficult to interpret, but mortality
TJ Key et al.192
rates show that death from prostate cancer is about ten
times more common in North America and Europe than in
Little is known about the aetiology of prostate cancer,
although ecological studies suggest that it is positively
associated with a Western-style diet5. The data from
prospective studies have not established causal or
protective associations for specific nutrients or dietary
factors3,4. Diets high in red meat, dairy products and
animal fat have frequently been implicated in the
development of prostate cancer, although the data are
not entirely consistent3,86–88. Randomised controlled trials
have provided substantial, consistent evidence that
supplements of b-carotene do not alter the risk for
prostate cancer67,68,89but have suggested that vitamin E89
and selenium90might have a protective effect. Lycopene,
primarily from tomatoes, has been associated with a
reduced risk in some observational studies, but the data
are not consistent91.
Hormones control the growth of the prostate, and
interventions that lower androgen levels are moderately
effective in treating this disease. Prospective studies which
have examined the possible associations between serum
hormone concentrations and prostate cancer risk have
suggested that risk may be increased by high levels of
bioavailable androgens92,93and of insulin-like growth
factor-I (IGF-I)94,95, although there are not sufficient data
to consider either of these associations as established. Diet
might affect prostate cancer risk by affecting hormone
levels, and recent data suggest that animal protein may
increase levels of IGF-I96,97.
Cancer of the urinary bladder was estimated to account
for 336,000 cases and 132,000 deaths in 200011. The
geographic variation in incidence is about 10-fold, with
relatively high rates in Western countries7. Smoking
increases the risk for bladder cancer6. Studies suggest
that high intakes of fruits and vegetables may reduce risk,
but this is not established and more prospective data are
Cancer of the kidney was estimated to account for 189,000
cases and 91,000 deaths in 200011. The range of
geographic variation in incidence is moderate, with the
highest incidence in Scandinavia and among the Inuit6.
Overweight/obesity is an established risk factor for cancer
of the kidney, and may account for up to 30% of kidney
cancers in both men and women100. There are only limited
data on the possible role of diet in the aetiology of kidney
cancer, but some studies have observed an increase in risk
with high intakes of meat and dairy products and a
reduced risk with high intakes of vegetables3.
Conclusions on the effects of diet on cancer risk
Strengths and weaknesses of the evidence
Attaining definitive evidence to confirm or refute effects of
specific dietary factors on risks of human cancers is
challenging and for many relationships may be imposs-
ible9. Ideally, each potential relationship would be tested
in multiple randomised trials to achieve a clear conclusion.
However, this is not feasible for many reasons, including
the large number of dietary constituents that could be
tested and the many different human cancers. In addition,
uncertainty about the time in life and number of years
before diagnosis that a specific aspect of diet may act
hinders the design and interpretation of randomised trials.
Practical problems with compliance in long-term studies
and the need for many thousands of subjects create further
obstacles. Finally, many dietary factors may not act in
isolation and it may be their interaction with other dietary,
lifestyle and/or genetic factors that may alter cell growth
and affect cancer risk. For these and other reasons,
randomised trials have contributed only modestly to
present knowledge about diet and cancer, and this is likely
to continue to be true for many years to come.
The primary alternative to randomised trials is observa-
tional studies of human cancers or their precursors,
interpreted in the light of other evidence including
metabolic studies, animal experiments and mechanistic
populations and among migrants have been of prime
importance in documenting the major role of environ-
mental factors in the aetiology of nearly all major human
cancers. However, from the beginning, epidemiologists
have recognised that firm conclusions about specific
aetiological factors cannot be based on comparisons of
by the multitude of lifestyle and other environmental
factors that vary geographically. Case-control and pro-
spective cohort studies within countries can provide better
control of potential confounding variables, because these
factors usually vary less within a geographic region and
they can be measured and controlled for in statistical
analyses. Until the last few years, case-control studies
provided the large majority of data on diet and cancer.
Concerns have existed that methodological biases, related
to both the selection of study participants and the recall of
diet after the diagnosis of cancer, could in some
circumstances seriously distort the results of case-control
studies. Now that a number of prospective studies are
providing data on diet and cancer incidence, these
concerns about the potential for bias in case-control
often been observed, even within the same study
population8,9. At the time of the 1997 WCRF/AICR review3
it was recognised that associations between dietary fat and
risk of breast cancer seen in case-control studies had not
been confirmed in prospective studies with substantial
Diet, nutrition and cancer 193
statistical power. Similar differences in results have now
been observed for fat intake in relation to incidence of
colon and lung cancers. A major conclusion of the 1997
review was that a greater intake of fruits and vegetables
would substantially reduce risks of a broad range of
cancers and decrease total cancer incidence by approxi-
mately 20%. However, most of the evidence was derived
from case-control studies and, again, prospective studies
have often found no or only weak support for the earlier
findings. In particular, prospective studies have not
supported earlier suggestions for strong inverse associ-
ations between overall intakes of fruits and vegetables and
risks of lung and colon cancer, and little relation has been
observed with breast cancer. Because rates of oral and
oesophageal cancer are low in affluent populations, these
Thus, conclusions regarding protective effects of fruits and
vegetables for these cancer sites should be viewed with
some caution until confirmed in prospective studies.
Although prospective cohort studies will often provide
the best available evidence regarding diet and cancer
relationships, like any study they also have potential
limitations that should be considered in the interpretation
of findings. As in almost all dietary studies, only a part of
the range of possible human intakes can be investigated.
Thus, conclusions need to be limited to the range of diets
investigated, in part because dose–response relationships
may be non-linear. As with randomised trials, conclusions
about findings need to be limited to the period in life or
interval between dietary assessment and cancer diagnosis
that was studied. Adequate precision in measurement of
dietary intakes is necessary to detect true associations; the
extensive literature on validity of dietary questionnaires,
and the ability of current dietary assessment methods to
predict cardiovascular disease incidence, strongly suggest
that major associations between dietary factors and cancer
risk can be detected. In addition, prospective studies offer
the opportunity for repeated measurements of dietary
intake, which can reduce the error in measurement of
long-term diet. However, because dietary assessments are
inevitably imperfect and the size of study populations is
finite, modest but still potentially important associations
are usually impossible to exclude entirely. For some
specific dietary factors, biochemical measurements can
improve assessments of intake, but for many aspects of
diet such measurements do not exist or enhance precision.
A fundamental challenge in nutritional epidemiology is
that foods are complex combinations of thousands of
chemical constituents, thus isolation of the active factors
can be difficult or impossible. For this reason, conclusions
will be most reliable for foods or food groups, although
data on supplement use can assist in evaluating
hypotheses related to specific nutrients. Because dietary
behaviours are often associated with other aspects of
lifestyle that could affect cancer risk, studies also need to
be evaluated for the degree to which confounding by such
variables has been addressed.
Because all forms of studies have constraints, in most
situations no single form of evidence will provide
definitive conclusions regarding diet and cancer relation-
ships. Thus, the best conclusions will be based on careful
and critical evaluation of all forms of evidence.
Summary of the evidence for dietary factors and
Dietary components that we believe to be convincingly or
probably related to the incidence of specific cancers are
summarised in Table 1, together with other dietary factors
Table 1 Diet, nutrition and cancer: levels of evidence
Level of evidenceDecrease riskIncrease risk
Convincing Physical activity (colon) Overweight and obesity (oesophagus, colorectum,
breast in postmenopausal women, endometrium,
Alcohol (oral cavity, pharynx, larynx,
oesophagus, liver, breast)
Chinese-style salted fish (nasopharynx)
Probable Fruits and vegetables (oral cavity,
oesophagus, stomach, colorectum*)
Physical activity (breast)
Preserved meat and red meat
Salt preserved foods and salt
Very hot (thermally) drinks and
food (oral cavity, pharynx, oesophagus)
Insufficient Fibre, soya, fish, n-3 fatty acids, carotenoids, vitamins
B2, B6, folate, B12, C, D, E, calcium,
zinc, selenium, non-nutrient plant constituents
(e.g. allium compounds, flavonoids, isoflavones,
Animal fats, heterocyclic amines, polycyclic
aromatic hydrocarbons, nitrosamines
*A protective effect of fruit and vegetable intake has been suggested by many case-control studies but has not been supported in several large prospective
studies, suggesting that if a benefit does exist it is likely to be modest.
TJ Key et al. 194
which were considered to be possibly related to cancer
risk but for which the evidence was considered
insufficient. Physical activity is also listed in Table 1
because it is related to energy balance and overweight/-
obesity; a full discussion of the effects of physical activity
on cancer risk is outside the scope of this paper, therefore,
we have based our evaluation on the conclusions in the
IARC Handbook on Weight Control and Physical
Dietary factors which convincingly increase risk
The nutritional factor for which the evidence was
impact on overall cancer rates is most important in
populations with Western cancer incidence patterns, is
overweight/obesity. Overweight/obesity is convincingly
related to risks for cancers of the oesophagus (adenocarci-
noma), colorectum, breast (postmenopausal), endome-
trium and kidney. Importantly, excess risk of these cancers
increases continuously with greater adiposity and is not
limited to clinical obesity (BMI over 30kg/m2). The large
increases in endogenous estrogen levels caused by excess
the higher risks of postmenopausal breast and endometrial
it has been suggested that hyperinsulinaemia may increase
the risk for colon cancer52,102. The WHO/IARC working
group on weight control and physical activity estimated
that in countries with high rates of cancers related to
overweight, excess body weight (BMI over 25kg/m2)
accounts for approximately 39% of endometrial, 25% of
kidney, 11% of colon, 9% of postmenopausal breast cancer
and 5% of total cancer incidence82,101. Although these
percentages will be lower in populations in some
developing countries where virally related cancers are
more important, the rapid increase in overweight/obesity
in developing countries means that cancers due to
overweight/obesity will become increasingly important
We recognise that overweight/obesity, a reflection of
excessive energy intake, can result from both over-
consumption of energy from food and low expenditure of
energyas physical activity; the relative importance of these
two factors can vary among individuals and populations.
Considerable attention has been given to the possibility
that the composition of the diet influences the probability
of body fat accumulation and thus, indirectly, risk of
cancer. Although the percentage of energy from dietary fat
has been hypothesised to be an important determinant of
body fat and the topic has been controversial, an
important effect of dietary fat has not been supported in
randomised trials lasting 1 year or more, and populations
consuming low fat/high carbohydrate diets can clearly
develop high rates of obesity103. Other dietary factors that
may potentially influence the accumulation of body fat
include high consumption of refined carbohydrate, highly
energy-dense food (i.e. high energy content relative to
volume or weight of food), and low fibre intake. However,
evidence based on long-term studies for these effects of
dietary composition is inadequate at present. Thus, at this
time the appropriate emphasis for weight control appears
to be limitation of excessive energy intake from any source
and the adoption of adequate daily physical activity.
Another aspect of diet clearly related to cancer incidence is
consumption of alcoholic beverages, which convincingly
increases the risk of cancers of the oral cavity, pharynx,
larynx, oesophagus, liver and breast (and probably
colorectum). The increase in risk appears to be primarily
due to alcohol per se rather than specific alcoholic
beverages. Whereas most of the excess risks occurs with
high alcohol consumption, a small (about 7%) increase in
risk of breast cancer has been observed with approxi-
mately one drink per day. Recent studies suggest that the
excess risk of breast and colon cancer associated with
alcoholconsumption maybe concentrated in persons with
low folate intake.
Food contaminated with aflatoxin convincingly increases
the risk of liver cancer. However, this contamination
occurs mainly in areas where hepatitis viruses are a major
cause of liver cancer, and the importance of aflatoxin in
the absence of hepatitis virus infections (for example, after
immunisation) is not clear.
Chinese-style salted fish
High intake of Chinese-style salted fish, predominantly
consumed in some Asian populations, convincingly
increases the risk of nasopharyngeal cancer.
Dietary factors which probably reduce risk
Fruits and vegetables
Overall, a high intake of fruits and vegetables probably
reduces the risks of cancers of the oral cavity, oesophagus,
stomach and colorectum. Previous reviews of diet and
cancer, including the 1997 WCRF/AICR review, have given
greater emphasis to increasing fruit and vegetable
consumption for cancer prevention, and have included
cancers of the larynx, lung, pancreas, breast and bladder.
At that time, however, the available literature was based
largely on case-control studies, and subsequent prospec-
tive studies have not supported important protective
effects for cancers of the lung and breast, and have
suggested that the reduction in risk for colorectal cancer
may be modest. These discordant results, which add to
concerns about the potential for bias in case-control
studies, also suggest the need for some caution regarding
Diet, nutrition and cancer195
conclusions about intake of fruits and vegetables and the
risks of oral, oesophageal and stomach cancers, which
have not been adequately examined in large prospective
studies. Furthermore, none of the dietary studies of
stomach cancer has controlled adequately for infection by
H. pylori, which is a potential confounding variable.
Although support for a broad and strong protective
effect of higher fruit and vegetable intake against cancer
incidence has weakened with the results from recent
studies, modest benefits of increasing fruit and vegetable
intake have not been excluded and probably do exist. The
issue of dose–response is important, and some evidence
suggests that a very low intake of fruits and vegetables,
e.g. less than 2 servings or 200g/d, is related toincreases in
risk compared with higher intakes, but that there may be
little additional benefit for intakes higher than about
400g/d51,81. Also, fruits and vegetables are extremely
heterogeneous, and it is possible that only specific foods
are related to risk for specific cancers. As examples, some
studies have suggested that intake of tomato products,
high in lycopene104, is inversely related to risk of prostate
cancer and that cruciferous vegetable intake is inversely
associated with bladder cancer incidence99. In these same
studies, overall fruit and vegetable consumption was not
associated with cancer risk. Should this be considered as
general support for a protective effect of fruits and
vegetables, or only for more specific relationships?
Another complexity can arise when a micronutrient in
the form of a supplement is shown to be related to cancer
risk. This might be construed as evidence that fruits and
vegetables containing this factor are protective against
cancer. However, this does not necessarily follow because
bioavailability of micronutrients in fruits and vegetables
might be low or antagonistic factors might be present.
Folate may provide such an example as there is now
considerable evidence that higher intake, mainly due to
use of multiple vitamins, may be related to lower risks of
colorectal and breast cancers. Also, in this situation, use of
supplements and fortified foods could mask a beneficial
effect of fruits and vegetables if folate were an important
protective component of these foods.
Preserved meat and red meat
In many studies, high intakes of preserved meat or red
meat have been associated with increased risk of
colorectal cancer, whereas the total fat content of the
diet does not appear to be related to risk. The components
of preserved and red meat that might increase colorectal
cancer risk are not established; heterocyclic amines
created by cooking, haeme iron, and specific fatty acids
have been proposed as explanations.
Salt preserved foods and salt
High intakes of salt-preserved foods and of salt probably
increases the risk of stomach cancer. Convincing evidence
would require confirmation in prospective studies and
evidence that this relationship was not confounded by H.
pylori infection. Notably, stomach cancer rates in the US
are now very low even though salt intake is not.
Very hot drinks and foods
Consumption of very hot drinks and foods typically
consumed in some cultures probably increases risk of
cancers of the oral cavity, pharynx and oesophagus.
Cancers not included in table
For cancers of the pancreas, lung, cervix and ovary, we did
not consider these to be convincing or probable evidence
of a dietary relationship. In earlier reviews, evidence had
been considered stronger for a protective effect of fruit
and vegetable consumption against lung cancer risk.
However, more recent prospective studies have found
weaker associations, and residual confounding by
cigarette smoking remains a concern. Although a weak
relation with fruit and vegetable intake is possible,
avoidance of smoking is the only effective way to
substantially reduce lung cancer rates.
Diets very high in starch and low in overall
micronutrient intake, consumed by poor populations in
many countries, have been associated with increased risks
of oral and oesophageal cancers. Isolation of the specific
micronutrients responsible has been elusive, but an
overall improvement of these poverty-related diets is
clearly warranted for health in general.
Conclusions on dietary factors and cancer
Since the 1981 Doll and Peto review on diet and cancer
mortality1, about one third of cancers have generally been
thought to be related to dietary factors. More recent
evidence suggests that this number may be too high, but a
revised quantitative estimate is beyond the scope of this
convincingly increases the risks of several common
cancers. After tobacco, overweight/obesity appears to be
the most important avoidable cause of cancer in
populations with Western patterns of cancer incidence.
Among non-smoking individuals in these populations,
avoidance of overweight is the most important strategy for
Public health policy with respect to nutrition and cancer
should be based on the best available scientific research.
In the previous section, we concluded that few dietary
effects on cancer risk have been established. Avoiding
overweight/obesity, limiting alcohol intake and increasing
physical activity will reduce cancer risk, as will limiting
consumption of Chinese-style salted fish and minimising
dietary exposure to aflatoxin in populations where these
dietary factors are important. Risk will probably be
decreased by increasing the average intake of fruits and
TJ Key et al.196
vegetables, and by limiting intake of preserved and red
meat, salt preserved foods and salt, and very hot drinks
and food. Public health policy should, therefore, be
focussed on these factors (Table 2). If other dietary factors
are established to affect cancer risk then these can be
added to existing policy frameworks, but at present the
other potentially important dietary factors are not
sufficiently well supported by evidence, and including
them in policy would risk confusing priorities and
diverting attention from the really important issues.
An earlier version of this paper was prepared as a
background paper for the Joint WHO/FAO Expert
Consultation on diet, nutrition and the porevention of
chronic diseases (Geneva, 28 January–1 February 2002).
The authors wish to thank Professor Tony McMichael,
National Centre for Epidemiology and Population Health,
Australia National University, Canberra, Australia, Dr Larry
N.Kolonel, Cancer Research Center of Hawaii, University
of Hawaii, Honolulu, USA, Dr Shaw Watanabe, Depart-
ment of Nutrition and Epidemiology, Tokyo University of
Agriculture, Tokyo, Japan, and Dr Shoichiro Tsugane,
Epidemiology & Biostatistics Division, National Cancer
Center Research Institute, Kashiwa-City, Japan, for their
thoughtful and constructive comments on the earlier
manuscript. The authors are particularly thankful to Dr
Elio Riboli, International Agency for Research on Cancer
(IARC), Lyon, France, for his valuable help and
contributions during the drafting of the manuscript.
1Doll R, Peto R. The causes of cancer: quantitative estimates
of avoidable risks of cancer in the United States today.
Journal of the National Cancer Institute 1981; 66:
Miller AB. Diet in cancer prevention. http://www.who.int/
World Cancer Research Fund. Food, Nutrition, and the
Prevention of Cancer: A Global Perspective. Washington,
DC: American Institute for Cancer Research, 1997.
COMA. Nutritional Aspects of the Development of Cancer
(Report of the Working Group on Diet and Cancer of the
Committee on Medical Aspects of Food and Nutrition
Policy). London: The Stationery Office, 1998.
Armstrong B, Doll R. Environmental factors and cancer
incidence and mortality in different countries, with special
reference to dietary practices. International Journal of
Cancer 1975; 15: 617–31.
International Agency for Research on Cancer. Cancer:
Causes, Occurrence and Control. IARC Scientific Publi-
cations No. 100. Lyon: IARC, 1990.
FerIay J, Bray P, Pisani P, Parkin DM. Globocan 2000:
Cancer incidence, mortality and prevalence worldwide,
Version 1.0. IARC CancerBase No. 5. http://www-dep.iarc.
fr/globocan/globocan.html (accessed Nov 3, 2001).
Giovannucci E, Stampfer MJ, Colditz GA, et al. A
comparison of prospective and retrospective assessments
of diet in the study of breast cancer. American Journal of
Epidemiology 1993; 137: 502–11.
Willett WC. Nutritional Epidemiology. New York: Oxford
University Press, 1998.
International Agency for Research on Cancer. Principles of
Chemoprevention. IARC Scientific Publications No. 139.
Lyon: IARC, 1996.
Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world
cancer burden: Globocan 2000. International Journal of
Cancer 2001; 94: 153–6.
International Agency for Research on Cancer. IARC
Monographs on the Evaluation of Carcinogenic Risks to
Humans, vol. 44. Alcohol drinking. Lyon: IARC, 1988.
Brown LM, Swanson CA, Gridley G, et al. Adenocarcinoma
of the esophagus: role of obesity and diet. Journal of the
National Cancer Institute 1995; 87: 104–9.
Cheng KK, Sharp L, McKinney PA, et al. A case-control
study of oesophageal adenocarcinoma in women: a
preventable disease. British Journal of Cancer 2000; 83:
International Agency for Research on Cancer. Overweight
and lack of exercise linked to increased cancer risk. IARC
Handbooks of Cancer Prevention. vol. 6. Geneva: World
Health Organisation, 2002.
World Health Organisation: International Agency for
Research on Cancer. Cancer: Causes, Occurrence and
Control. Lyon: IARC, 1990.
Steinmetz KA, Potter JD. Vegetables, fruit, and cancer
prevention: a review. Journal of the American Dietetic
Association 1996; 96: 1027–39.
Sharp L, Chilvers CE, Cheng KK, et al. Risk factors for
squamous cell carcinoma of the oesophagus in women: a
case-control study. British Journal of Cancer 2001; 85:
Table 2 Diet, nutrition and cancer: recommendations
1. Maintain BMI in range of
18.5–25kg/m2, and avoid weight gain
Engage in regular physical activity
Consumption of alcoholic beverages is
not recommended: if consumed, do
not exceed 2units/d (1unit is equivalent to approximately
10g of alcohol and is
provided by one glass of
beer, wine or spirits)
Minimise exposure to aflatoxin in
Chinese-style salted fish should only
be eaten in moderation, especially
during childhood. Overall consumption of
salt-preserved foods and salt should
Have a diet which includes
at least 400g/d of total fruit and
Meat: those who are not
vegetarian are advised to moderate
consumption of preserved meat (e.g.
sausages, salami, bacon, ham etc.)
and red meat (e.g. beef,
pork, lamb). Poultry and fish
(except Chinese-style salted fish, see
5. above) have been studied
and found not to be
associated with increased cancer risk
Do not consume foods or
drinks when they are at
a very hot (scalding hot)
Diet, nutrition and cancer 197
19 Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials
in Linxian, China: supplementation with specific vitamin/
mineral combinations, cancer incidence, and disease-
specific mortality in the general population. Journal of
the National Cancer Institute 1993; 85: 1483–92.
Li JY, Taylor PR, Li B, et al. Nutrition intervention trials in
Linxian, China: multiple vitamin/mineral supplementation,
cancer incidence, and disease-specific mortality among
adults with esophageal dysplasia. Journal of the National
Cancer Institute 1993; 85: 1492–8.
Yu MC. Nasopharyngeal carcinoma: epidemiology and
dietary factors. In: O’Neill IK, Chen J, Bartsch H, eds.
Relevance to Human Cancer of N-nitroso Compounds,
Tobacco Smoke and Mycotoxins. IARC Scientific Publi-
cations No. 105. Lyon: 1ARC, 1991, 39–47.
International Agency for Research on Cancer. IARC
Monographs on the Evaluation of Carcinogenic Risks to
Humans, vol 56. Some Naturally Occurring Substances:
Food Items and Constituents, Heterocyclic Aromatic
Amines and Mycotoxins. Lyon: IARC, 1993.
Doll R, Peto R. Epidemiology of cancer. In: Weatherall DJ,
Ledingham JGG, Warrell DA, eds. Oxford Textbook of
Medicine. Oxford: Oxford University Press, 1996, 197–221.
World Health Organisation. World Health Statistics Annual.
http://www.who.int/whosis/ (accessed Nov 10, 2001).
Helicobacter and Cancer Collaborative Group. Gastric
cancer and Helicobacter pylori: a combined analysis of 12
case control studies nested within prospective cohorts. Gut
2001; 49: 347–53.
Palli D. Epidemiology of gastric cancer: an evaluation of
available evidence. Journal of Gastroenterology 2000;
35(Suppl. 12): 84–9.
McCullough ML, Robertson AS, Jacobs EJ, Chao A, Calle EE,
Thun MJ. A prospective study of diet and stomach cancer
mortality in United States men and women. Cancer
Epidemiology Biomarkers & Prevention 2001; 10: 1201–5.
Botterweck AA, van den Brandt PA, Goldbohm RA. A
prospective cohort study on vegetable and fruit consump-
tion and stomach cancer risk in The Netherlands. American
Journal of Epidemiology 1998; 148: 842–53.
Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of
gastric dysplasia: randomized trial of antioxidant sup-
plements and anti-Helicobacter pylori therapy. Journal of
the National Cancer Institute 2000; 92: 1881–8.
Cummings JH, Bingham SA. Diet and the prevention of
cancer. British Medical Journal 1998; 317: 1636–40.
Hardman AE. Physical activity and cancer risk. Proceeding
of the Nutrition Society 2001; 60: 107–13.
Gooderham NJ, Murray S, Lynch AM, et al. Assessing
human risk to heterocyclic amines. Mutation Research
1997; 376: 53–60.
Kazerouni N, Sinha R, Hsu CH, Greenberg A, Rothman N.
Analysis of 200 food items for benzo[a]pyrene and
estimation of its intake in an epidemiologic study. Food
Chemistry and Toxicology 2001; 39: 423–36.
Bingham SA, Pignatelli B, Pollock JR, et al. Does increased
endogenous formation of N-nitroso compounds in the
human colon explain the association between red meat and
colon cancer? Carcinogenesis 1996; 17: 515–23.
Lund EK, Wharf SG, Fairweather-Tait SJ, Johnson IT.
Oral ferrous sulfate supplements increase the free
radical-generating capacity of feces from healthy volun-
teers. American Journal of Clinical Nutrition 1999; 69:
Norat T, Lukanova A, Ferrari P, Riboli E. Meat consumption
and colorectal cancer risk: a dose–response meta-analysis
of epidemiological studies. International Journal of
Cancer 2002; 98: 241–56.
Key TJ, Fraser GE, Thorogood M, et al. Mortality in
vegetarians and non-vegetarians: a collaborative analysis of
8300 deaths among 76,000 men and women in five
prospective studies. Public Health Nutrition 1998; 1:
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.
Burkitt DP. Related disease—related cause? Lancet 1969; 2:
La Vecchia C. Diet and human cancer: a review. European
Journal of Cancer Prevention 2001; 10: 177–81.
Hague A, Elder DJ, Hicks DJ, Paraskeva C. Apoptosis in
colorectal tumour cells: induction by the short chain fatty
acids butyrate, propionate and acetate and by the bile salt
deoxycholate. International Journal of Cancer 1995; 60:
Nagengast FM, Grubben MJ, van Munster IP. Role of bile
acids in colorectal carcinogenesis. European Journal of
Cancer 1995; 31A: 1067–70.
Potter JD, Steinmetz K. Vegetables, fruit and phytoestro-
gens as preventive agents. In: Stewart BW, McGregor D,
eds. Principles of Chemoprevention. IARC Scientific
Publication No. 139. Lyon: 1ARC, 1996, 61–90.
Jacobs DRJ, Marquart L, Slavin J, Kushi LH. Whole-grain
intake and cancer: an expanded review and meta-analysis.
Nutrition and Cancer 1998; 30: 85–96.
Bueno De Mesquita HB, Ferrari P, Riboli E, on behalf of
EPIC. Plantfoods and the risk of colorectal cancer in
Europe: preliminary findings. IARC Scientific Publications
Series. 2002; 156: 89–95.
Fuchs CS, Giovannucci EL, Colditz GA, et al. Dietary fiber
and the risk of colorectal cancer and adenoma in women.
New England Journal of Medicine 1999; 340: 169–76.
Michels KB, Edward G, Joshipura KJ, et al. Prospective
study of fruit and vegetable consumption and incidence of
colon and rectal cancers. Journal of the National Cancer
Institute 2000; 92: 1740–52.
Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-
fat, high-fiber diet on the recurrence of colorectal
adenomas. Polyp Prevention Trial Study Group. New
England Journal of Medicine 2000; 342: 1149–55.
Alberts DS, Martinez ME, Roe DJ, et al. Lack of effect of a
high-fiber cereal supplement on the recurrence of color-
ectal adenomas. Phoenix Colon Cancer Prevention
Physicians’ Network. New England Journal of Medicine
2000; 342: 1156–62.
Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J.
Calcium and fibre supplementation in prevention of
colorectal adenoma recurrence: a randomised intervention
trial. European Cancer Prevention Organisation Study
Group. Lancet 2000; 356: 1300–6.
Terry P, Giovannucci E, Michels KB, et al. Fruit, vegetables,
dietary fiber, and risk of colorectal cancer. Journal of the
National Cancer Institute 2001; 93: 525–33.
McKeown-Eyssen G. Epidemiology of colorectal cancer
revisited: are serum triglycerides and/or plasma glucose
associated with risk? Cancer Epidemiology Biomarkers &
Prevention 1994; 3: 687–95.
Franceschi S, Dal Maso L, Augustin L, et al. Dietary glycemic
load and colorectal cancer risk. Annals of Oncology 2001;
Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz
GA, Willett WC. Alcohol, low-methionine, low-folate diets,
and risk of colon cancer in men. Journal of the National
Cancer Institute 1995; 87: 265–73.
Glynn SA, Albanes D, Pietinen P, et al. Alcohol consump-
tion and risk of colorectal cancer in a cohort of Finnish
men. Cancer Causes & Control 1996; 7: 214–23.
Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin
use, folate, and colon cancer in women in the Nurses’
TJ Key et al.198
Health Study. Annals of Internal Medicine 1998; 129:
Choi SW, Mason JB. Folate and carcinogenesis: an
integrated scheme. Journal of Nutrition 2000; 130: 129–32.
Potter JD. Colorectal cancer: molecules and populations.
Journal of the National Cancer Institute 1999; 91: 916–32.
Blount BC, Mack MM, Wehr CM, et al. Folate deficiency
causes uracil misincorporation into human DNA and
chromosome breakage: implications for cancer and
neuronal damage. Proceedings of the National Academy
of Sciences of the United States of America 1997; 94:
Ma J, Stampfer MJ, Christensen B, et al. A polymorphism of
the methionine synthase gene: association with plasma
folate, vitamin B12, homocyst(e)ine, and colorectal cancer
risk. Cancer Epidemiology Biomarkers & Prevention 1999;
Sesink AL, Termont DS, Kleibeuker JH, Van Der Meer R.
Red meat and colon cancer: dietary haem-induced colonic
cytotoxicity and epithelial hyperproliferation are inhibited
by calcium. Carcinogenesis 2001; 22: 1653–9.
Baron JA, Beach M, Mandel JS, et al. Calcium supplements
and colorectal adenomas. Polyp Prevention Study Group.
Annals of the New York Academy of Sciences 1999; 889:
International Agency for Research on Cancer. IARC
Monographs on the Evaluation of Carcinogenic Risks to
Humans, vol 59. Hepatitis Viruses. Lyon: IARC, 1994.
Saracco G. Primary liver cancer is of multifactorial origin:
importance of hepatitis B virus infection and dietary
aflatoxin. Journal of Gastroenterology and Hepatology
1995; 10: 604–8.
Michaud DS, Giovannucci E, Willett WC, Colditz GA,
Stampfer MJ, Fuchs CS. Physical activity, obesity, height,
and the risk of pancreatic cancer. Journal of the American
Medical Association 2001; 286: 921–9.
Bjelke E. Dietary vitamin A and human lung cancer.
International Journal of Cancer 1975; 15: 561–5.
Hennekens CH, Buring JE, Manson JE, et al. Lack of effect
of long-term supplementation with beta carotene on the
incidence of malignant neoplasms and cardiovascular
disease. New England Journal of Medicine 1996; 334:
Omenn GS, Goodman GE, Thornquist MD, et al. Effectsof a
combination of beta carotene and vitamin A on lung cancer
and cardiovascular disease. New England Journal of
Medicine 1996; 334: 1150–5.
The Alpha-Tocopherol Beta Carotene Cancer Prevention
Study Group. The effect of vitamin E and beta carotene on
the incidence of lung cancer and other cancers in male
smokers. New England Journal of Medicine 1994; 330:
Feskanich D, Ziegler RG, Michaud DS, et al. Prospective
study of fruit and vegetable consumption and risk of lung
cancer among men and women. Journal of the National
Cancer Institute 2000; 92: 1812–23.
Voorrips LE, Goldbohm RA, Verhoeven DT, et al. Vegetable
and fruit consumption and lung cancer risk in the
Netherlands Cohort Study on diet and cancer. Cancer
Causes & Control 2000; 11: 101–15.
Key TJ, Verkasalo PK, Banks E. Epidemiology of breast
cancer. Lancet Oncology 2001; 2: 133–40.
Collaborative Group on Hormonal Factors in BreastCancer.
Breastfeeding and breast cancer: collaborative reanalysis of
individual data from 47 epidemiological studies in 30
countries, including 50,302 women with breast cancer and
96,973 women without the disease. Lancet 2002; 360:
Collaborative group on hormonal factors in breast cancer.
Alcohol, tobacco and breast cancer-collaborative reanalysis
of individual data from 53 epidemiological studies,
including 58,515 women with breast cancer and 95,067
women without the disease. British Journal of Cancer
2002; 87: 1234–45.
Dorgan JF, Baer DJ, Albert PS, et al. Serum hormones and
the alcohol-breast cancer association in postmenopausal
women. Journal of the National Cancer Institute 2001; 93:
Sellers TA, Kushi LH, Cerhan JR, et al. Dietary folate intake,
alcohol, and risk of breast cancer in a prospective study of
postmenopausal women. Epidemiology 2001; 12: 420–8.
Smith-Warner SA, Spiegelman D, Adami HO, et al. Types
of dietary fat and breast cancer: a pooled analysis of
cohort studies. International Journal of Cancer 2001; 92:
Wu AH, Pike MC, Stram DO. Meta-analysis: dietary fat
intake, serum estrogen levels, and the risk of breast cancer.
Journal of the National Cancer Institute 1999; 91: 529–34.
Holmes MD, Spiegelman D, Willett WC, et al. Dietary fat
intake and endogenous sex steroid hormone levels in
postmenopausal women. Journal of Clinical Oncology
2000; 18: 3668–76.
Key TJ, Allen NE. Nutrition and breast cancer. The Breast
2001; 10(Suppl. 3): 9–13.
Smith-Warner SA, Spiegelman D, Yaun SS, et al. Intake of
fruits and vegetables and risk of breast cancer: a pooled
analysis of cohort studies. Journal of the American Medical
Association 2001; 285: 769–76.
Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO.
Overweight as an avoidable cause of cancer in Europe.
International Journal of Cancer 2001; 91: 421–30.
Key TJ, Pike MC. The dose–effect relationship between
‘unopposed’ oestrogens and endometrial mitotic rate: its
central role in explaining and predicting endometrial
cancer risk. British Journal of Cancer 1988; 57: 205–12.
International Agency for Research on Cancer. IARC
Monographs on the Evaluation of Carcinogenic Risks to
Humans, vol 64. Human Papillomaviruses. Lyon: IARC,
Banks E, Beral V, Reeves G. The epidemiology of epithelial
ovarian cancer: a review. International Journal of
Gynecological Cancer 1997: 425–38.
Schuurman AG, van den Brandt PA, Dorant E, Goldbohm
RA. Animal products, calcium and protein and prostate
cancer risk in The Netherlands Cohort Study. British
Journal of Cancer 1999; 80: 1107–13.
Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM,
Giovannucci EL. Dairy products, calcium, and prostate
cancer risk in the Physicians’ Health Study. American
Journal of Clinical Nutrition 2001; 74: 549–54.
Michaud DS, Augustsson K, Rimm EB, Stampfer MJ, Willett
WC, Giovannucci E. A prospective study on intake of
animal products and risk of prostate cancer. Cancer Causes
& Control 2001; 12: 557–67.
Heinonen OP, Albanes D, Virtamo J, et al. Prostate
cancer and supplementation with alpha-tocopherol
and beta-carotene: incidence and mortality in a controlled
trial. Journal of the National Cancer Institute 1998; 90:
Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence
of prostate cancer with selenium supplementation: results
of a double-blind cancer prevention trial. British Journal of
Urology 1998; 81: 730–4.
Kristal AR, Cohen JH. Invited commentary: tomatoes,
lycopene, and prostate cancer. How strong is the evidence?
American Journal of Epidemiology 2000; 151: 124–7.
Eaton NE, Reeves GK, Appleby PN, Key TJ. Endogenous
sex hormones and prostate cancer: a quantitative review of
prospective studies. British Journal of Cancer 1999; 80:
Diet, nutrition and cancer199
93 Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Download full-text
Prospective study of sex hormone levels and risk of
prostate cancer. Journal of the National Cancer Institute
1996; 88: 1118–26.
Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-
like growth factor-I and prostate cancer risk: a prospective
study. Science 1998; 279: 563–6.
Stattin P, Bylund A, Rinaldi S, et al. Plasma insulin-like
growth factor-I, insulin-like growth factor-binding proteins
and prostate cancer risk: a prospective study. Journal of the
National Cancer Institute 2000; 92: 1910–7.
Allen NE, Appleby PN, Davey GK, Key TJ. Hormones and
diet: low insulin-like growth factor-I but normal bioavail-
able androgens in vegan men. British Journal of Cancer
2000; 83: 95–7.
Heaney RP, McCarron DA, Dawson-Hughes B, et al. Dietary
changes favorably affect bone remodeling in older adults.
Journal of the American Dietetic Association 1999; 99:
Zeegers MP, Goldbohm RA, van den Brandt PA. Consump-
tion of vegetables and fruits and urothelial cancer
incidence: a prospective study. Cancer Epidemiology
Biomarkers & Prevention 2001; 10: 1121–8.
Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett
WC, Giovannucci EL. Fruit and vegetable intake and
incidence of bladder cancer in a male prospective
cohort. Journal of the National Cancer Institute 1999; 91:
Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk
A. Obesity and renal cell cancer—a quantitative review.
British Journal of Cancer 2001; 85: 984–90.
International Agency for Research on Cancer. IARC
Handbooks of Cancer Prevention. Vol 6. Weight Control
and Physical Activity. Lyon: IARC, 2002.
Giovannucci E. Insulin and colon cancer. Cancer Causes &
Control 1995; 6: 164–79.
Willett WC. Is dietary fat a major determinant of body fat?
American Journal of Clinical Nutrition 1998; 67:
Giovannucci E, Clinton SK. Tomatoes, lycopene, and
prostate cancer. Proceedings of the Society for Experimental
Biology and Medicine 1998; 218: 129–39.
Note added in press—acrylamide
Acrylamide is a chemical classified by the International
Agency for Research on Cancer as a probable human
carcinogen1. This classification is based on experiments in
rats and mice, which show that high doses of acrylamide
increase the risk for several cancers, including cancers of
Swedish food survey reported that common foods such as
fried potatoes, potato crisps (chips), bread and breakfast
cereals contain moderately high levels of acrylamide2.
Subsequent studies showed that acrylamide is generated
when the amino acid asparagine is heated above 1008C in
asparagine3,4. Moderate acrylamide levels in common
foods have now been reported from several countries, and
these findings have raised concern that dietary acrylamide
may increase cancer risk in humans5. The intake of
acrylamide from food may be several hundred-fold lower
than the lowest dose at which adverse effects have been
observed in rats6, and at the time of writing (January 2003)
the only information concerning cancer risk in humans
comes from a case-control study in Sweden7. This study
estimated acrylamide intake from the reported intake of 10
foods, and observed no evidence that increasing intake of
food sources of acrylamide was associated with the risk for
cancers of the colorectum, kidney or bladder. Although
these first results are moderately reassuring, more data are
urgently needed from studies using questionnaires
validated for estimating acrylamide intake, or biomarkers
of acrylamide exposure.
1International Agency for Research in Cancer. Acrylamide.
IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans 1994; 60: 389–433.
Tarake E, Rydberg P, Karlsson P, Eriksson S, To ¨rnqvist M.
Analysis of acrylamide, a carcinogen formed in heated
foodstuffs. Journal of Agricultural and Food Chemistry 2002;
Mottram DS, Wedzicha BL, Dodson AT. Food chemistry:
acrylamide is formed in the Maillard reaction. Nature 2002;
Stadler RH, Blank I, Varga N, et al. Food chemistry: acrylamide
from Maillard reaction products. Nature 2002; 419: 449–50.
Food and Agriculture Organization/ World Health Organiz-
ation. FAO/WHO Consultation on the Health Implications or
Acrylamide in Food: Summary Report. Geneva: WHO, 2002.
Shaw I, Thomson B. Acrylamide food risk. Lancet 2003; 361:
Mucci LA, Dickman PW, Steineck G, Adami H-O, Augustsson
K. Dietary acrylamide and cancer of the large bowel, kidney,
and bladder: absence of an association in a population-based
study in Sweden. British Journal of Cancer 2003; 88: 84–9.
TJ Key et al. 200