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Unit of Nutrition and Cancer, International Agency for Research on Cancer (IARC), Lyon, France
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INTRODUCTION |
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 TOP INTRODUCTION European Prospective...SUMMARYREFERENCES |
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) as well as pioneering work on rodents in experimental
laboratory studies carried out in the 1940s (Tannenbaum 1940a
, 1940b
, 1942a
and 1942b
). During the first half of the century,
several researchers noticed that overfed rodents were less resistant to
the growth of transplanted tumors (Rous 1914
) and more
sensitive to the effect of chemical carcinogens (Tannenbaum 1942a
).
Several decades later, correlation studies showed that incidence of
(and mortality from) cancer of the breast, colorectum and prostate were
positively correlated with the foods most typically consumed in Western
societies (i.e., meat, total and animal fat, simple sugars) and
negatively correlated with the consumption of various vegetable foods
(grains, cereals and vegetable fiber) (Armstrong and Doll 1975
). Geographical correlation studies can indicate only that
disease risk and the prevalence of a given factor are correlated across
different populations; they are limited by the methodological and
practical possibility of taking into account confounding factors that
may create spurious correlations at the population level. During the
past 20 years, a considerable number of retrospective case-control
and, more recently, prospective cohort studies have been conducted to
investigate whether, in each given population, these dietary factors
were effectively related to cancer risk at the individual level.
Results of epidemiologic and experimental studies on nutrition and cancer have been reviewed in depth in recent years by three independent expert committees as follows:
);
);
). The three independent review committees reached broadly similar conclusions. Regarding dietary composition, the three reports agree that the most clearly identified associations are those between the consumption of vegetables and fruit and reduced risk of various cancers. These protective effects have been seen most consistently in studies on cancers of the digestive and respiratory tracts. Frequent, daily consumption of both vegetables and fruit is associated most strongly with a reduction in risk of cancers of the mouth, pharynx, larynx, esophagus, stomach and lung, whereas only consumption of vegetables, but not of fruit, is linked to a reduction in risk of colorectal cancer.
Regarding foods that have been identified consistently as being associated with increased cancer risk, the list is much shorter and is limited to meat and Cantonese-style salted fish. Red meat, mainly beef, but not poultry and fish, is associated with a modest increase in colorectal cancer risk. Consumption of Cantonese-style salted fish has been found to be associated with the risk of nasopharyngeal cancer, which is very frequent in some populations of south-east Asia, particularly southern China, but extremely rare in most other parts of the world.
Regarding fruit, vegetables and red meat, the three reports agreed on an important point, i.e., although their association with cancer risk can be considered to be reasonably well established on the basis of epidemiologic studies, no definite clear explanation exists for the biological mechanisms involved, even though a large number of experimental studies have been carried out and many different mechanisms have been tested on in vitro and in vivo models.
This conclusion leads to two main recommendations. First, it implies that no scientific support exists for a proven cancer-preventive effect of dietary supplements containing various cocktails of vitamins and minerals also found in vegetables and fruits. The only sound recommendation is therefore to eat lots of fruit and vegetables frequently. Second, it implies that more research is required on the biological links between vegetables and fruits and the carcinogenesis process, particularly with randomized supplementation trials and observational epidemiologic studies.
Another growing and promising area of research concerns the
relationship among anthropometric characteristics, physical activity
and cancer risk. The first evidence that overweight may be linked to
increased cancer risk dates back to the 1930s when Tannenbaum (1940a)
conducted a study on mortality in relation to height
and weight using the data of various life insurance companies in the
United States. Epidemiologic studies conducted during the past 20 years
have shown with various degrees of consistency that excess body mass
(usually estimated as weight/height2, or body
mass index) is associated with increased risk of cancer of the
endometrium, breast, colon and, possibly, kidney.
Recently, several prospective studies in which blood samples were
collected and stored at baseline from healthy subjects have shown that
high prediagnostic levels of endogenous steroid hormones, mainly
estrogens and testosterone, are associated with a three- to sixfold
increase in breast cancer risk (Berrino et al. 1996
,
Dorgan et al. 1996
, Hankinson et al. 1998
, Toniolo et al. 1995
), whereas one study
showed that high testosterone levels increase prostate cancer risk
(Gann et al. 1996
). These studies also found that low
levels of sex hormone binding globulin
(SHBG)3
are also associated with higher risk of breast cancer; SHBG is
synthesized in the liver and its production is down-regulated by
insulin. The link among overweight, a sedentary lifestyle and cancer
risk may well be mediated in part by these insulin-SHBG-steroid hormone
pathways for cancer of the breast (Kaaks 1996
), colon
(Giovannucci 1995
), prostate and possibly other cancers.
An additional important link between diet and cancer risk may exist
through the control of the production of insulin-like growth
factors (IGF) and their binding proteins (IGF-BP). Recent studies found
that high levels of IGF1 (adjusted over the
levels of IGF-BP3) were significant predictors of
the risk of developing cancer of the prostate (Chan et al. 1998
) and colon (Ma et al. 1999
). More recently,
we found in the New York Women’s Health Study that high levels of
c-peptide, a serum marker of insulin excretion, were strongly
associated with the risk of developing colon cancer (Kaaks et al. 2000
).
These results on endogenous hormones and anthropometry indicate that
the relationship between diet and cancer is much more complex than was
previously thought. Research on diet and cancer based solely on simple
dietary questionnaire measurements and mainly retrospective
case-control studies has led to the identification of some major
dietary patterns associated with cancer risk (particularly the balance
among vegetables, fruits and meat). Although these results are
sufficient to support some broad and nowadays widely accepted dietary
recommendations, cancer prevention would benefit from a better
understanding of the biological links between diet and cancer.
Laboratory investigations on human subjects combined with sound
prospective epidemiologic projects should lead us a step further. This
was the strategic choice made by the International Agency for Research
on Cancer (IARC) when it decided 10 years ago to give priority in
nutrition and cancer studies to the development of prospective cohort
studies with repositories of blood samples collected from healthy study
subjects (Coghlan 1991
). We present here the major
developments of the research strategy that led to the realization of
the European Prospective Investigation into Cancer and Nutrition
(EPIC).
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European Prospective Investigation into Cancer and Nutrition |
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TOPINTRODUCTIONEuropean Prospective...SUMMARYREFERENCES |
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EPIC was designed with the double aim of improving scientific knowledge on the nutritional factors involved in diet and, as a consequence, of providing the scientific bases for public health interventions directed to promoting healthier diet and lifestyle.
Study protocol.
The general protocol for subject recruitment and data collection was as follows. As a rule, eligible study subjects were from the general population residing in a given geographical area, i.e., a town or a province. There were, however, a few exceptions as follows: the French cohort was based on members of the health insurance group for state school employees (with the aim of facilitating long-term follow-up); a small component of the Italian and Spanish cohorts included members of local blood donor associations; and the Utrecht cohort was based on women attending breast cancer screening.
Eligible subjects were invited by mail to participate in the study. In some cases (e.g., blood donors) the first invitation was by personal contact. Those who accepted signed an informed consent form and the diet and lifestyle questionnaires were mailed to them to be completed, generally at home. Study subjects were then invited to a center for blood collection (venipuncture), anthropometric measurements (height, weight, waist, hip and sitting height) and to hand in the completed questionnaires.
Data were collected on a large number of lifestyle and health factors that are of interest in studies on nutrition and cancer because they may be related to nutritional status or may be known or suspected cancer risk factors. A common core set of questions and possible answers was agreed on and translated into national questionnaires. This included questions on the following:
In 1990, EPIC was initiated with methodological studies on dietary
assessment and pilot-feasibility studies on subject recruitment and
collection of questionnaire data and blood samples. These studies,
which took place in nine different countries between 1990 and 1993, led
to a series of publications. In particular, a supplement of the
International Journal of Epidemiology (Margetts et al. 1997
) was devoted to the validity of different dietary
assessment methods, questionnaires on physical activity and the
reproducibility of anthropometric measurements. These studies provided
precious information for the finalization of the study protocol. Three
dietary methods were adopted on the basis of the results of these
methodological studies conducted in 1990–1992:
In addition to the above dietary measurements obtained from all
study subjects, it was decided to implement in EPIC a novel
methodological approach to calibrate dietary measurements across
countries to correct for systematic over- or underestimation of dietary
intakes. For this purpose, a second dietary measurement was taken from
an 8–10% random sample of the cohort by using a computerized 24-h
diet recall method developed ad hoc (Slimani et al. 1999
, Voss et al. 1998
). We developed
statistical methods to correct for bias in relative risk estimates that
were due to systematic measurement errors in the baseline
questionnaire, thereby making the cohort-specific estimates more
comparable among study centers (Kaaks et al. 1994
,
Kaaks and Riboli 1997
).
Although this general protocol was common to all EPIC centers, the procedure for storage of blood samples differed between two groups of countries because the study was originally started in seven European countries (France, Germany, Greece, Italy, Netherlands, Spain and United Kingdom) in which the study followed as strictly as possible a common, jointly elaborated protocol. Aliquots of blood samples collected from subjects from these seven countries were stored in 28 plastic straws (12 plasma, 8 serum, 4 erythrocytes, 4 buffy coat for DNA) and then split into two sets of 14 straws each. One set was stored locally and one was shipped to IARC to be stored in liquid nitrogen at -196°C in the central biological bank. Later, four additional study centers located in Sweden (Malmö and Umeå) and two in Denmark (Copenhagen and Aarhus) joined EPIC as associated projects. The two Swedish cohorts had been started before EPIC and the Danish ones had been started in parallel with EPIC. Their protocols and questionnaires were adapted to be as close as possible to those used in EPIC. Blood samples from these four centers, however, were stored in tubes (not in plastic straws); thus, for practical reasons they are stored locally because the EPIC system set up at IARC was not suitable for storing tubes. In Sweden, the samples were kept in deep freezers at -70°C and in Denmark in nitrogen vapor.
Field work and subject recruitment.
Table 1
summarizes the number of subjects for whom questionnaire data and blood
samples were collected in each participating country. By September
1999, EPIC included 484,042 subjects who had provided questionnaire
data; of these, 387,256 also had blood samples collected and stored. In
addition, as planned in the design of the study for internal
calibration of dietary measurements (Kaaks et al. 1995a
and 1995b
), 24-h diet recalls were collected on a subsample of
33,200 subjects, corresponding to 
7% of the cohort. The age
distribution of the calibration sample was designed to be as close as
possible to the age distribution of the expected cancer cases during
the first 10 y of follow-up.
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and
3
provide the expected number of cancer cases, by cancer site and
country, expected to have occurred up to the end of 1998.
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In EPIC, cohort members are contacted 3–4 y after recruitment to obtain information on some aspects of lifestyle that are known or strongly suspected of being related to cancer risk, e.g., tobacco smoking, alcohol drinking, physical activity, weight, menstruation, pregnancies or menopause. In addition, a series of questions was added concerning whether the subjects had suffered from any major diseases. The first run of individual follow-up is on-going at present in most EPIC centers and has been completed in a few centers.
Follow-up aimed at the identification of cancer cases occurring among the EPIC cohort is based on population cancer registries in six of the participating countries (Denmark, Italy, Netherlands, Spain, Sweden and United Kingdom) and on a combination of methods including health insurance records, cancer and pathology registries and active follow-up through study subjects and their next of kin in three countries (France, Germany and Greece). Mortality data are also collected from either the cancer registry or mortality registries at the regional or national level.
A working group created in 1996 (End-point Committee) prepared a detailed protocol for the collection and standardization of clinical and pathological data on each cancer site—Guidelines for Collection of End-point Data in the EPIC Study (IARC, unpublished, 1998). The document is available from IARC upon request.
Currently, follow-up is being completed up to 31 December 1998. A delay of at least 18–24 mo in obtaining complete follow-up data is unavoidable because of the complex procedures followed by population-based cancer registries for the collection and verification of clinical and pathological diagnoses. On the other hand, these procedures provide complete and reliable follow-up data.
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SUMMARY |
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|
TOPINTRODUCTIONEuropean Prospective...SUMMARYREFERENCES |
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The EPIC study was designed to overcome these two limitations. First, EPIC includes populations with important variations in dietary intake, particularly of vegetables and fruit. Second, with the collection and storage of blood samples, EPIC can provide the material for investigating various nutrition-related metabolic and genetic factors and their possible interactions.
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FOOTNOTES |
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2 Supported by the Europe Against Cancer program of the European Commission.
3 Abbreviations used: BP, binding protein; EPIC, European Prospective Investigation into Cancer and Nutrition; IARC, International Agency for Research on Cancer; IGF, insulin-like growth factor; SHBG, sex hormone binding globulin.
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REFERENCES |
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TOPINTRODUCTIONEuropean Prospective...SUMMARYREFERENCES |
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