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This content is from the website of the European Union; Fact Sheet 3 Scientific Basis for Olive Oil, Mediterranean Diet and Cancer preventionAuthor: 1. Introduction Cancer accounts for about 20% of all deaths in European countries, but within Europe, there are significant differences in cancer mortality with generally higher rates in the northern and western countries and lower rates in the Mediterranean countries. There is strong evidence that these differences can be attributed to a large extent to dietary factors. Diet plays an important role in the pathogenesis of cancer, although the exact proportion of dietary involvement is still largely uncertain. It is estimated that about 35% - with a range from 10 to 70% - of all cancer deaths may be attributed to dietary factors. The nutritional factors may relate to the development of cancer in several ways: (1) a particular dietary component, food additives, or contaminants may act as carcinogens, cocarcinogens and/or promoters, (2) dietary constituents act as anticarcinogens, (3) nutrient deficiencies and/or excesses may lead to biochemical alterations that promote neoplastic processes, and (4) changes in the intake of selected macronutrients may induce metabolic and biochemical abnormalities that increase the risk for cancer. Current knowledge from different kinds of studies consistently shows that foods or food groups are more strongly associated with cancer risk than nutrients. There are some possible explanations for this phenomenon. The food component responsible for the causation of, or protection against, cancer, may be a minor component that has not been considered. For example, the protective effect of vegetables may be due not (or at least not only) to an antioxidant vitamin, but to other potential anticarcinogens that food composition tables do not contain. On the other hand, an effect may indeed be due to the anti-oxidant vitamin being investigated, but the weakness of the correlation may simply reflect the fact that the food tables can only give approximate and average values of the nutrient content, especially with respect to the micro-components. The nutrition-cancer hypothesis has been primarily based on ecological observations. Strong correlations between cancer and dietary habits have been found throughout the world, however, it is well known that correlation does not necessarily mean causation. Besides population studies information on the diet-cancer relationship in humans has derived from case-control and cohort studies. Unfortunately, the evidence from various types of data is partly inconsistent. Furthermore, due to the lack of interventional studies very little is known at present about the impact of dietary modifications or supplements on subsequent cancer rates. Although controlled intervention studies would strongly support the hypothesis of a causal link between diet and cancer, they have several disadvantages. First, a dietary intervention study of cancer risk needs to be very large, in order to receive the number of cases needed for statistical power. This makes such studies extremely expensive. Second, an intervention study can only run for a limited time, whereas cancer is the end-result of a process lasting years or even decades. In addition, there is a great problem of compliance, since it is nearly impossible to change dietary habits of the intervention group for at least a decade, and, simultaneously, to maintain the dietary habits of the control group unchanged. Due to these limitations, there are hardly any results from well-controlled, powerful interventional studies to provide the necessary strong evidence for an effect of single nutrients or specific non-nutrient components on cancer. The traditional diet in Mediterranean
countries is characterised by a high availability of potentially
„protective“ foods, such as fruit and vegetables. In addition, there
are findings indicating that olive oil as a main component of the Mediterranean
diet may also have a cancer-protective effect. The present paper reviews the
scientific evidence for the role of olive oil and the Mediterranean diet in
cancer prevention. Relevant findings of a relationship between foods, nutrients
and cancer risk will be discussed, and international recommendations on the
basis of current knowledge will be presented. 2. Cancer and Mediterranean diet 2.1 Role of body weight The relationship between body weight and cancer has been extensively studied. Obesity is a well-established risk factor for post-menopausal breast cancer and cancer of the prostate, endometrium, and gall-bladder. There is also evidence that obesity is a risk factor for renal-cell carcinoma and cervical cancer. The relationship between overweight and digestive tract cancers is difficult to study, because weight loss is an early symptom of such cancers. The mechanisms whereby over-nutrition and obesity may promote the development of cancer in humans are unknown. One hypothesis is that over-nutrition in general, regardless of the composition of the diet, is a risk factor for cancer. However, it is also conceivable that a higher intake of special dietary components, eg. dietary fat or potentially carcinogenic substances, may play a crucial role in obesity-related cancer. At the present stage it is justified
to conclude that obesity is an important risk factor for cancers at a large
number of sites, and, simultaneously, there is no evidence that it is
protective at any site. Therefore, the public health importance of avoiding
overweight and obesity is very clear. This is further supported by the fact
that obesity is also associated with a number of non-malignant diseases such as
gallstones, heart disease, diabetes etc. Due to the high consumption of fruit,
vegetables, and cereals, thus leading to a high content of complex
carbohydrates and dietary fibre, the Mediterranean diet is suitable for the
prevention of obesity and, as a consequence, for the prevention of
obesity-related cancer. There is a body of evidence from population studies associating total fat intake with cancer at a number of sites, particularly colon, breast, endometrium, ovary, prostate. All of these cancers are related to a Western-type diet and to excess energy intake. However, the evidence is far from clear. For example, at all sites there is simultaneously a strong association with total energy intake, and it is not clear which of these two is the primary factor. Prospective studies have failed to detect any relation between total fat intake and breast cancer (see below). Besides, another study suggests an even protective effect of fat intake due to the consumption of meat and dairy products against gastric carcinogenesis. International correlation studies have differentiated between per capita consumption of animal and vegetable fat. There is a positive correlation between colon, prostate, breast, and ovary cancer mortality rates and animal fat consumption per capita. Population studies as well as several case-control studies have particularly supported a strong correlation between animal-fat intake and colorectal cancer risk. In contrast, mortality rates of colon cancer are relatively low in Greece, Spain, and Southern Italy, where olive oil is by far the most common type of fat consumed. In a large prospective study animal fat was confirmed as a major risk factor for colorectal cancer, while vegetable fat was neutral and fish oil was protective. These studies suggest that not only the amount but the type of dietary fat is of importance in the aetiology of fat-related cancers. Vegetable fats/oils are considered to be neutral with regard to cancer risk, but there is little evidence for a special protective effect of vegetable oils per se. However, recent analyses suggest that actually olive oil may have a protective effect against cancer at different sites, particularly breast cancer, which will be discussed in detail below. Among the PUFA there is evidence from
human studies that fatty acids of the n-3 series are protective whereas the n-6
series appears to be neutral with respect to cancer risk. On the other hand, it should be mentioned that
the role of PUFA becomes less clear when also evaluating animal studies.
Investigations in laboratory animals have indicated that n-6 PUFA are more
likely to increase cancer risk than other types of fatty acids. Several
mechanisms whereby PUFA might promote the tumour development in animals are
discussed: (1) Peroxides produced from PUFA might activate cell proliferation,
(2) PUFA could increase membrane fluidity which could promote cell division, or
(3) PUFA might suppress the immune system which could allow for the development
of cancer by decreased „immune surveillance“. However, these
hypotheses should be assessed with great caution, and the findings have never
been confirmed in humans. 2.3 Role of protein In epidemiological studies it is very
difficult to separate the effects of animal fat and animal protein. In a recent
review of diet in the aetiology of cancer it is concluded that all of the
correlations observed between cancer risk and animal protein were secondary to
those caused by the animal fat component.
This conclusion has been confirmed by other groups. All in all, there is no
evidence showing that there is an independent relationship between protein
consumption and cancer risk. 2.4 Role of complex carbohydrates and dietary fibre As it is the case for dietary fat, the relation between complex carbohydrates and cancer risk is not clear. Although there is some evidence for a protective effect, the question has been complicated by methodological problems. Complex carbohydrates are a group of heterogenous substances, including starch, non-starch polysaccharides, and dietary fibre, and it is not clear to which component of the total complex carbohydrates protective effects can be attributed. These problems do not affect studies
of the relation between cancer and food intake. So, when relating high-fibre
food groups and cancers at various sites, it has been found that cereals are
highly protective against cancers of the colon, breast, endometrium, and
prostate. Case-control studies did not show
such consistent results, but a protective effect of high-fibre foods against
colorectal cancer could be confirmed in a prospective study by Willett et al. 2.5 Role of fruit and vegetables There is a body of epidemiological evidence based on population, cohort, and case-control studies that a high intake of fruit and vegetables, particularly raw vegetables, protects against cancers at different sites, especially those of the digestive and respiratory tracts, and the hormone related cancers. One important feature of fruit and vegetables is that they have an anti-carcinogenic action at a wide rage of sites, and, simultaneously, that there is not any positive correlation between fruit and vegetable intake and cancer. Fruits and vegetables contain a
variety of anti-carcinogenic agents. These include carotenoids, vitamin C and
E, dietary fibre, selenium, glucosinolate, indoles, flavonoids, protease
inhibitors, and plant sterols. These and other agents show both complementary
and overlapping mechanisms of action, including induction of detoxification
enzymes, antioxidant effects, inhibition of the formation of nitrosamine,
binding and dilution of carcinogens in the digestive tract, alteration of
hormone metabolism and immune system, and others. The exact mechanisms of
single agents, however, are largely unclear. Until now, only the actions of
anti-oxidant vitamins and pro-vitamins have been supported by human
epidemiology. It is likely that not a single agent functions as key agent, but
that all of them play some part in the protective action under some
circumstances. 3. Role of olive oil in cancer Various epidemiological studies
indicate that the regular consumption of olive oil is inversely associated with
cancer at different sites. Most of the studies address the relationship between
olive oil and breast cancer or gastric cancer. They will be detailed below.
Although there are also findings which suggest protective effects of olive oil
for cancer at other sites, eg. colon, endometrium and ovary, the evidence is limited, because the number of
studies is rather small, and their results can be not more than an indication
for a possible effect. 3.1 Risk of breast cancer Breast cancer incidence varies more than fivefold around the world, and the offspring of migrants moving from countries with low breast cancer incidence to countries with high incidence acquire rates close to those of the new country, suggesting that environmental and lifestyle influences are important in the aetiology of breast cancer. Diet may be a major factor in the international variation in the incidence of breast cancer. This is supported by the fact that the incidence of, and mortality from breast cancer is lower in Mediterranean countries than in countries of western and northern Europe or the United States. As already pointed out, breast cancer, as well as other types of cancer, is related to a Western-type diet with excess energy intake, high intake of animal products and animal fat, and low intake of vegetable foods. The Mediterranean diet, on the other hand, contains a variety of potentially protective food items such as fruit and vegetables. The content of animal fat is low, and olive oil is the major source of dietary fat. Based on the population studies it seems likely that dietary fat is a key factor in the relationship between diet and breast cancer. Evidence from animal experiments and case-control studies support the association between dietary fat intake and the incidence of breast cancer. However, a recent meta-analysis of seven large prospective cohort studies could not corroborate the association. In the included cohort studies, the baseline diet of a large number of women has been assessed and the diets of women who subsequently develop breast cancer have been compared with the diets of women who did not. In the analysis, information about 4,980 cases from studies including 337,800 women was available. The authors found no evidence for a positive association between total dietary fat intake and the risk of breast cancer. Relative risks for saturated, mono-unsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was no risk reduction even among women whose energy intake from fat was less than 20% of total energy intake. Correction for error in the measurement of nutrient intake did not substantially alter these findings. Nevertheless, despite these findings which focus on the effects of the nutrients fat and fatty acids, it cannot be overlooked that there is some evidence for an inverse correlation between breast cancer risk and olive oil consumption. Recently, four noteworthy case-control studies have especially examined the role of olive oil in the aetiology of breast cancer. All four studies point to a modest beneficial effect of olive oil consumption on breast cancer risk. One of two Spanish studies included 100 women with breast cancer and 100 hospital controls, who were interviewed using a food-frequency questionnaire. Cases reported significantly lower consumption of fruits, vegetables, and fish. They showed a lower intake of vitamin C and mono-unsaturated fatty acids (MUFA) as compared to the controls. After controlling for total energy intake the relative risk (RR) for women with the highest intake of MUFA was 0.3 as compared to those with the lowest intake. In the second Spanish study a validated semi-quantitative food-frequency questionnaire was completed by 760 women with histologically confirmed breast cancer and 990 randomly selected female controls. The study subjects were divided into quartiles according to their intake of food items and nutrients. Data were adjusted for total energy intake and other potential confounding factors by multiple logistic regression analysis. Neither the total fat intake nor the different types of fatty acids were significantly associated with breast cancer. There were negative associations observed for MUFA and oleic acid, but these trends did not reach statistical significance. However, a higher consumption of olive oil was significantly related to a lower risk of breast cancer (for highest vs. lowest quartile of consumption odds ratio (OD) = 0.66), with a significant dose-response trend). In Italy, data from a multi-centre case-control study, including 2,560 cases with confirmed breast cancer and 2,590 controls and using a validated food-frequency questionnaire, were analysed . The data were controlled for confounding factors by multiple logistic regression analysis. The results showed an inverse relationship of breast cancer risk with the intake of olive oil and also with other vegetable oils, but not with butter or margarine. One further study in Greece also tried to quantify the effect of consumption of olive oil with a comparable design as the studies mentioned above (820 cases, 1550 controls; food-frequency questionnaire; adjustment for confounding factors). Increased olive oil consumption was associated with significantly reduced breast cancer risk. The relative risk was 0.75 in the quintile with the highest intake. Again, there was no relationship between total fat intake and breast cancer risk. Although these studies give evidence for a protective role of olive oil against breast cancer, several questions remain: Is the inverse association between olive oil consumption and breast cancer indeed genuine and unconfounded ? And if the association is real and causal, is it specific for olive oil or does it apply to MUFA in general? Is the effect actually attributable to the fatty acid composition of olive oil or to its content of specific micronutrients (eg. vitamin E and other antioxidative substances)? In addition, the reported associations are modest, the possibility of selection bias can never be completely excluded, and residual confounding by vegetable intake is theoretically possible since vegetables frequently are consumed with olive oil and are also likely to protect against breast cancer. In summary, there is a great need for
future research work on the relationship between olive oil and breast cancer.
Nevertheless, the necessary caution should not overshadow that the existing
evidence consistently supports a protective role of olive oil in breast cancer
prevention. 3.2 Risk of gastric cancer Gastric cancer is the third most common cause of cancer mortality in the European Union. Among the European countries, Italy is one with the highest mortality rates for gastric cancer in both sexes. Within Italy a wide geographical variability for gastric cancer has been found, with high risk areas located in central-northern regions and low rates in southern Italy and on the islands (5). These findings are rather surprising, because usually gastric cancer rates are higher in low social classes and in less developed areas. Therefore, the decreasing geographical gradient from north to south is in contrast with most reports from other western countries and represents a specific Italian pattern. Since the limited information available suggests that dietary habits vary widely in different regions within Italy, it can be speculated that these differences in the diet play a role in the geographical variability of gastric cancer(5). One recent multi-centre case-control study evaluated possible reasons for the differences in cancer mortality, focusing on dietary factors. The study included 1015 cases with histologically confirmed gastric cancer and 1160 controls. Dietary patterns were assessed using a quantitative food-frequency questionnaire. The study subjects frequently consuming fresh fruits, citrus fruits, and raw vegetables had a gastric cancer risk reduced to only 30 % compared to those who only rarely consumed such foods. These findings were consistent with other studies. Furthermore, the consumption of olive oil, as well as of garlic and spices was inversely related to gastric cancer risk. On the other hand, the consumption of meat, salted and dried fish, and seasoned cheeses was associated with an increased risk of gastric cancer. Since there are no further
well-designed studies which evaluated the role of olive oil in gastric cancer
prevention and thus could support it, it must be stated that a protective
effect of olive oil is not proven until now. The only conclusion that can be
drawn at the present stage for gastric cancer prevention is that increased
fruit and vegetable intake seems to be helpful. 3.3 Olive oil and cancer - open questions Although all the findings concerning the role of olive oil in cancer prevention are encouraging, they need confirmation by further studies, particularly prospective cohort studies and well-designed, strictly controlled intervention studies. As already pointed out, intervention studies in the field of cancer are hard to conduct. They would be greatly facilitated if there were biological markers which (1) were proven as a risk factor for cancer, (2) could be easily measured in the laboratory and, especially, (3) were diet-dependent. Eg., one such biomarker is the excretion of secondary bile acids. It has been demonstrated that secondary bile acids induce cell proliferation and act as promoters for colon cancer. In addition, dietary intervention studies in humans have demonstrated that different diet regimens led to different faecal bile acid levels. To identify more valid parameters as risk factors for cancer at different sites is an important objective of current research work. Another question that arises is which component (or components) of olive oil is responsible for the eventual protective effect. The identity of olive oil is dominated by mono-unsaturated fatty acids (MUFA), but undoubtedly, olive oil is more than a mono-unsaturated fat. It is likely that the MUFA play a central role in the cancer-protective effect, but it is difficult to demonstrate this effect in epidemiological studies. In northern Europe and the United Stated most MUFA are supplied with animal products, ie., their intake is accompanied by a high intake of saturated fat, and the effects of SAFA and MUFA can be hardly evaluated independently. On the other hand, if olive oil is the primary source of MUFA, the diet simultaneously has a high content of antioxidative substances, which are also present in olive oil. Until now, there is not a single study which could precisely discriminate between the different types of fatty acids and which had adjusted the results for the other dietary confounding factors. An active effect, either protective or promoting, in the pathogenesis of cancer has not been proven either for oleic acid or for MUFA as a whole. Another explanation for a cancer-protective effect of olive oil could be that the responsible component would not be the MUFA but other components of the oil. It is possible that tocopherols or other micronutrients in olive oil are important mediators of its effects. Again, the evidence is limited, and no conclusive statements can be made at present. In summary, at this stage the
question on the role of olive oil in the pathogenesis of cancer cannot be
definitively answered. A beneficial effect of olive oil consumption on breast
cancer risk is highly likely although not conclusively established. The
knowledge with regard to cancer at other sites is less clear. However, even if
an active cancer-protective effect of olive oil could not be definitively
proven until now, there are on the other hand no studies at all which would
support a tumour-promoting effect of olive oil. Thus, as a conclusion, olive
oil is at least neutral with respect to tumorgenesis, and there is some
evidence that it is not simply non-toxic, but has its own protective effects.
4. International recommendations for cancer prevention Several health authorities have made dietary recommendations for cancer prevention. The recent guidelines of the American Cancer Society consist of six points (1):
Similar recommendations are given by the National Cancer Institute, but their guidelines differ from those of the American Cancer Society by specifying levels of nutrient intake for the general population (no more than 30% of total calories from fat and 20-30 grams of dietary fibre daily). The United States have started to implement these guidelines with a nationwide programme, called the „5-a-day for better health programme“. This programme is a joint campaign of health authorities, state, and food the industry. The recommendations are to consume mainly vegetable foods, to eat five or more portions of fruits and vegetables per day, and in addition, to eat six or more portions of breads, cereals or grain per day. With this strategy a simple and positive message is given in the context of healthy nutrition to the population. It is disseminated via super markets, restaurants, media, the public, and research. In the following years it will be evaluated if and to what extent the campaign has led to changes in the dietary habits in the United States. In Europe, the programme „Europe against cancer“ by the European Commission has worked out a codex for cancer control which has been updated in 1994. In the framework of this programme, there are also some recommendations concerning nutrition and diet:
In November 1996 the WHO conference
„nutrition in prevention and therapy of cancer“ took place in
Stuttgart, Germany. The purpose of this conference with internationally
established scientists was to summarise current knowledge in the field of
colon, gastric, breast, and lung cancer with regard to the role of nutrition in
their prevention and therapy. The resulting consensus statements will be
published in detail in the course of the year 1997. As a general policy
statement for reducing the risk of cancer it was formulated that fruits,
vegetables, and whole-meal cereals should be the main components of the daily
diet. Avoidance of obesity and of high alcohol intake as well as regular
physical activity can contribute to a reduction of cancer risk. In addition, it
was stated that there is no kind of diet with which colon, gastric, breast, or
lung cancer could be treated. 5. Summary and conclusions There is general consensus that diet is an important component in the aetiology of cancer. Scientific evidence is primarily derived from epidemiological studies as well as from animal and in vitro experiments. In the former, foods or food groups are more strongly associated with cancer risk than nutrients, and for many foods the results are not persuasive or consistent. Well-designed, strictly controlled intervention studies in humans which could support the role of single foods or nutrients in cancer prevention with sufficient strength are missing. Thus, the scientific evidence for detailed recommendations with respect to cancer prevention is limited. In Europe, but also in the United States, experts in the field of medicine and nutrition have lost much of their credibility in the eyes of the public, because sometimes dietary advice has been given on the basis of passionate belief rather than solid evidence, and has subsequently had to be withdrawn. In addition, risk-benefit analyses for recommendations must be carried out in the context of general health and not regarding one disease in isolation (13). For instance, it is known that there is an inverse correlation between the mortality from colon cancer which is associated with over-nutrition, and gastric cancer which is related to poor nutrition. So, any advice given for the prevention of cancer at one site must imply that it will not lead to an increase in cancer at another site. As a consequence of these deficiencies in knowledge and in the light of current evidence, only few recommendations are justifiable as formulated by international health authorities: Obesity should be avoided; vegetable foods should be the main components of the daily diet, ie. the intake of fruits, vegetables, and whole-grain cereals should be greatly increased; the amount of total fat should be reduced; the alcohol consumption should be limited. Furthermore, it is likely that it will be reasonable to advice the general public to eat decreased amounts of animal fat. These recommendations are largely in agreement with those internationally given for the prevention of cardiovascular risk factors and coronary heart disease The traditional Mediterranean diet is
characterised by a high consumption of fruits, vegetables, and cereals which
are the major sources of dietary fibre. Due to the high content of complex
carbohydrates it has, on average, a lower energy content than a high-fat diet
which makes it suitable for the prevention of obesity. The intake of animal
products and animal fat is low, most dietary fat is provided by olive oil.
Thus, the Mediterranean diet can be considered as an excellent example for a
diet complying with the requirements for a cancer-protective diet. This has
been confirmed by lower cancer mortality rates in the Mediterranean region as
compared to western and northern Europe and the United States. However, until
now, it is not known if the protective effect of the Mediterranean way of
eating is due to specific food items or nutrients, or to the presence and
interaction of a variety of protective components among nutrients and
non-nutrients. It is likely that olive oil is one of the relevant foods, but
its definitive role in cancer prevention remains to be proven.
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