This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Benetou, V. Articles by Trichopoulou, A. Search for Related Content PubMed PubMed Citation Articles by Benetou, V. Articles by Trichopoulou, A.

Vegetables and Fruits in Relation to Cancer Risk: Evidence from the Greek EPIC Cohort Study

¹ Department of Hygiene and Epidemiology, University of Athens Medical School; ² Hellenic Health Foundation, Athens, Greece; ³ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; and ⁴ Genetic and Epidemiology Cluster, IARC, Lyon, France

Requests for reprints: Vassiliki Benetou, Department of Hygiene and Epidemiology, University of Athens Medical School, 75 Mikras Asias Street, 115 27 Athens, Greece. Phone: 30-210-746-2074; Fax: 30-210-746-2079. E-mail: vben{at}nut.uoa.gr

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Introduction: Vegetables and fruits have long been considered as conducive to cancer prevention, but this view has recently been challenged. We investigated the relation of vegetable and fruit intake with total cancer occurrence in the population-based cohort of the Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC), which is characterized by high consumption of these foods.

Materials and Methods: For a median of 7.9 years, 25,623 participants (10,582 men, 15,031 women) were actively followed-up, contributing 188,042 person-years. Cancer at any site was diagnosed in 851 participants (421 men, 430 women). Dietary intakes were ascertained at enrollment through an extensive, validated, interviewer-administered food frequency questionnaire. Data were analyzed through Cox regression, controlling for potential confounders.

Results: An inverse association of cancer incidence with vegetables and fruits (mutually adjusted) was noted, reaching statistical significance for vegetables among women. When vegetables and fruits were combined, the inverse association with cancer occurrence was statistically significant for the entire cohort [hazard ratio per increasing quintile, 0.94; 95% confidence interval (95% CI), 0.88-0.99], as well as among women (hazard ratio per increasing quintile, 0.90; 95% CI, 0.83-0.98), but not among men (hazard ratio per increasing quintile, 0.95; 95% CI, 0.87-1.04).

Conclusions: In a general population-based Greek cohort, we have found evidence that consumption of vegetables and fruits is inversely associated with incidence of cancer overall, although the associations seem to be weaker than expected on the basis of case-control studies previously undertaken in Greece. (Cancer Epidemiol Biomarkers Prev 2008;17(2):387–92)

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Whether diet is responsible for almost 35% of total cancer mortality, as the classic report by Doll and Peto (1) postulated, or for 15% to 20%, as it was more recently suggested (2, 3), plant foods have been assumed to have considerable beneficial effects for cancer prevention. Indeed, in 1997, the World Cancer Research Fund summarized the published data as indicating that for five cancer sites (mouth and pharynx, esophagus, lung, stomach, and large bowel) there was "convincing" evidence that vegetables and/or fruits have a protective effect, whereas for another 11 cancer sites the existing evidence was either "probable" (larynx, pancreas, breast, and urinary bladder) or "possible" (corpus uteri, cervix uteri, kidney, liver, ovary, prostate, and thyroid gland) (4). Since 1997, inverse associations of vegetables and/or fruits with various cancer sites have been reported either from large case-control studies (5, 6) or from large cohort investigations (7-11), although in a major report from the International Agency for Research on Cancer (IARC) no association of any particular cancer with fruits and vegetables was considered as firmly established (12). It is also worth noting that although several null studies for particular cancer sites have been reported, no positive associations of any cancer site with either vegetables or fruits have been documented in any epidemiologic investigation. Thus, it was surprising that a combined analysis of two major cohorts, the Nurses' Health Study composed of 71,910 female participants and the Health Professionals' Follow-up Study with 37,725 male participants, indicated no association of fruit and vegetable intake with the incidence of all cancers (13).

In Greece, inverse associations of vegetables and/or fruits with several forms of cancer have been reported over the years from moderately sized case-control investigations (14-17). We have thus examined the association between these food categories and cancer occurrence overall in a general, population-based, cohort in Greece, which constitutes the Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC). This component cohort of EPIC is characterized by high consumption of vegetables and fruits as well as considerable variation in intake, and ascertainment of dietary exposures was done by specially trained personnel in face-to-face interviews. Moreover, the Greek EPIC cohort is population based, allowing approximate estimations of population attributable rates.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Recruitment and Approval
The enrollment of participants in the Greek component of EPIC took place between 1994 and 1999. A total of 28,572 participants from all over Greece were recruited. EPIC is a prospective cohort study conducted in 23 research centers in 10 European countries with the aim of investigating the role of biologic, dietary, lifestyle, and environmental factors in the etiology of cancer and other chronic diseases (18, 19). All procedures were in accordance with the Helsinki Declaration, all participants provided written informed consent, and the study protocol was approved by the ethics committees both at the IARC (a key participant in EPIC) and at the University of Athens Medical School.

Data on Diet
Usual dietary intake during the year preceding enrollment was assessed through a validated, semiquantitative, food frequency questionnaire including 150 foods and beverages, as well as several complex recipes (20, 21). The questionnaire, which was administered in person by specially trained interviewers, comprised 63 entries for vegetables, 5 entries for legumes, and 19 entries for fruits, including the entries from complex recipes. Because vegetables are consumed in much higher quantities than legumes (at least 50 times higher) and the two food groups are frequently not distinguished in the literature, we have integrated legumes into the vegetable group.

For each dietary item, participants were asked to report their frequency of consumption and portion size. This information was used for the estimation of consumed quantities (in grams per day) and, on the basis of a food composition data base that has been modified to accommodate the particularities of the Greek diet (22), for the estimation of total energy intake (in kilocalories per day).

Data on Other Variables
At enrollment, several sociodemographic and lifestyle characteristics, including detailed smoking and alcohol drinking habits, as well as dietary supplement intake, were recorded. Anthropometric measurements were also undertaken using standardized procedures and allowing the calculation of body mass index (in kilograms per square meter). Finally, on the basis of the frequency and duration of participation in occupational and leisure-time physical activities, an overall metabolic equivalent (MET)-hour per day index was calculated, expressing the average daily energy expenditure level (19, 23, 24).

Participants and Follow-up
From the original cohort of 28,572 participants, 1,696 (5.9%) were excluded because information from follow-up was not available. An additional 383 participants (1.3%) were excluded because they had prevalent cancer (excluding nonmelanoma skin cancer) and another 870 (3.0%) because they had missing values in one or more of the variables used in the analyses. Thus, information from a total of 25,623 participants was evaluated in this study.

Follow-up was active and conducted at regular time intervals through telephone contacts with the participants or, in case of death, their next of kin. A structured form was filled in by specially trained health professionals, and when an incident cancer was reported, verification was sought through pathology reports, medical records, discharge diagnoses, or death certificates according to the IARC guidelines for the collection of end-point data. Classification of cancer cases was done on the basis of the International Classification of Diseases for Oncology (ICD-O-2) (25). The median duration of follow-up was 7.9 years, for a total of 188,042 person-years. The outcome studied was the first diagnosis of any cancer (excluding nonmelanoma skin cancer). In some instances, when diagnosis of incident cancer was not reported, death from cancer was recorded (110 cases).

Statistical Analysis
All analyses were done with the use of STATA.7 statistical package. Frequency distributions were used for descriptive purposes. Medians and quartiles were used for dietary variables including energy intake. The date of first diagnosis of incident cancer (or the date of death from incident cancer when the date of diagnosis was not reported) was used for the calculation of time to event (cancer occurrence, death from causes other than cancer, or last contact till March 2007). Time to event was modeled through Cox proportional hazards regression, using as the main predictor variables vegetables (including legumes) and fruits, and in a separate model, the combination of vegetables and fruits in a single variable. All models were stratified by sex and adjusted simultaneously for age (<35, 35-44, 45-54, 55-64, and >65 years; categorically), years of formal education (5, 6-11, 12, and 13 years; categorically), smoking status (never smoker, former smoker, and five categories of current smoker: 1-10, 11-20, 21-30, 31-40, and 41 cigarettes per day; ordered), body mass index (in ordered quintiles), height (in ordered quintiles), physical activity expressed in MET-hours per day (in ordered quintiles), daily alcohol intake (per 10 g of ethanol; continuously), supplement intake (no, yes), and total energy intake (in ordered quintiles). In the Cox models, the assumption of proportionality was met (assessed through Schoenfeld goodness-of-fit test), no time-dependent covariates were used, and there was no colinearity among the variables.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
During 188,042 person-years of follow-up, a total of 851 cases of incident cancer were recorded.

Table 1 shows baseline characteristics of the study population and the cancer cases. The data in this table serve only descriptive purposes because mutual confounding and time to event are not accounted for. Of interest is the high body mass index among both men and women in this population. A high proportion of men and a substantial proportion of women are current smokers, whereas intake of dietary supplements is not uncommon among women, but it is rather limited among men.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In a cohort study undertaken among volunteers from the general population of Greece, consumption of vegetables (including legumes) and fruits combined was significantly inversely associated with cancer occurrence in the total cohort, after adjustment for several potential confounding variables including age, educational level, tobacco smoking, physical activity, and total energy intake. When vegetables and fruits were examined separately, indicative inverse associations with cancer occurrence were observed, which reached statistical significance for vegetables among women.

Until recently, it has generally been assumed that vegetables and/or fruits are inversely associated with cancer at several sites with supporting evidence mostly derived from case-control studies (1, 2, 4, 26, 27). Plausible mechanisms through which these food groups could convey protection against a spectrum of malignancies have also been proposed (28, 29).

Results from large cohort studies, focusing on specific cancer sites and reported with increasing frequency during the last decades, have supported a role of vegetables and/or fruits against the occurrence of cancer at certain sites (9, 10, 30-33). Nevertheless, the inverse associations observed in the cohort studies were generally weaker than those reported from the case-control investigations, the discrepancies being due to either recall and selection biases in case-control studies or imprecise dietary measurements in cohort investigations (34). Indeed, in a major report by IARC, no cancer site was deemed to be conclusively inversely related to intake of fruits and/or vegetables, although no evaluation for overall cancer occurrence was attempted (12). Moreover, recently, combined results from two major U.S. cohorts, the Nurses' Health Study and the Health Professionals' Follow-up Study, indicated no association between intake of vegetables and fruits and overall cancer occurrence (13).

Unlike that of Hung et al. (13), our data indicated a significant, albeit weak, inverse association between combined intake of vegetables and fruits and cancer occurrence. The association was stronger among women, although the interaction terms of intake by sex were not statistically significant. There are several possible explanations for the discrepancy of our results from those of Hung and colleagues. Schatzkin and Kipnis (35) noted that the null results reported by Hung and colleagues could reflect exposure misclassification in their study because the assessment tool used is subject to error, both random and systematic. They point out that because dietary exposures are examined in conjunction with energy intake and other covariates that have their own errors and may be variably correlated among themselves, an attenuation of a modest inverse association of vegetables and fruits with cancer occurrence cannot be excluded. Dekker and Verkerk (36) postulate that protection of vegetables and fruits is conveyed by certain components within them and that these components may have variable effects with variable latencies with respect to the various outcomes (cancer in different sites). Potter (37) speculates about genuine exposure variability over time and points out that when cancer is considered as a consolidated outcome, one has to take into account that some cancers may be strongly related to vegetables and fruits, and others not at all. Finally, Hung and colleagues argue that perhaps cancer risk is elevated only in individuals with low intake of vegetables and fruits and that supplement intake may distort the association of vegetables and fruits with cancer—the latter argument is also supported by the data of Olsen et al. (38). In our study, however, there was no evidence that the inverse association pattern was more evident among supplement nonusers than among users.

It is possible that the results of Hung et al. (13) approximate reality better and that the findings from the Greek EPIC cohort are an aberration. Selection and information bias, however, cannot be invoked to explain the findings of our study given its prospective cohort design and that possible confounders, including age, tobacco smoking, educational lever, physical activity, supplement intake, and energy intake, have been controlled for. Chance, although it cannot be completely dismissed, is an unlikely explanation of our findings given the overall pattern presented in Tables 4 and 5.

There are other potential explanations for the discrepancy noted between our results and those of Hung and colleagues. Dietary ascertainment in the Greek EPIC cohort was based on an interviewer-administered questionnaire, whereas the dietary questionnaires in the Nurses' Health Study and in the Health Professionals' Follow-up Study were self-administered. There is no evidence, however, that the Greek, interviewer-administered, questionnaire has generated more valid results than the self-administered one used in the American cohorts. It is also possible that the high consumption of fruits and, particularly, vegetables in certain segments of the Greek population facilitates the documentation of a log-linear association; it may be of importance that when vegetables and fruits were combined, the reduction of cancer risk was particularly evident in the upper two quintiles (Q4 and Q5). Finally, consumption of seasonal fresh vegetables and fruits is more likely in the Greek rather than the American population.

Strengths of our investigation are its prospective design, the employment of interviewer-administered validated research instruments, and the use as outcome of medically confirmed cases of incident cancer. Limitations of our study are the inability to separately examine individual cancer sites in relation to vegetable and fruit intake because of power limitations. This could lead to underestimation of the strength of association between vegetables and fruits and genuinely related cancer sites because overall cancer occurrence incorporates the occurrence of tumor sites for which there has been little or no evidence for an association with these foods (e.g., lymphoid neoplasms and prostate cancer). The use of time of cancer death as substitute for the time of cancer diagnosis for 110 of the 851 incident cancer cases is also a limitation. It should be noted, however, that in many instances in Greece, cancer diagnosis is hidden from the patient so that sensitivity of ascertainment is somewhat reduced, although specificity is very high because medical confirmation is required.

Calculation of cancer rates attributable to reduced consumption of vegetables and fruits would be of obvious importance. These calculations are hindered by the fact that attributable rates must rely on both the hazard ratios and the prevalence of the exposure (here reduced vegetable and fruit consumption), each of which has its own chance variation. Moreover, attributable rates are strictly interpretable when they rely on a random sample of the population. The Greek EPIC cohort, although population based, relies on volunteers. Nevertheless, we have attempted calculation of attributable rates using a simple procedure suggested by Wahrendorf (39). If every participant in the Greek EPIC cohort was consuming the quantities of vegetables and fruits of the upper (highest) quartile, then cancer incidence would be reduced by 4.5% among men and by 26% among women.

In conclusion, we have found evidence from a cohort study based on the general population of Greece that consumption of vegetables, and perhaps fruits, is inversely associated with cancer incidence. The association, however, seems to be somewhat weaker than would have been expected on the basis of case-control studies previously undertaken in Greece.

	Footnotes

 
Grant support: Europe against Cancer Program of the European Commission, the Greek Ministries of Health and Education, and the Hellenic Health Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/ 8/07; revised 11/14/07; accepted 11/16/07.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risk of cancer in the United States today. J Natl Cancer Inst 1981;66:1191–308.[Medline]
2. Lagiou P, Adami H-O, Trichopoulos D. Causality in cancer epidemiology. Eur J Epidemiol 2005;20:565–74.[Medline]
3. Willett WC. Diet, nutrition, and avoidable cancer. Environ Health Perspect 1995;103 Suppl 8:165–70.
4. World Cancer Research Fund Panel. Food, nutrition and the prevention of cancer: a global perspective. Washington (DC): American Institute of Cancer Research; 1997.
5. La Vecchia C, Chatenoud L, Francheschi S, Soler M, Parrazini F, Negri E. Vegetables and fruit and human cancer: update of an Italian study. Int J Cancer 1999;82:151–2.[CrossRef][Medline]
6. Francheschi S, Parpinel M, La Vecchia C, Favero A, Talamini R, Negri E. Role of different types of vegetables and fruits in the prevention of cancer of the colon, rectum, and breast. Epidemiology 1998;9:338–41.[CrossRef][Medline]
7. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst 2000;92:1812–23.[Abstract/Free Full Text]
8. Zhang SM, Hunter DJ, Posner BA, et al. Intakes of fruits, vegetables and related nutrients and the risk of non-Hodgkin's lymphoma among women. Cancer Epidemiol Biomarkers Prev 2000;9:477–85.[Abstract/Free Full Text]
9. Linseisen J, Rohrmann S, Miller AB, et al. Fruit and vegetable consumption and lung cancer risk: updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 2007;121:1103–14.[Medline]
10. Gonzalez CA, Pera G, Agudo A, et al. Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Cancer 2006;118:2559–66.[CrossRef][Medline]
11. Gonzalez CA, Riboli E. Diet and cancer prevention: where we are, where we are going. Nutr Cancer 2006;56:225–31.[Medline]
12. International Agency for Research on Cancer. Fruit and vegetables. IARC handbooks of cancer prevention. Vol. 8. Lyon: IARC; 2003.
13. Hung HC, Joshipura KJ, Jiang R, et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst 2004;96:1577–84.[Abstract/Free Full Text]
14. Manousos O, Day NE, Trichopoulos D, Gerovassilis F, Tzonou A, Polychronopoulou A. Diet and colorectal cancer: a case-control study in Greece. Int J Cancer 1983;32:1–5.[Medline]
15. Trichopoulos D, Ouranos G, Day NE, et al. Diet and cancer of the stomach: a case-control study in Greece. Int J Cancer 1985;36:291–7.[Medline]
16. Kalandidi A, Katsouyanni K, Voropoulou N, Bastas G, Saracci R, Trichopoulos D. Passive smoking and diet in the etiology of lung cancer among non-smokers. Cancer Causes Control 1990;1:15–21.[CrossRef][Medline]
17. Trichopoulou A, Katsouyanni K, Stuver S, et al. Consumption of olive oil and specific food groups in relation to breast cancer risk in Greece. J Natl Cancer Inst 1998;87:110–6.
18. Riboli E, Hunt KJ, Slimani N, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 2002;5:1113–24.[CrossRef][Medline]
19. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348:2599–608.[Abstract/Free Full Text]
20. Gnardellis C, Trichopoulou A, Katsouyanni K, Polychronopoulos E, Rimm EB, Trichopoulos D. Reproducibility and validity of an extensive semi-quantitative food frequency questionnaire among Greek school teachers. Epidemiology 1995;6:74–7.[Medline]
21. Katsouyanni K, Rimm EB, Gnardellis C, Trichopoulos D, Polychronopoulos E, Trichopoulou A. Reproducibility and relative validity of an extensive semi-quantitative food frequency questionnaire using dietary records and chemical markers among Greek school teachers. Int J Epidemiol 1997;26:S118–27.[Abstract/Free Full Text]
22. Trichopoulou A, Georga K. Composition tables of foods and Greek dishes. Athens (Greece): Parisianos; 2004.
23. Ainsworth BE, Haskell WL, Leon AS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 1993;25:71–80.
24. Trichopoulou A, Gnardellis C, Lagiou A, Benetou V, Trichopoulos D. Body mass index in relation to energy intake and expenditure among adults in Greece. Epidemiology 2000;11:333–6.[CrossRef][Medline]
25. International Classification of Diseases for Oncology. 2nd ed. Geneva: World Health Organization; 1990.
26. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 1991;2:325–57.[CrossRef][Medline]
27. World Cancer Report. International Agency for Research on Cancer. In: Steward B, Kleihues P, editors. Lyon (France): World Health Organization; 2003.
28. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 1991;2:427–42.[CrossRef][Medline]
29. Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 2007;55:224–36.[Medline]
30. Terry P, Giovannucci E, Mickels KB, et al. Fruit, vegetables, dietary fiber and risk of colorectal cancer. J Natl Cancer Inst 2001;93:525–33.[Abstract/Free Full Text]
31. Terry P, Nyren O, Yuen J. Protective effect of fruits and vegetables on stomach cancer in a cohort of Swedish twins. Int J Cancer 1998;76:35–7.[Medline]
32. 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. J Natl Cancer Inst 1999;91:605–13.[Abstract/Free Full Text]
33. Freedman ND, Park Y, Subar AF, et al. Fruit and vegetable intake and esophageal cancer in a large prospective cohort study. Int J Cancer 2007;15:2753–60.
34. Riboli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr 2003;78:559–69S.
35. Schatzkin A, Kipnis V. Could exposure assessment problems give us wrong answer to nutrition and cancer questions? J Natl Cancer Inst 2004;96:1564–5.[Free Full Text]
36. Dekker M, Verkerk R. Re: Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst 2005;97:607–8.[Free Full Text]
37. Potter J. Vegetables, fruit, and cancer. Lancet 2005;366:527–30.[CrossRef][Medline]
38. Olsen A, Stripp C, Christense J, Thomsen BL, Overvad K, Tjonneland A. Re: Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst 2005;97:1307–8.[Free Full Text]
39. Wahrendorf J. An estimate of the proportion of colo-rectal and stomach cancers which might be prevented by certain changes in dietary habits. Int J Cancer 1987;40:625–8.[Medline]

This article has been cited by other articles:

				A.R.M. R. Amin, O. Kucuk, F. R. Khuri, and D. M. Shin Perspectives for Cancer Prevention With Natural Compounds J. Clin. Oncol., June 1, 2009; 27(16): 2712 - 2725. [Abstract] [Full Text] [PDF]

				S. M George, Y. Park, M. F Leitzmann, N. D Freedman, E. C Dowling, J. Reedy, A. Schatzkin, A. Hollenbeck, and A. F Subar Fruit and vegetable intake and risk of cancer: a prospective cohort study Am. J. Clinical Nutrition, January 1, 2009; 89(1): 347 - 353. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Benetou, V. Articles by Trichopoulou, A. Search for Related Content PubMed PubMed Citation Articles by Benetou, V. Articles by Trichopoulou, A.