Annals of Oncology Advance Access originally published online on March 19, 2007
Annals of Oncology 2007 18(6):1104-1109; doi:10.1093/annonc/mdm078
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© 2007 European Society for Medical Oncology
epidemiology |
Flavonoids and laryngeal cancer risk in Italy
1 Istituto di Ricerche Farmacologiche ‘Mario Negri', Milan, Italy
2 Clinica Otorinolaringoiatrica, DNTB, Università Milano-Bicocca, Monza, Italy
3 International Epidemiology Institute, Rockville, USA
4 Department of Hygiene and Epidemiology, University of Athens Medical School, Goudi, Athens, Greece
5 Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano, Italy
6 International Agency for Research on Cancer, Lyon Cedex, France
7 Istituto di Igiene ed Epidemiologia, Universitá degli Studi di Udine, Udine, Italy
8 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
* Correspondence to: Dr M. Rossi, Laboratorio di Epidemiologia, Istituto di Ricerche Farmacologiche ‘Mario Negri', Via Eritrea 62, 20157 Milan, Italy. Tel: +39-02-39014-541; Fax: +39-02-33200231; E-mail: mrossi{at}marionegri.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: Flavonoids may play an important role in explaining the protective effect of vegetables and fruit against cancer.
Patients and methods: To investigate the relation between flavonoids and laryngeal cancer risk, we have applied data on the composition of foods and beverages in terms of six principal classes of flavonoids to a case–control study of laryngeal cancer conducted from 1992 to 2000 in Italy. Cases were 460 subjects with incident, histologically confirmed laryngeal cancer; controls were 1088 patients admitted for acute, non-neoplastic diseases. Odds ratios (OR) were estimated through multiple logistic regression models, including terms for sociodemographic and lifestyle factors, tobacco smoking, alcohol consumption and energy intake.
Results: Significant inverse relations were found for the highest versus the lowest quintile of intake for flavan-3-ols (OR = 0.64), flavanones (OR = 0.60), flavonols (OR = 0.32) and total flavonoids (OR = 0.60), although the overall trends in risk were significant only for flavanones and flavonols. No consistent associations were observed for isoflavones, anthocyanidins and flavones. The estimates did not differ substantially across strata of alcohol drinking, tobacco smoking, body mass index and education, and tended to persist even after controlling for vegetable and fruit intake.
Conclusion: This study provides support for a beneficial effect of selected flavonoids on laryngeal cancer risk.
Key words: case–control study, flavonoids, laryngeal cancer, phytoestrogens, risk factors
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Flavonoids are polyphenols present in vegetables, fruit and beverages of plant origin. These compounds have been categorised into six classes (i.e. isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols) according to their chemical structure and biological activity [1]. Because of their antioxidant, antimutagenic and antiproliferative properties [2–5], flavonoids may have a protective role on various chronic diseases, including cancer [6, 7], and may explain, at least in part, the inverse association between consumption of vegetables and fruit and the risk of several common neoplasms [8–10]. In fact, flavonoids have been inversely associated with risk of several cancers [11, 12], including those of the lung, digestive tract and breast [13–16].
As concerns laryngeal cancer, several studies have reported a favourable effect of fruit and vegetables [17–20]. To our knowledge, only one case–control study conducted in Uruguay [21], involving 34 cases, has investigated the relation between flavonoids and laryngeal cancer and has reported an inverse association [odds ratio (OR) = 0.6 for the highest versus the lowest tertile].
Herein, we analysed the relation between different classes of flavonoids and laryngeal cancer using data from a large multicentric study conducted in Italy.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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A case–control study of cancer of the larynx was conducted from 1992 to 2000 in the provinces of Milan and Pordenone, in northern Italy [22]. Cases were 460 subjects (415 men, 45 women; median age 61 years, range 30–80) admitted to the major teaching and general hospitals in the areas under study with incident, histologically confirmed squamous cell cancer of the larynx, diagnosed no longer than 1 year before the interview and with no history of cancer at other sites. Controls were 1088 subjects (863 men, 225 women; median age 61 years, range 31–79) admitted to the same hospitals as the cases for a wide spectrum of acute, non-neoplastic conditions, unrelated to smoking or alcohol consumption or to long-term modifications of diet. Controls were frequency matched with cases by age (5-year groups), sex, year of interview and area of residence. To compensate for the rarity of laryngeal cancer in women, a control-to-case ratio of about 5 was chosen for women, as opposed to about 2 for men. Twenty-nine per cent of the controls were admitted for traumas, 36% for other orthopaedic disorders, 12% for acute surgical conditions and 23% for miscellaneous other illnesses. Less than 5% of both cases and controls contacted refused to participate.
A structured questionnaire was administered by trained interviewers to cases and controls during their hospital stay. The questionnaire included information on sociodemographic characteristics, anthropometric measures, lifestyle habits, notably tobacco smoking and alcohol consumption, personal medical history and family history of cancer in first-degree relatives.
A food-frequency questionnaire (FFQ) was used to assess the patients’ usual diet in the 2 years before diagnosis, including 78 foods or beverages as well as complex recipes. Subjects were asked to indicate their average weekly frequency of consumption for each dietary item. The FFQ showed satisfactory reproducibility and validity [23, 24]. Selected nutrients and total energy intake were estimated using an Italian food composition database, supplemented with other published data [25, 26]. Food and beverage content of six classes of flavonoids (i.e. isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones and flavonols) was obtained from the US Department of Agriculture [27, 28], supplemented by data from other sources [29–31]. Major flavonoids included in these classes were genistein and daidzein for isoflavones, cyanidin and malvidin for anthocyanidins, epicatechin and catechin for flavan-3-ols, hesperitin and narigerin for flavanones, apigenin and luteolin for flavones and quercetin, myricetin and kaempferol for flavonols. In this population, isoflavones derived mainly from vegetable or bean soups and pulses, anthocyanidins from wine and red fruits, flavan-3-ols from tea, wine and fruits, flavanones from citrus fruit, flavones from cooked vegetables and flavonols from various common vegetables and fruit, as well as wine. Total flavonoids were calculated by summing up the six classes of flavonoids.
Quintiles based on the control distribution were computed both directly on the flavonoids and on the residuals of the regression of flavonoids on energy [32]. Since both analysis yielded similar results, only findings from the first approach are presented. ORs, and corresponding 95% confidence intervals (CIs), were estimated using unconditional multiple logistic regression models [33], including terms for quinquennia of age, sex, study centre, years of education, alcohol drinking, tobacco smoking, body mass index (BMI), occupational physical activity and nonalcohol energy intake. In alternative models, further terms for fruit and vegetable consumption and for intake of selected micronutrients were added.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Table 1 shows the distribution of 460 cases of laryngeal cancer and 1088 controls according to age, education, smoking habits, alcohol consumption and nonalcohol energy intake, separately for men and women. Cases reported significantly higher consumption of tobacco, alcohol and non-alcohol energy intake.
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Table 2 gives the mean daily intake of six classes of flavonoids and total flavonoids among controls and the ORs for laryngeal cancer according to quintile of intake and for subjects in the four upper quintiles of consumption combined as compared with those in the lowest one. The mean daily intake was 25.0 µg for isoflavones, 28.0 mg for anthocyanidins, 76.0 mg for flavan-3-ols, 32.4 mg for flavanones, 0.5 mg for flavones, 25.9 mg for flavonols and 162.9 mg for total flavonoids. Significant inverse relations were found for flavan-3-ols (OR = 0.64 for the highest versus the lowest quintile of intake), flavanones (OR = 0.60), flavonols (OR = 0.32) and total flavonoids (OR = 0.60), although the trends in risk were significant only for flavanones and flavonols. No significant associations emerged for isoflavones (OR = 0.73), anthocyanidins (OR = 0.77) and flavones (OR = 0.76). The ORs did not substantially change after exclusion of flavonoids derived from wine (65% of anthocyanidins, 30% of flavan-3-ols and 12% of flavonols). Further adjustment for total fruit and vegetable intake did not materially modify the associations for flavan-3-ols (OR = 0.68, 95% CI 0.47–1.02), flavanones (OR = 0.61, 95% CI 0.43–0.85) and flavonols (OR = 0.64, 95% CI 0.43–0.95), while for total flavonoids the OR became 0.80 (95% CI 0.54–1.20). Generally, results were not substantially altered after allowance for carotenoids, vitamin E and folate intake. The OR for flavanones became 0.83 when vitamin C was included in the model.
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Table 3 shows the ORs of selected flavonoids for subjects in the four upper quintiles of consumption as compared with those in the lowest one, in separate strata of tobacco smoking, alcohol drinking, BMI and education. Risk patterns were generally consistent across these strata, with no significant heterogeneity.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The results of the present study indicate that flavonoids, and in particular flavanones and flavonols, are inversely related to laryngeal cancer risk. For flavan-3-ols and total flavonoids, no linear dose–response relation was found, although subjects with an intake over the first quintile had reduced risk of laryngeal cancer. Our data are in agreement with those of the only other study conducted on flavonoids overall and laryngeal cancer [21].
The strengths and weaknesses of hospital-based case–control studies should be considered [33]. Dietary information can be influenced by recent diagnosis of cancer. However, the information collected referred to the habitual diet in the 2 years before diagnosis or hospital admission. Dietary habits of hospital controls may differ from those of the general population, but only patients admitted to hospital for acute conditions unrelated to major changes in diet and other lifestyle factors were included. Moreover, the same interview setting and catchment areas for cases and controls, and the almost complete participation, are reassuring with reference to information and selection bias. Among the limitations of this study is the issue of the suitability of US food composition data for flavonoids in the Italian diet. Moreover, it is difficult to evaluate the precision of exposure measurement due, in part, to the variability in plant flavonoid content attributable to geologic, climatic and meteorologic factors. Among the strengths of the study, there are its large dataset, the variable and relatively high intake of fruit and vegetables in this population [34, 35], the satisfactory reproducibility and validity of the FFQ [23, 24], and the ability to control for energy intake. Furthermore, the well-recognized risk factors for laryngeal cancer (tobacco, alcohol, education, etc.) were consistently observed in the present dataset [36], and were controlled for in the analyses.
Flavonoids have several important biological functions, which may be related to cancer risk. In vitro and animal model systems showed that they influence signal transduction pathways, stimulate apoptosis and inhibit inflammation and proliferation in human cancer cell lines [11]. Selected flavonoids may also increase transcription of phase II detoxifying enzymes, involved in the clearance of procarcinogenic substances [37].
Flavanones have been inversely related to gastric cancer in a Greek case–control study [13] and to esophageal cancer in an Italian study [38]. This is of particular interest given the similarities in risk factors between various neoplasms of the upper digestive and respiratory tract (mainly tobacco, alcohol, as well as a diet poor in vegetables and fruit) [9, 39], and with gastric cancer, too (i.e. tobacco, lower social class and various indicators of a poor diet) [40]. As also noted for laryngeal cancer, the inverse relation between flavanones, stomach and esophageal cancer was still persistent, although weakened, after allowance for vitamin C [13, 38]. Thus, flavanones may at least in part account for the consistent inverse relations observed between fruit consumption, especially citrus fruit, and laryngeal as well as other upper aerodigestive tract neoplasms [9, 41].
Flavonols have been inversely related to the risk of cancers of the stomach in a case–control study from Spain [42]; of the colorectum in an Italian case–control study [14]; of the lung in the Alpha-Tocopherol, ß-carotene Cancer Prevention Study and the Finnish Mobile Clinic Health Examination Survey [43–45] and of the prostate in the latter Finnish cohort [45]. In particular, kaempferol has been inversely related to stomach cancer risk [42] and myrcetin to prostate cancer [45]. It appears therefore that flavonols have a favourable effect on the risk of several neoplasms, mainly of the digestive and respiratory tract, where they could prevent damage to the mucosa, including damage due to oxidative stress resulting from tobacco smoking and alcohol drinking.
As concerns flavan-3-ols and total flavonoids, our results are compatible with the existence of a threshold effect of flavonoids, since only low intake of flavonoids appears to have a detrimental effect on laryngeal cancer in this population. However, this could simply suggest that a low intake of flavonoids may be an indicator of unfavourable dietary and lifestyle habits in spite of adjustment for several related factors.
There was an inverse trend in risk with isoflavones, although the trend was not linear and the OR for the highest level of intake was not significant. In our study, isoflavones derive mainly from beans, soy and soy products, whose consumption is limited in Italy, and this may explain the inconsistent relation observed.
In conclusion, we have found evidence that low levels of flavanones and flavonols may be associated with an increased risk of laryngeal cancer. This association could be partially responsible for the well-established inverse association between intake of fruit and vegetables and the occurrence of laryngeal cancer.
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Acknowledgements |
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The authors thank I. Garimoldi and M. P. Bonifacino for editorial assistance. This work was conducted with the contribution of the Italian Association for Cancer Research, the Italian League Against Cancer, and the Italian Ministry of Research (PRIN 2005).
Received for publication October 10, 2006. Accepted for publication February 6, 2007.
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