Diet and the Risk of Head and Neck Cancer: A Pooled Analysis in the INHANCE Consortium (original) (raw)

• Journal List
• HHS Author Manuscripts
• PMC3654401

Cancer Causes Control. Author manuscript; available in PMC 2013 May 15.

Published in final edited form as:

PMCID: PMC3654401

NIHMSID: NIHMS449439

Shu-Chun Chuang,1,2 Mazda Jenab,2 Julia E. Heck,3 Cristina Bosetti,4 Renato Talamini,5 Keitaro Matsuo,6 Xavier Castellsague,7 Silvia Franceschi,2 Rolando Herrero,8 Deborah M. Winn,9 Carlo La Vecchia,4,10 Hal Morgenstern,11 Zuo-Feng Zhang,3 Fabio Levi,12 Luigino Dal Maso,5 Karl Kelsey,13 Michael D. McClean,14 Thomas Vaughan,15 Philip Lazarus,16 Joshua Muscat,16 Heribert Ramroth,17 Chu Chen,15 Stephen M. Schwartz,15 Jose Eluf-Neto,18 Richard B. Hayes,19 Mark Purdue,9 Stefania Boccia,20,21 Gabriella Cadoni,22 David Zaridze,23 Sergio Koifman,24 Maria Paula Curado,2 Wolfgang Ahrens,25 Simone Benhamou,26 Elena Matos,27 Pagona Lagiou,28 Neonilla Szeszenia-Dabrowska,29 Andrew F. Olshan,30 Leticia Fernandez,31 Ana Menezes,32 Antonio Agudo,33 Alexander W. Daudt,34 Franco Merletti,35 Gary J. Macfarlane,36 Kristina Kjaerheim,37 Dana Mates,38 Ivana Holcatova,39 Stimson Schantz,40 Guo-Pei Yu,40 Lorenzo Simonato,41 Hermann Brenner,42 Heiko Mueller,42 David I. Conway,43 Peter Thomson,44 Eleonora Fabianova,45 Ariana Znaor,46 Peter Rudnai,47 Claire M. Healy,48 Gilles Ferro,2 Paul Brennan,2 Paolo Boffetta,49,50 and Mia Hashibe2,51

Shu-Chun Chuang

1Imperial College London, London, UK

2International Agency for Research on Cancer (IARC), Lyon, France

Mazda Jenab

2International Agency for Research on Cancer (IARC), Lyon, France

Julia E. Heck

3UCLA School of Public Health, Los Angeles, CA, USA

Cristina Bosetti

4Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

Renato Talamini

5Aviano Cancer Centre, Aviano, Italy

Keitaro Matsuo

6Aichi Cancer Center Research Institute, Nagoya, Japan

Xavier Castellsague

7Institut Català d'Oncologia, Barcelona, Spain

Silvia Franceschi

2International Agency for Research on Cancer (IARC), Lyon, France

Rolando Herrero

8Instituto de Investigación Epidemiológica, San José, Costa Rica

Deborah M. Winn

9National cancer institute, Bethesda, MA, USA

Carlo La Vecchia

4Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

10Department of Occupational Health, University of Milan, Milan, Italy

Hal Morgenstern

11Department of Epidemiology and Environmental Health Sciences and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

Zuo-Feng Zhang

3UCLA School of Public Health, Los Angeles, CA, USA

Fabio Levi

12Institut Universitaire de Medecine Sociale et Preventive, Lausanne, Switzerland

Luigino Dal Maso

5Aviano Cancer Centre, Aviano, Italy

Karl Kelsey

13Brown University, Providence, RI, USA

Michael D. McClean

14Boston University of Public Health, Boston, MA, USA

Thomas Vaughan

15Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Philip Lazarus

16Pen State College of Medicine, Philadelphia, USA

Joshua Muscat

16Pen State College of Medicine, Philadelphia, USA

Heribert Ramroth

17University of Heidelberg, Heidelberg, Germany

Chu Chen

15Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Stephen M. Schwartz

15Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Jose Eluf-Neto

18Departemento Medicina Preventiva, Universidade de Sao Paulo, Sao Paulo, Brazil

Richard B. Hayes

19New York University School of Medicine, NY, USA

Mark Purdue

9National cancer institute, Bethesda, MA, USA

Stefania Boccia

20Institute of Hygiene, Università Cattolica del Sacro Cuore, Rome, Italy

21IRCCS San Raffaele Pisana, Rome, Italy

Gabriella Cadoni

22Institute of Otorhinolaryngology, Catholic University of the Sacred Heart, Rome, Italy

David Zaridze

23Cancer Research Center, Moscow, Russia

Sergio Koifman

24Escola Nacional de Saude Publica, Rio de Janeiro, Brazil

Maria Paula Curado

2International Agency for Research on Cancer (IARC), Lyon, France

Wolfgang Ahrens

25Bermen Institute for Prevention Research and Social Med, Bermen, Germany

Simone Benhamou

26INSERM, Paris, France

Elena Matos

27Institute of Oncology Angel H. Roffo, Buenos Aires, Argentina

Pagona Lagiou

28Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Athens, Greece

Neonilla Szeszenia-Dabrowska

29Institute of Occupational Medicine, Lodz, Poland

Andrew F. Olshan

30University of North Carolina, School of Public Health, Chapel Hill, NC, USA

Leticia Fernandez

31Institute of Oncology and Radiology, Havana, Cuba

Ana Menezes

32Faculdade de Medicina Universidade Federal de Pelotas, Pelotas, Brazil

Antonio Agudo

33Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain

Alexander W. Daudt

34Hospital de Clinicas de Porto Allegre, Brazil

Franco Merletti

35Unit of Cancer Epidemiology, Turin, Italy

Gary J. Macfarlane

36School of Medicine and Dentistry, University of Aberdeen, Scotland, UK

Kristina Kjaerheim

37Cancer Registry of Norway, Oslo, Norway

Dana Mates

38Institute of Public Health, Bucharest, Romania

Ivana Holcatova

39Institute of Hygiene and Epidemiology, Prague, Czech Republic

Stimson Schantz

40Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA

Guo-Pei Yu

40Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA

Lorenzo Simonato

41Department of Environmental Medicine and Public Health, School of Medicine, University of Padova, Padova, Italy

Hermann Brenner

42German Cancer Research Center, Heidelberg, Germany

Heiko Mueller

42German Cancer Research Center, Heidelberg, Germany

David I. Conway

43Dental School, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

Peter Thomson

44University of Newcastle Dental School, Newcastle, UK

Eleonora Fabianova

45Specialized State Health Institute, Banská Bystrica, Slovakia

Ariana Znaor

46Croatian National Cancer Registry, Zagreb, Croatia

Peter Rudnai

47National Institute of Environmental Health, Budapest, Hungary

Claire M. Healy

48Trinity College School of Dental Science, Dublin, Ireland

Gilles Ferro

2International Agency for Research on Cancer (IARC), Lyon, France

Paul Brennan

2International Agency for Research on Cancer (IARC), Lyon, France

Paolo Boffetta

49The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA

50International Prevention Research Institute, Lyon, France

Mia Hashibe

2International Agency for Research on Cancer (IARC), Lyon, France

51University of Utah School of Medicine, Salt Lake City, UT, USA

1Imperial College London, London, UK

2International Agency for Research on Cancer (IARC), Lyon, France

3UCLA School of Public Health, Los Angeles, CA, USA

4Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

5Aviano Cancer Centre, Aviano, Italy

6Aichi Cancer Center Research Institute, Nagoya, Japan

7Institut Català d'Oncologia, Barcelona, Spain

8Instituto de Investigación Epidemiológica, San José, Costa Rica

9National cancer institute, Bethesda, MA, USA

10Department of Occupational Health, University of Milan, Milan, Italy

11Department of Epidemiology and Environmental Health Sciences and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

12Institut Universitaire de Medecine Sociale et Preventive, Lausanne, Switzerland

13Brown University, Providence, RI, USA

14Boston University of Public Health, Boston, MA, USA

15Fred Hutchinson Cancer Research Center, Seattle, WA, USA

16Pen State College of Medicine, Philadelphia, USA

17University of Heidelberg, Heidelberg, Germany

18Departemento Medicina Preventiva, Universidade de Sao Paulo, Sao Paulo, Brazil

19New York University School of Medicine, NY, USA

20Institute of Hygiene, Università Cattolica del Sacro Cuore, Rome, Italy

21IRCCS San Raffaele Pisana, Rome, Italy

22Institute of Otorhinolaryngology, Catholic University of the Sacred Heart, Rome, Italy

23Cancer Research Center, Moscow, Russia

24Escola Nacional de Saude Publica, Rio de Janeiro, Brazil

25Bermen Institute for Prevention Research and Social Med, Bermen, Germany

26INSERM, Paris, France

27Institute of Oncology Angel H. Roffo, Buenos Aires, Argentina

28Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Athens, Greece

29Institute of Occupational Medicine, Lodz, Poland

30University of North Carolina, School of Public Health, Chapel Hill, NC, USA

31Institute of Oncology and Radiology, Havana, Cuba

32Faculdade de Medicina Universidade Federal de Pelotas, Pelotas, Brazil

33Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain

34Hospital de Clinicas de Porto Allegre, Brazil

35Unit of Cancer Epidemiology, Turin, Italy

36School of Medicine and Dentistry, University of Aberdeen, Scotland, UK

37Cancer Registry of Norway, Oslo, Norway

38Institute of Public Health, Bucharest, Romania

39Institute of Hygiene and Epidemiology, Prague, Czech Republic

40Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA

41Department of Environmental Medicine and Public Health, School of Medicine, University of Padova, Padova, Italy

42German Cancer Research Center, Heidelberg, Germany

43Dental School, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

44University of Newcastle Dental School, Newcastle, UK

45Specialized State Health Institute, Banská Bystrica, Slovakia

46Croatian National Cancer Registry, Zagreb, Croatia

47National Institute of Environmental Health, Budapest, Hungary

48Trinity College School of Dental Science, Dublin, Ireland

49The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA

50International Prevention Research Institute, Lyon, France

51University of Utah School of Medicine, Salt Lake City, UT, USA

Corresponding Author: Mia Hashibe, Ph.D., Division of Public Health, Department of Family & Preventive Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT, 84108, Phone: 801-587-3034, Fax: 801-587-3353, ude.hatu@ebihsaH.aiM

Supplementary Materials

Appendix.

GUID: 7983FDD9-D071-4CB9-87CF-4BA03B8AE4AC

02.

GUID: 757CD2D0-C843-462C-BBCA-CED151CA7508

Abstract

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake, was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random effects logistic regression model. An inverse association was observed for higher frequency intake of fruit (4th vs. 1st quartile OR=0.52, 95% CI=0.43–0.62, p_trend_<0.01) and vegetables (OR=0.66, 95% CI=0.49–0.90, p_trend_=0.01). Intake of red meat (OR=1.40, 95% CI=1.13–1.74, p_trend_=0.13) and processed meat (OR=1.37, 95% CI=1.14–1.65, p_trend_<0.01) were positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR=0.90, 95% CI=0.84–0.97).

Keywords: Diet, head and neck cancer, fruit and vegetable, red meat, processed meat

Introduction

Head and neck cancer (HNC), defined as cancers of the oral cavity, oropharynx, hypopharynx, and larynx, is the sixth most common cancer in the world, accounting for about 900,000 cases and 300,000 deaths in 2008 [1]. Tobacco smoking and alcohol drinking are the two most important risk factors for HNC [2], contributing to over 70% of HNC cases [3]. Other important risk factors include passive smoking [4,5], human papillomavirus (HPV) infection [6], low body mass index (BMI) [7], and family history of cancer [8].

The inverse association of fruits and vegetables against HNC have been reported in many epidemiologic studies [9–16]. The recent World Cancer Research Fund (WCRF) report into diet and cancer summarized that the evidence was strong enough to support a probable causal relationship for a decreased HNC risk with non-starchy vegetables, fruits, and food containing carotenoids [17]. However, the evidence of the role of other food groups and the risk of HNC is inconsistent. Meat consumption was suggested to be a risk factor for several cancers [10,17–19], including HNC [9,15,20–22], but the association was not consistent [11,23]. Dairy products were positively associated with HNC in an American study [23], but the association was not observed in an Eastern European [11] or international study [24]. Even for vegetables, the evidence for cruciferous vegetables was not sufficient to make a conclusion in relation to HNC risks [11,12,17,23–31]. Moreover, residual confounding from smoking is still a major concern for the observed associations.

The International Head and Neck Cancer Epidemiology (INHANCE) Consortium is a collaboration of research groups leading large molecular epidemiology case-control studies of HNC (http://inhance.iarc.fr/). The consortium covers populations from Europe, North America, Latin America, India, Japan, and Australia. The large sample size enables us to explore the association between diet and HNC risk within never smokers to avoid the residual confounding from smoking. The geographic coverage helps us to explore the dietary effects on different background fruit and vegetable consumption levels. We took advantage of the data from the consortium to explore the associations between food groups and the risk of HNC.

Methods

The current analysis included 22 of the 26 studies in the consortium pooled data version 1.3. Compared with a previous publication [3], the current dataset included a US multicenter study [32], the MSKCC study [33], the Seattle-LEO study [34], the Western Europe study [9], the Saarland study [35], the Heidelberg study [36], and the Japan study [37]. Appendix 1 lists the recruitment periods, study designs (hospital- or population-based study), and participating rates for each study. There were 14,852 head and neck cancer cases and 22,987 controls.

Cases and controls with missing data on age, sex, or race/ethnicity, and cases with missing information on the site of origin of their cancer were excluded (332 cases and 250 controls). In total, 14,520 cases and 22,737 controls were included in the analysis. Among the cases, 3,859 were oral cancer, 4,755 were pharyngeal cancer, 1,513 were cancer of the oral cavity or pharynx not otherwise specified, 4,073 were laryngeal cancer and 320 overlapping (Table 1). Written informed consent was obtained from all study subjects and the studies were approved by relevant ethics committees at each of the institutes involved. Questionnaires were collected from all the individual studies, to assess the comparability of the collected data and of the wording of interview questions among the studies. Data from individual studies were received with personal identifiers removed. Each data item was checked for illogical or missing values and inconsistencies were resolved as necessary. Details on harmonizing questionnaire data have been published previously [2]. Briefly, the definitions for ever-smoking and drinking are different across studies. We reclassified ever tobacco smokers as those who have smoked at least 100 cigarettes or 100 cigars or 100 pipes in their lifetime. In our previous analyses, drinking (>3 drinks/day) was associated with an increased HNC risk [2] among never smokers, thus we classified heavy drinker as those who have consumed alcohol three or more drinks/day.

Table 1

Characteristics of the study population

Food questionnaires were designed by each individual study. For our analysis, we considered questionnaire wordings to group the food items (Appendix 2). In brief, four major food categories were grouped into: vegetables, fruits, animal products, and others (cereals and grains). Several food items and sub-food categories were identified within each major food categories. Two units were used in the analyses: center-specific quartiles among the controls for food groups and frequency per week (arbitrary chosen cutoffs: <once per week, 1–3 times per week, 3–7 times per week, and ≥7 times per week) for single food items. A score which indicated high consumption of fruit and vegetable intake (0 for the lowest quartile and 3 for the highest quartile) and low red meat (0 for the highest quartile and 3 for lowest quartile) was created for each subject by summing up the scores in each food group. The association between dietary pattern scores and HNC risk was only considered for studies which contributed to all of the three food groups (fruit, vegetable, and red meat; Aviano, Italy Multicenter, Switzerland, Seattle, Tampa, Los Angeles, Puerto Rico, Latin America, Boston, US Multicenter, MSKCC, Seattle-LEO, Western Europe, and Japan).

The associations between food groups/items and HNC risk were assessed by estimating odds ratios (OR) and 95% confidence intervals (CI) with unconditional logistic regression models for each study. Pooled ORs were estimated with a random-effects logistic regression model [38]. To adjust for the potential confounders, the models included age (5-year categories), sex, race/ethnicity (categories), center, education level (categories), packyears of cigarette smoking (continuous), duration of cigar smoking (continuous), duration of pipe smoking (continuous), intensity of alcohol drinking (continuous), and weight (kg, continuous). Information on ethnicity was not collected in the Central Europe, Saarland, and Heidelberg studies. In these studies, all subjects were classified as non-Hispanic white, since the large majority of these populations are expected to be white. Information on education was not collected in the France, Rome, and Japan studies. Weight was not available in the Seattle and Heidelberg studies. Multiple imputations with the PROC MI procedure in the SAS package was applied to impute the missing values of education, considering case-control status, age, sex, race, and study regions. For the Japan study, education was imputed by case-control status, age, and sex, according to the Asian population in the North American studies, because the socioeconomic status in Japan is expected to be similar to that in the North American countries. Stratified analyses were conducted by cancer site (oral cavity, pharynx, oropharynx, and larynx), age (<45 years and ≥45 years), sex, race (White, Black, Hispanic, Asian, and Brazilian), geographic region (Europe, North America, Latin America, and Asia and others), study type (hospital-based and population-based), tobacco smoking status (never, former, and current), and intensity of alcohol drinking (≤3 drinks per day and >3 drinks per day). Heterogeneity across stratum was assessed by I2 statistics and Q test [39]. Subset analyses were conducted according to the completeness of dietary questionnaire (all, at least 30% completed, at least 50% completed, and at least 80% completed) and in the studies which aimed at getting dietary habits at least one year before disease diagnosis/interview.

Analyses were performed using SAS 9.1. Heterogeneity tests were performed by STATA SE11. All tests were two sided and statistical significance was assessed at the level of 0.05.

Results

Table 1 summarizes the characteristics of cases and controls from all studies. Overall, controls included more individuals who were women, were younger, had higher education, and had a heavier average weight than the cases.

Heterogeneity across studies was detected for almost all food groups/items. Pooled results from random-effects model were reported. Table 2 presents the OR and 95% CI for vegetables and the HNC risks. Overall vegetable intake (excluding potatoes) showed an inverse association with HNC (4th vs. 1st quartile: OR=0.66, 95% CI=0.49–0.90, p_trend_=0.01). Similar associations were observed for non-starchy vegetables, especially green vegetables and allium vegetables, but not for cruciferous vegetables. Consumption of green salad, lettuce, and fresh tomatoes more than 7 times per week were associated with lower HNC risks compared to consumption less than once per week. Potato intake was associated with an increased risk of HNC (OR=1.24, 95% CI=1.05–1.46), especially for fried potatoes (OR=2.97, 95% CI=1.40–6.32).

Table 2

Odds ratios (OR) and 95% confidence intervals (CI) for vegetable intake and head and neck cancer risk

Lower head and neck cancer risks were also observed for higher fruit intake (Table 3). Individuals who had the highest overall fruit intake had lower HNC risk (4th vs. 1st quartile OR =0.52, 95% CI=0.43–0.62, p_trend_<0.01), especially with the highest intake of citrus fruits and apples and pears. On the other hand, higher intake of several meat products showed an increased risk for HNC (Table 4), notably for red meat (beef + pork: OR=1.40, 95% CI=1.13–1.74, p_trend_=0.13) and processed meats (OR=1.37, 95% CI=1.14–1.65, p_trend_<0.01), while white meat (poultry + fish) seemed to be inversely associated (OR=0.68, 95% CI=0.55–0.84, p_trend_<0.01). Higher egg consumption was also associated with higher HNC risk (OR=1.44, 95% CI=1.12–1.86). No associations between cereals and grains and HNC risk were observed in these analyses (Table 5). Appendix 3 and Appendix Figure 1–6 show the results from the stratified analyses for the major findings. Ethnicity and study region seemed to be the major source of heterogeneity (_I2_=73% for race and 83% for region for the association between red meat intake and HNC risk, and 59% for race, and 53% for region for the association with vegetable intake). A higher dietary pattern score, which indicated higher consumption of fruit and vegetable and lower consumption of red meat, was associated with lower HNC risk (Table 6, OR for each score increment=0.90, 95% CI=0.84–0.97, p_trend_=0.01).

Table 3

Odds ratios (OR) and 95% confidence intervals (CI) for fruit intake and head and neck cancer risk

Table 4

Odds ratios (OR) and 95% confidence intervals (CI) for meat and eggs and head and neck cancer risk

Table 5

Odds ratios (OR) and 95% confidence intervals (CI) for cereal and grain products and head and neck cancer risk

Table 6

Odds ratios (OR) and 95% confidence intervals (CI) for dietary pattern scores1 and head and neck cancer risks

Table 7 presents the association between major food groups and HNC risks among subjects who were never smokers and light drinkers. Fruit intake was inversely associated with HNC risk (4th vs. 1st quartile: OR=0.66, 95% CI=0.48–0.92, p_trend_=0.27), red meat intake was positively associated with HNC risk (OR=1.55, 95% CI=1.15–2.10, p_trend_=0.19), and a high score was associated with lower HNC risk (7–9 vs. 0–2, OR=0.48, 95% CI=0.32–0.74, p_trend_=0.04).

Table 7

Odds ratios (OR) and 95% confidence intervals (CI) for selected food groups and head and neck cancer risks among never smokers and light drinkers (<=3 drinks/day)

Discussion

Results from our data support the conclusions from earlier studies that a higher frequency of fruit and vegetable intake were inversely associated with HNC risk [9–15,19,22,24,26–28,30,40–47] and red meat and processed meat were positively associated with increased risks of HNC [9,15,16,20–22,28,31,40]. The associations were consistent among subjects who were never smokers and light drinkers. A dietary pattern high in fruit and vegetable and low in red meat intake was associated with decreased HNC risk. Ethnicity and study region could be the major sources of heterogeneity.

The associations between vegetable and HNC were observed mostly in smokers or heavy drinkers but not in never-smokers and light drinkers; this could be explained by residual confounding from smoking or drinking because smokers tend to consume more energy from alcohol and less energy from vegetables [48] and the measurement error might be correlated between diet and smoking behavior. In the present study, we adjusted for packyears of cigarette smoking as well as for duration of cigar and pipe use and drinking intensity for alcohol consumption, thus the residual confounding effect should have been minimized, although it might not be completely eliminated. Removing smoking and drinking variables from the regression model, the OR was 0.56 (95% CI=0.41–0.76) comparing the 4th to the 1st quartile; the ORs were 0.64 (95% CI=0.47–0.88) if adjusted for smoking variables and 0.59 (95% CI=0.44–0.79) if adjusted for drinking variable. All of these estimates were stronger than the full model estimate, OR=0.66, 95% CI=0.49–0.90 (Table 2). Reductions of the HNC risk in never smokers and light drinkers were observed with non-starchy vegetables and carrots (data not shown). An explanation for the limited association in never smokers could be that nutrients in vegetables, such as vitamin C, vitamin E, folate, fibre, and flavonoids, could modulate the carcinogenic effects of smoking by reducing the smoke-induced oxidative damage or inflammatory responses [49–52], thus the effects can only be observed in smokers. An alternative explanation is that the etiology of HNC in never smokers might be different from that in smokers [53–55], such as HPV, an established risk factor for oropharyngeal cancers [56]. A study has reported that HPV infection may modify the association between fruit intake and HNC risk [57].

We observed heterogeneity in the Asian (_I2_=58.8%, p=0.033; Appendix figure 1). The p for heterogeneity was 0.74 if removing the Asians from the meta-analysis. Nevertheless, higher vegetable intake was associated with lower HNC risk in the Asian population.

Fruit intake was inversely associated with HNC in the current analyses, as previously reported [9,10,12,15,19,22,24,26–28,30,40–47,58], especially for citrus fruits, and apples and pears. Smoking status did not seem to influence the associations between fruit and HNC risk in the current analyses, as reported by other studies [10,27,28,30,41,42,58]. The inverse associations from fruit intake were consistent across subsites of HNC, strata of age and sex, and study type, i.e. population controls and hospital controls (Appendix Figure 2).

In terms of other food groups, we observed increased risks for a high frequency of red meat consumption (including beef and pork) and processed meat. Red meat and processed meat are convincing causes of colorectal cancer and suggestive causes of esophageal and lung cancers [17,21,59,60]. The mechanisms behind red meat and processed meat and cancer risks include iron over-storage or the oxidative stress resulting from free radicals [17] and the carcinogens generated or added during meat preparation [61] or preservation [17]. This increased risk was observed not only by comparing the relative high to the relative low consumption but also by comparing individuals who ate beef or pork greater than seven times per week to those who ate less than once per week.

On the other hand, we observed an inverse association between red meat and HNC risk from studies in Asia. This could be because that the Japanese population (the only study contributed to this sub-analyses) generally consumes less red meat [62] and more vegetables [17,63] than populations from the North America or Western Europe.

In contrast, we observed an inverse association between white meat (a combination of poultry, fish, and shellfish) and HNC. The epidemiological evidence for the association between white meat and HNC has been inconsistent. A prospective investigation in the US (the NIH-AARP cohort, [64]) found an inverse association between poultry and fish intake and digestive and respiratory cancers, including a strong inverse association between poultry intake and laryngeal cancer among women. The authors attributed the inverse association to the red meat substitution effects. Relative to red meat, poultry and fish are lower in saturated fat and heme iron and may result in less exposure to free radicals or carcinogens generated during the processing of red meat or processed meat [64]. Alternatively, poultry is high in zinc, which might protect against oxygen radicals and lipid peroxidation that can promote carcinogenesis [65]. Fish contains omega-3 fatty acids, which is associated with better immune function [66]. However, poultry and fish intake could be an indicator of general nutritional status. Nevertheless, the heterogeneity was not evident in any subgroups (Appendix Figure 4) and a decreasing trend (though not statistical significant) was observed among never smoker and light drinkers (Table 7). Mutual adjustment for red and white meat did not change the associations between HNC and white and red meat substantially.

We also observed an increased risk for consuming more than three eggs per week compare to less than one egg per week. The association has been observed previously, but results have been inconsistent [15,16,25,27–29,31,40,44–47,67–69]. We performed principal component analysis on food items for each study in our consortium. Egg consumption showed an association with meat intake in most of the studies: Milan, Aviano, Italy Multicenter, Switzerland, Central Europe, Seattle, North Carolina, Tampa, Los Angeles, Latin America, Boston, US Multicenter, MSKCC, Seattle-LEO, and Japan. On the other hand, there were associations between egg intake and fruit and vegetable intakes for other studies: France, Puerto Rico, IARC Multicenter, and Saarland. Egg consumption might be a marker of special diet requirements. However, stratification by fruit, vegetable, red meat, or processed meat intake did not alter the observed positive associations.

Because high intake of some dietary items might be correlated with lower intake of other items, we addressed this pattern with a score, which reflects high intake of fruit and vegetable and low intake of red meat. We observed that a higher score was associated with a reduced HNC risk. The association was consistent across subsites of HNC, sex, race, region, type of controls, dietary information at least one year before diagnosis or interview, and completeness of FFQ (Appendix Figure 6) and was retained in the never smoker and light drinker population (Table 7). This observation further strengthens the fact that healthier dietary habit, i.e. high fruit and vegetable and low red meat intake, plays a role in HNC.

Although our study included a large numbers of subjects from studies from different geographic areas with different dietary patterns, these properties may be also a limitation of the study. Though we assessed that heterogeneity may have partly been due to study design or characteristics of the study populations, there were other potential source of heterogeneity that we were not able to control. First, questionnaires were not standardized but each study had its own questionnaire aiming at their specific population and testing for different hypotheses. To overcome this limitation, we have tried to group the detailed food items into broad food groups and analyzed the food groups and food items in both relative (quartiles) and absolute frequencies (times/week), using a random-effect model. Second, the quantity of food consumed was not available for most of the studies. All of the above may contribute to the observed heterogeneity across studies. Other limitations include: total energy intake, an important confounder for dietary intake analysis, was not available for all studies. We adjusted for weight to address this limitation because weight would reflect the energy intake in middle-aged adults [70]. A subset analysis restricted to studies that provided total energy intake showed that the point estimates did not substantially change after adjustment for total energy intake or weight. Multiple comparisons were made; some of the observed association might be due to chance. Although there were some limitations from difficulties in standardizing questionnaires, our study provided unique opportunities to explore differences in subgroups and potential sources of heterogeneity. Unlike meta-analysis, we had individual level data in our database. All data were evaluated and standardized across all studies [2], thus we were able to adjust the potential confounders consistently.

Generally speaking, previous case-control studies on diet and HNC risks reported stronger associations than did cohort studies [10, 12, 22]. While recall bias could result in relatively strong associations in case-control studies, behavior change after recruitment in cohort studies could also dilute the associations. In addition, the inclusion criteria for the control group might alter the true distribution of exposures in the base population (selection bias). Hospital-based studies excluding controls with diseases that share risk factors with HNC might increase the selection probability of unexposed controls, if the exposure is associated with the risk factors, and bias the estimates away from null. Nevertheless, no heterogeneity was observed between population- and hospital-based studies, and case-control studies and cohort studies yield similar messages on diet and HNC risks, i.e. lower HNC risks with higher fruit and vegetable consumption and lower meat consumption, especially red meat. Our study further provides evidence of these associations among never smokers and light drinkers.

Supplementary Material

Appendix

02

Acknowledgement

Shu-Chun Chuang worked on this study during the tenure of a Special Training Award from the International Agency for Research on Cancer.

Funding

This INHANCE Consortium was supported by a grant from the US National Institutes of Health (NIH), National Cancer Institute (NCI) (R03CA113157) and National Institute for Dental and Craniofacial Research (NIDCR; R03DE016611). The individual studies were funded by the following grants: Milan study: Italian Association for Research on Cancer (AIRC). Aviano: Italian Association for Research on Cancer (AIRC), Italian League against Cancer and Italian Ministry of Research. France study: Swiss League against Cancer (KFS1069-09-2000), Fribourg League against Cancer (FOR381.88), Swiss Cancer Research (AKT 617) and Gustave-Roussy Institute (88D28). Italy Multicenter study: Italian Association for Research on Cancer (AIRC), Italian League against Cancer and Italian Ministry of Research. Swiss study: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse (KFS-700, OCS-1633). Central Europe study: World Cancer Research Fund and the European Commission’s INCO-COPERNICUS Program (Contract No. IC15-CT98-0332). Seattle study: National Institutes of Health (NIH) US (R01CA048996, R01DE012609). North Carolina study: National Institutes of Health (NIH) US (R01CA61188), and in part by a grant from the National Institute of Environmental Health Sciences (P30ES010126). Tampa study: National Institutes of Health (NIH) US (P01CA068384, K07CA104231, R01DE13158). Los Angeles study: National Institute of Health (NIH) US (P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667) and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center. Puerto Rico study: jointly funded by National Institutes of Health (NCI) US and NIDCR intramural programs. Latin America study: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundac¸a˜o de Amparo a` Pesquisa no. Estado de Sa˜o Paulo (FAPESP) (No 01/01768-2), and European Commission (IC18-CT97-0222). IARC Multicenter study: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government (FIS 97/0024, FIS 97/0662, BAE 01/5013), International Union Against Cancer (UICC), and Yamagiwa-Yoshida Memorial International Cancer Study Grant. Boston study: National Institutes of Health (NIH) US (R01CA078609, R01CA100679). Rome study: AIRC (Italian Agency for Research on Cancer). US Multicenter study: The Intramural Program of the National Cancer Institute, National Institutes of Health, USA. MSKCC study: NIH (R01CA51845). Seattle-LEO study: NIH(R01CA30022). Western Europe Study: European Commission’s 5th Framework Program (Contract No. QLK1-2001-00182), Italian Association for Cancer Research, Compagnia di San Paolo/ FIRMS, Region Piemonte, and Padova University (Contract No. CPDA057222). Saarland study: Ministry of Science, Research and Arts Baden-Wϋrttemberg. Heidelberg study: Grant No. 01GB9702/3 from the German Ministry of Education and Research. Japan study: Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan (17015052) and grant for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan (H20-002)

Footnotes

Conflict of interest statement

None declare.

Reference List

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr. [Google Scholar]

2. Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99(10):777–789. [PubMed] [Google Scholar]

3. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18(2):541–550. [PMC free article] [PubMed] [Google Scholar]

4. Secretan B, Straif K, Baan R, et al. A review of human carcinogens--Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009;10(11):1033–1034. [PubMed] [Google Scholar]

5. Lee YC, Boffetta P, Sturgis EM, et al. Involuntary smoking and head and neck cancer risk: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2008;17(8):1974–1981. [PMC free article] [PubMed] [Google Scholar]

6. IARC Working Group. Human Papillomaviruses. 2007:1–689. [Google Scholar]

7. Gaudet MM, Olshan AF, Chuang SC, et al. Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Int J Epidemiol. 2010;39(4):1091–1102. [PMC free article] [PubMed] [Google Scholar]

8. Negri E, Boffetta P, Berthiller J, et al. Family history of cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer. 2009;124(2):394–401. [PMC free article] [PubMed] [Google Scholar]

9. Lagiou P, Talamini R, Samoli E, et al. Diet and upper-aerodigestive tract cancer in Europe: the ARCAGE study. Int J Cancer. 2009;124(11):2671–2676. [PubMed] [Google Scholar]

10. Freedman ND, Park Y, Subar AF, et al. Fruit and vegetable intake and head and neck cancer risk in a large United States prospective cohort study. Int J Cancer. 2008;122(10):2330–2336. [PubMed] [Google Scholar]

11. Sapkota A, Hsu CC, Zaridze D, et al. Dietary risk factors for squamous cell carcinoma of the upper aerodigestive tract in central and eastern Europe. Cancer Causes Control. 2008;19(10):1161–1170. [PubMed] [Google Scholar]

12. Boeing H, Dietrich T, Hoffmann K, et al. Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Cancer Causes Control. 2006;17(7):957–969. [PubMed] [Google Scholar]

13. Edefonti V, Bravi F, La Vecchia C, et al. Nutrient-based dietary patterns and the risk of oral and pharyngeal cancer. Oral Oncol. 2010;46(5):343–348. [PubMed] [Google Scholar]

14. Edefonti V, Bravi F, Garavello W, et al. Nutrient-based dietary patterns and laryngeal cancer: evidence from an exploratory factor analysis. Cancer Epidemiol Biomarkers Prev. 2010;19(1):18–27. [PubMed] [Google Scholar]

15. Bosetti C, La Vecchia C, Talamini R, et al. Food groups and laryngeal cancer risk: a case-control study from Italy and Switzerland. Int J Cancer. 2002;100(3):355–360. [PubMed] [Google Scholar]

16. Franceschi S, Favero A, Conti E, et al. Food groups, oils and butter, and cancer of the oral cavity and pharynx. Br J Cancer. 1999;80(3–4):614–620. [PMC free article] [PubMed] [Google Scholar]

17. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington, DC: AICR; 2007. [Google Scholar]

18. Lam TK, Cross AJ, Consonni D, et al. Intakes of red meat, processed meat, and meat mutagens increase lung cancer risk. Cancer Res. 2009;69(3):932–939. [PMC free article] [PubMed] [Google Scholar]

19. La Vecchia C, Chatenoud L, Franceschi S, Soler M, Parazzini F, Negri E. Vegetables and fruit and human cancer: update of an Italian study. Int J Cancer. 1999;82(1):151–152. [PubMed] [Google Scholar]

20. Aune D, De SE, Ronco A, et al. Meat consumption and cancer risk: a case-control study in Uruguay. Asian Pac J Cancer Prev. 2009;10(3):429–436. [PubMed] [Google Scholar]

21. Tavani A, La Vecchia C, Gallus S, et al. Red meat intake and cancer risk: a study in Italy. Int J Cancer. 2000;86(3):425–428. [PubMed] [Google Scholar]

22. Lucenteforte E, Garavello W, Bosetti C, La Vecchia C. Dietary factors and oral and pharyngeal cancer risk. Oral Oncol. 2009;45(6):461–467. [PubMed] [Google Scholar]

23. Peters ES, Luckett BG, Applebaum KM, Marsit CJ, McClean MD, Kelsey KT. Dairy products, leanness, and head and neck squamous cell carcinoma. Head Neck. 2008;30(9):1193–1205. [PMC free article] [PubMed] [Google Scholar]

24. Kreimer AR, Randi G, Herrero R, Castellsague X, La VC, Franceschi S. Diet and body mass, and oral and oropharyngeal squamous cell carcinomas: analysis from the IARC multinational case-control study. Int J Cancer. 2006;118(9):2293–2297. [PubMed] [Google Scholar]

25. Franceschi S, Bidoli E, Baron AE, et al. Nutrition and cancer of the oral cavity and pharynx in north-east Italy. Int J Cancer. 1991;47(1):20–25. [PubMed] [Google Scholar]

26. Zheng W, Blot WJ, Shu XO, et al. Risk factors for oral and pharyngeal cancer in Shanghai, with emphasis on diet. Cancer Epidemiol Biomarkers Prev. 1992;1(6):441–448. [PubMed] [Google Scholar]

27. Sanchez MJ, Martinez C, Nieto A, et al. Oral and oropharyngeal cancer in Spain: influence of dietary patterns. Eur J Cancer Prev. 2003;12(1):49–56. [PubMed] [Google Scholar]

28. Rajkumar T, Sridhar H, Balaram P, et al. Oral cancer in Southern India: the influence of body size, diet, infections and sexual practices. Eur J Cancer Prev. 2003;12(2):135–143. [PubMed] [Google Scholar]

29. Lissowska J, Pilarska A, Pilarski P, et al. Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland. Eur J Cancer Prev. 2003;12(1):25–33. [PubMed] [Google Scholar]

30. Tavani A, Gallus S, La VC, et al. Diet and risk of oral and pharyngeal cancer. An Italian case-control study. Eur J Cancer Prev. 2001;10(2):191–195. [PubMed] [Google Scholar]

31. Garrote LF, Herrero R, Reyes RM, et al. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer. 2001;85(1):46–54. [PMC free article] [PubMed] [Google Scholar]

32. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48(11):3282–3287. [PubMed] [Google Scholar]

33. Park JY, Schantz SP, Lazarus P. Epoxide hydrolase genotype and orolaryngeal cancer risk: interaction with GSTM1 genotype. Oral Oncol. 2003;39(5):483–490. [PMC free article] [PubMed] [Google Scholar]

34. Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB. Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis. 2007;28(7):1455–1462. [PubMed] [Google Scholar]

35. Haug U, Hillebrand T, Bendzko P, et al. Mutant-enriched PCR and allele-specific hybridization reaction to detect K-ras mutations in stool DNA: high prevalence in a large sample of older adults. Clin Chem. 2007;53(4):787–790. [PubMed] [Google Scholar]

36. Ramroth H, Dietz A, Becher H. Interaction effects and population-attributable risks for smoking and alcohol on laryngeal cancer and its subsites. A case-control study from Germany. Methods Inf Med. 2004;43(5):499–504. [PubMed] [Google Scholar]

37. Suzuki T, Matsuo K, Hasegawa Y, et al. One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci. 2007;98(9):1439–1446. [PMC free article] [PubMed] [Google Scholar]

38. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. [PubMed] [Google Scholar]

39. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. [PMC free article] [PubMed] [Google Scholar]

40. Levi F, Pasche C, La VC, Lucchini F, Franceschi S, Monnier P. Food groups and risk of oral and pharyngeal cancer. Int J Cancer. 1998;77(5):705–709. [PubMed] [Google Scholar]

41. La Vecchia C, Negri E, D'Avanzo B, Franceschi S, Decarli A, Boyle P. Dietary indicators of laryngeal cancer risk. Cancer Res. 1990;50(15):4497–4500. [PubMed] [Google Scholar]

42. La Vecchia C, Negri E, D'Avanzo B, Boyle P, Franceschi S. Dietary indicators of oral and pharyngeal cancer. Int J Epidemiol. 1991;20(1):39–44. [PubMed] [Google Scholar]

43. Kjaerheim K, Gaard M, Andersen A. The role of alcohol, tobacco, and dietary factors in upper aerogastric tract cancers: a prospective study of 10,900 Norwegian men. Cancer Causes Control. 1998;9(1):99–108. [PubMed] [Google Scholar]

44. Takezaki T, Hirose K, Inoue M, et al. Tobacco, alcohol and dietary factors associated with the risk of oral cancer among Japanese. Jpn J Cancer Res. 1996;87(6):555–562. [PMC free article] [PubMed] [Google Scholar]

45. De Stefani E, eo-Pellegrini H, Mendilaharsu M, Ronco A. Diet and risk of cancer of the upper aerodigestive tract--I. Foods. Oral Oncol. 1999;35(1):17–21. [PubMed] [Google Scholar]

46. De Stefani E, Boffetta P, Ronco AL, et al. Dietary patterns and risk of cancer of the oral cavity and pharynx in Uruguay. Nutr Cancer. 2005;51(2):132–139. [PubMed] [Google Scholar]

47. Kapil U, Singh P, Bahadur S, Dwivedi SN, Singh R, Shukla N. Assessment of risk factors in laryngeal cancer in India: a case-control study. Asian Pac J Cancer Prev. 2005;6(2):202–207. [PubMed] [Google Scholar]

48. Dyer AR, Elliott P, Stamler J, Chan Q, Ueshima H, Zhou BF. Dietary intake in male and female smokers, ex-smokers, and never smokers: the INTERMAP study. J Hum Hypertens. 2003;17(9):641–654. [PMC free article] [PubMed] [Google Scholar]

49. Panda K, Chattopadhyay R, Chattopadhyay DJ, Chatterjee IB. Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Free Radic Biol Med. 2000;29(2):115–124. [PubMed] [Google Scholar]

50. Northrop-Clewes CA, Thurnham DI. Monitoring micronutrients in cigarette smokers. Clin Chim Acta. 2007;377(1–2):14–38. [PubMed] [Google Scholar]

51. Garavello W, Rossi M, McLaughlin JK, et al. Flavonoids and laryngeal cancer risk in Italy. Ann Oncol. 2007;18(6):1104–1109. [PubMed] [Google Scholar]

52. Fioretti F, Bosetti C, Tavani A, Franceschi S, La Vecchia C. Risk factors for oral and pharyngeal cancer in never smokers. Oral Oncol. 1999;35(4):375–378. [PubMed] [Google Scholar]

53. Dahlstrom KR, Little JA, Zafereo ME, Lung M, Wei Q, Sturgis EM. Squamous cell carcinoma of the head and neck in never smoker-never drinkers: a descriptive epidemiologic study. Head Neck. 2008;30(1):75–84. [PubMed] [Google Scholar]

54. Farshadpour F, Hordijk GJ, Koole R, Slootweg PJ. Non-smoking and non-drinking patients with head and neck squamous cell carcinoma: a distinct population. Oral Dis. 2007;13(2):239–243. [PubMed] [Google Scholar]

55. Lajer CB, von BC. The role of human papillomavirus in head and neck cancer. APMIS. 2010;118(6–7):510–519. [PubMed] [Google Scholar]

56. Bouvard V, Baan R, Straif K, et al. A review of human carcinogens--Part B: biological agents. Lancet Oncol. 2009;10(4):321–322. [PubMed] [Google Scholar]

57. Meyer MS, Applebaum KM, Furniss CS, et al. Human papillomavirus-16 modifies the association between fruit consumption and head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3419–3426. [PMC free article] [PubMed] [Google Scholar]

58. Foschi R, Pelucchi C, Dal Maso L, et al. Citrus fruit and cancer risk in a network of case-control studies. Cancer Causes Control. 2010;21(2):237–242. [PubMed] [Google Scholar]

59. La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and prevention of oral cancer. Oral Oncol. 1997;33(5):302–312. [PubMed] [Google Scholar]

60. Levi F, Pasche C, Lucchini F, Bosetti C, La Vecchia C. Processed meat and the risk of selected digestive tract and laryngeal neoplasms in Switzerland. Ann Oncol. 2004;15(2):346–349. [PubMed] [Google Scholar]

61. Zheng W, Lee SA. Well-done meat intake, heterocyclic amine exposure, and cancer risk. Nutr Cancer. 2009;61(4):437–446. [PMC free article] [PubMed] [Google Scholar]

62. Tzoulaki I, Brown IJ, Chan Q, et al. Relation of iron and red meat intake to blood pressure: cross sectional epidemiological study. BMJ. 2008;337:a258. [PMC free article] [PubMed] [Google Scholar]

63. Zhou BF, Stamler J, Dennis B, et al. Nutrient intakes of middle-aged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens. 2003;17(9):623–630. [PMC free article] [PubMed] [Google Scholar]

64. Daniel CR, Cross AJ, Graubard BI, Hollenbeck A, Park Y, Sinha R. Prospective investigation of poultry and fish intake in relation to cancer risk. Cancer Prev Res (Phila) 2011 [PMC free article] [PubMed] [Google Scholar]

65. Rogers MA, Thomas DB, Davis S, Vaughan TL, Nevissi AE. A case-control study of element levels and cancer of the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev. 1993;2(4):305–312. [PubMed] [Google Scholar]

66. MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA. 2006;295(4):403–415. [PubMed] [Google Scholar]

67. Nair U, Bartsch H. Metabolic polymorphisms as susceptibility markers for lung and oral cavity cancer. IARC Sci Publ. 2001;154:271–290. [PubMed] [Google Scholar]

68. Aune D, De SE, Ronco AL, et al. Egg consumption and the risk of cancer: a multisite case-control study in Uruguay. Asian Pac J Cancer Prev. 2009;10(5):869–876. [PubMed] [Google Scholar]

69. Bosetti C, Talamini R, Levi F, et al. Fried foods: a risk factor for laryngeal cancer? Br J Cancer. 2002;87(11):1230–1233. [PMC free article] [PubMed] [Google Scholar]

70. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr. 1997;65(4 Suppl):1220S–1228S. [PubMed] [Google Scholar]