IJC International Journal of Cancer
Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: Multicentre, prospective cohort study Christina Bamia1, Pagona Lagiou1,2,3, Mazda Jenab4, Antonia Trichopoulou1,5, Veronika Fedirko4,6, Krasimira Aleksandrova7, Tobias Pischon7,8, Kim Overvad9, Anja Olsen10, Anne Tjïnneland10, Marie-Christine Boutron-Ruault11,12,13, Guy Fagherazzi11,12,13, Antoine Racine11,12,13, Tilman Kuhn14, Heiner Boeing7, Anna Floegel7, Vasiliki Benetou1,5, Domenico Palli15, Sara Grioni16, Salvatore Panico17, Rosario Tumino18, Paolo Vineis19,20, H.B(as) Bueno-de-Mesquita20,21,22, Vincent K. Dik22, Nirmala Bhoo-Pathy23,24, Cuno S. P. M. Uiterwaal23, n Quiro s29, Raul Zamora-Ros4,30, Esther Molina-Montes31,32,33, Elisabete Weiderpass25,26,27,28, Eiliv Lund25, J. Ramo 33,34 33,35 €rn Lindkvist38, Peter Wallstro €m39, Maria-Dolores Chirlaque , Eva Ardanaz , Miren Dorronsoro36,37, Bjo 40,41 42 43 43,44 45 Lena Maria Nilsson , Malin Sund , Kay-Tee Khaw , Nick Wareham , Kathryn E. Bradbury , Ruth C. Travis45, 4 4 4 20 Pietro Ferrari , Talita Duarte-Salles , Magdalena Stepien , Marc Gunter , Neil Murphy20, Elio Riboli20 and Dimitrios Trichopoulos2,3,5 1
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece 3 Department of Epidemiology, Harvard School of Public Health, Boston, MA 4 International Agency for Research on Cancer (IARC-WHO), Lyon, France 5 Hellenic Health Foundation, Athens, Greece 6 Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, GA 7 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany 8 €ck Center for Molecular Medicine (MDC) Berlin-Buch, Berlin, Germany Molecular Epidemiology Group, Max Delbru 9 Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark 10 Danish Cancer Society Research Center, Copenhagen, Denmark 11 Inserm, Centre for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, Villejuif, Paris, France 12 Paris South University, UMRS 1018, Villejuif, Paris, France 13 IGR, F-94805, Villejuif, Paris, France 14 German Cancer Research Center (DKFZ), Heidelberg, Germany 15 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, Italy 16 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 17 Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy 18 Cancer Registry and Histopathology Unit, "Civic—M.P. Arezzo" Hospital, Ragusa, Italy 19 HuGeF—Human Genetics Foundation, Torino, Italy 20 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom 21 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 22 Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands 23 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 24 Faculty of Medicine, Julius Centre, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia 25 Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsï, Norway 26 Department of Research, Cancer Registry of Norway, Oslo, Norway 27 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 28 Samfundet Folkh€alsan, Helsinki, Finland 29 Public Health Directorate, Asturias, Spain 30 Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain 31 Andalusian School of Public Health, Granada, Spain 32 n Biosanitario de Granada (Granada.bs), Granada, Spain Instituto de Investigacio 33 CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain
Key words: hepatocellular carcinoma, liver cancer, coffee, tea, EPIC Abbreviations: CI: confidence intervals; EPIC: European Prospective Investigation into Cancer and nutrition; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HR: hazard ratio; LRtest: likelihood ratio test DOI: 10.1002/ijc.29214 History: Received 9 May 2014; Accepted 20 Aug 2014; Online 15 Sep 2014 Correspondence to: Dr. Christina Bamia, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, Medical School, 75 Mikras Asias St., 115 27 Goudi, Athens, Greece, Tel.: 130-210-7462096, Fax: 130-210-7462079, E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
Epidemiology
2
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Coffee, tea and hepatocellular carcinoma
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Epidemiology Department, Murcia Regional Health Council, Murcia, Spain Navarre Public Health Institute, Pamplona, Spain 36 Basque Regional Health Department, Public Health Direction, Donostia, San Sebastian, Spain 37 Biodonostia Research Institute CIBER Epidemiology and Public Health CIBERESP, San Sebastian, Spain 38 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 39 €, Sweden Department of Clinical Sciences, Nutrition Epidemiology Research Group, Lund University, Malmo 40 Public Health and Clinical Medicine, Nutritional Research, Umea˚ University, Umea˚, Sweden 41 Arcum, Arctic Research Centre at Umea˚ University, Umea˚, Sweden 42 Experimental Surgery, Department of Surgical and Perioperative Sciences/Surgery, Umea University, Umea, Sweden 43 University of Cambridge, Cambridge, United Kingdom 44 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 45 Nuffield Department of Population Health, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom 35
Epidemiology
Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16–0.50, p-trend < 0.001]. The corresponding association of tea with HCC risk was 0.41 (95% CI: 0.22–0.78, p-trend 5 0.003). There was no compelling evidence of heterogeneity of these associations across strata of important HCC risk factors, including hepatitis B or hepatitis C status (available in a nested case–control study). The inverse, monotonic associations of coffee intake with HCC were apparent for caffeinated (p-trend 5 0.009), but not decaffeinated (p-trend 5 0.45) coffee for which, however, data were available for a fraction of subjects. Results from this multicentre, European cohort study strengthen the existing evidence regarding the inverse association between coffee/tea and HCC risk. Given the apparent lack of heterogeneity of these associations by HCC risk factors and that coffee/tea are universal exposures, our results could have important implications for high HCC risk subjects.
What’s new? Could coffee and tea consumption protect from liver cancer? The answer is yes! In this first multi-center European cohort study, intake of coffee and, to a lesser extent, tea was associated, in a dose-dependent manner, with lower risk of hepatocellular carcinoma. For the most loyal coffee consumers, risk was reduced by 72%. No protection was observed with decaffeinated coffee. As caffeinated coffee and tea are almost universal exposures, these results may have important implications for individuals at high risk for liver cancer.
Hepatocellular carcinoma (HCC) accounts for 85–95% of primary liver cancer cases.1 Several risk factors have been identified, but with respect to diet only alcohol, obesity2 and aflatoxin3 have been documented. The role of other dietary exposures is still under investigation.4 Since 2000, the association of coffee and tea consumption with HCC risk has been investigated in case–control and cohort studies conducted mostly in Asia, where exposure patterns to these beverages differ compared to western countries; two cohort studies on coffee intake were conducted in Europe (Finland)5,6 and none in the USA. In a major review, the evidence regarding the indicated associations was considered inconclusive.7 Recent meta-analyses, however, pointed to a statistically significant inverse association of coffee intake with primary liver cancer or HCC,8 as well as, a suggestive inverse association of tea intake with primary liver cancer.9
The earlier studies differed in the extent of adjustment for important HCC risk factors. Moreover, coffee and tea were, in general, considered separately, even though they may act as mutual confounders in their respective associations with HCC risk. In the context of the European Prospective Investigation into Cancer and nutrition (EPIC), we investigated the associations of coffee (overall, caffeinated, decaffeinated) and tea consumption with HCC risk. This is the first cohort study on the topic undertaken in a multiethnic European population.
Methods Participants
EPIC investigates the role of biological, dietary and lifestyle factors in the aetiology of cancer and other chronic diseases. More than 521,000 apparently healthy men and women, aged C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
1901
Bamia et al.
Assessment of diet
Dietary intakes over the previous year were assessed at enrolment through validated centre-specific questionnaires which enquired also about cups of coffee and tea consumption per day, week or month.11 In some centres, additional information on caffeinated and decaffeinated coffee consumption was obtained [Germany, Greece, Italy (except Ragusa and Naples), Netherlands, and United Kingdom]. Information on tea consumption was not available in Norway. Data on type of tea were not available. Based on the information collected by the questionnaires, beverage intakes were calculated in each centre in ml/day in order to take into account differences in cup sizes by region. Total energy intake was calculated through the EPIC Nutrient-Data-Base.12 Assessment of lifestyle, somatometry and medical history
At enrolment, standardized questionnaires were used to record sociodemographic, lifestyle and medical history data. Measurements of weight, height and waist/hip circumferences were undertaken for most participants—in France, Norway and Oxford, self-reported weight and height were recorded for the majority of the participants. Follow-up of study population and case ascertainment
Incident HCC cases and vital status were ascertained in most centres through record linkage with cancer and death registries. In France, Germany and Greece a combination of methods was used including health insurance records, pathology registries and active follow-up through mailed questionnaires/telephone interviews. Reported incident cancers were subsequently verified through pathology reports, medical records and discharge diagnoses. Cancer incidence was coded according to the International Classification of DiseasesOncology-2. HCC was defined as C22.0. Censoring dates for cancer incidence for centres using registry data ranged from December 2004 (Asturias (Spain)) to December 2008 [Turin (Italy), Sweden and Norway]. For C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
centres using active follow-up, last contact ranged from July 2005 (France) to June 2010 [Heidelberg (Germany)]. From the 521,330 EPIC participants, we excluded 23,818 with prevalent cancer, 4,383 with insufficient follow-up, 78 cases with metastatic cancer or ineligible information on histology, 6,192 with no dietary and 60 with no lifestyle questionnaires. Eventually, 486,799 participants including 201 incident HCC cases were analysed. Nested case–control study
Within EPIC, a nested case–control study, using data as of 2006 on 125 HCC cases and 250 matched controls was conducted.13 For these, serum levels of hepatitis B surface antigen and antibodies to hepatitis C virus (anti-HCV) were determined at the Centre de Biologie Republique laboratory in Lyon, France. Design and methods of this study have been described elsewhere.13 Controls were selected from those alive and free of cancer at the time of diagnosis of the case. Matching criteria included study centre, sex, age at the time of blood collection, date and time of day of blood collection. Women were additionally matched by menopausal status and by use of exogenous hormones. Statistical analysis
The associations of coffee, caffeinated/decaffeinated coffee, and tea intake with HCC risk were investigated through Cox proportional hazard models. Age at exit was the underlying time variable defined as the age of: HCC diagnosis (case); diagnosis of any other incident cancer (censored); death for participants who died without cancer (censored); last followup for those alive and with no cancer (censored). Age at recruitment was the entry time. All models were stratified by recruitment age (1-year intervals) and study centre. Coffee intake was considered in sex-specific quintiles (Q1– Q5). For tea, due to the large number of nonconsumers (153,097/450,921, 34%), five categories of intake (C1–C5) were created: nonconsumers (C1) and the sex-specific quartiles (C2–C5) among consumers. Both variables were considered categorically and per one-level increments. Norway was excluded from tea analyses, as no relevant data were available. Due to potential between-countries variations in coffee/ tea volume and concentration, we also based estimation of quintiles of coffee and categories of tea on sex- and countryspecific intakes in order to check the robustness of our findings. Linear trends were evaluated using the medians of quintiles/categories as continuous variables in the Cox models. In additional models, coffee and tea were mutually adjusted for. In analyses by type of coffee, only data from 163,672 participants (Germany, Netherlands and United Kingdom), for whom the sum of caffeinated and decaffeinated coffee equals the total amount of coffee intake, were included. Due to the large number of nonconsumers of decaffeinated coffee (35%) we considered 3 categories for this beverage: (i) C1: nonconsumers, (ii) C2: consumers below the median (among consumers), and (iii) C3: consumers at/above the median
Epidemiology
25–70 years, were recruited between 1992 and 2000 in 23 centres from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and United Kingdom). The participants were selected from the general population, except for France (women—members of health insurance plans), Utrecht and Florence (women—breast cancer screening), Naples and Norway (women only), the Oxford cohort (which includes a large proportion of vegetarian volunteers) and subsamples of the Italian and Spanish cohorts (mainly members of blood donor associations). Details of EPIC are given elsewhere.10 The study was approved by the Ethical Review Board of the International Agency for Research on Cancer, and by the local Ethics Committees in the participating centres. Participants gave informed consent before enrolment. Procedures were in line with the Helsinki declaration.
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Coffee, tea and hepatocellular carcinoma
Table 1. Distribution of study participants by quintiles1 of coffee intake, as well as, by country of origin and baseline characteristics Quintiles of coffee intake (ml/day) Q1
Q2
Median (range): males
17.3 (0–83.3)
140.5 (83.3–200.4) 375 (200.5–476.9) 556.4 (477.2 to 830.4) 1000 (831.3–4500)
Q3
Q4
Q5
Median (range): females
3.8 (0–60)
125.9 (60–191.9)
290.4 (191.9–375) 500 (375–580.2)
856.9 (580.3–6250)
France
22.1
21.9
27.0
16.9
12.0
Italy
35.6
56.7
7.4
0.3
0.04
Spain
44.7
34.0
17.8
2.8
0.7
United Kingdom
26.7
20.5
10.9
21.7
20.1
Country2 (%)
The Netherlands
8.2
5.0
21.8
29.0
36.0
Greece
22.3
43.8
26.1
6.3
1.5
Germany
11.9
11.2
32.4
27.9
16.7
Sweden
7.7
10.5
27.7
32.4
21.7
Denmark
7.4
6.6
3.1
27.0
55.9
Norway
14.4
7.2
30.8
25.9
21.7
Age, Mean (SD) (years)
50 (11)
52 (10)
51 (9)
51 (10)
52 (9)
Males
20.4
19.6
21.5
18.5
20.0
Females
20.1
21.2
18.7
20.4
19.6
Sex2 (%)
2
Self-reported diabetes mellitus (%) No
20.2
21.0
19.6
19.7
19.5
Yes
24.7
24.9
19.3
15.6
15.5
Unknown
16.2
12.0
18.3
25.5
28.0
23.2
26.9
17.9
14.6
17.4
2
Educational level (%) None/primary
Technical/professional/secondary 17.6
17.3
20.4
22.5
22.3
University degree/longer
20.1
18.9
21.3
21.4
18.4
Not specified
26.7
22.5
12.4
21.2
17.3
Never
24.8
23.0
19.6
19.0
13.6
Former
18.0
19.0
20.5
21.6
21.0
Epidemiology
Smoking2 (%)
Current
12.6
18.0
17.9
19.5
32.0
Unknown
20.7
19.9
25.8
19.2
14.3
23.5
21.2
19.9
18.6
16.8
Moderate
16.3
19.8
19.3
21.8
22.8
High3
17.1
21.6
18.8
19.4
23.2
20.1
19.4
20.0
21.0
19.5
Ethanol intake (g/day)2 (%) Low3 3
2
2
Body mass index (kg/m ) (%) 25 >25–
Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: Multicentre, prospective cohort study Christina Bamia1, Pagona Lagiou1,2,3, Mazda Jenab4, Antonia Trichopoulou1,5, Veronika Fedirko4,6, Krasimira Aleksandrova7, Tobias Pischon7,8, Kim Overvad9, Anja Olsen10, Anne Tjïnneland10, Marie-Christine Boutron-Ruault11,12,13, Guy Fagherazzi11,12,13, Antoine Racine11,12,13, Tilman Kuhn14, Heiner Boeing7, Anna Floegel7, Vasiliki Benetou1,5, Domenico Palli15, Sara Grioni16, Salvatore Panico17, Rosario Tumino18, Paolo Vineis19,20, H.B(as) Bueno-de-Mesquita20,21,22, Vincent K. Dik22, Nirmala Bhoo-Pathy23,24, Cuno S. P. M. Uiterwaal23, n Quiro s29, Raul Zamora-Ros4,30, Esther Molina-Montes31,32,33, Elisabete Weiderpass25,26,27,28, Eiliv Lund25, J. Ramo 33,34 33,35 €rn Lindkvist38, Peter Wallstro €m39, Maria-Dolores Chirlaque , Eva Ardanaz , Miren Dorronsoro36,37, Bjo 40,41 42 43 43,44 45 Lena Maria Nilsson , Malin Sund , Kay-Tee Khaw , Nick Wareham , Kathryn E. Bradbury , Ruth C. Travis45, 4 4 4 20 Pietro Ferrari , Talita Duarte-Salles , Magdalena Stepien , Marc Gunter , Neil Murphy20, Elio Riboli20 and Dimitrios Trichopoulos2,3,5 1
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece 3 Department of Epidemiology, Harvard School of Public Health, Boston, MA 4 International Agency for Research on Cancer (IARC-WHO), Lyon, France 5 Hellenic Health Foundation, Athens, Greece 6 Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, GA 7 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany 8 €ck Center for Molecular Medicine (MDC) Berlin-Buch, Berlin, Germany Molecular Epidemiology Group, Max Delbru 9 Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark 10 Danish Cancer Society Research Center, Copenhagen, Denmark 11 Inserm, Centre for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, Villejuif, Paris, France 12 Paris South University, UMRS 1018, Villejuif, Paris, France 13 IGR, F-94805, Villejuif, Paris, France 14 German Cancer Research Center (DKFZ), Heidelberg, Germany 15 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, Italy 16 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 17 Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy 18 Cancer Registry and Histopathology Unit, "Civic—M.P. Arezzo" Hospital, Ragusa, Italy 19 HuGeF—Human Genetics Foundation, Torino, Italy 20 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom 21 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 22 Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands 23 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 24 Faculty of Medicine, Julius Centre, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia 25 Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsï, Norway 26 Department of Research, Cancer Registry of Norway, Oslo, Norway 27 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 28 Samfundet Folkh€alsan, Helsinki, Finland 29 Public Health Directorate, Asturias, Spain 30 Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain 31 Andalusian School of Public Health, Granada, Spain 32 n Biosanitario de Granada (Granada.bs), Granada, Spain Instituto de Investigacio 33 CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain
Key words: hepatocellular carcinoma, liver cancer, coffee, tea, EPIC Abbreviations: CI: confidence intervals; EPIC: European Prospective Investigation into Cancer and nutrition; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HR: hazard ratio; LRtest: likelihood ratio test DOI: 10.1002/ijc.29214 History: Received 9 May 2014; Accepted 20 Aug 2014; Online 15 Sep 2014 Correspondence to: Dr. Christina Bamia, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, Medical School, 75 Mikras Asias St., 115 27 Goudi, Athens, Greece, Tel.: 130-210-7462096, Fax: 130-210-7462079, E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
Epidemiology
2
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Coffee, tea and hepatocellular carcinoma
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Epidemiology Department, Murcia Regional Health Council, Murcia, Spain Navarre Public Health Institute, Pamplona, Spain 36 Basque Regional Health Department, Public Health Direction, Donostia, San Sebastian, Spain 37 Biodonostia Research Institute CIBER Epidemiology and Public Health CIBERESP, San Sebastian, Spain 38 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 39 €, Sweden Department of Clinical Sciences, Nutrition Epidemiology Research Group, Lund University, Malmo 40 Public Health and Clinical Medicine, Nutritional Research, Umea˚ University, Umea˚, Sweden 41 Arcum, Arctic Research Centre at Umea˚ University, Umea˚, Sweden 42 Experimental Surgery, Department of Surgical and Perioperative Sciences/Surgery, Umea University, Umea, Sweden 43 University of Cambridge, Cambridge, United Kingdom 44 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 45 Nuffield Department of Population Health, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom 35
Epidemiology
Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16–0.50, p-trend < 0.001]. The corresponding association of tea with HCC risk was 0.41 (95% CI: 0.22–0.78, p-trend 5 0.003). There was no compelling evidence of heterogeneity of these associations across strata of important HCC risk factors, including hepatitis B or hepatitis C status (available in a nested case–control study). The inverse, monotonic associations of coffee intake with HCC were apparent for caffeinated (p-trend 5 0.009), but not decaffeinated (p-trend 5 0.45) coffee for which, however, data were available for a fraction of subjects. Results from this multicentre, European cohort study strengthen the existing evidence regarding the inverse association between coffee/tea and HCC risk. Given the apparent lack of heterogeneity of these associations by HCC risk factors and that coffee/tea are universal exposures, our results could have important implications for high HCC risk subjects.
What’s new? Could coffee and tea consumption protect from liver cancer? The answer is yes! In this first multi-center European cohort study, intake of coffee and, to a lesser extent, tea was associated, in a dose-dependent manner, with lower risk of hepatocellular carcinoma. For the most loyal coffee consumers, risk was reduced by 72%. No protection was observed with decaffeinated coffee. As caffeinated coffee and tea are almost universal exposures, these results may have important implications for individuals at high risk for liver cancer.
Hepatocellular carcinoma (HCC) accounts for 85–95% of primary liver cancer cases.1 Several risk factors have been identified, but with respect to diet only alcohol, obesity2 and aflatoxin3 have been documented. The role of other dietary exposures is still under investigation.4 Since 2000, the association of coffee and tea consumption with HCC risk has been investigated in case–control and cohort studies conducted mostly in Asia, where exposure patterns to these beverages differ compared to western countries; two cohort studies on coffee intake were conducted in Europe (Finland)5,6 and none in the USA. In a major review, the evidence regarding the indicated associations was considered inconclusive.7 Recent meta-analyses, however, pointed to a statistically significant inverse association of coffee intake with primary liver cancer or HCC,8 as well as, a suggestive inverse association of tea intake with primary liver cancer.9
The earlier studies differed in the extent of adjustment for important HCC risk factors. Moreover, coffee and tea were, in general, considered separately, even though they may act as mutual confounders in their respective associations with HCC risk. In the context of the European Prospective Investigation into Cancer and nutrition (EPIC), we investigated the associations of coffee (overall, caffeinated, decaffeinated) and tea consumption with HCC risk. This is the first cohort study on the topic undertaken in a multiethnic European population.
Methods Participants
EPIC investigates the role of biological, dietary and lifestyle factors in the aetiology of cancer and other chronic diseases. More than 521,000 apparently healthy men and women, aged C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
1901
Bamia et al.
Assessment of diet
Dietary intakes over the previous year were assessed at enrolment through validated centre-specific questionnaires which enquired also about cups of coffee and tea consumption per day, week or month.11 In some centres, additional information on caffeinated and decaffeinated coffee consumption was obtained [Germany, Greece, Italy (except Ragusa and Naples), Netherlands, and United Kingdom]. Information on tea consumption was not available in Norway. Data on type of tea were not available. Based on the information collected by the questionnaires, beverage intakes were calculated in each centre in ml/day in order to take into account differences in cup sizes by region. Total energy intake was calculated through the EPIC Nutrient-Data-Base.12 Assessment of lifestyle, somatometry and medical history
At enrolment, standardized questionnaires were used to record sociodemographic, lifestyle and medical history data. Measurements of weight, height and waist/hip circumferences were undertaken for most participants—in France, Norway and Oxford, self-reported weight and height were recorded for the majority of the participants. Follow-up of study population and case ascertainment
Incident HCC cases and vital status were ascertained in most centres through record linkage with cancer and death registries. In France, Germany and Greece a combination of methods was used including health insurance records, pathology registries and active follow-up through mailed questionnaires/telephone interviews. Reported incident cancers were subsequently verified through pathology reports, medical records and discharge diagnoses. Cancer incidence was coded according to the International Classification of DiseasesOncology-2. HCC was defined as C22.0. Censoring dates for cancer incidence for centres using registry data ranged from December 2004 (Asturias (Spain)) to December 2008 [Turin (Italy), Sweden and Norway]. For C 2014 UICC Int. J. Cancer: 136, 1899–1908 (2015) V
centres using active follow-up, last contact ranged from July 2005 (France) to June 2010 [Heidelberg (Germany)]. From the 521,330 EPIC participants, we excluded 23,818 with prevalent cancer, 4,383 with insufficient follow-up, 78 cases with metastatic cancer or ineligible information on histology, 6,192 with no dietary and 60 with no lifestyle questionnaires. Eventually, 486,799 participants including 201 incident HCC cases were analysed. Nested case–control study
Within EPIC, a nested case–control study, using data as of 2006 on 125 HCC cases and 250 matched controls was conducted.13 For these, serum levels of hepatitis B surface antigen and antibodies to hepatitis C virus (anti-HCV) were determined at the Centre de Biologie Republique laboratory in Lyon, France. Design and methods of this study have been described elsewhere.13 Controls were selected from those alive and free of cancer at the time of diagnosis of the case. Matching criteria included study centre, sex, age at the time of blood collection, date and time of day of blood collection. Women were additionally matched by menopausal status and by use of exogenous hormones. Statistical analysis
The associations of coffee, caffeinated/decaffeinated coffee, and tea intake with HCC risk were investigated through Cox proportional hazard models. Age at exit was the underlying time variable defined as the age of: HCC diagnosis (case); diagnosis of any other incident cancer (censored); death for participants who died without cancer (censored); last followup for those alive and with no cancer (censored). Age at recruitment was the entry time. All models were stratified by recruitment age (1-year intervals) and study centre. Coffee intake was considered in sex-specific quintiles (Q1– Q5). For tea, due to the large number of nonconsumers (153,097/450,921, 34%), five categories of intake (C1–C5) were created: nonconsumers (C1) and the sex-specific quartiles (C2–C5) among consumers. Both variables were considered categorically and per one-level increments. Norway was excluded from tea analyses, as no relevant data were available. Due to potential between-countries variations in coffee/ tea volume and concentration, we also based estimation of quintiles of coffee and categories of tea on sex- and countryspecific intakes in order to check the robustness of our findings. Linear trends were evaluated using the medians of quintiles/categories as continuous variables in the Cox models. In additional models, coffee and tea were mutually adjusted for. In analyses by type of coffee, only data from 163,672 participants (Germany, Netherlands and United Kingdom), for whom the sum of caffeinated and decaffeinated coffee equals the total amount of coffee intake, were included. Due to the large number of nonconsumers of decaffeinated coffee (35%) we considered 3 categories for this beverage: (i) C1: nonconsumers, (ii) C2: consumers below the median (among consumers), and (iii) C3: consumers at/above the median
Epidemiology
25–70 years, were recruited between 1992 and 2000 in 23 centres from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and United Kingdom). The participants were selected from the general population, except for France (women—members of health insurance plans), Utrecht and Florence (women—breast cancer screening), Naples and Norway (women only), the Oxford cohort (which includes a large proportion of vegetarian volunteers) and subsamples of the Italian and Spanish cohorts (mainly members of blood donor associations). Details of EPIC are given elsewhere.10 The study was approved by the Ethical Review Board of the International Agency for Research on Cancer, and by the local Ethics Committees in the participating centres. Participants gave informed consent before enrolment. Procedures were in line with the Helsinki declaration.
1902
Coffee, tea and hepatocellular carcinoma
Table 1. Distribution of study participants by quintiles1 of coffee intake, as well as, by country of origin and baseline characteristics Quintiles of coffee intake (ml/day) Q1
Q2
Median (range): males
17.3 (0–83.3)
140.5 (83.3–200.4) 375 (200.5–476.9) 556.4 (477.2 to 830.4) 1000 (831.3–4500)
Q3
Q4
Q5
Median (range): females
3.8 (0–60)
125.9 (60–191.9)
290.4 (191.9–375) 500 (375–580.2)
856.9 (580.3–6250)
France
22.1
21.9
27.0
16.9
12.0
Italy
35.6
56.7
7.4
0.3
0.04
Spain
44.7
34.0
17.8
2.8
0.7
United Kingdom
26.7
20.5
10.9
21.7
20.1
Country2 (%)
The Netherlands
8.2
5.0
21.8
29.0
36.0
Greece
22.3
43.8
26.1
6.3
1.5
Germany
11.9
11.2
32.4
27.9
16.7
Sweden
7.7
10.5
27.7
32.4
21.7
Denmark
7.4
6.6
3.1
27.0
55.9
Norway
14.4
7.2
30.8
25.9
21.7
Age, Mean (SD) (years)
50 (11)
52 (10)
51 (9)
51 (10)
52 (9)
Males
20.4
19.6
21.5
18.5
20.0
Females
20.1
21.2
18.7
20.4
19.6
Sex2 (%)
2
Self-reported diabetes mellitus (%) No
20.2
21.0
19.6
19.7
19.5
Yes
24.7
24.9
19.3
15.6
15.5
Unknown
16.2
12.0
18.3
25.5
28.0
23.2
26.9
17.9
14.6
17.4
2
Educational level (%) None/primary
Technical/professional/secondary 17.6
17.3
20.4
22.5
22.3
University degree/longer
20.1
18.9
21.3
21.4
18.4
Not specified
26.7
22.5
12.4
21.2
17.3
Never
24.8
23.0
19.6
19.0
13.6
Former
18.0
19.0
20.5
21.6
21.0
Epidemiology
Smoking2 (%)
Current
12.6
18.0
17.9
19.5
32.0
Unknown
20.7
19.9
25.8
19.2
14.3
23.5
21.2
19.9
18.6
16.8
Moderate
16.3
19.8
19.3
21.8
22.8
High3
17.1
21.6
18.8
19.4
23.2
20.1
19.4
20.0
21.0
19.5
Ethanol intake (g/day)2 (%) Low3 3
2
2
Body mass index (kg/m ) (%) 25 >25–
