PROTECTIVE EFFECT OF GREEN TEA ON THE RISKS OF CHRONIC GASTRITIS AND STOMACH CANCER

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1 Int. J. Cancer: 92, (2001) 2001 Wiley-Liss, Inc. Publication of the International Union Against Cancer PROTECTIVE EFFECT OF GREEN TEA ON THE RISKS OF CHRONIC GASTRITIS AND STOMACH CANCER Veronica Wendy SETIAWAN 1,Zuo-Feng ZHANG 1 *,Guo-Pei YU 2,Qing-Yi LU 3,Yong-Liang LI 4,Ming-Lan LU 5,Ming-Rong WANG 6, Chun Hua GUO 6,Shun-Zhang YU 7,Robert C. KURTZ 8 and Chung-Cheng HSIEH 9 1 Department of Epidemiology, UCLA School of Public Health, and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA 2 Biostatistics and Epidemiology Service, New York Eye and Ear Infirmary, New York, NY, USA 3 Center for Human Nutrition, UCLA School of Medicine, Los Angeles, CA, USA 4 School of Public Health, Columbia University, New York, NY, USA 5 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 6 Yangzhong County Anti-Epidemic Station, Yangzhong County, Peoples Republic of China 7 Department of Epidemiology, School of Public Health, Shanghai Medical University, Shanghai, Peoples Republic of China 8 Gastroenterology and Nutrition Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 9 Division of Biostatistics and Epidemiology, University of Massachusetts Cancer Center, Worcester, MA, USA Despite the declining trend, stomach cancer remains the second most common cancer worldwide. We examined the role of green tea consumption on chronic gastritis and stomach cancer risks. Apopulation-based case-control study was conducted in Yangzhong, China, with 133 stomach cancer cases, 166 chronic gastritis cases, and 433 healthy controls. Epidemiologicdatawerecollectedbystandardquestionnaire and odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models in SAS. Inverse association was observed between green tea drinking and chronicgastritisandstomachcancerrisks.afteradjustingfor age,gender,education,bodymassindex,pack-yearsofsmoking and alcohol drinking, ORs of green tea drinking were 0.52 (95% CI: ) and 0.49 (95% CI: ) for stomach cancer and chronic gastritis, respectively. In addition, doseresponserelationshipswereobservedwithyearsofgreentea drinkinginbothdiseases.theresultsprovidefurthersupport on the protective effect of green tea against stomach cancer. This is the first time that green tea drinking was found to be protective against chronic gastritis, which may be of importance when designing intervention strategies for stomach cancer and its pre-malignant lesions in the high-risk population Wiley-Liss, Inc. Key words: green tea; stomach cancer; chronic gastritis; risk factors; epidemiology Stomach cancer remains the second most frequent cancer after lung cancer worldwide. Thirty-eight percent of stomach cancer casesintheworldoccurinchina,whereitcontinuestobethemost common cancer in both sexes. In 1990, the age-standardized incidence rates were 43.6/100,000 (male) and 19.0/100,000 (female). 1 Pathology and epidemiologic studies have shown the progression of chronic gastritis to atrophy, thence to intestinal metaplasia, subsequently to dysplasia and to the intestinal type of stomach cancer. 2 From acohort study in Colombia, the progression of chronic atrophic gastritis to stomach cancer was found to be slow. 3 This slow process may allow opportunities to inhibit progression through intervention studies if the risk and protective factors of stomach precancerous lesions are known. Tea is grown in about 30 countries and is the most widely consumedbeverageintheworld. 4 Allteaisderivedfromoneplant (Camellia Sinensis); 78% manufactured in the world being black, 20% green and 2% oolong. is primarily consumed in Asian countries, such as Japan and China, and some parts in North Africa and the Middle East. 5 polyphenols may affect carcinogenesis because of theirantioxidativeactivities,abilitytoinhibitnitrosationreactions, modulation of carcinogen-metabolizing enzymes, trapping of ultimatecarcinogensandtheabilitytoinhibitcellproliferation-related activities. 6 From in vitro and animal studies, 7,8 polyphenolic extracts from green tea have been shown to enhance the activities of phase II detoxifying enzymes, Glutathione-s-tranferases. Several epidemiologic studies have shown an inverse associationbetweengreenteadrinkingandstomachcancer, 9 14 whileone study in Taiwan showed an increased risk of stomach cancer associated with green tea drinking. 15 One study in Japan has evaluated the role of hot green tea drinking on the risk of chronic gastritis and stomach cancer, however, no obvious association was found for both diseases. 16 Inthis study, we evaluated the possible role of green tea consumption on the risk of chronic gastritis and stomach cancer by controlling for potential confounding factors, including age, gender, education, pack-years of smoking, alcohol drinking and body mass index. SUBJECTS AND METHODS Background YangzhongCity(formerlyYangzhongCounty,priorto1995)is an island situated on Yangtze River in Jiangsu province, southeast of China. It has one of the highest rates of alimentary cancer in the world. The average annual death rate from stomach cancer in 1995, adjusted for world standard population, was 127/100,000 and as high as 1,862/100,000 among the men aged years old. Study population As previously described, 17 acase-control study was conducted in Yangzhong City in Jiangsu province. Data included interviewquestionnairedataandmedicalrecordreview.thetwocasegroups included patients with stomach cancer and chronic gastritis (either superficial or atrophic). The healthy control group was arandom sample from local population on the island where the cases came from. Stomachcancercases.Eligiblecaseswereallpatientsexamined at Yangzhong Central Hospital Endoscopy Unit between January 1, 1995 and June 30, 1995 with pathologically confirmed diagnoses of stomach adenocarcinoma. Once the stomach cancer cases were diagnosed in the Endoscopic Unit, they were immediately Grantsponsor:NIHNationalCancerInstitute,DepartmentofHealthand Human Services; Grant numbers: CA77954, CA09142 and CA16042; Grant sponsors: University of California-Los Angeles Jonsson Comprehensive Cancer Center Foundation and the Weissman Fund. *Correspondence to: Department of Epidemiology, UCLA School of Public Health, CHS, Box , Los Angeles, CA , USA. Fax: zfzhang@ucla.edu Received 31 May 2000; Revised 7 August and 30 October 2000; Accepted 3November 2000 Published online 16 March 2001

2 PROTECTIVE EFFECT OF GREEN TEA 601 interviewed by the interviewer at the hospital. We interviewed all incident patients with stomach cancer during the study period who consented to be interviewed with the following restrictions: patients must be newly diagnosed, not restricted by age, in stable medical condition as determined by their physician and willing to participate. The study was restricted to those who lived in Yangzhong for at least one year. In the six-month study period, we recruited a total of 200 patients with esophageal or stomach cancer from the Endoscopic Unit. Of these, 67 patients with esophageal cancer were excluded. We had a total of 133 incident cases with stomach cancer in this study, which represented 80% of all new cases diagnosed in the same study period in Yangzhong (166 stomach cancer cases during the study period were estimated from the incidence of stomach cancer in Yangzhong during the 6-month period in 1995). Blood specimens were collected in 63% (84 of 133) of stomach cancer patients who had an interview. Chronic gastritis cases. Eligible cases were randomly selected patients at Yangzhong Central Hospital Endoscopy Unit between January 1, 1995 and June 30, 1995, with pathologically confirmed diagnoses of chronic gastritis (either superficial or atrophic). We interviewed the randomly selected incident patients with chronic gastritis who consented to be interviewed with the following restrictions: patients must be newly diagnosed, not restricted by age, in stable medical condition as determined by their physician and willing to participate. The study was restricted to people who lived in Yangzhong for at least 1 year. In the 6-month study period, we approached 205 patients and interviewed 166 patients with chronic gastritis (81%) from the Endoscopic Unit. Of these, more than 95% were chronic atrophic gastritis cases. Blood specimens were collected in 88% (146 of 166) of patients with chronic gastritis who had an interview. Controls. Eligible controls were healthy and cancer-free individuals. We interviewed all randomly selected eligible controls during the study period with the following criteria: not restricted by age and willing to participate. The study was restricted to people who lived in Yangzhong for at least 1 year. They were randomly selected from a name list of residents in each village in Yangzhong. Following the selected list, the interviewer located the controls who consented to be interviewed, explained the study, interviewed them at their homes and collected a5mlormore blood sample. A total of 477 potential healthy controls were approached, and 433 controls had completed interviews (91%). Blood specimens were collected in 99% (429 of 433) of population controls who had an interview. Histologic diagnosis The cases received an upper gastrointestinal endoscopic examination and biopsies were taken from 7 predetermined sites in the stomach: 4 from antrum, 1 from the angulus and 1 each from the lesser and greater curvature of the body. Pathologic diagnoses were made according to the criteria proposed by the Chinese Association of Gastric Cancer. The details of the classification criteria, along with photographs of superficial gastritis, chronic atrophic gastritis, intestinal metaplasia and dysplasia, were previously presented by You et al. 18 Epidemiologic data collection We interviewed cases and controls using a standard epidemiological questionnaire. The information was collected on demographic factors, occupational history, medical history, family history of digestive cancers (first-degree relatives), dietary habits, smoking and alcohol drinking history, body weight and height. Patients medical records were abstracted for relevant clinical data including endoscopy and pathology examinations. drinker was defined as anyone who reported drinking green tea only. Information was also collected on frequency of green tea drinking (number of cups per week), duration of green tea drinking (years) and amount of green tea consumption (kg per month). Statistical methods The effects of green tea drinking on the risk of chronic gastritis and stomach cancer were estimated with the odds ratios (OR) and their 95% confidence intervals (CI) derived from logistic regression analysis in SAS. Body mass index (kg/m 2 ) was calculated by dividing the body weight by the squared of height. The categorizations of green tea consumption variables were based on their distributions in the controls. As cutoff points, we used the median distribution of our controls. Number of cups per week was categorized into non, 1 21 and 21. Years of tea drinking was categorized into non, 1 13 and 13 years. Among green tea, there were 1 chronic gastritis case and 28 controls without years of tea drinking information and 2 stomach cancer cases, 7 chronic gastritis cases and 27 controls without cups per week information. Dummy variables were used in logistic regression analysis to estimate OR for each category of exposure. Three stages of analysis were performed to estimate crude OR, adjusted OR (controlling for gender and continuous variables of age and education) and further adjusted OR. Based on prior knowledge and confounding assessment, age (continuous), gender, education (continuous), pack-year of smoking (continuous), body mass index (continuous), and alcohol drinking (yes/no), were included in the model when estimating the further adjusted OR. Only the results of further adjusted analyses were presented in this paper. The trend test for ordered variables was computed by assigning score j to jth exposure level of categorical variable (j 1,2,...) and treating the categorical variable as a continuous predictor in the logistic regression models. RESULTS From the distribution of demographic and other variables (Table 1), we found that stomach cancer cases were generally older and more male than both chronic gastritis cases and controls. The mean of body mass index was the lowest in stomach cancer cases followed by chronic gastritis cases and controls. More smokers and alcohol were found among stomach cancer cases than among controls. In order to identify potential confounders, we categorized the potential confounders by green tea drinking and disease status. Table 2 shows the distribution of demographic factors and other selected variables among stomach cancer cases, chronic gastritis cases and controls by green tea drinking status. The means of age of green tea and non- were similar in stomach cancer and chronic gastritis cases. A slightly older green tea TABLE I DISTRIBUTIONS OF DEMOGRAPHIC VARIABLES IN STOMACH CANCER CASES, CHRONIC GASTRITIS, AND CONTROLS Variables Stomach cancer (%) Chronic gastritis (%) Controls (%) Age (years) Mean Gender Male 93 (69.9) 114 (68.7) 214 (49.4) Female 40 (30.1) 52 (31.3) 219 (50.6) Education Illiterate 42 (32.6) 26 (16.7) 103 (24.3) Primary 66 (51.2) 56 (35.9) 170 (40.1) Middle 16 (12.4) 43 (27.6) 111 (26.2) High School 5 (3.9) 31 (19.9) 40 (9.4) BMI (kg/m 2 ) Mean Smoking No 68 (51.1) 90 (54.2) 282 (65.1) Yes 65 (48.9) 76 (45.8) 151 (34.9) Pack-years of smoking Mean Alcohol drinking No 79 (59.4) 111 (66.9) 292 (67.4) Yes 54 (40.6) 55 (33.1) 141 (32.6)

3 602 SETIAWAN ET AL. TABLE II DISTRIBUTIONS OF DEMOGRAPHIC AND OTHER SELECTED VARIABLES AMONG STOMACH CANCER CASES, CHRONIC GASTRITIS CASES, AND CONTROLS BY GREEN-TEA DRINKING STATUS Variables Stomach cancer n 133 Chronic gastritis n 166 Controls n 433 Age (years) Mean p p p Gender Male 36 (97.3) 56 (59.0) 55 (91.7) 57 (54.8) 133 (76.9) 73 (29.2) Female 1 (2.7) 39 (41.0) 5 (8.3) 47 (45.2) 40 (23.1) 177 (70.8) Education Illiterate 5 (13.9) 37 (40.2) 1 (1.7) 25 (26.0) 18 (10.7) 84 (34.1) Primary 17 (47.2) 48 (52.2) 19 (32.8) 36 (37.5) 53 (31.5) 109 (44.3) Middle 12 (33.3) 4 (4.3) 21 (36.2) 21 (21.9) 66 (39.3) 45 (18.3) High School 2 (5.6) 3 (3.3) 17 (29.3) 14 (14.6) 31 (18.5) 8 (3.3) BMI (kg/m 2 ) Mean p p p Smoking No 9 (24.3) 59 (62.1) 17 (28.3) 72 (69.2) 67 (38.7) 210 (84.0) Yes 28 (75.7) 36 (37.9) 43 (71.7) 32 (30.8) 106 (61.3) 40 (16.0) Pack-years of smoking Mean p p p Alcohol drinking Non 13 (35.1) 66 (69.5) 33 (55.0) 76 (73.1) 73 (42.2) 216 (86.4) Drinkers 24 (64.9) 29 (30.5) 27 (45.0) 28 (26.9) 100 (57.8) 34 (13.6) p p p TABLE III THE ODDS RATIOS (OR) AND 95% CONFIDENCE INTERVALS OF GREEN-TEA DRINKING VARIABLES IN CHRONIC GASTRITIS AND STOMACH CANCER Variables Controls (%) Chronic gastritis (%) Chronic gastritis further adjusted OR 1 Stomach cancer (%) Stomach cancer further adjusted OR 1 drinking No 250 (59.1) 104 (63.4) (72.0) 1.00 Yes 173 (40.9) 60 (36.6) 0.49 ( ) 37 (28.0) 0.52 ( ) No of cup per week Non 250 (63.1) 104 (66.2) (73.1) (23.5) 31 (19.8) 0.47 ( ) 26 (20.0) 0.70 ( ) (13.4) 22 (14.0) 0.52 ( ) 9 (6.9) 0.39 ( ) p for trend Tea drinking history Non 250 (63.3) 104 (63.8) (72.0) years 77 (19.5) 41 (25.2) 0.75 ( ) 13 (9.8) 0.73 ( ) 13 years 68 (17.2) 18 (11.0) 0.34 ( ) 24 (18.2) 0.57 ( ) p for trend Adjusted for age, gender, education, body mass index, pack-years of smoking, and alcohol drinking. non- than were observed in controls. Age is considered a potential confounder in this study because age has been shown to be associated with stomach cancer. For gender, more men than women were green tea. Gender is also considered as a potential confounder, based on prior knowledge and our observation. Education level of stomach cancer cases who drank green tea was most concentrated among the primary level. In both chronic gastritis and controls, the green tea were concentrated in the middle level. Education level was considered as a marker for socioeconomic status in this study and it was adjusted for in our analyses. No obvious relationship was observed between body mass index and green tea drinking in the three groups. Body mass index, however, was associated with stomach cancer, therefore we included body mass index as a potential confounding factor in our analysis. Table 2 also shows the distribution of potential risk factors of stomach cancer by green tea drinking and disease status. Among green tea, the highest percentage of smokers was found in stomach cancer (76%), followed by chronic gastritis (72%) and control group (61%). The highest mean of pack-years smoking was observed in stomach cancer cases, followed by chronic gastritis and control group who were green tea. Pack-year of smoking was adjusted for in the analyses as potential confounder. Among stomach cancer cases and controls who drank green tea, the proportions of alcohol were 65% and 58%, respectively. Among chronic gastritis cases who drank green tea, there were less alcohol (45%). A total of 72% of stomach cancer cases, 63% chronic gastritis cases, and 58% of controls were not tea (data not shown). Among those who drank tea, the majority (97% stomach cancer cases, 98% chronic gastritis cases, and 95% controls) drank only green tea. Our analyses were based on these subjects who only drank green tea, therefore 1 stomach cancer case, 1 chronic gastritis case and 9 controls who consumed only black or jasmine tea were excluded from the analyses. Table 3 shows the odds ratios (OR) and the 95% confidence intervals (CI) of green tea drinking variables in chronic gastritis

4 PROTECTIVE EFFECT OF GREEN TEA 603 and stomach cancer. The highest percentage of non-green tea was found in stomach cancer cases (72%), followed by chronic gastritis cases (63%) and controls (59%). Protective effect of green tea was observed in stomach cancer with a further adjusted OR of 0.52 (95% CI: ). In addition, with increased frequency of green tea drinking and years of green tea drinking, a decreased risk of stomach cancer was shown. drinking also showed protective effect against chronic gastritis (OR 0.49; 95% CI: ) and a dose-response relationship was observed with duration of green tea drinking. DISCUSSION First, several methodological issues need to be discussed. Our study is population based, therefore, it is less susceptible to selection bias because the healthy controls were selected from the same population from which the cases arose. The response rates were relatively high for our case groups and controls: 80% for stomach cancer cases, 81% for chronic gastritis and 91% for controls. If risk factors for stomach cancer and chronic gastritis were more prevalent among those who refused to participate in our study, an underestimation of OR may result. On the other hand, if risk factors were more prevalent in controls who refused to participate, this may lead to overestimation of OR. With the high response rates, however, the magnitude of under- or overestimation is likely to be small. In a case-control study, potential misclassification of exposure and disease status needs to be considered. data that we collected include green tea drinking status, number of cups per week, years of drinking and monthly family consumption in kg. drinking status should not be subjected to much misclassification, however, people may not remember precisely the time they started drinking green tea or how many cups per week they drank. If the misclassification occurs nondifferentially in cases and in controls, then we may underestimate the effect of green tea on the risk of stomach cancer and chronic gastritis. All our cases were pathologically confirmed, therefore, the disease misclassification may be minimized. However, with high prevalence of chronic gastritis in the Chinese population, 18 potential disease misclassification cannot be excluded. It is possible that our controls had undiagnosed chronic gastritis, which may result in an underestimation of the association. To minimize confounding effects, age, gender, education, body mass index, pack-years of smoking and alcohol drinking were adjusted for as potential confounders in our analyses. In this study, the mean age of controls was similar to that of the chronic gastritis cases. Individuals in the control group and the chronic gastritis group were much younger than the stomach cancer cases. There may be a cohort effect of green tea drinking on the association under study. If the older generation had a lower percentage of green tea and the younger generation had a relatively higher percentage of green tea, the protective effect we observed may be overestimated because of the cohort effect. If the older generation had a higher percentage of green tea drinking and younger generation had a lower percentage of green tea, the observed association may be underestimated. Statistically adjusting for age in the multivariate analyses may not fully remove the possible cohort effects. Fortunately, we did not observe obvious difference on green tea effects between stomach cancer and chronic gastritis. If there is a cohort effect, a great difference of green tea effect between stomach cancer and chronic gastritis should be observed because chronic gastritis cases were significantly younger than stomach cancer cases. This observation indicates that the possibility of cohort effect on green tea drinking may be minimal. We found that green tea had a 48% reduced risk of stomach cancer than non after adjusting for potential confounders. In addition, we observed among green tea a decreased risk of stomach cancer with increasing frequency and duration of tea drinking. From several in vitro, animal and epidemiologic studies, green tea has been found to be protective against cancer. 6 Polyphenols isolated from green tea have been shown to have antioxidant activities 19,20 and the ability to inhibit nitrosation 21 in both in vitro and animal studies. N-Nitroso compounds have been implicated as etiologic factors of stomach cancer 22 and the protective effect of green tea may be due to its ability to inhibit the endogeneous formation of these nitroso compounds. This is the first study to show that green tea had a 51% lower risk of chronic gastritis than non after adjusting for potential confounders. In addition, among green tea, a decreased risk with increasing duration of tea drinking was observed. One study has evaluated the effect of hot green tea drinking on the risk of chronic atrophic gastritis, but it did not find any association between green tea and the risk of chronic gastritis. 16 Chronic gastritis, especially chronic atrophic gastritis, has been implicated as a precancerous lesion of stomach cancer. 23 Chronic gastritis is a common inflammatory disease and has been associated with H. Pylori infection. Because of the loss of acid-secreting parietal cells in chronic atrophic gastritis cases, an increase in ph and numbers of anaerobic bacteria in the stomach may result. These anaerobic bacteria reduce nitrate to nitrite, which can then react with other nitrogen-containing compounds to produce N- nitroso carcinogens. Antioxidants, such as ascorbic acid, have been shown to inhibit the nitrosation process and they may be involved at the early stage of chronic gastritis. 2 H. pylori infection can inhibit ascorbic acid secretion into the stomach. Ascorbic acid may also play a role in blocking the nitrosation of amines and related compounds in the stomach microenvironment. 24 Because green tea contains antioxidants, it may have an inhibitory effect against the development of chronic atrophic gastritis and halt the progression to stomach cancer. If green tea has a protective effect against chronic gastritis, it may be used as a potential preventive agent for those who are at high risk of developing stomach cancer. In conclusion, our results suggest that green tea may be protective against both chronic gastritis and stomach cancer in the Chinese population. This is the first epidemiologic study to show the protective effect of green tea on the risk of chronic gastritis in a Chinese population. 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