Green Tea Drinking and Stomach Cancer in Jiangsu Province, People’s Republic of China Correspondence and Reprint Requests:

Outline

This chapter will document population-based case-control studies in Jiangsu Province, an ideal area for green tea study and a very high risk area for stomach cancer in China. The relationship between green tea drinking and stomach cancer were examined in Jiangsu province from 1995-2007 with a series of studies: first study in Yangzhong with 133 cases and 433 controls in 1995 ¹, the second stage study with 206 cases and 415 controls in Taixing in 2000 ² and the final confirmation study in Dafeng includes over 649 cases and 1832 controls in 2007 (unpublished data, 2007). The possible biological and molecular mechanisms were examined and explored. The future direction of green tea study and the possibility of using green tea as a potential chemopreventive agent for stomach cancer intervention are suggested.

Epidemiology of Stomach Cancer

Stomach cancer is the fourth most common cancers worldwide with an estimated 934,000 new cases per year in 2002 (8.6% of new cancer cases). However, stomach cancer remains the second most common cause of death from cancer (700,000 deaths annually). Almost two-thirds of the cases occur in developing countries ³. The geographical distribution of stomach cancer is characterized by wide international variations; high-risk areas (ASR in men, >20 per 100,000) include Eastern Asia (China, Japan), Eastern Europe, and parts of Central and South America. Incidence rates are low (<10 per 100,000) in men in South Asia, North and East Africa, North America, and Australia and New Zealand³.

China is considered as high risk area of stomach cancer. It is the second most frequent disease in both sexes with an estimated 393,938 incident cases (male: 264,460; female: 128,478) according to Globocan 2002, which accounts for 42% of patients with stomach cancer worldwide. High mortality areas include southeastern coastal, west-central and northeastern areas ⁴. A national cancer mortality survey in the People’s Republic of China showed that cancer comprised approximately 10% of total deaths, with stomach cancer as the top killer ⁵. Stomach cancer is one of the most fatal cancers in China, with a 5-year survival of 18%.

Jiangsu province is considered as a high cancer incidence and mortality area in China. The cancer incidence and mortality rates are higher than the national average level. According to 1990-92′ s investigation, the mortality rates was about 160/100,000, which is 50% higher than the national average mortality rate (108/100,000).⁶ Among top 30 counties with the highest cancer mortality rates in
China, Jiangsu Province had 9 counties. It was estimated that 120,000 cancer patients died in Jiangsu annually, accounting for 10% of overall cancer deaths in China, even though the population in Jiangsu Province only accounts for 5% of China national population. Since 1970’s, cancer has been ranked as the number one killer in Jiangsu Province. The top four cancer sites are cancers of liver, stomach, esophagus and lung, accounting for over 80% of all cancer deaths in Jiangsu Province.

Risk and Protective Factors for Stomach Cancer

The etiology of stomach cancer is believed to be multi-step and multifactorial. Epidemiologic studies have identified major known risk factors for stomach cancer including Helicobacter pylori (HP) infection, nitrite and nitrosamine intake, meat and processed meat intake, preserved fish, vegetable and smoked food intake, high salty food intake, malnutrition, tobacco smoking and possibly alcohol drinking ^7-10. The possible protective factors include fruit and vegetable intake, vitamin C and possibly green tea drinking ¹¹.

The prevalence of HP infection is between 60-88% in Asian countries and approximately 30% in Western populations ¹². It has been estimated that HP infection contribute 47% of stomach cancer cases in the developing countries ¹³. HP infection leads to chronic atrophic gastritis, metaplasia, and dysplasia, precursors of stomach cancer. In 1994, the International Agency for Research on Cancer (IARC) classified H. pylori as a carcinogen, or cancer-causing agent, despite conflicting results at the time. However, many studies have supported the conclusion with a positive association between HP infection and stomach cancer ^14-16. A combined analysis of 12 case-control studies nested within prospective cohorts found a relative risk of 5.9 for non-cardia cancer associated with H pylori infection ¹⁷. In China, cohort and case-control studies have reported positive association between HP infection and stomach cancer ^{18, 19}. However, some other case-control studies of the association between HP infection and risk of stomach cancer have been negative in Chinese population ^{1, 2}. The major reasons are that HP will disappear from gastric tissues when cancer lesion is developed, leading to a relatively low prevalence of HP infection in stomach cancer cases, and that the population prevalence in China is relatively high, resulting in relatively higher prevalence of HP among controls.

Green Tea Drinking and Stomach Cancer

Tea is the most widely consumed beverage in the world ²⁰ and all tea is derived from one plant (Camella sinensis). The majority of tea manufactured in the world is black tea, accounting for 78%. About 20% of produced tea is green tea, and 2% oolong tea. Green tea is primarily consumed in Asian countries, such as Japan and China. Green tea contains polyphenols, commonly known as catechins. Some major green tea catechins are (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), (−)-epicatechin (EC), (+)-gallocatechin, and (+)-catechin.

Tea polyphenols as antitumor agents have been reported to target multiple organs including the digestive tract, liver, lung, pancreas, mammary gland, and skin. Most animal models and in vitro studies have shown that they have antimutagenic
and anti-oxidative properties that can inhibit various human cancer cell lines and also have no serious adverse effects. N-nitroso compounds formed in the human stomach have been implicated as etiological factors of stomach cancer. It is also suggested that Green Tea may inhibit HP infection.

Fifteen case-control studies ^{1, 2, 21-33} and ten prospective cohort or nested case-control studies ^34-43 have been conducted to elucidate the relationship between green tea drinking and stomach cancer. The results of these epidemiologic studies are summarized in Tables 20.1 and 20.2.

A Population-Based Case-Control Study in Yangzhong City, Jiangsu ¹, the First Study in 1995:

Introduction

Professor Guopei Yu of Shanghai Medical University, China and Professor Chung-Cheng Hsieh of Harvard University School of Public Health are pioneers in the research of relationship between green tea drinking and stomach cancer in Chinese population. They published together the first epidemiological investigation of green tea drinking and reduced risk of stomach cancer in mainland China in a teacher’s cohort in Shanghai, with a strong protective effect of green tea drinking on the risk of stomach cancer in 1991²⁵. With the involvement of Professor Shun-Zhang Yu of Shanghai Medical University, they further conducted a population-based case-control study of stomach cancer with large numbers of cases and controls and reported strong protective effect of green tea on the risk of stomach cancer in Shanghai ²⁸. Based on the convincing results in Shanghai, they started to explore the green tea effect in Jiangsu Province and selected Yangzhong county as their study base because of the extremely high incidence and mortality of stomach cancer. They further collaborated with Professor Zuo-Feng Zhang at Memorial Sloan-Kettering Cancer Center, New York in the aspects of molecular epidemiology of stomach cancer. The population-based case-control study in Yangzhong was conducted to examine the following hypotheses: a) are green tea drinking associated with reduced risk of both stomach cancer and its premalignant lesion chronic atrophic gastritis after controlling for potential confounding factors? and b) if green tea is associated with reduced risk of both stomach cancer and its premalignant lesion, are there any dose-response relationship?

Yangzhong City (formerly Yangzhong County, prior to 1995) 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 70-74 years old. About 40% of general population are green tea drinkers in Yangzhong.

Study Population

A case-control study was conducted in Yangzhong City, Jiangsu province. Data included interview-questionnaire data, medical record review, and blood samples for assaying Helicobacter pylori infection and molecular markers. The two case groups included patients with stomach cancer and chronic gastritis (either superficial or atrophic). The healthy control group was a random sample from local population on the island, where the cases came from.

Stomach Cancer Cases: Eligible cases were all patients examined 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 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 six-month period in 1995). Blood specimens were collected in 63% (84 of 133) of stomach cancer patients who had an interview.

Table 20.1 Case-Control Studies of Green Tea and Stomach Cancer

Author, year	Country	Consumption	OR (95% CI)/RR (95% CI)	Confounder Adjustment
Tajima, 1985²¹	Japan 93 cases, 186 hospital controls	> 4 times/day	0.64 (NA)	Age and sex
Kono, 1988 ²²	Japan 139 cases, 2574 hospital controls, 278 population controls	Cases vs. hosp controls Low Medium High High* (>10 cups/day) Cases vs. pop. Controls High* (>10 cups/day)	1.0 1.1 0.6 0.5 (0.3-1.1) 0.3 (0.1-0.7)	Age, sex, smoking, oranges and other fruits
Kato, 1990 ²³	Japan 427 cases, 3014 controls 1414 chronic atrophic gastritis cases, 3014 controls	Male Hot green tea Non-drinkers 1-4 cups/day >5 cups/day Female Hot green tea Non-drinkers 1-4 cups/day >5 cups/day Male Hot green tea Non-drinkers 1-4 cups/day >5 cups/day Female Hot green tea Non-drinkers 1-4 cups/day >5 cups/day	1.00 1.14 (0.82-1.60) 1.01 (0.70-1.47) 1.00 0.71 (0.45-1.14) 0.81 (0.51-1.27) 1.00 1.04 (0.83-1.30) 1.00 (0.78-1.29) 1.00 1.46 (1.16-1.83) 1.19 (0.93-1.51)	Age and residence
Lee, 1990²⁴	Taiwan 210 cases, 810 hospital controls	No Yes	1.0 (NA) 2.0 (NA)	Smoking, alcohol drinking, salted meat, fried food, fermented bean, milk intake
Yu, 1991²⁵	China 84 cases, 2676 controls	Strong tea (type not specified)	0.3 (0.1-0.7)	Age, sex, income, family history of stomach cancer/other cancer, history of TB, blood type, smoking, alcohol, fruit and milk intake
Hoshiyama 1992²⁶	Japan 294 cases, 294 population controls, 202 hospital controls	Use vs. pop controls Low (<4cups/day) Medium (5-7cups/day) High (>8cups/day) Use vs. hosp controls Low (<4cups/day) Medium (5-7cups/day) High (>8cups/day)	1.0 1.0 (0.7-1.4) 0.8 (0.5-1.3) 1.0 1.3 (0.8-2.0) 1.3 (0.8-2.1)	Age, sex, administrative division and smoking status
Inoue, 1994²⁷	Japan 668 cases, 668 hospital controls	Not every day Every day	1.00 1.09 (0.83-1.43)	Sex
Author, year	Country	Consumption	OR (95%CI)/RR (95%CI)	Confounder Adjustment
Yu, 1995²⁸	China 711 cases, 711 controls	Users Pylori Temperature Boiling hot Hot Warm/cold	0.71 (0.54-0.93) 0.29 (0.13-0.68) 1.18 (0.75-1.86) 0.63 (0.46-0.87) 0.51 (0.29-0.91)	Age, sex, residence, education, birthplace, alcohol drinking and smoking
Ji, 1996²⁹	China 1124 cases, 1451 controls	Men Non-drinkers Drinkers Tea leaf (g/year) <1,200 >1,200-<2,000 >2,000-<3,000 >3,000 Women Non-drinkers Drinkers Tea leaf (g/year) <1,200 >1,200	1.0 0.96 (0.77-1.21) 1.06 (0.76-1.49) 1.15 (0.82-1.61) 0.88 (0.64-1.24) 0.76 (0.55-1.27) 1.0 0.77 (0.52-1.13) 0.74 (0.45-1.21) 0.81 (0.46-1.43)	Age, income, education (women), alcohol drinking and smoking (men)
Inoue, 1998³⁰	Japan 896 cases, 21128 non-cancer outpatients	Rarely Occasional Daily 1-3 cups/day 4-6 cups/day 7+ cups/day	1.00 1.00 (0.77-1.44) 0.96 (0.70-1.32) 1.01 (0.74-1.39) 0.69 (0.48-1.00)	Age, sex, years and season of hospital visit, smoking, alcohol drinking, coffee and black tea drinking, physical exercise, fruit, rice and beef intakes
Gao, 1999 ³¹	Jiangsu, China 153 case 234 controls	0 gram/month 1-199g/month 200+ g/month	1.0 0.54 (0.28-1.04) 0.44 (0.24-0.80)	Age and gender
Setiawan, 2001¹	Yangzhong, China 133 cases, 433 healthy controls	Non-drinkers 1-21 cups/week 21+ cups/week	1.00 0.47 (0.27-0.80 0.52 (0.28-0.99) p for trend: 0.0479	Age, gender, education, body mass index, pack-years of smoking, alcohol drinking
Takezaki, 2001³²	Pizhou, Jiangsu, China 187 cases 333 controls	Never 1-149 g/month 150+ g/month	1.0 0.79 (0.47-1.33) 0.83 (0.47-1.48)	Age, gender, smoking and drinking
Gao, 2002³³	Huaian, China	0 g/month > 1g/month	1.00 0.38 (0.24-0.62)	Age and sex
Mu, 2005²	Taixing, Jiangsu, China 206 cases 415 controls	Never 1-125 g/month 125-250 g/month 250+/month	1.00 1.09 (0.53-2.23) 0.44 (0.19-1.01) 0.39 (0.17-0.91) p for trend: 0.0118	age (continuous variable), gender (male or female), education (continuous), income (continuous variable), body mass index (continuous variable), pack-year of smoking (continuous), alcohol drinking (1=never, 2=seldom, 3=often, 4=everyday), very hot food eating habit, H. pylori infection (CagA + or −), stomach disease history and family history of stomach cancer.
Galanis, 1998³⁴	US (Hawaii) 5233 men, 6297 women 108 cases	Men & women None 1 2+	1.0 1.3 (0.7-2.1) 1.5 (0.9-2.3)	Age, sex, education and birthplace
Nakachi, 2000³⁵	Japan 8552 general residents 140 cases	Both gender <3 cups 10+ cups Men <3 cups 10+ cups Women <3 cups 10+cups	1.0 0.59 (0.35-0.98 1.0 0.54 (0.22-1.34) 1.0 0.57 (0.34-0.98)
Tsubono, 2001³⁶	Japan 11902 men, 14409 women 419 cases	<1 cup/day 1-2 cups/day 3-4 cups/day > 5 cups/day	1.0 1.1 (0.8-1.6) 1.0 (0.7-1.4) 1.2 (0.9-1.6)	Age, sex, health insurance, peptic ulcer, smoking, alcohol drinking, rice, black tea, coffee drinking, meat intake, vegetables, fruits and bean-paste soup
Nagano, 2001³⁷	Japan 14873 men 23,667 women 901 cases	0-1 time/day 2-4 times/day 5+ times/day	1.0 1.0 (0.82-1.2) 0.95 (0.76-1.2)	City, gender, radiation exposure, smoking status, alcohol drinking, BMI, education level, calendar time.
Sun, 2002³⁸	China, prospective study, nested case-control Cases=190 Controls=772 Urine EGC	Urinary EGC Negative Positive (4+years)	1.00 0.52 (0.28-0.97)	Matched on age, date of sample collection, residence, and adjusted for helicobactor pylori seropositivity, smoking, alcohol drinking, and level of serum carotenes
Hoshiyama 2002³⁹	Japan, prospective cohort study (JACC) Men: 2,849,605 PY 240 cases Women: 4,024,456PY 119 cases	Men <1 1-2 3-4 5-9 >=10 Women <1 102 3-4 5-9 >=10	1.0 1.6 (0.9-2.9) 1.1 (0.6-1.9) 1.1 (0.6-1.9) 1.0 (0.5-2.0) P for trend: 0.634 1.0 1.1 (0.5-2.5) 1.0 (0.5-2.1) 0.8 (0.4-1.6) 0.7 (0.3-2.0) P for trend: 0.48	Age, smoking, sex, history of peptic ulcer, family history of stomach cancer, consumption of rice, miso soup, green-yellow vegetables, white vegetables, fruits, and preference for salty foods
Koizumi, 2003⁴⁰	Japan, two cohort studies Cohort 1: 31,345 199,748 PY, 419 cases Cohort 2: 47,605 290,599 PY, 314 cases	<1 1-2 3-4 >=5	1.01 1.0 (0.80-1.27) 0.89 (0.70-1.13) 1.06 (0.86-1.30) p for trend: 0.61	Age, sex, type of health insurance, parental history of gastric cancer, history of peptic ulcer, cigarette smoking, alcohol consumption, pickled vegetables, bean-paste soup.
Hoshiyama 2004⁴¹	Japan, Nested Case-Control Study from cohort (JACC study) 151 cases, 265 controls	<1 cup/day 1-2 3-4 5-9 >=10	1.0 1.3 (0.6-2.8) 1.0 (0.5-1.9) 0.8 (0.4-1.6) 1.2 (0.6-2.5) p for trend: 0.899	Age, smoking, sex, H. pylori, history of peptic ulcer, family history of stomach cancer, education, consumption of rice, miso soup, green-yellow vegetables, white vegetables, fruits, and preference for salty foods
Sasazuki, 2004⁴²	Japan JPHC Study 34832 men 38111 women 892 cases 665 male cases 227 female cases	Distal Stomach Cancer <1 cup/day 1-2 3-4 5+ <1 cop/day 1-2 3-4 5+	Men: 1.0 0.88 (0.65-1.17 0.85 (0.64-1.12) 0.88 (0.67-1.16) Women 1,0 0.92 (0.58-1.47) 1.05 (0.69-1.60) 0.53 (0.33-0.85)	Age, area, smoking
Sauvaget, 2005⁴³	38,576 A-bomb survivors 485,575 PY 1270 cases	<2 time/day 2-4 5+	1.0 1.03 (0.89-1.19) 1.06 (0.89-1.25)	Sex, age, city, radiation dose, smoking, education level

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 one year. In the six-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 who were willing to participate. The study was restricted to people who lived in Yangzhong for at least one 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 home, and collected a 5 ml or more 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.

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. Patient’s medical records were abstracted for relevant clinical data including endoscopy and pathology examinations. Green tea 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).

Major Results

Tables 20.3 and 20.4 show the odds ratios (OR) and the 95% confidence intervals (CI) of green tea drinking variables and stomach cancer and chronic gastritis. The highest percentage of non-green tea drinkers 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. In addition, both frequency of green tea drinking and years of green tea drinking were related to a reduced risk of stomach cancer. Green tea drinking also showed protective effect against chronic gastritis and a dose-response relationship was observed with duration of green tea drinking.

Introduction

Before the year of 2000, there have been a total of 12 epidemiological studies of green tea and stomach cancer, including one cohort study ³⁴ and 11 case-control studies ^21-31 (Tables 20.1 and 20.2). Only four studies showed strong protective effect of green tea drinking on stomach cancer
and no of those studies has demonstrated strong dose-response relationship ^{22, 25, 28, 31}. The epidemiological evidence on green tea drinking and stomach cancer was still unclear at that time. We felt strongly to repeat our own finding on green tea drinking in a City near by Yangzhong. We selected Taixing City, which is across the Yangtze River from Yangzhong. In working with Professor Shun-Zhang Yu and Dr. Lina Mu of Shanghai Medical University School of Public Health, Drs. Hua Wang and Jinkou Zhao of Jiangsu CDC, and Dr. Baoguo Ding of Taixing CDC, We launched the second population-based casescontrol study in 2000 in Taixing City. The
major purpose of the study was designed as a second stage study to confirm the observation of green tea drinking and stomach cancer and to assess the possible interactions between green tea drinking and other risk/protective factors as well as molecular genetic markers. We have also decided to expend our study to three major cancer sites in Taixing, including cancers of the stomach, esophagus, and liver.

Table 20.3 The odds ratios (OR) and 95% confidence intervals of green-tea drinking variables and stomach cancer in Yang Zhong, Jiangsu, China, 1995

Variables		Cases (%)	Controls (%)	Adjusted OR^*
Green tea drinking
	No	95 (72.0)	250 (59.1)	1.00
	Yes	37 (28.0)	173 (40.9)	0.52 (0.29-0.94)
	No of cup per week
	Nondrinkers	95 (73.1)	250 (63.1)	1.00
	1-21	26 (20.0)	93 (23.5)	0.70 (0.36-1.36)
	>21	9 (6.9)	53 (13.4)	0.39 (0.15-1.01)
	P for trend			0.0479
Tea drinking history
	Nondrinkers	95 (72.0)	250 (63.3)	1.00
	1-13 years	13 (9.8)	77(19.5)	0.73 (0.33-1.62)
	> 13 years	24(18.2)	68 (17.2)	0.57 (0.28-1.14)
	P for trend			0.1051
^*Adjusted for age, gender, education, body mass index, pack-year of smoking, and alcohol drinking

Table 20.4 The odds ratios (OR) and 95% confidence intervals of green-tea drinking variables and chronic gastritis in Yang Zhong, Jiangsu, China, 1995

Variables		Cases (%)	Controls (%)	Adjusted OR^*
Green tea drinking
	No	104 (63.4)	250 (59.1)	1.00
	Yes	60 (36.6)	173 (40.9)	0.49 (0.31-0.77)
No of cup per week
	Nondrinkers	104 (66.2)	250 (63.1)	1.00
	1-21		93 (23.5)	0.47 (0.27-0.80)
	>21	31 (19.8)	53 (13.4)	0.52 (0.28-0.99)
	P for trend	22 (14.0)		0.0141
Tea drinking history
	Nondrinkers	104 (63.8)	250 (63.3)	1.00
	1-13 years	41 (25.2)	77 (19.5)	0.75 (0.47-1.25)
	> 13 years	18 (11.0)	68 (17.2)	0.34 (0.17-0.66)
	P for trend			0.0021
^*Adjusted for age, gender, education, body mass index, pack-year of smoking, and alcohol drinking