Risk Factors Investigation, Randomized Factorial Trial And Initial Epidemiological Evaluation To Comprehensive Prevention For Precancerous Gastric Lesions In High Risk Area With Gastric Cancer

IntroductionGastric cancer represents the fourth most common cancer and second leading cause of cancer-related death worldwide. Its prevalence in 1999 was 138.6/105 according to the report of WHO, and the estimated current incidence of gastric cancer in 2002 is approximately 16.2/105 persons/year, with highest incidences in Eastern Asia. Additionally, the prevalence of gastric cancer in China is among the highest in the world. In China, the prevalence and mortality rate of gastric cancer were 300.9/105 and 29.3/105, respectively. In 2007, approximately 400,000 cases were diagnosed in China, and it is forecasted that the indication population will grow 2.3 percent per year between 2007 and 2012.There is an obvious clustering of geographical distribution of gastric cancer in the country, with the high mortality being mostly located in rural areas. Zhuanghe city, lying in the coastal area of Eastern-Liaoning peninsula, is the area of high morbidity of gastric cancer in north China. Its mortality of gastric cancer is 49.55/105 in male and 22.23/105 in female. In the beginning of 1980s, the Cancer Institute of China Medical University set up a researching ground in the city, where a general investigation on etiology, epidemiology and geographic pathology of gastric cancer was accomplished in the past 25 years. Although the mortality of gastric cancer has declined over the past decades on the basis of large-scale prevention and diagnosis of forepart-gastric cancer, it is insufficient to meliorate the high incidence of gastric cancer only depended on early diagnosis. However, early prevention and cutting off the lapse of gastric cancer is becoming the keystone. Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages:chronic gastritis; atrophy; intestinal metaplasia; and dysplasia. It causes excessive cell replication, an event well known to increase cancer risk because of potentiation of the action of carcinogens and the possibility of increased rate of endogenous mutations. These results indicated that gastric carcinogenesis is a multistep nature, and chronic gastritis; atrophy; intestinal metaplasia; and dysplasia are deemed to the precancerous gastric lesions of gastric cancer. To slow the progression of precancerous gastric lesions may reduce the incidence of gastric cancer. Most studies showed that the incidence of precancerous gastric lesions is related to dietary factors and life-style, etc.. If these relative factors were eliminated or decreased, the incidence and mortality of precancerous gastric lesions would be lowered, and then, the incidence and mortality of gastric cancer may be decreased. Thus, it is very important to investigate the risk factors of these precancerous gastric lesions and find an effective comprehensive preventive method for gastric cancer.H pylori are also the cause of other gastric diseases, such as peptic ulcer, gastric mucosa-associated lymphoma. Especially corpus-predominant H pylori-induced gastritis has been identified as an important risk factor for gastric cancer development. It has been confirmed that the development of gastric cancer spans over several decades sequentially starting with the acquisition of H pylori infection and the development of chronic active gastritis. It was suggested that H pylori infection leads to an increased risk, in the order of 4 to 9 folds, of developing precancerous gastric conditions especially when the infection occurs in childhood. In 1994 the International Agency for Research on Cancer (IARC) monograph committee classified H pylori as a class I carcinogen to humans. The prevalence of H pylori infection in adults from Zhuanghe is more than 60%, compared to 12% from Shenyang. A previous research from the high-risk area in Zhuanghe reported that there is a significantly positive relationship between gastric diseases or precancerous lesions and H pylori infection, suggesting there may be some relationship between Hpylori infection and gastric cancer incidence in these area.A series of epidemiological investigation and comprehensive preventive approaches had been applied during the course from "Nine-five" to "Ten-five" by the Cancer Institute of China Medical University in order to explore an effective comprehensive preventive approach to reduce the incidence of precancerous lesions, find the dubious risk factors and improve the health consciousness and ability of people. The initiative effect of intervention approaches by epidemiological study was evaluated in this paper.Materials and Methods1. Epidemiological investigation of high risk populationDuring the period of "Eleven-five", in 2008, three villages were selected randomly for investigation. Persons with history of gastric illness, history of family gastric cancer and older than thirty-five years old were selected as suspected high risk population from selected villages according to the epidemiological survey in the two-round screening.1179 persons without gastric cancer diseases were further investigated and grouped as high risk population of gastric cancer. All study investigators and staff members successfully completed a training program that oriented them both to the aims of the study and to the specific tools and methodologies employed. At the training sessions, interviewers were given detailed instructions on administration of the study questionnaire. This questionnaire includes:general conditions (age, sex, occupation, marriage, culture level, number of people in family and income et al.); habit of bite and sup (smoking, drinking, history of gastric illness and history of family gastric cancer and so on), and clinic symptom (bellyache, bulge, nausea, disgorge, and so on)2. Intervention approachesDuring the course of "Nine-five", in 1997, sixteen villages were sampled as the intervention groups based on location, economic level, and proportion of population in each intervention group village. Persons with history of gastric illness, history of family gastric cancer and older than thirty-five years old were selected as suspected high risk population from selected villages according to the epidemiological survey in the two-round screening. After two-round screenings, persons were treated with antibiotics, Chinese herb medicine, and nutritional therapy, based on X-ray, HP detected, and gastroscopic and pathological examination. The design of the drug intervention was as the following table1. In this study,361 persons with the whole information were selected to evaluate the effects of intervention.3. Evaluation of effect to intervention approachesThere are 34 towns, namely 361 villages in Zhuanghe country with total population of approximate 900 000. Stratified sampling and cluster sampling were applied to define the intervention group and the control group during course of "Nine-five". Each village in this county was stratified into two groups according to location geographically close seaside or not, then the sampled villages were defined by cluster sampling in the two groups, and the number of the sampled villages in each group was proportional villages were used as the samples.Sixteen villages were sampled as the intervention groups, other 14 villages were used as the control based on location, economic level, and proportion of population in each intervention group village.16 870 in the intervention group, and 14 900 in the control group were observed, respectively. The age and sex were proportional in each group.During the course of "Nine-five",16 villages were sampled as the intervention groups (Ⅰgroup), other 14 villages were used as the control (Ⅱgroup). During the course of "Ten-five", base on the results of former prevention ad cure, intervention approaches was continued conducted inⅠgroup as former but without drugs intervention; Screening of gastric cancer was conducted in groupⅡwithout drug intervention. At the same time, forty villages were randomly selected, screening of gastric cancer without drug intervention was conducted in twenty villages (groupⅢ), and the other twenty villages were defined as control (groupⅣ).The prospective cohort study was applied to observe the samples. The cause of all death including gastric cancer from 1996 to 2005 was documented in both intervention group and control groups. The screened patients with gastric cancer were observed and reported annually.4. StatisticsContinuous variables were given as the mean±SD and categorical variables as the percentage in each subgroup. Associations between categorical variables were tested by the use of contingency tables and theχ2 test. Comparisons between continuous variables between groups were performed by Student's t-test. Multivariate logistic regression analyses were used to test significant determinants of hypertension status. The relative risk (RR) and attributable risk percent (AR%) of intervention on death of gastric cancer were calculated. The survival rate of all the screened patients with gastric cancer was evaluated. All data analyses were conducted using SAS 8.12 (Statistics/Data Analysis) software. A two-tailed probability value of <0.05 was considered to be statistically significant. Results1. Investigation of Precancerous Gastric Lesions(1) The effect of gender and age on the type of precancerous gastric lesionsOverall,98.81%(1165/1179) of the subjects had precancerous gastric lesions. The overall prevalence of precancerous gastric lesions was slightly higher among men (99.10%) than among women (98.55%), but the difference was not statistically significant. The constituent ratio of types of precancerous gastric lesions between genders was significantly different. With the age older, there was a decrease trend in supreficial gastritis (Z=3.23,p< 0.001), and an increasing trend in atrophic gastritis (Z=2.02, p=0.02).(2) Clinic symptoms of precancerous gastric lesionsAccording to the compositor of percent, the clinic symptoms of precancerous gastric lesions was bellyache, heart rot, bulge, acid regurgitation, belch, inappetence. Compared among the groups, the percent of acid regurgitation and belch were higher among the subjects suffered from supreficial gastritis, atrophic gastritis and gastric ulcer than that among subjects with superficial atrophic gastritis (p<0.05).(3) Effects of personal factors on the type of precancerous gastric lesionsFor all the participants, the prevalence of gastric epithelial dysplasia was higher among subjects with education level=junior college. The workers and the subjects with the number of population in family>4 were at greater risk of developing supreficial gastritis and superficial atrophic gastritis (x2=6.20,p=0.013).(4) Effects of smoking and drinking on the precancerous gastric lesionsThe prevalence of atrophic gastritis, gastric ulcer and gastric epithelial dysplasia was higher in the smokers than no-smokers (x2=11.49,p=0.043), and the prevalence of gastric ulcer and gastric epithelial dysplasia increased with the increase in number of cigarette smoked and years of smoked. Drinkers were more suffered from atrophic gastritis compared with no-drinkers, and the prevalence of atrophic gastritis and gastric ulcer among drinkers were 17.71% and 16.15%, respectively, which were higher than that among control groups.(5) The relationship between life-type and precancerous gastric lesionsAmong the subjects whose salt intake was>6g, the prevalence of gastric ulcer increased with the increase in the intake of table salt (p<0.05), however, the effects of the other life-type factors on precancerous gastric lesions were not significantly.(6) Multiple regression analysisAfter multiple logistic regression analysis and adjusted the effects of the other factors, garlic eating was shown to confer protection against the development of gastric ulcer (OR=1.83,95%CⅠ:1.09-3.07). Subjects liking deep-fry have a higher risk of developing gastric epithelial dysplasia, the odds ratio was 1.78 (95%CⅠ:1.01-3.12).2. Effects of drug treatment on the precancerous gastric lesionsAt baseline, there were no statistically significant differences in the distributions of histopathology categories the groups. However, the distribution of histopathology categories in the H. pylori treatment group differed statistically significantly from that in the placebo group, and the ratios of normal of histopathology categories increased to 12.19%, even later of 18 months after stop treatment, the rate of normal subjects was retained 9.42%.(2) Changes of HP infection rateThe percent of HP infection was statistically significantly decreased to 71.23% after H. pylori treatment. Among the no-H.-pylori treatment groups, there was not significantly difference after treatment.(3) The effects of drug in different combination on the rate of HP positivityThe percent of HP infection was statistically significantly decreased after H. pylori treatment, especially for the group treatment with antibiotics+Chinese herb medicine.(4) The effects of drug in different combination on the level of serum PG The level of PGⅠand PGⅠ/PGⅡwere statistically significantly higher among the groups treatment with antibiotics+Chinese herb medicine and with antibiotics+ nutritional therapy after H. pylori treatment. Among the subjects with H. pylori (-), the level of PGⅠ/PGⅡwas lower in the group of Chinese herb medicine compared with the group of placebo.(5) The changes of distributions of histopathology categoriesAfter H. pylori treatment, the distributions ratios of histopathology categories were statistically significantly differed among the groups treatment with antibiotics, antibiotics+Chinese herb medicine, and antibiotics+Chinese herb medicine+ nutritional therapy compared with the groups treatment with placebo. Among the subjects without H. pylori infection, the distributions ratios of histopathology categories were statistically significantly differed only among the group treatment with Chinese herb medicine+nutritional therapy.(6) Lapse of histopathology categoriesAmong the subjects who were H. pylori-seropositive, after treatment with antibiotics among the 19 subjects with atrophic gastritis, five lapsed to superficial gastritis and six lapsed to superficial atrophic gastritis. Among the 20 subjects who had atrophic gastritis, nine lapsed to superficial gastritis and four lapsed to superficial atrophic gastritis, even later 18 months after stop treatment, one patient lapsed to normal.3. Evaluation of comprehensive prevention to gastric cancer(1) Mortality of gastric cancerThe mortality rate of gastric cancer in Zhuanghe from 1996 to 2000 was between 45.21/105 to 63.29/105, the annual rate was 53.24/105, which was higher than the average rate in China (29.31/105). During the course of "Ten-five", the mortality rate of gastric cancer in from 2001 to 2005 was between 34.00/105 to 48.84/105, the annual rate was 38.97/105, which was lower than the average rate during the course of "Nine-five". (2) Mortality of gastric cancer in different groupsThe annual mortality rates of gastric cancer in the groupⅠduring post-intervention period (1997-2000) was lower significantly that that in pre-intervention period (1996), however, no statistical tendency of descending of mortality was found after 2001. There was not significantly change of gastric cancer mortality among the groupⅡ. The tendency of descending in mortality of gastric cancer was observed in groupⅢ, but not in group IV.(3) Cumulative mortality rate and relative risk analysisThe intervention approaches can reduce the death of gastric cancer. The attribute risk percent of the intervention was 42.94%, which indicated that intervention reduced gastric cancer death by 42.94% of all population.(4) Survival analysisDuring the time from 1997 to 2005,67 patients with gastric cancer were detected by screening. The one-year, three year and five year survival rate of the screened patients with cancer was 0.9403 (95%CⅠ:0.8837-0.9969),0.7435 (95%CI: 0.6382-0.8488) and 0.6372 (95%CI:0.5051-0.7693) respectively.Conclusion1.Overall,98.81%(1165/1179) of the subjects had precancerous gastric lesions. Smoking, drinking, marriage conditions, education level, income and number of population in family affected the distribution of histopathology categories among these persons with high risk factor for gastric cancer. The prevalence of gastric ulcer increased with the increase in the intake of table salt.2. The percent of HP infection was statistically significantly decreased after H. pylori treatment, and also, the serum level of PGI, PGⅡand PGⅠ/PGⅡwere statistically significantly changed. The distribution of histopathology categories in the H. pylori treatment group differed statistically significantly from that in the placebo group.3. The effects of drug intervention had time limition, and the validity of drug intervention may be holded in one year. It is more suitable to analyze and evaluate the initial effect of comprehensive prevention and treatment of gastric cancer than mortality analysis.4. The intervention approaches can reduce the death of gastric cancer, and prolong the time of survival and improve the survival rate.