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Intervention trial to prevent gastric cancer and its precursors in Linqu Wei-cheng you Peking University School of Oncology Beijing Cancer Hospital Beijing Institute for Cancer Research Background ◆ Cancer is the first or second leading cause of death worldwide, and 6,700,000 people die of cancer in 2002 ◆ In China, 2,200,000 new cancer cases, and 1,600,000 people die of cancer in 2002 ◆ Cost: 78 billions USD per year in USA, and 80 billions RMB in China Cancer Incidence and Mortality in the world in 2002 (Male) Age-adjusted incidence rate of cancer in China (/100,000) IARC 2002 Cancer Incidence in Beijing from 1998 to 2006 (/10万) 260 210 男 160 女 110 60 1998 1999 2000 2001 2002 2003 2004 2005 2006 Current problems A little improvement in overall cancer treatment in the past two decades Poor quality life of cancer patients Family and social burdens Economic high cost What can we do ? Cancer prevention is better than treatment. Cancer prevention is the most effective means of reducing the incidence and mortality of cancer. 21st Century - Cancer Prevention and Quality of Life Strategy development Our goals in cancer control: Lower incidence rates Lower mortality rates Better care & quality of life Basic Research, Clinical Management, and Prevention Gastric Cancer (GC) ◆ The second leading cancer worldwide ◆ 360,000 people die of GC in China ◆ A heavy burden for the family and society ◆ Effective prevention is not available Five year survival rates of gastric cancer Survival rates (%) 100 80 60 40 20 0 I II III Cancer Stage VI The Causes of Gastric Cancer ◆ Biological factors: H.pylori infection ◆ Diet and Nutrition: salted food, grain moldy, low vitamin C level ◆ Alcohol ◆ Cigarette Smoking ◆ Genetics: gene polymorphisms ◆ Others: possible risk factors H. pylori associated gastric carcinogenesis Eradication Chronic Gastritis Atrophic Gastritis Intestinal Metaplasia Dysplasia Carcinoma H. pylori infection and gastric cancer Helicobacter & Cancer Collaboration Group. GUT 2001 ◆ ◆ H.pylori accounts for 40-60% of gastric cancers 1994, International Agency for Research on Cancer (IARC) classified H.pylori as a class I carcinogen. Gastric cancer control strategy in China ◆ Tobacco control ◆ H.pylori infection control ◆ Early detection ◆ Health life-style and diet project Linqu County ◆ A rural area of Shandong Province ◆ One of the highest GC mortality rates ( 70/105 males and 25/105 females ) ◆ Major GC is Intestinal-type Epidemiological study in a high-risk area The high-risk area is a unique resource in China Advances: ◆ Provided direct evidence from human ◆ Stable population ◆ Representative 1995- To reduce the incidence rate Intervention of IM, DYS and GC trial 1990-1994 Risk of progression to GC Cohort study of precancerous gastric lesions 1989-1990 Survey of precancerous gastric lesions Prevalence of lesions 1984-1987 Case-control study 1983 Survey of cancer mortality rate Risk and protective factors Site of gastric mucosa biopsy 3400 participants, aged 35-64. Angulus Body Antrum 2:Lesser curvature of Body Anterior Wall 3:Greater curvature of Body 4:Angulus Lesser Curvature 5:Anterior wall of Antrum 6:Posterior wall of Antrum Posterior Wall 7: Lesser curvature of Antrum 8: Greater curvature of Antrum Greater Curvature ORs for GC according to baseline histopathology 1989 Baseline pathology SG/CAG 1994 Follow-up progression OR 95%CI 1.0 Sup IM 17.4 1.5-202 Deep IM 29.3 3.9-219 M or S DYS 104.2 9.7-999 (You et al. Int J Cancer 1999, 83:615-619) Correspondence analysis between gastric lesions and biopsy sites 0.3 DYS GC 0.2 Angulus Lesser curvature of Body 0.1 Dim2 IM Lesser curvature of Antrum Normal/SG 0.0 Posterior wall of Antrum CAG Anterior wall of Antrum Greater curvature of Body -0.1 ● -0.2 Greater curvature of Antrum -0.3 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Dim1 0.2 0.4 0.6 0.8 1.0 ORs for progression to DYS and GC according to H. pylori status at follow-up 1994 follow-up progression to DYS or GC 1989 H. pylori infection No progression Progression (n) (n) OR(95%CI) (-) 443 35 1.0 (+) 1247 164 1.8(1.2-2.6) (You et al. JNCI 2000; 92:1607-1612) Intervention trial in Linqu (1) (1995-2003) In 1995, 3365 subjects were randomly assigned to receive three interventions or placebos, including an antibiotic treatment of H. pylori. Interventions Two-week treatment for H. pylori infection Omeprazole 20mg + Amoxicillin 1g Bid Daily nutritional supplementation VC 250mg + VE 100Iu + Selenium 37.5ug Bid Garlic preparation 400mg Bid Science 1995; 270:1149-1151 Geometric means of Vitamin E for treated and placebo groups (ug/dL) 2100 Geometric Mean 1900 治疗组 1700 1500 1300 1100 对照组 900 700 500 Qtr1 Qtr2 Qtr3 Qtr5 Qtr6 Qtr7 Qtr8 Qtr9 Effects of treatment on the odds of severe CAG/IM/DYS/GC OR of Severe CAG/IM/DYS/GC 95% CI 1999 H. pylori treatment 2003 H. pylori treatment 0.77 0.62-0.95 0.60 0.47-0.75 You et al. JNCI, 2006; 98:974-983 Effects of H. pylori treatment on GC GC Total No. % H.pylori treatment 19 1130 0.0168 Placebo 27 1128 0.0239 p =0.23 You et al. JNCI, 2006; 98:974-983 IF=15.2 Intervention trial in Linqu (2) (2002-2006) H. pylori infection and over-expression of cyclooxygenase-2 (COX-2) are associated with gastric cancer and its precursors. We evaluated the effect of H. pylori eradication and use of celecoxib as chemoprevention for precursors of gastric lesions. Interventions One-week treatment for H. pylori infection Omeprazole Amoxicillin Clarithromycin 20mg, bid 1g, bid 500mg, bid Celecoxib for 2 years 200mg, bid Compliance compliance rate(%) 100 98 96 94 92 90 88 86 1 3 5 7 9 11 13 15 months after follow-up 17 19 21 23 Effects on the precancerous gastric lesions Regression OR 95%CI Placebo 1.0 Anti-Hp+celecoxib 1.22 0.81-1.83 Anti-Hp+placebo 1.65 1.10-2.48 Placebo+celecoxib 1.54 1.02-2.32 Changes of COX-2 expression and evolution of precancerous gastric lesions by different interventions Regression vs No regression COX-2 Reduction COX-2 No change COX-2 Increase Ptrend Placebo 1.00 1.07 (0.73-1.57) 0.79 (0.50-1.25) 0.2901 Anti-Hp+celecoxib 1.00 0.55 (0.37-0.81) 0.31 (0.20-0.48) <0.0001 Anti-Hp+placebo 1.00 0.69 (0.47-1.01) 0.45 (0.27-0.73) 0.0013 Placebo+celecoxib 1.00 0.68 (0.45-1.02) 0.45 (0.28-0.71) 0.0007 Interventions and changes of PGE2 level Interventions Changes OR(95%CI) 33.88 1.0 Anti-Hp+celecoxib -13.10 33.4(3.6-310.2) Anti-Hp+placebo -16.36 143.0(14.8-1375.4) -3.81 33.9(3.9-293.3) Placebo Placebo+celecoxib Interventions and changes of COX-2 methylation Increase/no change Reduction Anti-Hp+celecoxib 1.00 1.83 (1.24-2.70) Anti-Hp+placebo 1.00 2.97 (2.00-4.41) Placebo+celecoxib 1.00 1.68 (1.15-2.46) Interventions Eradication of H. pylori and gastric cancer Ann Intern Med 2009;151:121-128 Questions ? Because the end point of our two trials was to assess the effect of H. pylori treatment on the precancerous gastric lesions, and the previous five intervention trials yielded mixed results on gastric cancer. It remains for the large trial to demonstrate that H. pylori treatment reduces gastric cancer incidence rate. A large intervention trial in Linqu (2009-2015) Peking University School of Oncology International Digestive Cancer Alliance Technische Universität München Study Design Participants: 200,000 ( aged 25-54 years ) Villages: 500 Intervention: Eradication of H. pylori End point: Reduction 30% of GC Designs: Benefit for eradication of H. pylori If eradication of H. pylori could reduce 30% of GC (120,000 new GCs), it can save 800 millions USD per year in China according to incidence of GC. Funding: Ministry of Science and Technology ¥ 5,030,000 IDCA/TUM $ 1,000,000 Beijing Double-Crane Pharmaceutical Co. LTD Symposium of Large Trial in Linqu County A pilot study in Linqu To seek a therapy with a high efficacy, low-toxicity and easy administration. The quadruple therapy regimens Bismuth potassium citrate 300 mg (bid) Metronidazole 500mg (tid) Tetracycline 750 mg (tid) Omeprazole 20 mg (bid) European Journal of Gastroenterology & Hepatology 2009 Initiation in State Guesthouse (2009,6) Bavarian Delegation Visiting Beijing Cancer Hospital Further Objectives ◆ To study biomarkers and mechanisms of gastric cancer and its precursors ◆ ◆ A workshop will be held from June 10-13 in Beijing, and more than 30 scientists will be there. Funding will be raised from Government and Industries worldwide. Systematical Studies Molecular Studies Epidemiological Survey Endoscopic Examination Check Interventions Summary Identified the risk and protective factors for GC in a high-risk population Revealed that eradication of H. pylori or celecoxib treatment may reduce the prevalence of precancerous gastric lesions, as well as favorable effects on GC. Thanks!