Intervention trial to prevent gastric cancer and its precursors in Linqu
Intervention trial to prevent gastric cancer and its precursors in Linqu
Wei-cheng youWei-cheng you
Peking University School of OncologyPeking University School of Oncology Beijing Cancer HospitalBeijing Cancer HospitalBeijing Institute for Cancer ResearchBeijing 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
60
110
160
210
260
1998 1999 2000 2001 2002 2003 2004 2005 2006
男女
( /10万)
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
Cancer prevention is better than treatment. Cancer prevention is the most effective means of reducing the incidence and mortality of cancer.
What can we do ?
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
◆ 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
Gastric Cancer (GC)
0
20
40
60
80
100
Surv
ival ra
tes
(%)
I I I I I I VI
Cancer Stage
Five year survival rates 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
The Causes of Gastric Cancer
H. pylori associated gastric carcinogenesis
Chronic Gastritis
DysplasiaIntestinal Metaplasia
Carcinoma
AtrophicGastritis
Eradication
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 rate
s ( 70/105 males and 25/105 females
)
◆ Major GC is Intestinal-type
The high-risk area is a unique resource in China
Advances:
◆ Provided direct evidence from human
◆ Stable population
◆ Representative
Epidemiological study in a high-risk area
1995-Intervention
trial
1983Survey of cancer mortality rate
1984-1987Case-control study
1989-1990 Survey of precancerous gastric lesions
1990-1994 Cohort study of
precancerous gastric lesions
To reduce the incidence rate
of IM, DYS and GC
Risk of progression
to GC
Prevalence of
lesions
Risk and protective factors
2 : Lesser curvature of Body 3 : Greater curvature of Body 4 : Angulus 5 : Anterior wall of Antrum 6 : Posterior wall of Antrum 7: Lesser curvature of Antrum 8: Greater curvature of Antrum
Site of gastric mucosa biopsy
BodyAngulus
Antrum Anterior Wall
Lesser Curvature
Posterior Wall
Greater Curvature
3400 participants, aged 35-64.
ORs for GC according to baseline histopathology
1989
Baseline pathology
1994 Follow-up progression OR 95%CI
SG/CAG
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)
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0
Dim1
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3 DYSDYSGCGC
Lesser curvature of Antrum
Angulus
Posterior wall of AntrumPosterior wall of AntrumCAGCAG
Anterior wall of AntrumAnterior wall of Antrum
● ● Greater curvature of AntrumGreater curvature of Antrum
Lesser curvature of BodyLesser curvature of Body
Normal/SGNormal/SG
Greater curvature of BodyGreater curvature of Body
IMIM
Dim
2D
im2
Correspondence analysis between gastric lesions and biopsy sites
ORs for progression to DYS and GC according to H. pylori status at follow-up
1994 follow-up progression to DYS or 1994 follow-up progression to DYS or GCGC
1989
H. pylori infection
No progression
(n)
Progression
(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; 270:1149-1151Science 1995; 270:1149-1151
Geometric means of Vitamin E for treated and placebo groups (ug/dL)
500
700
900
1100
1300
1500
1700
1900
2100
Qtr1 Qtr2 Qtr3 Qtr5 Qtr6 Qtr7 Qtr8 Qtr9
Geo
met
ric
Mea
n 治疗组治疗组
对照组对照组
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
0.77 0.62-0.95
2003 H. pylori treatment
0.60 0.47-0.75
You et al. JNCI, 2006; You et al. JNCI, 2006; 98:974-98398:974-983
Effects of H. pylori treatment on GC
GC Total No. %
H.pylori
treatment19 1130 0.0168
Placebo 27 1128 0.0239p =0.23
You et al. JNCI, 2006; You et al. JNCI, 2006; 98:974-98398:974-983
IF=15.2
Intervention trial in Linqu ( 2 )
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.
(2002-2006)
Interventions
One-week treatment for H. pylori infection Omeprazole 20mg, bid
Amoxicillin 1g, bid
Clarithromycin 500mg, bid
Celecoxib for 2 years 200mg, bid
86
88
90
92
94
96
98
100
1 3 5 7 9 11 13 15 17 19 21 23
months af ter fol l ow-up
comp
lian
ce r
ate(
%)
Compliance
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
Regression vs No regressionCOX-2 Reduction
COX-2No change
COX-2Increase
Ptrend
Placebo 1.001.07 (0.73-
1.57)0.79 (0.50-
1.25)0.2901
Anti-
Hp+celecoxib1.00
0.55 (0.37-0.81)
0.31 (0.20-0.48)
<0.0001
Anti-Hp+placebo 1.000.69 (0.47-
1.01)0.45 (0.27-
0.73)0.0013
Placebo+celecox
ib1.00
0.68 (0.45-1.02)
0.45 (0.28-0.71)
0.0007
Changes of COX-2 expression and evolution of precancerous gastric lesions by different interventions
Interventions and changes of PGE2
level Interventions Changes OR(95%CI)
Placebo 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)
Placebo+celecox
ib
-3.81 33.9(3.9-293.3)
Interventions and changes of COX-2 methylation
InterventionsIncrease/no
changeReduction
Anti-Hp+celecoxib 1.001.83 (1.24-
2.70)
Anti-Hp+placebo 1.002.97 (2.00-
4.41)
Placebo+celecoxib 1.001.68 (1.15-
2.46)
Ann Intern Med 2009;151:121-128
Eradication of H. pylori and gastric cancer
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.
Questions ?
A large intervention trial in Linqu (2009-2015)
Peking University School of OncologyInternational 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.
Bismuth potassium citrate 300 mg (bid)
Metronidazole 500mg (tid)
Tetracycline 750 mg (tid)
Omeprazole 20 mg (bid)
The quadruple therapy regimens
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.
Endoscopic Examination
Molecular Studies
Check Interventions
Epidemiological Survey
Systematical Studies
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.
ThanksThanks!!