Transcript H. pylori

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!