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!!