Global screening and eradication of Helicobacter pylori

Peter MalfertheinerKlinik für Gastroenterologie, Hepatologie und Infektiologie

Otto‐von‐Guericke‐Universität Magdeburg

Points to consider

• Size of the problem• Options for solution• H.pylori screening and eradication

Alcohol

Main effect on the esophagus!

No ? influence on gastric carcinogenesis

Franke DigDis 2005

Global burden of cancer• 7.9 million (= 13% of all deaths) worldwide in 2007• 72% of all cancer deaths in 2007 occurred in low- and middle-income

countries• Gastrointestinal- represent highest contingent

• Gastric cancer „ranks“ sadly second concerning death rate

WHO Fact sheet N° 297, July 2008

Age-standardized Incidence Rates for Gastric Cancer Data shown per 100,000

Parkin DM et al. Global Cancer Statistics, 2002

• Geographic distribution of gastric shows wide international variations.

• High-risk areas (ASR in men, >20 per 100,000) include East Asia (China, Japan), Eastern Europe, and parts of Central and South America.

• Incidence rates are low (<10 per 100,000 in men) in Southern Asia, North and East Africa, North America, and Australia and New Zealand

40% of patients with no dyspeptic symptoms

• Dyspepsia

• nausea and vomit

• Epigastric pain

• no appetite

• weight loss

GASTRIC CANCERVariable symptoms,usually as red flags in advanced stage

Points to consider

• Size of the problem

•Options for solution other than• H.pylori screening and eradication

Gastric cancer prevention

•Options for solution• Diet change• Stop smoking• chemoprevention

Vegetables / citrus fruits

• Protective effect?– High content of anti-oxidants, Vit A / E / C– Vegetables „possibly“ and fruits „likely“ protective– Garlic: 1 positive meta-analysis, overall: contrary results

Gonzalez Int J Cancer 2006Bae Gastric Cancer 2008

0.72 [0.64 – 0.81]

Salt• Increased risk in case of higher

salt intake (up to 2.5-fold)• Heterogenous results• Influence decreasing in

Western countries (refridgerators, modern means of food conservation)

Interference with the mucosal barrier

Higher occurence of nitroso-compounds

Peleteiro BrJCanc 2011Sjödahl CancEpidBiomPrev 2008Tsugane CancSci 2005Fox&Wang NEJM 2001

! Influence only in case of pre-existing gastric mucosal damage

H. pylori !

Slide withheld at request of author

Online Lecture Library

Slide withheld at request of author

Online Lecture Library

Chemo-Prevention

• Antioxidants (H. pylori lower bio-availability of Vit C)

• COX- inhibitors (ASA, NSAIDs, COX-2-Inhib.)

Points to consider

• Size of the problem• Options for solution• H.pylori screening and eradication

Screen and treat H. pylori in prevention of gastric cancer

RATIONALE behind

H. pylori infection and gastric cancer link ••Epidemiology

•Histological cascade

• Molecular events in gastric carcinogenesis

• Experimental models (cell biology, animal models)

Cases – Controls

n 68 n 360

Exclusion: T4 gastric cancerSerum taken > 90 day following gastrectomyCag A not considered if H. pylori negative

H. pylori + Cag - OR 3,7 18,3

H. pylori + Cag + OR 5,7 28,4

Brenner et al., Am J Epidemiol 2004, 159:252-258

Necessary condition for gastric cancer development

H.pylori and Gastric Cancer

EpidemiologyHow relevant is the location?distal versus proximal

How relevant is the histological type?intestinal versus diffuse

Gastric cancer

Siewert Br J Surg 1998

proximal

distal

AEG: Adenocacrinoma of the oesophagogastric junction

Tumor allocation

AEG IIAEG IIIProx. 1/3 corpus

Dist. 2/3 corpusAntrum

H.pylori infection with similar association in proximal AEG I-II and distal gastric cancerBornschein et al DDW 2009

Gastric cancer

in corpus

intestinal type

Gastric cancersubcardialintestinal type

Screen and treat H. pylori in prevention of gastric cancer

H. pylori infection and gastric cancer link

••Role of host genes

•Bacterial virulence factors

• Ambiental and nutritional factors

El Omar et al Gastroenterology 2000

0

5

10

15

20

25

30

35

Hypochlorhydria Atrophy

27%

34%

relatives of gastric cancer patients (n100), H. pylori prevalence 63%

3% 5%

control subjects (n 100) ), H. pylori prevalence 64%%

of s

ubje

cts

H.pylori plusgeneticpre-

disposition..IL 1 –beta polymorphisms

H. pylori and gastric cancer

Increased polymorphisms of pro-inflammatory genes and risk of non-cardia gastric cancer

Polymorphisms of IL-1β(o), IL-1 receptor antagonist, TNFα, and IL-10 conferred a greater risk for gastric cancer

ORs (95% CI) •Single gene 2.8 (1.6-5.1) •Two genes 5.4 (2.7-10.6)•Three or four genes 27.3 (7.4-99.8)

El-Omar EM, et al. Gastroenterology,2003;124:1193-201

H. pylori virulence factors

increase the risk of gastric cancer

Cag A, Vac A and others

cause stronger inflammatory reaction-preneoplastic conditions

Pro-inflammatory cytokine gene polymorphismsIL-1B-511*TIL-1RN*2*2IL-10 ATA haplotypeTNF-A-308*A

Innate immune response gene polymorphismsTLR4+896*G

Bacterial factorsCag AVac A s1/i1/m1

Environmental factorssmokingdiet

Bacterial-Host- Environmental factors

in H. pylori-related gastric cancer

Gastric cancer

SUMMARY

H. pylori infection and gastric cancer: A prospective endoscopy study

• 1526 patients with NUD, DU, GU or gastrichyperplasia (GH)

• Endoscopy: enrollment and every 1-3

years Uemura et al, N Engl J Med 2001; 345:784

Hp- Hp+ NUD GU GH DU

0

2,9

4,7

3,4

2,2

00

1

2

3

4

5Incidence of gastric cancer (%)

• Metaanalysis 6 studies >6000 patients

Fuccio et al Ann Int Med 2009

H.pylori eradication and gastric cancer prevention

Number needed to treat 227!

7

11

0

10

20%

OAM Placebo

OAM Placebo

P=0.95

0

5

0

10

20%

OAM Placebo

OAM Placebo

6

Gastric cancerGastric cancer in subjects with no preneoplastic changes on entry

Eradication H. pylori infection In a general population prevents gastric cancer:

A 7-year prospective randomized placebo-controlled study

Wong et al. JAMA2004

p=0.025

Where is the point of no return?

Probability of regression of the pre-neoplastic lesions

Gastric cancer

Prob

abili

ty o

f reg

ress

ion

Infection with H.pylori

Atrophic gastritisIntestinal

metaplasia

Dysplasia

months years decades

Chronic active gastritis

H. pylori and gastric cancer

Fukase et al Lancet 2008

H.pylori eradication after EMR of early gastric cancer=never to late!!!!!!

• 3 year follow up:

• gastric cancer relapse– controls: 24– After eradication: 9

•OR for metachronous NPL0.353 (95% CI 0.161-0.775)

•HR (intent. to treat)0.339 (95% CI 0.157-0.729)

Does H. pylori eradication therapy for PUD prevent gastric cancer ?

Mabe et al. World J Gastroenterol 2009;15(34):4290-97

„Yamagata Prefecture, Japan“Study 2000-2007, follow up 5,6 years

4133 patients with PUD

Gastric cancer

0,21 %/year

Gastric cancer

0,50 %/year

Eradication therapy no Eradication therapy

Mabe et al. World J Gastroenterol 2009;15(34):4290-97

Proportion free of gastric cancer in the eradication group was compared according to results of eradication therapy, using Kaplan-Meier analysis.

H. pylori eradication in the prevention of gastric cancer

ERADICATIONNNT 227

But consider additional benefits:Ulcer prevention,cure of dyspepsia,extragastric disease

Global screening andH.pylori eradication?

NoBut……

Surveillance for gastric cancer –DECISION MODEL

Yearly endoscopy for 10 years after newly detected gastric IM in 10.000 Americans

- estimated gastric cancer incidence 1,8%/year

- 556 (3738) endoscopies for detection of 1 gastric cancer

- US $ 72.519 per life year gained

Hassan et al Helicobacter 2010; 15:221

Geographic differences in gastric cancer incidence explained by differences between H. pylori strains

Yamaoka Y. et al. Internal Medicine. 2008; 47(12):1077-83

Present distribution of six main H. pylori genotypes

The circles coincide with countries in which the H. pylori genotypes have been

examined

Gastric cancer

Actions to take

Screening for early gastric cancer

Screening & treating H.pylori

Surveillance of chronic gastritis and IM

Gastric cancer screening and subsequent risk of gastric cancer

Population 42.150 36 % screened by photofluorography

2 fold decrease in gastric cancer mortality in screened vs non screened

13 years follow up

Lee KJ et al, Int. J. Cancer 2006;118,9

Gastric cancer screening associated with reduced risk of mortality

RR 0.54CI 0.36-0.74

179 cancer deaths

636incident cancer

Gastric cancer

studies from Japan show a twofold risk reduction for gastric cancer mortality

Lee at al. Int J Cancer 2006

Significant higher number of early gastric cancer with screening endoscopy

Hosokawa et al. Scand J Gastroenterol 2008

Nam et al. Europ J Gastroenterol Hepatol 2009

•Population based screening

How to select subjects at risk

for gastric cancer development?

At presentNo role for determinationof cytokine related gene polymorphisms

No role for determination of bacterial virulence

What about histology???

Risk gastritisWell established

Multifocal atrophyaccompaniedby intest. metaplasia

Auto immune Corpus-predominant with antrum normal

Initial infection

Antrum predominant,Minimal corpus Involvement

gastriccancerGastric Cancer

Chronic gastritis phenotypein gastric cancer

Host susceptibilty. Bacterial strain virulenceenvironment

Chronic atrophic gastritis

Atropphy and Intestinal Metaplasia

Narrow band imaging

Atrophic gastritis

Atrophic border

Atrophie

mit intestinaler Metaplasie

Atrophic gastritis an IM

HistologyAbnormalities atBase Line

All HP+Patients(n=1246)

HP+ Patientswith Gastric Ca

(n=36)

Relative Risk(95% CI)*

Grade of atrophyNone or mild 381 3 (0.8) 1.0Moderate 657 18 (2.7) 1.7 (0.8–3.7)

Severe 208 15 (7.2) 4.9 (2.8–19.2)

Distribution of gastritisAntrum predominant 699 2 (0.3) 1.0Pangastritis 337 14 (4.2) 15.6 (6.5–36.8)

Corpus predominant 210 20 (9.5) 34.5 (7.1–166.7)

N Uemura. N Engl J Med 2001; 345:794-9Follow up period 7-8 yrs

H. pylori infection – Surveillance Risk assessment of gastritis progression to gastric cancer

1

2

Operative link for gastritis assessment (OLGA)

Rugge et al. APT 2010;31:1104

OLGIM for surveillancede Vries et al. Helicobacter2010;15:259

Adapted from Vauhkonen et al. Best Pract. and Res. Clin. Gastroenterol. 20,4,2006

diffuse gastric cancer intestinal gastric cancer

adenomadysplasia

atrophic gastritisintestinal metaplasia

Chronicactive gastritisH. pylori

normal

„genetic disposition“transmitted CHD1-mutation

Methylation: CDH1, DAP-K,HRASLS, LOX, MGMT,p14, RAR-ßAmplification: C-MET, K-SAMMutation: CHD1, TP53Expression: hTERT

CIMP/Microsatellite-InstabilityMethylation: p16, COX-2, GSTP1, hMLH1, MGMT, RASSF1A, RUNX3, TFF1Amplification: ERBB2Mutation: K-RAS, TP53LOH: APC, MCC, TP53

Expression: CDX1/2, COX-2, hTERT

Mutation: APC, TP53Methylation: APC, CDH1, DAP-K, hMLH1, p14, THBS1, TIMP-3Expression: EGFR, TGF-

adenoma

Endoscopic surveillance of gastric premalignant lesions improves cancer survival

Whiting et al. Gut 2002; 50: 278-81

Surveillance practice of pre-malignant gastric lesions- a long term nationwide study in the Netherlands

Cohort study 1991-2004

90,316 patients

-24% atrophic gastrits-67% intest. Metaplasia-9% dysplasia

Follow up 2005

25,793 patients1.7 % gastric cancer

-3.4% initial atrophic gastritis-7% initial intest. Metaplasia-17% initial mild/moder. dysplasia-68% initial severe dysplasia

Surveillance!!de Vries et al. Gastroenterology 2008

Surveillance for gastric cancer

Cost effectivness for endoscopy based surveillancerequires malignancy to occur

at a prevalence of > 6%

Yeh et al. Gastrointest Endosc. 2010 Jul;72(1):33-43

•Single life time screening at age 20,30,40 

• single life time screening and rescreening of individuals with negative results

• universal treatment for H. pylori infection at age 20,30,40

Yeh et al. Int J Cancer 2009

H. pylori infection & prevention of gastric cancer

Three models tested in China

GC risk reduction by 15 %

‐ 1500 US$/live year saved

GC risk reduction by 17 %

‐ 2500 US$/live year saved

Screening/Surveillance for gastric cancer

correlation of low pepsinogen I

with corpus prevalent atrophic gastritis

94%

PEPSINOGEN combined with H. pylori antibodies best option

Lombardo et al. Clin Chem Lab Med. 2010 Sep;48(9):1327-32

Serological markers

• Screening for preneoplastic conditions

Gastrin 17

Pepsinogen I + IIPI/II-Ratio

H.pylori-Antibodies+

„Gastropanel“

Watabe et al. Gut 2005; 54: 764-8

The annual incidence of gastric cancer in a Japanese cohort in relation to H. pylori and pepsinogens at baseline

0,4 0,6

3,5

6

0

1

2

3

4

5

6

7

Hp-neg Hp-pos Hp-pos Hp-neg

Normal pepsinogens Low pepsinogens

0/00N=9293

Rationale ofScreening Methods

Endoscopy

Best detection rate (up to 87%)

Most expensive

Most invasive

Gastro-Panel

Less invasive

Relatively cheap

Alone not sufficient(preselects for endoscopy)

13C-UBT

Cheap

Non invasive

„Only“ H.pylori detected, not mucosal lesions

PGI PGII PGI/II G17B G17S HpAB

Atrophic gastritis in corpus low low highAtrophic gastritis in antrum low low highAtrophic gastritis in both a / c low low low low

Non-atrophic gastritis high

Non-atrophic gastritis, H.pylori high high

(GERD) (Low

http://www.gastropanel.net/ Condition of gastric mucosa - atrophic gastritis especially of

corpus and antrum (normal, gastritis / atrophic gastritis) & H. pylori infection

PG I, PG II and gastrin-17 levels describe structure & function More severe atrophic gastritis in corpus, the lower the

pepsinogen I and ratio of pepsinogen I / II More severe atrophic gastritis of antrum, the lower is gastrin-17

GastroPanel®: Diagnosis by an antibody test

Atrophy and Intestinal Metaplasia

Pepsinogen lowGastrin highH.Pylori serology negativeCag A positive

H. pylori and Gastric Cancer

How to proceed in practice?

• Family history• Gastropanel

•Endoscopy plus histology

• Bacterial virulence factors

• Inflammatory Gen- Polymorphisms

• nutrition habits

• smoking

Risk gastritis

Follow up

H.pylori-Eradication and GC-Prevention Hazards

Lee and Moss, Expert Opin Ther Targets 2007; Malfertheiner et al, AJG 2005; Meyer et al, Ann Intern Med 2002

Limitations of Eradication Therapy for GC-Prevention

Complex therapy (multi-agent) Compliance?

Availability(Developing countries) strict indication

Increasing resistance(Clarithromycin/Metronidazole)

Critical point of timefor eradication

Maastricht 3

Statement: H. pylori infection is the most common proven

risk factor for human non-cardia gastric cancer.

Level of Evidence: n.a. Grade of Recommendation: A

97,7

2,30

25

50

75

100

I agree I don't agree

97,7

2,30

25

50

75

100

I agree I don't agreeValues in percentage

Gut 2007

Maastricht 3

Statement: H. pylori eradication has the potential to prevent gastric

cancer gastric cancer.

Level of Evidence: n.a. Grade of Recommendation: A

97,7

2,30

25

50

75

100

I agree I don't agree

97,7

2,30

25

50

75

100

I agree I don't agreeValues in percentage

Malfertheiner et al Gut 2007

Malfertheiner et al J. Dig. Dis. 2010

The incidence of gastric cancer in the community to be targeted

Screening reserved for risk groups and risk populations

Identifying high risk groups

Concluding considerations

„ it is not enough to know,it must also be put into practice“