GGastric adenocarcinomaastric adenocarcinoma

ד"ר הוברט אילהמנהלת המרכז לגידולים במערכת העיכולמכון שרתהדסה עין כרם

0507874799ayalah@hadassah.org.il

Gastric cancer epidemiology

• 4th most commonly diagnosed cancer

• Still the 2nd most common cause of cancer-related death globally

• Global incidence rates

• Almost 1,000,000 cases

• Nearly 700,000 deaths

• Global decline in mortality

• Incidence of gastro-oesophageal (GE) junction cancer rapidly increasing

Gastric Cancer – Epidemiological Trends

Reduction in gastric cancer mortality could be due to a number of factors– Earlier detection

– Improved understanding of the disease and associated improved treatments and clinical management

– Improvements in refrigeration

– Diet • Reduced intakes of salted, pickled, smoked, and other

chemically preserved foods

• Increased consumption of fresh fruit and vegetables

• Improved housing, sanitation and living standards with a resulting reduction in Helicobacter pylori

The incidence of gastric cancer is highest in Asia

Parkin DM, et al. CA Cancer J Clin 2005; 55:74–108.

Japan

China

Eastern Europe

South America

Southern Europe

Micro/Polynesia

Central America

Caribbean

Middle Africa

Western Europe

Northern Europe

Western Asia

South-Eastern Asia

Southern Africa

Eastern Africa

Northern America

South Central Asia

Melanesia

Northern Africa

Western Africa

62.1 26.1

41.4 19.2

29.6 12.8

24.2 12.2

18.0 8.7

15.7 8.3

15.2 10.8

13.6 6.7

13.4 12.6

12.8 6.6

12.4 5.9

11.6 6.4

9.9 4.2

8.5 4.5

3.7

7.4 5.5

7.4 3.4

6.9 3.6

6.3 4.6

4.4 2.5

3.4 3.6

8.2

70 60 50 40 30 20 10 0 10 20 30 40 50 60 70

Age-standardised incidence(per 100,000)

Australia/New Zealand

Males

Females

Stomach Cancer

World Health Organization. Mortality database.

Age-Standardized Mortality Trends: Males

JapanUKUSA

90

80

70

60

50

40

30

20

10

0

Rat

e p

er 1

00,0

00

1950 1960 1970 1980 1990 2000Yr

Esophageal CancerJapanUKUSA

11

10

7

6

5

4

3

2

1

0

Rat

e p

er 1

00,0

00

1950 1960 1970 1980 1990 2000Yr

9

8

Gastric cancer aetiology• Gastric cancer is a multifactorial disease

Environmental risk factors (~90%)

Genetic risk factors (8–10%) GE junction Body of stomach

Achlorhydria Gastro-oesophagealreflux disease (GERD)

Helicobacter pylori infection

Pernicious anaemia Obesity High dietary nitrate/ nitrite content

Blood group A Low consumption of fruit, vegetables

Tobacco use

Li-Fraumeni syndrome(p53 mutation)

High consumption ofred meat, alcohol

Tobacco use

Low consumption of fruit, vegetables

Gastric CancerPathogenesis

Karpeh MS, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1092-1126.

Mucosal Atrophy + Increased Gastric pH

Bacterial Overgrowth

Direct Bacteria-Induced Injury + Increased Production of Nitrites and N-nitroso compounds

Intestinal Metaplasia

Gastric Carcinoma

Anatomic classification

• Site of origin

• Proximal (incidence on the increase)

• GE junction = cardia

• Fundus

• Distal

• Corpus

• Antrum

Gastric CancerHistology

95% of gastric neoplasms are adenocarcinomas

Other subtypes include:

– Squamous cell carcinoma

– Adenoacanthoma

– Carcinoid tumors

– Gastric stromal tumor (leiomyosarcoma)

– Primary lymphoma

Karpeh MS, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001:1092-1126.

Microscopic histologic typesMicroscopic histologic types

The most widely used classification system is that of Lauren

• Intestinal: arises from precancerous lesions, more common in men, dominant type where gastric cancers are epidemic, differentiated, tends to form glands

• Diffuse: little cell cohesion, tendency for submucosal spread and early metastases, worse prognosis

0

50

100

150

200

250

300

350 IntestinalDiffuseMixed

Patients

Distribution of histological subtypes among countries

Bang YJ, et al. J Clin Oncol 2009.n=2759

TNMTNM Primary tumor (T)

Principal factor is degree of penetrationof stomach wall by carcinoma

Tx : Primary tumor cannot be assessed T0 : No evidence of primary tumor Tis : Carcinoma in situ : intraepithelial tumor without invasion of the lamina propria T1 : Tumor invades lamina propria or submucosa T2 : Tumor invades muscularis propria or the subserosa T3 : Tumor penetrates the serosa without invading adjacent structures T4 : Tumor invades adjacent structures

Nodal involvement (N)

Nx : Regional lymph nodes cannot be assessedN0 : No regional lymph nodes within 3 cm of

the edge of the primary tumorN1 : Metastasis in 1 to 6 regional lymph nodesN2 : Metastasis in 7 to 15 regional lymph nodesN3 : Metastasis in more than 15 regional lymph nodespN0 : histological examination of a regional lymphadenectomy specimen will ordinarily include 15 or more lymph nodes

TNMTNM

SubmucosapT1A

B

pT2A

B

pT3

pT4

Mucosa

Muscularispropria

Subserosa

Serosa

<5%20%

40%

70%

90%

Primary tumor Lymph nodes

Increased depth of penetration is associated Increased depth of penetration is associated with increased lymph node metastaseswith increased lymph node metastases

Increased depth of penetration is Increased depth of penetration is associated with a poor prognosisassociated with a poor prognosis

Penetration 5-yr survival

Mucosa 100%

Submucosa 92%

Muscularis propria 42-73%

Subserosa 29-55%

Serosa 0-7%

No nodes

5-yr surv

N1 1-6 46%

N2 7-15 30%

N3 >15 10%

Increased level of lymph node involvement is associated with decreased survival

Gastric cancer stageand survival rates

Disease Stage TMN 5-yr survival rates

Early 0 Tis, N0, M0 89%

IA T1, N0, M0 78%

IB T1, N1, M0 orT2a/b, N0, M0

58%

II T1, N2, M0 orT2a/b, N1, M0 or

T3, N0, M0

34%

Advanced IIIA T2a/b, N2, M0 orT3, N1, M0 or

T4, N0, M0

20%

IIIB T3, N2, M0 8%

IV T1–3, N3, M0 or T4, N1–3, M0 or

any T, any N, M1

7%

Treatment

Treatment options according to TNM status

T1–2, N0, M0• Early stage ,Surgery alone

• Locally advanced :Risk of relapse is high after surgery alone• Adjuvant/neoadjuvant chemotherapy and radiation followed by

attempt at curative surgery

• Metastatic : Chemotherapy• Palliative surgery and/or radiation if indicated

Curative care options

• Surgery is the only curative therapy for gastric cancer (curative surgical resection, R0)

• Total gastrectomy or oesophagogastrectomy

• Subtotal gastrectomy

• Lymphadenectomy

• Debate regarding the most appropriate surgical procedures

(D2 vs. D1 resection)

• Irrespective of the surgical procedure, high recurrence rate

after surgery

Lymph nodes N1groupes 1-6

Lymph nodes N2groupes 7-11 (13)

Lymph node dissection extension : D1 vs D2

Curative care options

• Pre-operative (neoadjuvant) therapy• Downstaging of disease may

facilitate resection

• Post-operative (adjuvant) therapy

SWOG 9008/INT 0116RESECTED GASTRIC CANCER

RESECTED

STAGE IB-IV (M0)

GASTRIC

ADENOCARCINOMA

R

A

N

D

O

M

OBSERVATION

5-FU/LV RADIATION 5- FU/LV X2

5-FU/LV 5-FU/LV

SCHEMA

Macdonald et al, N Engl J Med 2001

INT 0119 - SWOG 9008

Surgery Surgery chemo RT

p-value

Median DFS 19 months 30 months p=0.001

3y survival Med. Survival

40% 28 months

50% 35 months

p=0.03

J McDonald et al, NEJM 2001

Gastric Cancer: Postoperative Adjuvant Chemoradiotherapy

Gastric Cancer: Neoadjuvant Chemo in Locally Advanced Disease

• Data from non-randomized phase II and small randomized trials show feasibility of chemotherapy followed by surgery.

• Rationale:• gastric cancer is chemosensitive

downstaging is realistic• eradication of microscopic metastases?• better tolerance of pre- than postoperative chemotherapy• selection of patients who benefit from adjuvant treatment

Curative treatment programs

Neoadjuvant (Chemotherapy)

SURGERY

Adjuvant (Chemotherapy and Radiation therapy)

MAGIC trial

503 patients 503 patients with gastric with gastric

cancercancer

Surgery only (S)Surgery only (S)

ECFx3ECFx3surgery surgery ECFx3 (CSC)ECFx3 (CSC)

Allum WH, et al. Proc Am Soc Clin Oncol 2003;22:2493 (abst 998)Cunningham et al. Proc Am Soc Clin Oncol 2005;308s (abst 4091)

R

S CSC

Curative resection 69% 79% p=0.02pT1-2 36% 54% p=0.01pN0-1 71% 80% p=0.10PFS (mo) 14 20 p=0.0001MS (mo) 20 24 p=0.009

Palliative care options

• The objective is to manage symptoms, improve QoL and prolong life

• Chemotherapy• Multiple drug chemotherapy regimens are used• Response rates 30–50%; median OS ≤1 year

• Surgery• Palliative resection of affected gastric component may be

indicated (i.e. if risk of obstruction is high)

• Radiotherapy• Palliative radiotherapy to reduce pain or symptoms

AGENTS

• Cisplatine• Anthracyclines• 5FU(xeloda,S1) • Mitomycine C• Etoposide• Methotrexate• Taxanes• Campto• Oxaliplatine• Herceptin• Rmucirumab

Potential predictive factors of efficacy

TS DPD Topo I MSI ERCC-1 EGF

HER2 in gastric cancer

• Approximately 16% of patients with advanced adenocarcinoma of the stomach or GE junction have HER2-positive disease

• HER2 has predictive value in gastric cancer

• Accurate HER2 testing is essential to identify patients who may benefit from treatment with trastuzumab

1. Bang YJ, et al. J Clin Oncol 2009; 27:Abstract 4556.2. van Cutsem E, et al. J Clin Oncol 2009; 27:Abstract LBA4509.

IHC negative (0)

No staining or membrane staining in <10% of cells

IHC negative (1+)

Faint/barely perceptible membrane staining in >10% of cells; cells only stained in part of membrane

IHC equivocal (2+)

Weak to moderate complete or basolateral membrane staining in >10% of cells

IHC positive (3+)

Strong complete or basolateral membrane staining in

• >10% of cells in resection specimens or

• cohesive IHC 3+ clones irrespective of size (i.e.<10%) in biopsy samples

IHC scoring criteria forgastric cancer

ToGA trial design

HER2-positiveadvanced GC

(n=584)

5-FU or capecitabinea + cisplatin(n=290)

R

aChosen at investigator’s discretion GEJ, gastroesophageal junction

5-FU or capecitabinea + cisplatin

+ trastuzumab(n=294) Stratification factors

− advanced vs metastatic − GC vs GEJ− measurable vs non-measurable− ECOG PS 0-1 vs 2− capecitabine vs 5-FU

Phase III, randomized, open-label, international, multicenter study

1Bang et al; Abstract 4556, ASCO 2009

3807 patients screened1

810 HER2-positive (22.1%)

113

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

1.0

0.8

0.6

0.4

0.2

0.0

363432302826242220181614121086420

Time (months)

11.8 16.0

FC + H

FC

Events

120136

HR

0.65

95% CI

0.51, 0.83

MedianOS

16.011.8

Event

0.1

0.3

0.5

0.7

0.9

218 198

40

53

124

2011

228 218

196 170

170 141

142 112

12296

10075

8453

6539

5128

10

00

No. at risk

3920

2813

Sout

h Af

rica

(n=27

)

Guate

mal

a (n

=53

)Cos

ta R

ica

(n=59

)

Aust

ralia

(n=61

)

Japa

n (n

=41

0)

Kore

a (n

=68

7)

China

(n=59

0)

Russia

(n=45

9)

Turk

ey (n

=58

)

Indi

a (n

=11

8)

Taiw

an (n

=34

)

Denm

ark

(n=33

)

Italy (n

=99

)

Fran

ce (n

=78

)

UK (n

=13

2)

Germ

any

(n=17

3)

Portug

al (n

=67

)

Belg

ium

(n=14

)

Spai

n (n

=12

2)Finl

and

(n=21

)

Mex

ico

(n=67

)

Pana

ma

(n=40

)

Braz

il (n

=97

)

Peru

(n=16

8)

%

0

5

10

15

20

25

30

35

22%

Asia/Pacific EuropeSouth/Central

AmericaOther

Patients with IHC 3+ or FISH+ disease

Bang YJ, et al. J Clin Oncol 2009; 27:Abstract 4556.

Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation

Novel Methods for Molecular Assessment

Analysis of circulating tumor cells

– Currently limited by technology (~ 50% of patients)

– New platforms in development

– Suitable for all biomarker analysis

– Potential to replace tissue biopsy

Analysis of circulating tumor DNA

– Tumor DNA mutational testing

– Potential for broader role?