Transcript T36pt Herceptin Medium Orange

‫‪Gastric adenocarcinoma‬‬
‫ד"ר הוברט אילה‬
‫מנהלת המרכז לגידולים במערכת העיכול‬
‫מכון שרת‬
‫הדסה עין כרם‬
0507874799
[email protected]
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
Japan
China
Eastern Europe
South America
Southern Europe
Micro/Polynesia
Central America
Caribbean
Middle Africa
Western Europe
Northern Europe
Western Asia
Australia/New Zealand
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
8.2
7.4
5.5
7.4
3.4
6.9
3.6
6.3
4.4
60
50
40
30
20
10
Females
2.5
3.4
70
Males
4.6
3.6
0
10
20
30
40
50
60
70
Age-standardised
incidence
(per 100,000)
Parkin DM, et al. CA Cancer J Clin 2005; 55:74–108.
Age-Standardized Mortality Trends: Males
90
80
Stomach Cancer
11
Japan
UK
USA
10
Esophageal Cancer
Japan
UK
USA
9
70
60
50
40
30
Rate per 100,000
Rate per 100,000
8
7
6
5
4
3
20
10
0
1950 1960 1970 1980 1990 2000
Yr
World Health Organization. Mortality database.
2
1
0
1950 1960 1970 1980 1990 2000
Yr
Gastric cancer aetiology
• Gastric cancer is a multifactorial disease
Environmental risk factors (~90%)
Genetic risk factors (8–10%)
Achlorhydria
Pernicious anaemia
Blood group A
Li-Fraumeni syndrome
(p53 mutation)
GE junction
Body of stomach
Gastro-oesophageal
reflux disease (GERD)
Helicobacter pylori infection
Obesity
High dietary nitrate/ nitrite
content
Low consumption of fruit,
vegetables
Tobacco use
High consumption of
red meat, alcohol
Low consumption of fruit,
vegetables
Tobacco use
Gastric Cancer
Pathogenesis
Mucosal Atrophy + Increased Gastric pH
Bacterial Overgrowth
Direct Bacteria-Induced Injury + Increased
Production of Nitrites and N-nitroso compounds
Intestinal Metaplasia
Gastric Carcinoma
Karpeh MS, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1092-1126.
Anatomic classification
• Site of origin
• Proximal (incidence on the increase)
• GE junction = cardia
• Fundus
• Distal
• Corpus
• Antrum
Gastric Cancer
Histology

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 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
Be U
Po lg K
rt iu
ug m
Au Ja al
st pa
ra n
Fr li
a
De an
nm ce
a
It rk
a
Sp ly
a
Ch in
Br in
So G a a
ut er zi
h ma l
Af ny
r
Ru ic
ss a
Ko ia
Ta re
iw a
In an
Tu di
rk a
Gu P ey
at er
em u
Co Pa al
st na a
a ma
Fi Ri
nl ca
Me an
xi d
co
Distribution of histological
subtypes among countries
Patients
350
300
n=2759
Intestinal
Diffuse
Mixed
250
200
150
100
50
0
Bang YJ, et al. J Clin Oncol 2009.
TNM

Primary tumor (T)
Principal factor is degree of penetration
of 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
TNM
 Nodal involvement (N)
Nx : Regional lymph nodes cannot be assessed
N0 : No regional lymph nodes within 3 cm of the
edge of the primary tumor
N1 : Metastasis in 1 to 6 regional lymph nodes
N2 : Metastasis in 7 to 15 regional lymph nodes
N3 : Metastasis in more than 15 regional lymph
nodes
pN0 : histological examination of a regional
lymphadenectomy specimen will ordinarily
include 15 or more lymph nodes
Increased depth of penetration is associated
with increased lymph node metastases
Primary tumor
Lymph nodes
pT1A
B
Mucosa
<5%
Submucosa 20%
pT2A
Muscularis
propria
40%
B
pT3
Subserosa
pT4
Serosa
70%
90%
Increased depth of penetration is
associated with a poor prognosis
Penetration
5-yr survival
Mucosa
100%
Submucosa
92%
Muscularis propria
42-73%
Subserosa
29-55%
Serosa
0-7%
Increased level of lymph node involvement
is associated with decreased survival
No
nodes
5-yr
surv
N1
1-6
46%
N2
7-15
30%
N3
>15
10%
Gastric cancer stage
and survival rates
Disease Stage
Early
Advanced
TMN
5-yr survival rates
0
Tis, N0, M0
89%
IA
T1, N0, M0
78%
IB
T1, N1, M0 or
T2a/b, N0, M0
58%
II
T1, N2, M0 or
T2a/b, N1, M0 or
T3, N0, M0
34%
IIIA
T2a/b, N2, M0 or
T3, N1, M0 or
T4, N0, M0
20%
IIIB
T3, N2, M0
8%
T1–3, N3, M0 or
T4, N1–3, M0 or
any T, any N, M1
7%
IV
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 node dissection extension :
D1 vs D2
Lymph nodes N1
groupes 1-6
Lymph nodes N2
groupes 7-11 (13)
Curative care options
• Pre-operative
(neoadjuvant) therapy
• Downstaging of disease may
facilitate resection
• Post-operative (adjuvant)
therapy
SWOG 9008/INT 0116
RESECTED GASTRIC CANCER
SCHEMA
R
RESECTED
A
STAGE IB-IV (M0)
N
GASTRIC
D
ADENOCARCINOMA
O
M
OBSERVATION
5-FU/LV
5-FU/LV
5-FU/LV RADIATION
5- FU/LV
X2
Macdonald et al, N Engl J Med 2001
Gastric Cancer: Postoperative
Adjuvant Chemoradiotherapy
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: 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
Surgery only (S)
503 patients
with gastric
cancer
R
ECFx3
Curative resection
pT1-2
pN0-1
PFS (mo)
MS (mo)
surgery
S
CSC
69%
36%
71%
14
20
79%
54%
80%
20
24
ECFx3 (CSC)
p=0.02
p=0.01
p=0.10
p=0.0001
p=0.009
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)
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 scoring criteria for
gastric cancer
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
ToGA trial design
Phase III, randomized, open-label, international, multicenter study
3807 patients screened1
810 HER2-positive (22.1%)
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
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
aChosen
at investigator’s discretion
GEJ, gastroesophageal junction
1Bang
et al; Abstract 4556, ASCO 2009
OS in IHC2+/FISH+ or IHC3+
(exploratory analysis)
Event
Median
Events OS
HR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + H
FC
11.8
0
2
4
6
120
136
16.0
11.8
95% CI
0.65 0.51, 0.83
16.0
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No.
at risk
228 218 196 170 142 122 100 84
218 198 170 141 112 96 75 53
65
39
51 39
28 20
28
13
20 12
11 4
11
3
5
3
4
0
1
0
0
0
Patients with IHC 3+ or FISH+
disease
%
35
Asia/Pacific
Europe
South/Central
America
Other
30
25
22%
20
15
10
5
0
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?