Gastric cancer

The department of Gastroenterology

Shanghai Ren-Ji Hospital

Zhi Hua Ran ()
Gastric
Cancer
Epidemiology
Forth common
types of cancer
Second most common
cancer related death
Geographic
variations
(ten times)
Continuing
decline
Primarily a decline
of distal GC

(2000)
(2000)
Geographic variations
Geographic distribution of mortality rates
for gastric cancer in males in China
Gastric
Cancer
Environmental
factors
H. pylori Genetic factors
Etiological Factors of Gastric Cancer
Precancerous
changes
The role of H. Pylori infection in
gastric carcinogensis
Type I carcinogen
1994 by IARC
Epidemiological
studies
Animal modes
(Mongolian gerbil)
Gastric Cancer
Attributable risk
50%~73%
Honda et al . 1998
Watanabe et al. 1998
RF: 2.8~6 folds
Environmental factors
Environmental factors are involved
Japanese immigrants in US: 25%
Second generation: >50%
Subsequent generations: comparable to
General US population
Environmental factors
Lower socioeconomic
status
Tobacco/alcohol
Fresh vegetable/fruits
/Micronutrition
Poor food storage
Eating salted/
Smoked food
Mucosal damage
Pro-carcinogen/
Carcinogen
Lack of antioxidant
GC
Genetic factors
The majority of gastric tumor are sporadic in nature

There are rare inherited gastric cancer predisposition traits
such as germline p53 (Li-Fraumeni syndrome)
E-cadherin (CDH1) alterations
in diffuse gastric cancers
Precancerous changes
Precancerous lesions
Precancerous
conditions
Precancerous lesions
Defined as those pathological changes predisposed to
gastric cancer
dysplasia

10% of patients may progress in severity
majority of patients either regress or remain stable
High-grade dysplasia may be only a transient phase in the
progression to gastric cancer
occurs in atrophic gastritis or intestinal metaplasia
Nature history of gastric dysplasia
No
Dysplasia
Mild
Dysplasia
Moderate
Dysplasia
High-grade
Dysplasia
Gastric
adenocarcinoma
5 years 5 years
5 years
3 months-2 years
10%
10%
50%-90%
60%
60%
10%
Precancerous condition
Defined as those clinical setting with higher risk of
developing gastric cancer

Chronic atrophic gastritis
Gastrectomy
Pernicious anemia
Menetriers disease
Chronic gastric ulcer
Gastric polyps

Postulated sequence of histologic events in the progression to
gastric adenocarcinoma and potential contributory factors
H. Pylori Other factors
Chronic
Superficial
Gastritis
Intestinal
Metaplasia
Atrophic
Gastritis
Dysplasia
FAP or
Adenomas
Gastric
Adenocarcinoma
Other factors
Association Strong
Association
Correa hypothesis
Pathology
Stages
Morphology
Pathohistologic classification
Metastasis
Stages
Early stage
limited in the mucosa and submucosa layers, no matter
with or without lymph node metastasis
Classified by the Japanese Society for Gastric Cancer
<1cm <0.5cm

Advanced stage
invaded over submucosa
According to Bormann classification
TNM classification (UICC)
0 Tis N
0
M
0
III A T
2
N
2
M
0

I A T
1
N
0
M
0
T
3
N
1
M
0

I B T
1
N
1
M
0
T
4
N
0
M
0

T
2
N
0
M
0
III B T
3
N
2
M
0

II T
1
N
2
M
0
IV T
4
N
2
M
0

T
2
N
1
M
0
T
1~3
N
3
M
0

T
3
N
0
M
0
any T any N M
1

Morphology---early stage
Morphology---early stage
Morphology---early stage
Morphology ---advanced stage
Pathohistologic classification
Histology
Adenocarcinoma 90%
Lymphoma 5%
Stromal 2%
Carcinoid <1%
Metastasis <1%
Adenosquamous/squamous <1%
Miscellaneous <1%
Origin (Lauren)

Intestinal type
associated with most environmental risk factors
carries a better prognosis
shows no familial history

Diffuse type
consists of scattered cell clusters with poor prognosis

Growth pattern (Ming)


Expanding type
grew en mass and by expansion
resulting in the formation of discrete tumor nodules
with relatively good prognosis

Infiltrative type
invaded individually
with poor prognosis
Metastasis
Direct invasion
Lymph node dissemination
Blood spread
Intraperitoneal colonization
Special term
Blumer shelf
A shelf palpable by reactal examination, due to metastatic
tumor cells gravitating from an abdominal cancer and
growing in the rectovesical or rectouterine pouch

Krukenberg tumor
A tumor in the ovary by the spread of stomach cancer
Clinical manifestation
Signs and Symptoms
Early Gastric Cancer
Asymptomatic or silent 80%
Peptic ulcer symptoms 10%
Nausea or vomiting 8%
Anorexia 8%
Early satiety 5%
Abdominal pain 2%
Gastrointestinal blood loss <2%
Weight loss <2%
Dysphagia <1%
Signs and Symptoms

Advanced Gastric Cancer
Weight loss 60%
Abdominal pain 50%
Nausea or vomiting 30%
Anorexia 30%
Dysphagia 25%
Gastrointestinal blood loss 20%
Early satiety 20%
Peptic ulcer symptoms 20%
Abdominal mass or fullness 5%
Asymptomatic or silent <5%
Duration of symptoms
Less than 3 month 40%
3-12 months 40%
Longer than 12 month 20%
Special signs & terms
Linitis plastica: diffusely infiltrating with a rigid stomach

Virchows node: supraclavicular lymphadenopathy (left)

Irishs node: axillary lymphadenopathy

Sister Mary Josephs node: umbilical lymphadenopathy
Sister Mary Josephs node
Laboratory tests




Iron deficiency anemia
Fecal occult blood test (FOBT)
Tumor markers (CEA, Ca19-9)
Diagnosis

Endoscopic diagnosis
--- biopsy needed for definitive diagnosis

Radiologic diagnosis

Detection of early gastric cancer
Endoscopic diagnosis
In patients with signs and symptoms suggestive of
GC, and/or with compatible risk factors or paraneoplastic
conditions, the diagnostic procedure of choice could be
an endoscopic examination

The diagnostic criteria for early or advanced gastric
cancer under endoscopy are based on the JRSGC and
Bormanns classification
Endoscopic features of gastric cancer
Radiologic diagnosis
For reasons of cost and availability, radiography may
sometimes be the first diagnostic procedure performed

Classic radiography signs of malignant gastric ulcer
asymmetric/distorted ulcer crater
ulcer on the irregular mass
irregular/distorted mucosal folds
adjacent mucosa with obliterated /distorted area gastricae
nodularity, mass effect, or loss of distensibility
Radiologic diagnosis
Distal GC
Proximal GC Linitis plastica
Detection of early gastric cancer
Endoscopic screening
general population or high risk persons

Careful observation

Japan is the only country that had conducted large
nationwide mass population screening of asymptomatic
individuals for gastric malignancy
Differential diagnosis
Gastric Cancer
Gastric Ulcer
Complications
GI bleeding 5%

Pylorus/cardia obstruction

Perforation ulcer type
Treatment
Surgical resection
EMR
Adjuvant therapy
Palliative therapy
Endoscopic mucosal resection
Gastric cancer
lesion confined
to mucosa layer
Endoscopic ultrasound
(EUS) is helpful in
stageing GC
Endoscopic mucosal resection
Endoscopic mucosal resection
Chemotherapy
Adjuvant chemotherapy may increase 5 years survival
rates and decrease the relapse rates

Combination chemotherapy are recommended
Tumor Cell Kinetics
S
G2
G1
M
G0
Death
Temporally
non-dividing cells
(souse of tumor recurrence)
Proliferating cells
(tumor growth)
Non-proliferative cells
hs~ds
2~30h
2h
1~2h
Classification of anti-tumor agents
Traditional classification


Classification based on cell kinitics


Traditional classification
Alkylating agents(): They counteract cancerous cell
division by cross-linking the two DNA strands in the double
helix so that they cannot separate. Such as chlorambucil(
, cyclophosphamide,() ,thiotepa(), and
busulfan ().

Alkylating agent
Traditional classification
Antimetabolites() hey replace natural substances as
building blocks in DNA molecules, thereby altering the function of
enzymes required for cell metabolism and protein synthesis.

Including: purine antagonists
(6-)
pyrimidine antagonists
(5-5-)
folate antagonists
()
Traditional classification
Antitumor antibiotic()They act by binding with
DNA and preventing RNA (ribonucleic acid) synthesis, a key
step in the creation of proteins, which are necessary for cell
survival.


Doxorubicin ()
Mitomycine ()
Bleomycin ()
Traditional classification
Plant alkaloids()They are antitumor agents derived
from plants. These drugs act specifically by blocking the
ability of a cancer cell to divide and become two cells.
Although they act throughout the cell cycle, some are more
effective during the S- and M- phases, making these drugs cell
cycle specific.

Vinblastine
Vincristine
Taxol
Irinotecan (CPT-11):
Camptothecin
Hydroxycamptothecin
Elemene:

Traditional classification
Steroidal()

Estrogen --- Diethylstilbestro()
Ethinylestradiol()
Progestational hormone ---
Medroxyprogesterone()
Estrogen angonist --- Tamoxifan()

Corticostidals
Traditional classification
Others ()

Platins --- Cisplatin ()
Carboplatin()
Oxaliplatin ()

Norcantharidin ()


Classification based on cell kinetics
Cell cycle non specific agents (CCNSA)



Cell cycle specific agents (CCSA)


Cell cycle non specific agents
May kill cells at all cell cycle, including G
0


Alkylating agents()antitumor antibiotics(
) steroids

May affect predominantly on one specific cell cycle

Dose dependant effects

Administrated intermittently with large dose
Cell cycle specific agents
May kill the proliferative cells, G
0
cells not sensitive

Of proliferative cells, cells in S phase and M phase
may more susceptitable

Including Antimetabolites (S phase) and Plant alkaloids
(M phase)

Time dependent effects

Administrated continuously with lower dose
Principles of Combination
Chemotherapy
Only those agents proven effective should be used
Each agent used should have a different mechanism of action
Each drug should have a different spectrum of toxicity
Each drug should be used at maximum dose
Agents with similar dose-limiting toxicities can be combined
safely only by reducing doses, resulting in decreased effects
Component of chemotherapeutic regime of
advanced gastric cancer
-Fu based regime ---predominant
LV/5F-u, 5-Fu CIV)
derivative new drugs (CAPE,S-1)

-FuPts() are the basis of combination
therapy for AGC

Triple regime containing anthracene
Evaluation of -Fu treatment during past
four decades
-FuAGC

5Fu 5Fu I.V.Drip 5Fu b. LV/5Fu CIV FP+EPI,Taxanes,CPTs
RR% 15% 30%
40% >50%
FT-207 UFT,5-DFUR S-1, CAPE
FP: 5-FU+CDDP, b(bolus), CIV(continuous intravenous infusion)
Latest advancement of 5-Fu application
LV bio-regulation: exogenous LV may enhance the inhibitory
effect of 5-Fu TS
Administration of LV/5-Fu: LV first, followed by 5-Fu
Standard (Mayo Clinic)
LV 20mg/m
2
b. 5-Fu 425 mg/m
2
b.
LV 200mg/m
2
I.V. 2h, 5-Fu 370 mg/m
2
b.
CIV: CIV enhance the cytotoxic effects of 5-FU
600~1500mg/m2 CIV 24h x 2d,q2w
300~800mg/m2 CIV 24h x 5d, q3w
Capecitabine (Xeloda)
5-Fu+Pts combination regime


5-Fu + CDDP (HD,LD) both are effective
HD CDDP --- cytotoxic effect
LD CDDP --- bio-regulation effect
HD vs LD CDDP to treat AGC: same RR%
LD CDDP + 5-Fu: conductive to adding third drug

The recommondated dose:
HD CDDP 50~100mg/m
2
I.V. 4h,q3w
LD CDDP 15~20mg/m
2
I.V. 2h, x5d q3w

Oxaliplatin is more commomly employed in combination regime

Chemotherapy
Regimen Approximate Survival
Response rate Benefit
Fluorouracil +doxorubicin 30% No
+ mitomycin (FAM)
Fluorouracil + doxorubicin 30% No
Semustine (FAMe)
Fluorouracil + doxorubicin 30% No
+ cisplatin (FAP)
Etoposide + doxorubicin 40% No
+ cisplatin (EAP)
Etoposide + leucovorin 30% No
+ fluorouracil (ELF)
Fluorouracil +doxorubicin 40% Unconfirmed
+ methotrexate (FAMTX)
AIM OF COMBINATION THERAPY
I NCREASED EFFI CACY
Different mechanisms of action Compatible side effects
Different mechanisms of resistance
ACTIVITY SAFETY
Side effects of chemotherapy
Mucositis


Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia



Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis
Metal stent
Prognosis
The TNM classification/staging of gastric cancer is the
best prognostic indicator

The 5 years survival rate depends on the depth of gastric
cancer invasion

Patients in whom tumors are resectable for cure also
have good prognosis

Prevention
Eradication of H. Pylori infection in those high risk
population
family history of gastric cancer
chronic gastritis with apparent abnormality (atrophy, IM)
post early gastric cancer resection
gastric ulcer

Management of dietary risk factor
intake adequate amount of fruits, vegetables
minimize their intake of salty/smoked foods

Prevention
Tightly follow up those with precancerous condition


Endoscopic or radiologic screening