Transcript Gastric cancer The department of Gastroenterology Shanghai Ren-Ji Hospital Zhi Hua Ran (冉志华)

Gastric cancer
The department of Gastroenterology
Shanghai Ren-Ji Hospital
Zhi Hua Ran (冉志华)
Epidemiology
Second most common
cancer related death
(2000)
Forth common
types of cancer
(2000)
Gastric
Cancer
Geographic
variations
(ten times)
Continuing
decline
Primarily a decline
of distal GC
Geographic variations
Geographic distribution of mortality rates
for gastric cancer in males in China
Etiological Factors of Gastric Cancer
H. pylori
Genetic factors
Gastric
Cancer
Environmental
factors
Precancerous
changes
The role of H. Pylori infection in
gastric carcinogensis
Epidemiological
studies
RF: 2.8~6 folds
Type I carcinogen
1994 by IARC
Attributable risk
50%~73%
Animal modes
(Mongolian gerbil)
Gastric Cancer
Honda et al . 1998
Watanabe et al. 1998
Environmental factors
Japanese immigrants in US: 25%
Second generation: >50%
Subsequent generations: comparable to
General US population
Environmental factors are involved
Environmental factors
Lower socioeconomic
status
Mucosal damage
Poor food storage
Fresh vegetable/fruits
/Micronutrition
Pro-carcinogen/
Carcinogen
Tobacco/alcohol
Lack of antioxidant
Eating salted/
Smoked food
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
5 years
5 years
10%
No
Mild
Dysplasia
Dysplasia
60%
adenocarcinoma
Dysplasia
60%
5 years
3 months-2 years
Gastric
Moderate
50%-90%
10%
10%
High-grade
Dysplasia
Precancerous condition
• Defined as those clinical setting with higher risk of
developing gastric cancer
Chronic atrophic gastritis
Gastrectomy
Pernicious anemia
Menetrier’s disease
Chronic gastric ulcer
Gastric polyps
Postulated sequence of histologic events in the progression to
gastric adenocarcinoma and potential contributory factors
Correa hypothesis
H. Pylori
Other factors
Chronic
Superficial
Gastritis
FAP or
Adenomas
Gastric
Adenocarcinoma
Intestinal
Metaplasia
Atrophic
Gastritis
Association
Other factors
Dysplasia
Strong
Association
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
N0
M0
I A
T1
N0
I B
T1
II
III A
T2
N2
M0
M0
T3
N1
M0
N1
M0
T4
N0
M0
T2
N0
M0
III B
T3
N2
M0
T1
N2
M0
IV
T4
N2
M0
T2
N1
M0
T1~3
N3
M0
T3
N0
M0
any T any N
M1
Morphology---early stage
Morphology---early stage
Morphology---early stage
Morphology ---advanced stage
Pathohistologic classification
Histology
Adenocarcinoma
Lymphoma
Stromal
Carcinoid
Metastasis
Adenosquamous/squamous
Miscellaneous
90%
5%
2%
<1%
<1%
<1%
<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
Peptic ulcer symptoms
Nausea or vomiting
Anorexia
Early satiety
Abdominal pain
Gastrointestinal blood loss
Weight loss
Dysphagia
80%
10%
8%
8%
5%
2%
<2%
<2%
<1%
Signs and Symptoms
Advanced Gastric Cancer
Weight loss
Abdominal pain
Nausea or vomiting
Anorexia
Dysphagia
Gastrointestinal blood loss
Early satiety
Peptic ulcer symptoms
Abdominal mass or fullness
Asymptomatic or silent
60%
50%
30%
30%
25%
20%
20%
20%
5%
<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
• Virchow’s node:
supraclavicular lymphadenopathy (left)
• Irish’s node:
axillary lymphadenopathy
• Sister Mary Joseph’s node:
umbilical lymphadenopathy
Sister Mary Joseph’s 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
Bormann’s 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
2h
Non-proliferative cells
G2
1~2h
M
S
Death
2~30h
G1
hs~ds
Proliferating cells
(tumor growth)
G0
Temporally
non-dividing cells
(souse of tumor recurrence)
Classification of anti-tumor agents
Traditional classification
Classification based on cell kinitics
Traditional classification
Alkylating agents(烷化剂): They counteract cancerous cell
division by cross-linking the two DNA strands in the double
helix so that they cannot separate. Such as chlorambucil(苯丁酸
氮芥）, cyclophosphamide,(环磷酰胺) ,thiotepa(塞替派), and
busulfan (白消安).
Alkylating agent
Traditional classification
Antimetabolites(抗代谢类)： Ｔhey 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
(巯基嘌呤、磺硫嘌呤钠、6-硫鸟嘌呤)
pyrimidine antagonists
(5-氟尿嘧啶、阿糖胞苷、5-氟尿嘧啶脱氧核苷)
folate antagonists
(甲氨碟呤)
Traditional classification
Antitumor antibiotic(抗癌抗生素)：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 (柔红霉素)
Mitomycine (丝裂霉素)
Bleomycin (博莱霉素)
Traditional classification
Plant alkaloids(植物碱)：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：
长春花碱
Vincristine：
长春新碱
Taxol：
紫杉醇
Irinotecan (CPT-11): 依立替康
Camptothecin：
喜树碱
Hydroxycamptothecin：羟基喜树碱
Elemene:
榄香烯乳
Traditional classification
Steroidal(激素类) ：
Estrogen --- Diethylstilbestro(已烯雌酚)
Ethinylestradiol(炔雌醇)
Progestational hormone --Medroxyprogesterone(甲羟孕酮)
Estrogen angonist --- Tamoxifan(他莫昔酚)
羟三苯氧胺
Corticostidals
Traditional classification
Others (其它)：
Platins --- Cisplatin (顺铂)
Carboplatin(卡铂)
Oxaliplatin (草酸铂)
Norcantharidin (去甲斑螯素)
Classification based on cell kinetics
Cell cycle non specific agents (CCNSA)
细胞周期非特异性药物
Cell cycle specific agents (CCSA)
细胞周期特异性药物
Cell cycle non specific agents
May kill cells at all cell cycle, including G0
Alkylating agents(烷化剂)、antitumor antibiotics(抗癌抗
生素) 、 steroids（激素类）
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, G0 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
• ５-Fu based regime ---predominant
（LV/5F-u, 5-Fu CIV)
derivative new drugs (CAPE,S-1)
• ５-Fu＋Pts(铂类) are the basis of combination
therapy for AGC
• Triple regime containing anthracene
Evaluation of ５-Fu treatment during past
four decades
５-Fu主导AGC治疗四十年
年代
5Fu应用
１９６０～１９８５
5Fu I.V.Drip
RR%
15%
衍化新药
FT-207
１９８５～１９９０
5Fu b.
30%
UFT,5’-DFUR
１９９０～
２０００～
LV/5Fu CIV
FP+EPI,Taxanes,CPTs
40%
S-1, CAPE
FP: 5-FU+CDDP, b(bolus), CIV(continuous intravenous infusion)
>50%
口服新药联合化疗
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/m2 b. 5-Fu 425 mg/m2 b.
LV 200mg/m2 I.V. 2h, 5-Fu 370 mg/m2 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/m2 I.V. 4h,q3w
LD CDDP 15~20mg/m2 I.V. 2h, x5d q3w
Oxaliplatin is more commomly employed in combination regime
Chemotherapy
Regimen
Fluorouracil +doxorubicin
+ mitomycin (FAM)
Fluorouracil + doxorubicin
Semustine (FAMe)
Fluorouracil + doxorubicin
+ cisplatin (FAP)
Etoposide + doxorubicin
+ cisplatin (EAP)
Etoposide + leucovorin
+ fluorouracil (ELF)
Fluorouracil +doxorubicin
+ methotrexate (FAMTX)
Approximate
Response rate
Survival
Benefit
30%
No
30%
No
30%
No
40%
No
30%
No
40%
Unconfirmed
AIM OF COMBINATION THERAPY
INCREASED EFFICACY
ACTIVITY
Different mechanisms of action
Different mechanisms of resistance
SAFETY
Compatible side effects
Side effects of chemotherapy
Mucositis
Alopecia
Pulmonary fibrosis
Nausea/vomiting
Cardiotoxicity
Diarrhea
Cystitis
Local reaction
Sterility
Renal failure
Myalgia
Myelosuppression
Neuropathy
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