Gastric cancer

1
Gastric cancer

• The department of Gastroenterology
• Shanghai Ren-Ji Hospital
• Zhi Hua Ran (???)

2
Epidemiology
Second most common cancer related death
Forth common types of cancer
(2000)
(2000)
Gastric Cancer
Geographic variations (ten times)
Continuing decline
Primarily a decline of distal GC
3
Geographic variations
4
Geographic distribution of mortality rates
for gastric cancer in males in China
5
Etiological Factors of Gastric Cancer
H. pylori
Genetic factors
Gastric Cancer
Environmental factors
Precancerous changes
6
The role of H. Pylori infection in gastric
carcinogensis
Epidemiological studies
RF 2.86 folds
Type I carcinogen 1994 by IARC
Attributable risk 5073
Animal modes (Mongolian gerbil)
Gastric Cancer
Honda et al . 1998 Watanabe et al. 1998
7
Environmental factors
Japanese immigrants in US 25
Second generation gt50
Subsequent generations comparable to General US
population
Environmental factors are involved
8
Environmental factors
Lower socioeconomic status
Mucosal damage
Poor food storage
Fresh vegetable/fruits /Micronutrition
Pro-carcinogen/ Carcinogen
GC
Tobacco/alcohol
Lack of antioxidant
Eating salted/ Smoked food
9
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

10
Precancerous changes
Precancerous lesions
Precancerous conditions
11
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

12
Nature history of gastric dysplasia
5 years
5 years
10
No Dysplasia
Mild Dysplasia
Moderate Dysplasia
60
60
5 years
10
3 months-2 years
10
High-grade Dysplasia
Gastric adenocarcinoma
50-90
13
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

14
Postulated sequence of histologic events in the
progression to gastric adenocarcinoma and
potential contributory factors
Correa hypothesis
H. Pylori
Other factors
FAP or Adenomas
Other factors
Chronic Superficial Gastritis
Gastric Adenocarcinoma
Intestinal Metaplasia
Atrophic Gastritis
Dysplasia
Association
Strong Association
15
Pathology
Stages
Morphology
Pathohistologic classification
Metastasis
16
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
• lt1cm lt0.5cm
• Advanced stage
• invaded over submucosa
• According to Bormann classification

17
TNM classification (UICC)
0 Tis N0 M0 III A
T2 N2 M0 I A T1
N0 M0 T3
N1 M0 I B T1 N1
M0 T4 N0
M0 T2 N0 M0
III B T3 N2 M0 II
T1 N2 M0 IV
T4 N2 M0 T2
N1 M0 T13
N3 M0 T3 N0
M0 any T any N
M1
18
Morphology---early stage
19
Morphology---early stage
20
Morphology---early stage
21
Morphology ---advanced stage
22
Pathohistologic classification

• Histology
• Adenocarcinoma 90
• Lymphoma 5
• Stromal 2
• Carcinoid lt1
• Metastasis lt1
• Adenosquamous/squamous lt1
• Miscellaneous lt1

23
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

24
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

25
Metastasis
Direct invasion
Lymph node dissemination
Blood spread
Intraperitoneal colonization
26
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

27
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
  lt2
• Weight loss
  lt2
• Dysphagia
  lt1

28
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 lt5

Duration of symptoms Less than 3 month
40 3-12 months 40 Longer than
12 month 20
29
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

30
Sister Mary Josephs node
31
Laboratory tests
Iron deficiency anemia
Fecal occult blood test (FOBT)
Tumor markers (CEA, Ca19-9)
32
Diagnosis

• Endoscopic diagnosis
• --- biopsy needed for definitive
  diagnosis
• Radiologic diagnosis
• Detection of early gastric cancer

33
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

34
Endoscopic features of gastric cancer
35
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

36
Radiologic diagnosis
Proximal GC
Linitis plastica
Distal GC
37
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

38
Differential diagnosis
Gastric Cancer
Gastric Ulcer
39
Complications

• GI bleeding 5
• Pylorus/cardia obstruction
• Perforation ulcer type

40
Treatment
Surgical resection
EMR
Adjuvant therapy
Palliative therapy
41
Endoscopic mucosal resection
Gastric cancer lesion confined to mucosa layer
Endoscopic ultrasound (EUS) is helpful in
stageing GC
42
Endoscopic mucosal resection
43
Endoscopic mucosal resection
44
Chemotherapy

• Adjuvant chemotherapy may increase 5 years
  survival rates and decrease the relapse rates
• Combination chemotherapy are recommended

45
Tumor Cell Kinetics
Non-proliferative cells
G2
2h
12h
M
S
Death
G0
230h
hsds
G1
Temporally non-dividing cells (souse of tumor
recurrence)
Proliferating cells (tumor growth)
46
Classification of anti-tumor agents

• Traditional classification
• Classification based on cell kinitics

47
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
48
Traditional classification
Antimetabolites(????) 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
(???????????6-????)
pyrimidine antagonists
(5-??????????5-????????)
folate antagonists (????)
49
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 (????)
50
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 ????
51
Traditional classification
Steroidal(???) Estrogen ---
Diethylstilbestro(????)
Ethinylestradiol(???) Progestational hormone
--- Medroxyprogesterone(????)
Estrogen angonist --- Tamoxifan(????)
?????
Corticostidals
52
Traditional classification
Others (??) Platins --- Cisplatin (??)
Carboplatin(??)
Oxaliplatin (???)
Norcantharidin (?????)
53
Classification based on cell kinetics

• Cell cycle non specific agents (CCNSA)
• ??????????
• Cell cycle specific agents (CCSA)
• ?????????

54
Cell cycle non specific agents
May kill cells at all cell cycle, including G0
Alkylating agents(???)?antitumor
antibiotics(?????) ? steroids(???) May affect
predominantly on one specific cell cycle Dose
dependant effects Administrated intermittently
with large dose
55
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
56
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

57
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-FuPts(??) are the basis of combination
  therapy for AGC
• Triple regime containing anthracene

58
Evaluation of 5-Fu treatment during past four
decades
5-Fu??AGC?????
??
19601985
19851990
1990
2000
5Fu??
5Fu I.V.Drip
5Fu b.
LV/5Fu CIV
FPEPI,Taxanes,CPTs
40
gt50
RR
15
30
????
FT-207
UFT,5-DFUR
S-1, CAPE
????????
FP 5-FUCDDP, b(bolus), CIV(continuous
intravenous infusion)
59
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
6001500mg/m2 CIV 24h x 2d,q2w
300800mg/m2 CIV 24h x 5d, q3w Capecitabine
(Xeloda)
60
5-FuPts 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 50100mg/m2 I.V. 4h,q3w LD CDDP
1520mg/m2 I.V. 2h, x5d q3w Oxaliplatin is more
commomly employed in combination regime

61
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)

62
AIM OF COMBINATION THERAPY

• INCREASED EFFICACY

ACTIVITY
SAFETY
Different mechanisms of action
Compatible side effects Different mechanisms
of resistance
63
Side effects of chemotherapy
Alopecia Pulmonary fibrosis Cardiotoxicity Lo
cal reaction Renal failure Myelosuppression Phl
ebitis

• Mucositis
• Nausea/vomiting
• Diarrhea
• Cystitis
• Sterility
• Myalgia
• Neuropathy

64
Metal stent
65
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

66
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

67
Prevention

• Tightly follow up those with precancerous
  condition
• Endoscopic or radiologic screening