Gastric cancer .ppt - Gastric cancer by liwenting

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									   Gastric cancer

The department of Gastroenterology
     Shanghai Ren-Ji Hospital


    Zhi Hua Ran (冉志华)
                  Epidemiology

Forth common                          Second most common
types of cancer                        cancer related death
     (2000)                                    (2000)


                      Gastric
                      Cancer
                                             Geographic
 Continuing                                  variations
   decline                                   (ten times)

                    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                 Precancerous
   factors                      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    Pro-carcinogen/
   /Micronutrition          Carcinogen
                                               GC

  Tobacco/alcohol
                         Lack of antioxidant
   Eating salted/
   Smoked food
                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                          Moderate
Dysplasia                        Dysplasia                     Dysplasia
                                              60%
                   60%
                                                         5 years

                                                        10%
                           3 months-2 years
                                                                     10%
Gastric                       50%-90%         High-grade
adenocarcinoma                                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                 FAP or            Other factors
                                                Adenomas




 Chronic                                                            Gastric
Superficial                        Intestinal
                                   Metaplasia                   Adenocarcinoma
 Gastritis




                    Atrophic                    Dysplasia
                    Gastritis




                 Association                        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   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           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           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%    Duration of symptoms
Abdominal pain                50%    Less than 3 month    40%
Nausea or vomiting            30%    3-12 months          40%
Anorexia                      30%    Longer than 12 month 20%
Dysphagia                      25%
Gastrointestinal blood loss   20%
Early satiety                  20%
Peptic ulcer symptoms          20%
Abdominal mass or fullness      5%
Asymptomatic or silent         <5%
    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
                                  Non-proliferative cells
        2h   G2
                        1~2h
                        M
 S                                                           Death

2~30h                                    G0
                     hs~ds
               G1
        Proliferating cells            Temporally
         (tumor growth)             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         1960~1985             1985~1990            1990~        2000~

  5Fu应用           5Fu I.V.Drip            5Fu b.        LV/5Fu CIV   FP+EPI,Taxanes,CPTs

  RR%               15%                    30%             40%          >50%


  衍化新药              FT-207            UFT,5’-DFUR       S-1, CAPE    口服新药联合化疗




  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/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                      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
                    INCREASED EFFICACY




          ACTIVITY                      SAFETY


   Different mechanisms of action    Compatible side effects
Different mechanisms of resistance
      Side effects of chemotherapy
                                  Alopecia
Mucositis



                         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

								
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