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,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, 起重机 立体停车设备 电动葫芦 ,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: 2.86 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 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,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,hsds,230h,2h,12h,,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)： 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 (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,-Fu based regime -predominant （LV/5F-u, 5-Fu CIV) derivative new drugs (CAPE,S-1) -FuPts(铂类) are the basis of combination therapy for AGC Triple regime containing anthracene,,Evaluation of -Fu treatment during past four decades,-Fu主导AGC治疗四十年,年代,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 6001500mg/m2 CIV 24h x 2d,q2w 300800mg/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 50100mg/m2 I.V. 4h,q3w LD CDDP 1520mg/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 + doxorubic