胃癌_MDT-青岛梁军

1、 胃癌多学科综合治疗胃癌多学科综合治疗 青岛大学医学院附属医院青岛大学医学院附属医院 梁军梁军胃癌的流行病学胃癌的流行病学氟尿嘧啶类药物在胃癌中应用氟尿嘧啶类药物在胃癌中应用胃癌的多学科综合治疗胃癌的多学科综合治疗全球每年全球每年: 934 000 新患者新患者 ，700 000 死亡，死亡， 5年生存率年生存率 20% Parkin DM et al. CA Cancer J Clin 2005;55:74108Parkin DM et al. CA Cancer J Clin 2005;55:74108Yang L. World J Gastroenterol. 2006;12;1720Y

2、ang L. World J Gastroenterol. 2006;12;1720 20 / 100 000 20 / 100 000 10 / 100 000 10 / 100 000 10 10 20 / 100 00020 / 100 000 胃癌发病率胃癌发病率The majority of gastric cancer cases (42%) occur in China中国胃癌的发病率及死亡率Incidence & Mortality of GC in China200025625620051812148595942

3、200525311019722212388397843发病人数男性死亡人数发病人数女性死亡人数2562562005181214859594225311019722212388397843050000100000150000200000250000300000200528.837.113.317.4200032.741.91519.5死亡率（每100,000人）男性发病率（每100,000人）死亡率（每100,000人）女性发病率（每100,000人）32.741.91519.528.837.113.317.401020304050死亡率（每100,000人）发病率（每100,000人）死亡率（

4、每100,000人）发病率（每100,000人）男性女性Yang L. World J Gastroenterol, 2006发生率高低东亚西方食管胃结合部癌少多早期胃癌常见少见标准术式D2D0-1术后5年生存率50-70% 30%标准的辅助治疗术后化疗(S-1)术后放化疗围手术期化疗ECF晚期胃癌的标准治疗S-1+CDDPCape+CDDPECF DCF，EOX5Patient referralEndoscopic and pathological diagnosisSURGERYSURGERY目前中国胃癌治疗的主要模式目前中国胃癌治疗的主要模式Current schema of gastr

5、ic cancer Current schema of gastric cancer managementmanagementIt is so late, It is so late, unresectableunresectable, go to , go to chemotherapychemotherapyHurry, take it to the Hurry, take it to the operating table operating table immediatelyimmediately！胃癌的流行病学胃癌的流行病学氟尿嘧啶类药物在胃癌中应用氟尿嘧啶类药物在胃癌中应用胃癌的多

6、学科综合治疗胃癌的多学科综合治疗RR 15% 20-30% 2372% 40%19601960s 1970-80s 1970-80s 1990s 1990s s 200020005-fu5-fu基础基础ECFECF,LFEP,LFEP5-FU+/-LV/P5-FU+/-LV/PFAMTXFAMTXEAP,EAP,FAPFUPFUPFAMFAMELFUFTMUFTM卡陪他滨卡陪他滨, S-1, S-1紫杉烷紫杉烷奥沙利铂奥沙利铂CPT-11,CPT-11,靶向治疗靶向治疗OS 4-5m 6-7m 6m 8 m 1991年，年，JCO报道了一报道了一项项EORTC的的III期临床期临床试验研究结果

7、，显示试验研究结果，显示FAMTX方案比方案比FAM具具有更高的有效率和生存有更高的有效率和生存优势，因此，优势，因此，FAMTX被许多学者推荐为当时被许多学者推荐为当时的标准方案。的标准方案。 DDP1993年年ECF和和FAMTX方案方案比较，中位生存时间、客观比较，中位生存时间、客观有效率更佳。在欧洲，有效率更佳。在欧洲，ECF方案被认为是进展期胃癌化方案被认为是进展期胃癌化疗的标准方案。但是，该方疗的标准方案。但是，该方案中因为表阿霉素有心脏毒案中因为表阿霉素有心脏毒性，其应用有很多争议性，其应用有很多争议。1997年年CF与与FAM及及5-FU比较，比较，CF方案方案的结果并不亚于的

8、结果并不亚于ECF方案，且没有阿霉素方案，且没有阿霉素带来的毒副反应。许带来的毒副反应。许多亚洲和美国学者更多亚洲和美国学者更倾向于选择倾向于选择CF作为推作为推荐方案。荐方案。 胃癌的化疗历程胃癌的化疗历程1980年年John S Macdonald博士最博士最先证实了先证实了FAM方案方案的有效性：可以使的有效性：可以使进展期胃癌患者的进展期胃癌患者的中位生存期达到中位生存期达到5.5个月，且耐受性好个月，且耐受性好,1950 1960 1970 1980 1990 20005-FUHeidelberger 1957TegafurSynthesized in 1967UFTFirst Ap

9、provedin Japan 1983S-1Developed 90CapecitabineApproved by FDA 1998FurtulonSynthesized in 19765-FU IVRoche, 1962FurtulonApprovedin Japan 1987肿瘤选择性肿瘤选择性,口服口服肿瘤内激活肿瘤内激活/口服口服静脉静脉非肿瘤选择性非肿瘤选择性,口服口服卡陪他滨卡陪他滨S-1S-1CPT-11CPT-11紫杉烷紫杉烷奥沙利铂奥沙利铂靶向治疗靶向治疗热点问题：希罗达是否能替代5-FUCunningham et al. New Eng J Med 2008Epirubic

10、in 50mg/m2 day 1Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2 day 15-FU 200mg/m2/day continuous infusion vs Capecitabine 500625mg/m2 twice daily continuousFor 24 weeks: eight cycles every 3 weeks Epirubicin Cisplatin 5-FU Epirubicin Oxaliplatin 5-FUEpirubicinCisplatinXelodaEpirubicinOxaliplatin XelodaR一

11、线治疗进展期胃癌及食道胃接合部癌一线治疗进展期胃癌及食道胃接合部癌12Months2430.20.01.00HR=0.80 (95% CI: 0.660.97)Log-rank p=0.0211.29.9EOX(n=244)ECF (n=263)概概率率ITT populationCunningham et al. NEJM 2008既往未治疗的进展期胃既往未治疗的进展期胃癌癌 n=316随机随机卡培他滨卡培他滨 (1000mg/m2 bd D1-14) /顺铂顺铂 (80mg/m2 D1) (XP) q3w5-FU (800mg/m2/day D1-5) /顺铂顺铂(80

12、mg/m2 D1) (FP) q3wEstimated probabilityHR=0.81 (95% CI: 0.631.05)HR upper limit 1.250PFS/Months24681012141618202224261.00.20.0XP (n=139) FP (n=137)Kang et al. Ann Oncol 2009PS 0-1PS 1Age 60Age 60局部进展期组局部进展期组转移组转移组Overall effect0.400.500.600.700.800.901.0001.40Capecitabine betterH

13、azard Ratio5FU betterOkines, et al. annals of oncology 2009 MayMarkus Moehler, Multidisciplinary management of gastric and gastroesophageal cancers；World J Gastroenterol 2008 June 28; 14(24): 3773-3780胃癌的流行病学胃癌的流行病学氟尿嘧啶类药物在胃癌中应用氟尿嘧啶类药物在胃癌中应用胃癌的多学科综合治疗胃癌的多学科综合治疗Surgery-oriented Treatment ModelSurgica

14、l exploration first Generally total or subtotal gastrectomy with or without systemic lymph node dissectionAdjuvant chemotherapy for allSupportive care for metastatic diseasesSurgical ExplorationBeijing Cancer Hospital (1995-2005): n=2312Beijing Cancer Hospital (1995-2005): n=2312ExplorationExplorati

15、onGastrostomyGastrostomy or or ileostomyileostomyOthersOthersTotalTotal3644686Looking backward to find what is not so perfect 胃癌不同分期外科治疗的地位不同GC Metastasis and Treatment N NEMRSN, WedgeD2 gastrectomyD2 + ChemoAny surgeon can cureNo surgeon can cureSurgeon-dependentSurgeon-dependentSurgeonOncologistSu

16、rgeonOncologistRadiation oncologistSurgeonOncologistRadiation oncologistPathologistsRadiologistsNursingPatient Referral Confirmatory DiagnosisStaging DiagnosisData Collection MDTDecision Making Combined modality therapy is effective for patients with localized gastric cancer.MDT for gastric cancer m

17、anagement worldwide is warranted.Surgery remains the most important treatment for GCAdequate margin of complete resection has become the basic principles of radical gastrectomyLymphadenectomyPrimary tumor resectionPortal system - LiverFrom Sano T. 2007Peritoneal seedingFrom Sano T. 2007Lymphatic sys

18、tem Systemic circulationFrom Sano T. 2007D0/D1D2Regional node metastasisFrom Sano T. 2007D0D1D2The MRC Randomized Surgical Trial.Cuschieri A et al. Br J Cancer 79: 1522-1530, 1999 两组间并未看到明显的生存差异两组间并未看到明显的生存差异Dutch D1D2 trial共1078例患者入组，其中711例（D1组381例；D2组331例）纳入研究D1=standardized limited lymphadenectom

19、y. D2=standardized extended lymphadenectomy.Ilfet Songun, et al.Lancet Oncol 2010; 11: 4394915-YEAR OVERALL SURVIVALD1: 21% (85 of 380, 95% CI 1726) ;D2: 29% (98 of 331, 2434) (P=0.34).D1组的胃癌相关死亡率显著高于D2组（P=0.01）Dutch D1D2 trialIlfet Songun, et al.Lancet Oncol 2010; 11: 43949D2D2组的局部复发及区域复发率均显著低于组的局部

20、复发及区域复发率均显著低于D1D1组，而两组从随访组，而两组从随访2.52.5年开始年开始体现出这种趋势体现出这种趋势（40 of 330 12% vs 82 of 380 22% 40 of 330 12% vs 82 of 380 22% ； 37 of 330 11% vs 65 of 380 17% 37 of 330 11% vs 65 of 380 17%）Dutch D1D2 trialIlfet Songun, et al.Lancet Oncol 2010; 11: 43949D0D1D2淋巴结清扫范围在国际上仍有争论淋巴结清扫范围在国际上仍有争论但已开始逐步达成共识但已开始

21、逐步达成共识胃癌根治术应在大规模的肿瘤中心由有经验的外科医生完成，同时需包括区域淋巴结胃癌根治术应在大规模的肿瘤中心由有经验的外科医生完成，同时需包括区域淋巴结胃胃周淋巴结清扫（周淋巴结清扫（D1D1），以及伴随腹腔干具名血管的淋巴结（），以及伴随腹腔干具名血管的淋巴结（D2D2）。NCCN胃癌指南 v2010.2N Engl J Med (2006) 355(1):1120PFSOSMedian Follow-up of 4 YearsThe Primary End Point Was Overall SurvivalChemotherapyThree Preoperative Cycles

22、 of ECFThree Postoperative Cycles of ECFTherapyPerioperative Chemotherapy & Surgery (250 Patients)Surgery Alone (253 Patients). Randomly Assigned Patients With Resectable AdenocarcinomaStomachEsophagogastric JunctionLower EsophagusThe Perioperative-chemotherapy Group had a Higher likelihood of O

23、verall Survival & Progression-free Survival Overall Survival(OS) Hazard Ratio For Death, 0.75 95 % Confidence Interval, 0.60 To 0.93; P=0.009 Five-year Survival Rate, 36 Percent Vs. 23 PercentProgression-free Survival(PFS) Hazard Ratio For Progression, 0.66 95% Confidence Interval, 0.53 To 0.81;

24、 P0.0015-FU/LV for 5 daysRadiation 45Gy+5-FU/LV5-FU/LV for 5 days X2Surgery aloneStage IBIVM0R0 resectionn=556Macdonald et al. N Engl J Med 2001;345:731-8Overall Survival by Treatment Arm0%20%40%60%80%100%024487296120144Months After Registration5-FU+leucovorin+RTObservationN282277Events192214Mediani

25、n Months3527P = .006Adjuvant Chemoradiation: INT 0116The importance of curative surgery necessitates neoadjuvant chemotherapy for advanced gastric cancer Survival curve of different surgery of gastric cancer patients (Kaplan-meier method) 0: curative resection; 1: palliative resection (p0.05) From A

26、ugust 2005 to December 2007, 193 eligible patients were recruited, NACT 105 cases PI: Professor Jiafu Ji, M.D.Organized by Chinese Surgical Association & Chinese Anticancer Association8 large hospitals enrolled in this studyStudy group: Oxaliplatin/CF/5-FuTime: 2005-2007Oxaliplatin and 5-flurour

27、acil/leucovorin (FOLFOX7) as Perioperative Treatment versus Adjuvant Alone in Locally Advanced Resectable Gastric Cancer: BJSA-01 Study Design and Interium Results.Ji JF, Li ZY, Wu AW, Liu YH, Zhang ZT, Wang S, Ye YJ, Li R, Li ZXASCO GI meeting 2007 新辅助化疗的优势Advantage of Neoadjuvant chemotherapyNAC i

28、ncreases the R0 resection rate by shrinkage of the metastatic nodes and primary tumor.Post Adjuvant Chemo (PACx) shows usually lower compliance due to high morbidity, mainly caused by combined resection of pancreas for advanced cases, and weakness and change of digestive organ function after gastrec

29、tomy which often cause difficulty of oral intake and appetite loss. NAC shows high compliance. Early treatment of micrometastasis in distant site may improve survival. 多学科综合治疗多学科综合治疗术后化疗术后化疗多学科治疗多学科治疗胃癌胃癌术前化疗术前化疗手术手术术前放化疗术前放化疗手术手术食管食管-胃交界肿瘤胃交界肿瘤术前化疗术前化疗手术手术术后化疗术后化疗手术手术术后放化疗术后放化疗手术手术多学科治疗胃癌术前化疗手术食管-胃

30、交界肿瘤OEO 2手术手术术前化疗术前化疗5-FU / Cisplatin两个两个周期，然后手术周期，然后手术n=400n=402US Intergroup 113手术手术术前化疗术前化疗5-FU / Cisplatin三个周期，然后手术，三个周期，然后手术，再续以两个周期术后化疗再续以两个周期术后化疗n=216n=227MRC Lancet 2002 Allum et al J Clin Oncol 2009Kelsen et al NEJM 1996 JCO 2007p=NSOEO 2US Intergroup 113Allum et al JCO 2009; Kelsen et al J

31、CO 2007中位随访中位随访: 6 years中位随访中位随访: 8.8 yearsp=0.03Thirion et al ASCO 2007多学科治疗胃癌术前化疗手术术前放化疗手术食管-胃交界 术前化疗术前化疗术前放化疗术前放化疗病例数病例数64 62pCR2% 15.6%总生存总生存中位中位21.1 months 33.1 months3-year27.7% 47.4%局部肿瘤无进展率局部肿瘤无进展率3-year59% 76.5%住院期间死亡率住院期间死亡率3.8% 10.2%Stahl et al J Clin Oncol 2009Stahl et al J Clin Oncol 20

32、09HR: 0.67; 95%CI: 0.41, 1.07; p=0.1多学科治疗多学科治疗胃癌胃癌术前化疗术前化疗手术手术术前放化疗术前放化疗手术手术食管食管-胃交界肿瘤胃交界肿瘤手术手术术后化疗术后化疗作者作者 杂志杂志纳入纳入病例数病例数死亡的死亡的Odds ratio研究数研究数 (95% CI)Hermans (1993) J Clin Oncology 112,0960.88 (0.78-1.08)Earle (1999)Eur J Cancer 131,9900.80 (0.66-0.97)Mari (2000)Ann Oncology 203,6580.82 (0.75-0.8

33、9)Janunger (2002) Eur J Surg 213,9620.84 (0.74-0.96)Panzini (2002)Tumori 173,1180.72 (0.62-0.84)Zhao (2008)Cancer Invest 153,2120.90 (0.84-0.96)Sun et al Br J Surg 2009胃癌术后胃癌术后S1 单药辅助化疗单药辅助化疗 III期临床随机对照研究期临床随机对照研究（ACTS-GC，日本），日本）1059 例例(stage II/III ，D2)随访随访3年年 S-1 单药组单药组529 casesOS:80.1%OS:70.1%单纯手术组单纯手术组530 cases备注：备注：S-1治疗治疗12个月，个月， 80 mg/m2/d x 4 周周, 休息休息2周；周；78%的病例完成的病例完成 了了6个月治疗，个月治疗，71%完成了完成了12个月个月 3/4度毒性反应少见度毒性反应少见 (恶心、腹泻恶心、腹泻3-4%)Sakuramoto S et al. N Engl J Med 2007;357:1810-1820 新型口服氟尿嘧啶类药物:Tegafur (5FU前体药物)吉美嘧啶奥替拉西三药复合制剂首次证实对首次证实对D2切除术后辅助切除术后辅助化疗有意义化疗有意