胃癌_MDT-青島梁軍

1、 胃癌多學(xué)科綜合治療胃癌多學(xué)科綜合治療 青島大學(xué)醫(yī)學(xué)院附屬醫(yī)院青島大學(xué)醫(yī)學(xué)院附屬醫(yī)院 梁軍梁軍胃癌的流行病學(xué)胃癌的流行病學(xué)氟尿嘧啶類藥物在胃癌中應(yīng)用氟尿嘧啶類藥物在胃癌中應(yīng)用胃癌的多學(xué)科綜合治療胃癌的多學(xué)科綜合治療全球每年全球每年: 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 胃癌發(fā)病率胃癌發(fā)病率The majority of gastric cancer cases (42%) occur in China中國胃癌的發(fā)病率及死亡率Incidence & Mortality of GC in China200025625620051812148595942

3、200525311019722212388397843發(fā)病人數(shù)男性死亡人數(shù)發(fā)病人數(shù)女性死亡人數(shù)2562562005181214859594225311019722212388397843050000100000150000200000250000300000200528.837.113.317.4200032.741.91519.5死亡率（每100,000人）男性發(fā)病率（每100,000人）死亡率（每100,000人）女性發(fā)病率（每100,000人）32.741.91519.528.837.113.317.401020304050死亡率（每100,000人）發(fā)病率（每100,000人）死亡率（

4、每100,000人）發(fā)病率（每100,000人）男性女性Yang L. World J Gastroenterol, 2006發(fā)生率高低東亞西方食管胃結(jié)合部癌少多早期胃癌常見少見標(biāo)準(zhǔn)術(shù)式D2D0-1術(shù)后5年生存率50-70% 30%標(biāo)準(zhǔn)的輔助治療術(shù)后化療(S-1)術(shù)后放化療圍手術(shù)期化療ECF晚期胃癌的標(biāo)準(zhǔn)治療S-1+CDDPCape+CDDPECF DCF，EOX5Patient referralEndoscopic and pathological diagnosisSURGERYSURGERY目前中國胃癌治療的主要模式目前中國胃癌治療的主要模式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！胃癌的流行病學(xué)胃癌的流行病學(xué)氟尿嘧啶類藥物在胃癌中應(yīng)用氟尿嘧啶類藥物在胃癌中應(yīng)用胃癌的多

6、學(xué)科綜合治療胃癌的多學(xué)科綜合治療RR 15% 20-30% 2372% 40%19601960s 1970-80s 1970-80s 1990s 1990s s 200020005-fu5-fu基礎(chǔ)基礎(chǔ)ECFECF,LFEP,LFEP5-FU+/-LV/P5-FU+/-LV/PFAMTXFAMTXEAP,EAP,FAPFUPFUPFAMFAMELFUFTMUFTM卡陪他濱卡陪他濱, S-1, S-1紫杉烷紫杉烷奧沙利鉑奧沙利鉑CPT-11,CPT-11,靶向治療靶向治療OS 4-5m 6-7m 6m 8 m 1991年，年，JCO報道了一報道了一項項EORTC的的III期臨床期臨床試驗研究結(jié)果

7、，顯示試驗研究結(jié)果，顯示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優(yōu)勢，因此，優(yōu)勢，因此，F(xiàn)AMTX被許多學(xué)者推薦為當(dāng)時被許多學(xué)者推薦為當(dāng)時的標(biāo)準(zhǔn)方案。的標(biāo)準(zhǔn)方案。 DDP1993年年ECF和和FAMTX方案方案比較，中位生存時間、客觀比較，中位生存時間、客觀有效率更佳。在歐洲，有效率更佳。在歐洲，ECF方案被認(rèn)為是進展期胃癌化方案被認(rèn)為是進展期胃癌化療的標(biāo)準(zhǔn)方案。但是，該方療的標(biāo)準(zhǔn)方案。但是，該方案中因為表阿霉素有心臟毒案中因為表阿霉素有心臟毒性，其應(yīng)用有很多爭議性，其應(yīng)用有很多爭議。1997年年CF與與FAM及及5-FU比較，比較，CF方案方案的結(jié)果并不亞于的

8、結(jié)果并不亞于ECF方案，且沒有阿霉素方案，且沒有阿霉素帶來的毒副反應(yīng)。許帶來的毒副反應(yīng)。許多亞洲和美國學(xué)者更多亞洲和美國學(xué)者更傾向于選擇傾向于選擇CF作為推作為推薦方案。薦方案。 胃癌的化療歷程胃癌的化療歷程1980年年John S Macdonald博士最博士最先證實了先證實了FAM方案方案的有效性：可以使的有效性：可以使進展期胃癌患者的進展期胃癌患者的中位生存期達到中位生存期達到5.5個月，且耐受性好個月，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腫瘤選擇性腫瘤選擇性,口服口服腫瘤內(nèi)激活腫瘤內(nèi)激活/口服口服靜脈靜脈非腫瘤選擇性非腫瘤選擇性,口服口服卡陪他濱卡陪他濱S-1S-1CPT-11CPT-11紫杉烷紫杉烷奧沙利鉑奧沙利鉑靶向治療靶向治療熱點問題：希羅達是否能替代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、線治療進展期胃癌及食道胃接合部癌一線治療進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既往未治療的進展期胃既往未治療的進展期胃癌癌 n=316隨機隨機卡培他濱卡培他濱 (1000mg/m2 bd D1-14) /順鉑順鉑 (80mg/m2 D1) (XP) q3w5-FU (800mg/m2/day D1-5) /順鉑順鉑(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局部進展期組局部進展期組轉(zhuǎn)移組轉(zhuǎn)移組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胃癌的流行病學(xué)胃癌的流行病學(xué)氟尿嘧啶類藥物在胃癌中應(yīng)用氟尿嘧啶類藥物在胃癌中應(yīng)用胃癌的多學(xué)科綜合治療胃癌的多學(xué)科綜合治療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療的地位不同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 兩組間并未看到明顯的生存差異兩組間并未看到明顯的生存差異Dutch D1D2 trial共1078例患者入組，其中711例（D1組381例；D2組331例）納入研究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組的胃癌相關(guān)死亡率顯著高于D2組（P=0.01）Dutch D1D2 trialIlfet Songun, et al.Lancet Oncol 2010; 11: 43949D2D2組的局部復(fù)發(fā)及區(qū)域復(fù)發(fā)率均顯著低于組的局部

20、復(fù)發(fā)及區(qū)域復(fù)發(fā)率均顯著低于D1D1組，而兩組從隨訪組，而兩組從隨訪2.52.5年開始年開始體現(xiàn)出這種趨勢體現(xiàn)出這種趨勢（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淋巴結(jié)清掃范圍在國際上仍有爭論淋巴結(jié)清掃范圍在國際上仍有爭論但已開始逐步達成共識但已開始

21、逐步達成共識胃癌根治術(shù)應(yīng)在大規(guī)模的腫瘤中心由有經(jīng)驗的外科醫(yī)生完成，同時需包括區(qū)域淋巴結(jié)胃癌根治術(shù)應(yīng)在大規(guī)模的腫瘤中心由有經(jīng)驗的外科醫(yī)生完成，同時需包括區(qū)域淋巴結(jié)胃胃周淋巴結(jié)清掃（周淋巴結(jié)清掃（D1D1），以及伴隨腹腔干具名血管的淋巴結(jié)（），以及伴隨腹腔干具名血管的淋巴結(jié)（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 新輔助化療的優(yōu)勢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. 多學(xué)科綜合治療多學(xué)科綜合治療術(shù)后化療術(shù)后化療多學(xué)科治療多學(xué)科治療胃癌胃癌術(shù)前化療術(shù)前化療手術(shù)手術(shù)術(shù)前放化療術(shù)前放化療手術(shù)手術(shù)食管食管-胃交界腫瘤胃交界腫瘤術(shù)前化療術(shù)前化療手術(shù)手術(shù)術(shù)后化療術(shù)后化療手術(shù)手術(shù)術(shù)后放化療術(shù)后放化療手術(shù)手術(shù)多學(xué)科治療胃癌術(shù)前化療手術(shù)食管-胃

30、交界腫瘤OEO 2手術(shù)手術(shù)術(shù)前化療術(shù)前化療5-FU / Cisplatin兩個兩個周期，然后手術(shù)周期，然后手術(shù)n=400n=402US Intergroup 113手術(shù)手術(shù)術(shù)前化療術(shù)前化療5-FU / Cisplatin三個周期，然后手術(shù)，三個周期，然后手術(shù)，再續(xù)以兩個周期術(shù)后化療再續(xù)以兩個周期術(shù)后化療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中位隨訪中位隨訪: 6 years中位隨訪中位隨訪: 8.8 yearsp=0.03Thirion et al ASCO 2007多學(xué)科治療胃癌術(shù)前化療手術(shù)術(shù)前放化療手術(shù)食管-胃交界 術(shù)前化療術(shù)前化療術(shù)前放化療術(shù)前放化療病例數(shù)病例數(shù)64 62pCR2% 15.6%總生存總生存中位中位21.1 months 33.1 months3-year27.7% 47.4%局部腫瘤無進展率局部腫瘤無進展率3-year59% 76.5%住院期間死亡率住院期間死亡率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多學(xué)科治療多學(xué)科治療胃癌胃癌術(shù)前化療術(shù)前化療手術(shù)手術(shù)術(shù)前放化療術(shù)前放化療手術(shù)手術(shù)食管食管-胃交界腫瘤胃交界腫瘤手術(shù)手術(shù)術(shù)后化療術(shù)后化療作者作者 雜志雜志納入納入病例數(shù)病例數(shù)死亡的死亡的Odds ratio研究數(shù)研究數(shù) (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胃癌術(shù)后胃癌術(shù)后S1 單藥輔助化療單藥輔助化療 III期臨床隨機對照研究期臨床隨機對照研究（ACTS-GC，日本），日本）1059 例例(stage II/III ，D2)隨訪隨訪3年年 S-1 單藥組單藥組529 casesOS:80.1%OS:70.1%單純手術(shù)組單純手術(shù)組530 cases備注：備注：S-1治療治療12個月，個月， 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個月治療，個月治療，71%完成了完成了12個月個月 3/4度毒性反應(yīng)少見度毒性反應(yīng)少見 (惡心、腹瀉惡心、腹瀉3-4%)Sakuramoto S et al. N Engl J Med 2007;357:1810-1820 新型口服氟尿嘧啶類藥物:Tegafur (5FU前體藥物)吉美嘧啶奧替拉西三藥復(fù)合制劑首次證實對首次證實對D2切除術(shù)后輔助切除術(shù)后輔助化療有意義化療有意