NCCN胃癌临床实践指南中国版解读沈琳PPT文档.ppt

Copyright 2005 American Cancer Society,Age-standardized Incidence Rates for Stomach Cancer in world.,From Parkin,D.M.et al.CA Cancer J Clin 2005;55:74-108.,世界胃癌年龄调整发病率,对1990-1992年中国的1/10万人口死因抽样调查资料中胃癌死亡情况进行分析,胃癌粗死亡率(crude mortality rate)25.2/10 万（M：32.8/10 万，F：17.0/10 万），占全部恶性肿瘤死亡的23.2%，恶性肿瘤死亡中第一位。（男性是女性1.9倍）中国胃癌世界人口调整死亡率(mortality rates adjusted by the world population)男性：40.8/10 万，女性：18.6/10 万，分别是欧美发达国家的4.2-7.9 倍，3.8-8.0 倍有明显的地区差异和城乡差别。全国抽样调查263个点，胃癌调整死亡率在2.5-153.0/10万之间，Urban areas:15.3/10 万;Rural areas:24.4/10万，是城市的1.6 倍,NCCN共识分类,1类：基于高水平的证据，NCCN达成共识，推荐应用2A类：基于包括临床经验在内的稍低水平证据，NCCN达成共识，推荐应用。2B类：基于包括临床经验在内的稍低水平证据，NCCN未达成统一共识（但无较大分歧）。3类：NCCN对该建议的适宜性存在较大分歧。除非特别说明，本指南中所有的建议均达成2A类共识。,NCCN 胃癌临床实践指南 2008第1版指南更新主要变化总结,（GAST-1）：workup：PET/CT扫描和EUS作为可选的检查项目。（GAST 2）：要求多学科会议讨论患者所有三个治疗途径的抉择 T2以上分期患者将术前化疗作为一类推荐首选治疗手段。术前放化疗作为2B类的首选治疗手段。（GAST3）：R0术后分期T2 N0M0及以上者，如术前采用ECF方案化疗，术后可选择ECF继续（1类）（GAST5）：follow up：近端胃大部或全胃切除者，应监测并补充Vit B12（GASTA）：增加综合治疗模式原则新页（GASTB、C）：更新外科及系统化疗原则（GASTA）：新增放疗原则新页,NCCN guidelines-Gastric Cancer Chinese version 1.2008,在整个治疗指南中将chemotherapy/RT 更改为 chemoradiation将salvage 改为palliative,与2007版类似,注意：除了特别指出的情况，所有推荐的治疗都是2A证据的。临床试验：NCCN认为对于任何一个肿瘤病人参加临床实验都获得最佳治疗.要特别鼓励参与临床试验。,强调多学科评估和协作！,多学科综合治疗模式有益于局部进展期胃癌患者（1类证据）NCCN专家组基本观点：不鼓励单一学科成员单方面进行治疗决策。具备以下条件，可能给局部进展期胃癌患者以最佳的综合治疗：例会形势实用（一周或2周一次），相关学科的机构和个人定期来共同回顾患者的详细资料。每次例会，各相关学科都要积极参与，包括肿瘤外科，肿瘤内科，消化科，放射科，病理科。此外，最好还能包括营养科，社工，护理以及其他支持学科。所有长期的治疗策略要在全面分期检查完成后再进行，最好在所有治疗开始之前。决策前共同回顾原始的医学数据而非单纯阅读报告。多学科团队做出共识推荐并摘要记录在案，对每位患者是有益的。特定患者的主要治疗小组或医生应尊重以及考虑多学科团队所做出的共识推荐。反馈部分患者的治疗随访结果，对整个多学科团队是有效的实例教育方式。在例会期间，正式的定期复习相关文献，对整个多学科团队是高效的教育方式。,分期CT扫描EUS判断病灶范围腹腔镜有助于部分患者的分期不能根治性切除标准局部进展期:3/4站淋巴结转移,大血管受侵或被包绕远处转移或腹膜种植(包括腹腔脱落细胞学阳性可切除肿瘤T1者在有经验者可采用内镜下胃粘膜切除T1-T3合适的肿瘤切缘4 cm（5 cm）,镜下阴性推荐D1/D2淋巴结清扫,应至少检查15个淋巴结，并结合位置清扫到2站淋巴结 T4应切除受累部位不做常规脾切除,除非脾脏受累或脾门受侵可考虑留置空肠营养管姑息手术可以接受切缘阳性，淋巴结不强求清扫胃肠短路或营养管,外科治疗原则,NCCN v.1.2008 Gastric Cancer,结合淋巴结数目以及累及区域分期,Japanese Gastric cancer associati（JGCA),腹腔细胞学（CY）CY0 腹腔细胞学良性或无法确定CY1 腹腔细胞学未见癌细胞CYx 未作其它远处转移（M）M0 腹膜、肝、腹腔细胞学外无远处转移M1 腹膜、肝、腹腔细胞学外有远处转移Mx 不清楚 分期,表2 日本胃癌学会（JGCA）分期（1998年第13版*）原发肿瘤（T）T1 肿瘤侵犯粘膜层和/或粘膜肌层(M)和/或粘膜下层(SM)T2 肿瘤侵犯固有肌层(MP)或浆膜下层(SS)T3 肿瘤穿透浆膜(SE)T4 肿瘤侵犯邻近结构(SI)Nx 不明局部淋巴结（N）淋巴结分站分组（见ST-3）淋巴结转移程度N0 无淋巴结转移证据N1 第一站淋巴结有转移，第二、三站淋巴结无转移N2 第二站淋巴结有转移，第三站淋巴结无转移N3 第三站淋巴结有转移Nx 区域淋巴结无法评估肝转移（H）H0 无肝转移H1 有肝转移Hx 不清楚腹膜转移（P）P0 无腹膜转移P1 有腹膜转移,*本分期源自 Japanese Gastric Cancer Association.Japanese Classification of Gastric Carcinoma-2nd English Edition.Gastric Cancer(1998)1:1024肿瘤可以穿透固有肌层达胃结肠韧带或肝胃韧带或大小网膜，但没有穿透这些结构的脏层腹膜。在这种情况下，原发肿瘤的分期为T2。如果穿透覆盖胃韧带或网膜的脏层腹膜，则应当被分为T3期。肿瘤侵犯大、小网膜、食管和十二指肠不作为T4,经胃壁内扩展至十二指肠或食管的肿瘤分期取决于包括胃在内的这些部位的最大浸润深度。M1的种类应注明：LYM:淋巴结；PLE:胸膜；MAR:骨髓；OSS:骨；BRA:脑；MEN:脑膜；SKI:皮肤；OTH:其它,Regional LN Group According to Location of Tumor,LD/L,Sasako et al:the long-term outcome of survival：D2 vs D2+,no statistically significant difference69%vs 70%,p=0.57,HR:1.03,(95%CI:0.77-1.37).Sasako M,Sano T,Yamamoto S,et al.Randomized phase III trial of standard D2 versus D2+para-aortic lymph node(PAN)dissection(D)for clinically M0 advanced gastric cancer:JCOG9501.J Clin Oncol 2006.24(18S):LBA4015.,扩大根治 or D2?循证医学证据,A prospective randomized controlled clinical trialin Taiwan:D2 vs D1 5-year survival D2 dissection was superior to D1 dissection 59.5%vs 53.6%,p=0.041;HR:0.49,p=0.002 Wu CW,Hsiung CA,Lo SS,et al.Nodal dissection for patients with gastric cancer:A randomized controlled trial.Lancet Oncol 2006;7:309-315进一步的临床试验，特别是观察手术前后的辅助治疗应该基于D2式手术！,D1 or D2?循证医学证据,适合于所有胃癌胃切除标本原发性胃癌胃切除标本的检查原发性肿瘤*外科切缘评估淋巴结评估原发性胃癌的组织学类型Lauren分类，1965日本胃癌研究协会（JRSGC）分类，1981WHO分类，2000病理学分期（pTNM）应包括下列参数：肿瘤的恶性程度（分级）浸润的深度淋巴结的部位、数目及阳性数远端及近端外科切缘状况,注释胃癌原发肿瘤检查应包括：肿瘤在胃粘膜确切位置及肿瘤范围；肿瘤距近端和远端外科切缘的距离；肿瘤大体形态，包括肿瘤大小、早期胃癌的形态类型；肿瘤切面，浸润胃壁情况。外科切缘评估：胃切除标本有远端及近端切缘：部分切除标本，远端切缘是十二指肠，近端切缘是胃体；全胃切除标本，远端切缘是十二指肠，近端切缘是食管。外科切缘有3种情况：R0：外科切缘干净；R1：外科切缘镜下阳性；R2：外科切缘肉眼阳性。建议切除的近端切缘应距肿瘤边缘5cm，同时应常规术中切缘冰冻检查。淋巴结评估：见ST-1/2/3。根据胃切除时淋巴结清扫的范围分为：D0：淋巴结清扫的范围不包括所有N1淋巴结；D1：淋巴结清扫的范围不包括所有N2淋巴结；D2：淋巴结清扫的范围不包括所有N3淋巴结。按照AJCC标准，因为被检查淋巴结的数量和淋巴结阳性率之间有正相关，应检查至少15个淋巴结。,胃癌组织学类型Lanren分类（1965）：肠型；弥漫型JRSGC分类（1981）：乳头状型 管状型 低分化型 粘液型 印戒细胞型WHO分类（2000）腺癌 肠型 弥漫型 乳头状腺癌 管状腺癌 粘液腺癌 印戒细胞癌 腺鳞癌 鳞状细胞癌 小细胞癌 未分化癌 其它 胃腺癌组织学分级：高分化；中分化；低分化；未分化病理学分期（pTNM）病理学分期与胃癌预后极其相关，早期胃癌预后极好，5年生存率达90%。建议使用AJCC/UICC分类，在病理报告中N分期可增加标注JRSGC要求的淋巴结部位。,病理诊断原则,系统化疗原则 NEW,遵照原始文献报道的药物剂量/方案,合理用药并进行适当调整患者合适的器官功能和体力状况充分考虑化疗的毒性和益处,并始终与患者及家属讨论/交流,并进行患者教育,警示并防治不良反应,避免严重合并症及缩短持续时间患者化疗期间仔细观察,及时治疗合并症,并适当监测患者血液学改变化疗阶段及时评估疗效和长期合并症,Update of 2008.v.1 NCCN version,可切除胃癌围手术期化疗-MAGIC trial,胃癌（占85%）或低位食管癌（15%）,ECF*3cs-手术-ECF 3cs,单一手术,N=2505Y 38%,N=2535Y 23%,ECF:E 50mg/m2C 60mg/m2FU 200mg/m2/d civ,D.Cuuningham 2005 ASCO abs 4001,Cunningham et al,NEJM 2006,*No pathologic complete responses,可切除胃癌围手术期化疗-MAGIC trial,Cunningham et al,NEJM 2006,Cunningham et al,NEJM 2006,可切除胃癌围手术期化疗-MAGIC trial,Overall Survival,可切除胃癌围手术期化疗 5-FU+DDP in AGC/LE-FFCD 9703 trial,FP 23cs（98例）-手术-FP 2 3cs(RR+SD n+)（54例）,单一手术,N=1135Y DFS 34%,N=1115Y DFS 21%,FP:5-FU 800mg/m2 d1-5 ciDDP 100mg/m2 d1Q4w随访 5.7Y,贲门、胃89食管11,可切除胃癌围手术期化疗 5-FU+DDP in AGC/LE-FFCD 9703 trial,HR 0.65,V.Boige et al,ASCO 2007 abstr 4510,可切除胃癌围手术期化疗Patient data-based meta-analysis:CT+S vs S,从12随机试验,2284 患者中筛选出2102患者,涉及9个试验,中位随访时间5.3年CT+S vs S HR 0.87 P=0.003 转化为5年绝对生存率提高4%R0切除率 67%vs 62%p=0.03,P.G.Thirion et al,ASCO 2007 abstr 4512,GAST-C 1 of 2:preoperative chemoradiation,2008.v.1NCCN guideline：Paclitaxel/docetaxel+fluoropyrimidine(5-FU or capecitabine)category 2B；Recommendation of Chinese version:Docetaxel might be changed;Category 2B to 3.,Reason:Study about Paclitaxel/5FU+RT is only phase II.No prospective studies has been searched on docetaxel/5-FU+RT(medline).,？,Preoperative chemoradiation:phase IIPhase II Trial of Preoperative Chemoradiation in Patients With Localized Gastric Adenocarcinoma(RTOG 9904):Quality of Combined Modality Therapy and Pathologic ResponseJaffer A.Ajani JCO 2006：24（24）：3593,Phase:IIPatients：43 cases with localized GC(12%IB;37%II;52%III).，20 center Methods:2cys of 5FU+CF+DDPCRT(infusional 5FU+weekly paclitaxel)Resection（5 to 6 weeks after chemoradiotherapy was completed.）Result：path CR：26%R0 resection：77%,1 year：more patients with path CR(82%)are living than those with less than path CR(69%）,GAST-C 1 of 2:preoperative chemoradiation,2008.v.1NCCN guideline：Paclitaxel/docetaxel+fluoropyrimidine(5-FU+capecitabine)category 2B；Recommendation of Chinese version:Docetaxel might be changed;Category 2B to 3.,Update of 2008.v.1 NCCN version,Postoperative chemotherapy?,Stage IB-IV(M0)D0 和 D1占90%,GAST-3:T3,T4 or any T,N1 after R0 resection,2008.v.1NCCN guideline：RT,45-50.4Gy+concurrent 5-FU based radiosensitization(preferred)+5-FUleucovorin or ECF if received preoperatively（category 1）Recommendation of Chinese version:Add foot noteIf D0/D1 resection:agreed the above;If D2 resection:postoperative chemotherapy recommended.,Evidence：D0/D1 operation consists more than 90%in INT0116；2 Meta analysis about adjuvant chemotherapyGASC-study,Patients:23 trials，4919 ptsMethods:Adjuvant chemotherapy arm(Arm A):2441 Observation arm(Arm B):2478 Results:3y Survival rate:60.6%in Arm A,53.4%in Arm B(RR:0.85,95%CI:0.800.90)DFS:Arm B had a shorter DFS(RR:0.88,95%CI:0.770.99)Recurrence rate:Arm A had a lower recurrence rate(RR:0.78,95%CI:0.710.86)Grade 3/4 of AE(myelosuppression and GI):more frequently in Arm A.Conclusion:Adjuvant chemotherapy could improve the survival rate and disease-free survival rate in gastric cancer after curative resection and reduce the relapse rate.,META analysis of Adjuvant chemotherapy 1An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancerEuropean Journal of Surgical Oncology(EJSO)2008.02.002,META analysis of Adjuvant chemotherapy 2The role of postoperative adjuvant chemotherapy following curative resection for gastric cancer:a meta-analysisShu-Liang Zhao;Jing-Yuan Fang.Renji Hospital,Shanghai,China.Cancer Investigation,May2008,Vol.26 Issue 3,p317-325,Patients:15 trials，3212 pts，Methods:Surgery+adjuvant chemotherapy vs Surgery onlyResults:RR for death in the treated group was 0.90(P=0.0010).Little or no significant benefits were suggested in subgroup analyses between different population and regimens either.Conclusion:Postoperative adjuvant chemotherapy for gastric cancer confers slightly significant benefits compared to the surgery only group.,Postoperative adjuvant chemotherapy S1 monotherapyAdjuvant chemotherapy for gastric cancer with S-1,an oral fluoropyrimidine.Sakuramoto,S N Engl J Med，2007，357：1810-1820,1004 cases(stage II/III，D2,3 years follow up*,Randomized phase III trial comparing S-1 monotherapy versus surgery alone for stage II/III gastric cancer patients(pts)after curative D2 gastrectomy(ACTS-GC study).2007Gastrointestinal cancer symposium,sasako M,*12/2005 showed that HR of death for S-1 to C was 0.57,trial was recommended to stop.09/2006 HR of death for S-1 was 0.68.,Conclusions:Adjuvant chemotherapy with S-1 for gastric cancer is feasible and effective.This regimen can be the standard treatment for stage II/III gastric cancer pts after curative D2 dissection.,ACTS-GC study JCOG,Postoperative chemoradiation might be a good option to compensate the insufficiency of the surgery such as D0/D1 resection.Adjuvant chemotherapy shows survival benefit compared with surgery alone,especially after D2 resection for patients with stage II or higher.,Postoperative adjuvant chemotherapy Conclusion:,GAST-3：after R1 resection,2008.v.1NCCN guideline：RT,45-50.4Gy+concurrent 5-FU-based radiosensitization(preferred)+5-FUleucovorinRecommendation of Chinese version:To add“Clinical trials”as another option.,Reason：R1 resection is not radical,till now,no standard therapy has been accepted,it should be better to find the appropriate ones by clinical studies.,Update of 2008.v.1 NCCN version,No DDP+fluoropyrimidine(5-FU or capecitabine or S1)2BNo paclitaxel-based regimens；,V325 研究结果,TCF(多西紫杉醇、顺铂、5FU)是用于预后较好的患者的一项新的治疗选择,Moiseyenko et al,JCO 2007,*34级毒性包括：81的非血液学毒性反应，75的血液学毒性反应中30伴有中性粒细胞减少性发热,CPT-11 for AGC期多中心临床研究（2003 ASCO）FFCD 9803 法国,Bouche O et al.J Clin Oncol2004;22:431927,CPT-11联合5-FU治疗AGC-III期临床试验（2005 ASCO）,N=170CPT-11 80mg/m2CF 500mg/m25FU 2000mg/m2 civ1/W x 6w,N=163CDDP 100mg/m2 d15FU 1000mg/m2/d d1-5Q4W,N=333 AGC,RR 54（31.8%）42（25.8%）TTP 5.0m 4.2m(p=0.088)TTF 4.0m 3.4m(p=0.002)OS 9.0m 8.7m p0.53,M.Dank 2005 ASCO abs 4003,REAL-2:疗效（Efficacy）,Cunningham et al.ASCO 2006 LBA 4017,REAL 2:安全性 safety outcomes,Oxaliplatin联合EPI、5-FU/CF治疗晚期胃癌的临床多中心研究 china,用药方法乐沙定 100mg/m2 d1EPI 50mg/m2 d1CF 200mg/m2 d1-35-FU 500mg/m2 CIV d1-3每3周重复，治疗至少3个周期评价疗效及毒性反应,CR 2例（5.6%）PR 13例（36.1%）SD 17例（47.2%）总有效率41.7%。其中初治患者9/20（45%）复治患者6/16（37.5%）,主要不良反应：骨髓抑制：-OANC7/36（19.4%），OPLT3/36（8.3%），O Hb4/36（11.1%），O神经末梢毒性 4/36（11.1%），,以EPI为基础的三药联合可行！EOX有明显生存优势！,ML17032:CAPE vs 5-FU in AGCtrial design,FPCisplatin80 mg/m2 3-hour i.v.infusion5-FU c.i.800 mg/m2/day;d15 q3w,XPCisplatin80 mg/m2 3-hour i.v.infusionCapecitabine 1000 mg/m2 twice daily;d114 q3w,KPS 70%1875 yearsAdvanced and/ormetastatic gastric cancer(AGC)1 measurable lesionNo prior treatment for AGC,RANDO MIZATION,Superior response rate with XP vs.FP,ML17032:XP vs FPprogression-free survival.HR 0.81,Estimated probability,HR=0.81(95%CI:0.631.04)Compared to HR upper limit 1.25,p=0.0008,1.0,0.8,0.6,0.4,0.2,0.0,Per protocol analysis,相似的血液学不良发应 XP vs.FP,A Phase II Trial of Capecitabine plus DDP in AGCChina,2002.6-2003.5,N=145,Cape 1000mg/m2 Bid d1-14 DDP 20mg/m2 iv d1-5 q3W130pts evaluable:98M/32F Age:53.7ys,Results,CR 10(8%)PR 48(37%)SD 51(39%)PD 21(16%)OS 12m,Safety：grade 3-4 adverse event 5%,-2005,2006 ASCO,first-line chemotherapy with fluorouracil,leucovorin and oxaliplatin(FLO)versus fluorouracil,leucovorin and cisplatin(FLP),FLOF 2600mg/m2 24h infusion,L 200mg/m2,oxaliplatin 85mg/m2 q2w,FLPF 2000mg/m2 24h infusion,qwL 200mg/m2,qw cisplatin 50mg/m2,q2w.,Total 220 pts Median age 64 yrs Advanced and/ormetastatic gastric cancer(AGC),RANDO MIZATION,S.Al-Batran,J.Hartmann,ASCO 2006,The primary end point was TTP,Superior Performance with FLO vs.FLP,S.Al-Batran,J.Hartmann,ASCO 2006,Phase II Study of S-1 DDP vs 5-FU+DDP for Gastric Cancer(PI:ML Jin),C:5-FU+DDP,A:S-1,B:S-1+DDP,randomization,Assumed 180 cases，60 cases per arm，enrollment completedObjective：RR,TTP,Pathologically confirmed，unrectable，measurable leasions,Evidence：SC-101 study 2008 ASCO meeting,:Arm B compared with Arm C,P0.05:Arm B compared with Arm A and C,P0.05:Arm B compared with Arm A and C,P0.05,*:Arm B compared with Arm A,P0.05,Evidence：SC-101 study 2008 ASCO meeting,Elderly chemo-nave pts(=65 years)with measurable metastatic or recurrent gastric cancer,armX(N=46,Median age=71.0 years)Capecitabine(1,250 mg/m2 bid,D1-14 every 3 weeks),arm S(N=45,Median age=70.5 years)S-1(4060 mg bid D1-28 every 6 weeks),randomly,10/2004-4/2006,A randomized multi-center phase II trial：capecitabine(X)versus S-1(S)as first-line treatment in elderly patients with mAGC,Y.Kang,D.Shin 2007 ASCO Annual Meeting,A randomized study:the activity and safety of capecitabine vs S-1 in elderly pts with AGC phase II Y.Kang,JCO,2007 ASCO Meetings Proceedings Part I.Vol 25,No.18S:4546),Evidence：capecitabine vs S-1,Evidence：capecitabine vs S-1 toxity,Update of 2008.v.1 NCCN version,DDP+fluoropyrimidine(5-FU or capecitabine or S1)2B,a randomized phase II trial of the Swiss Group for Clinical Cancer Research.Chemotherapy-naive patientsECF vs DC vs DCF,Evidence 1:docetaxelRoth AD,Fazio N,et al,J Clin Oncol.2007 Aug 1;25(22):3217-23.,a randomized phase II study in Germanypatients with untreated,advanced gastric adenocarcinoma.,Evidence 2:docetaxelThuss-Patience PC,Kretzschmar A,et al：J Clin Oncol.2005 Jan 20;23(3):494-501.,a randomized phase II trial106 patients includedwDCF vs wDXwDCF:DOC 30mg/m2 d1 d8;DDP 60mg/m2;5-Fu 200mg/m2 civ wDX DOC 30 mg/m2 d1d8;CAPE 1600 mg/m2 d1-14,Evidence 3:docetaxel（Weekly）N.Tebbutt,et al,Asco 2007,4528.,Evidence:paclitaxel vs docetaxelPaclitaxel versus docetaxel for advanced gastric cancer:a randomized phase II trial in combination with infusional 5-fluorouracil.Park SH et al,Anticancer Drugs.2006 Feb;17(2):225-9,Phase:II,randomized Patients：77 cases with measurable metastatic gastric cancer(PF vs DF).Methods:PXL+5-Fu vs DOC+5-FuResult：response rate(42 vs 33%,P=0.53)overall survival(9.9 vs 9.3 m;P=0.42)grade 3/4 toxicities(68 vs 85%;P=0.09)Global quality of life:similar pain,dyspnea,constipation and diarrhea favored PFConclusion:Both PF and DF appear to have efficacy against metastatic gastric cancer,with different,but acceptable,safety profiles.,Update of 2008.v.1 NCCN version,DCF modification：PF/DF/wDCF/DC/DX/PX should be added,2008.v.1NCCN guideline:Recommendation of Chinese version:To add cisplatin plus fluoropyrimidine(5-FU or capecitabine)category 2BTo add fluoropyrimidine(5-FU or capecitabine)for old patients or poor performance status.Category 2B,GAST-C 1 of 2:metastatic or locally advanced cancer,GAST-C 1 of 2:preoperative chemoradiation Docetaxel might be changed;Category 2B to 3.GAST-3:T3,T4 or any T,N1 after R0 resection Add foot note:If D0/D1 resection:agreed the ab