进展期胃癌化疗规范及方案优化选择.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2021/1/5,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,进展期胃癌化疗规范及方案优化选择,进展期胃癌化疗规范及方案优化选择进展期胃癌化疗规范及方案优化选择,上海,(2002-2004):,发病率仍高,:,恶性肿瘤中，男性占第二位，女性占第三位,疾病部位,:,胃窦最常见,为,39.88%,小弯为,12.68%,中国大城市中胃癌的发病率,J sur concepts,practice 2008,vol 13,No 1 24-29,北京,(2003-2007),2021/1/5,2,中国胃癌发病的特点,J Surg Concepts Pract 2008,Vol.13,No.1,：,24,上海市胃癌发病流行现况,早诊率低,治疗水平差异大,国内高水平的临床研究少，循证医学依据较少,更要求规范治疗行为，统一诊疗标准，特别是综合治疗,2021/1/5,3,2007.v.1,2008.v.1,2009.v.2,2010.v.2,FU/CF,Fu-based,DDP-based,Oxa-based,Taxanes-based,IRI-based,ECF,DCF ECF,mECF,IRI+DDP,OXA+FU,IRI+FU,mDCF,（,PF/DF/wDCF/DC/DX/PX,5FU+DDP,Oral fluoropyrimidines,DCF ECF mECF,IRI+DDP,OXA+FU,IRI+FU,mDCF,PTX-based,5FU+DDP,Oral fluoropyrimidines,Post-oper chemo,DCF,ECF,mECF,IRI+DDP,OXA+FU,IRI+FU,mDCF,PTX-based,Trastuzumab,TS-1 combination?,BSC?,NCCN,胃癌治疗指南中国版,药物治疗部分,遵循,循证医学原则，结合亚洲现状和水平以及中国国情,2007.v.1,至,2009.v.2,，目前正修订,2010.v.2,版,2021/1/5,4,Randomized Phase III Study,In First Line For AGC,Study,Regimen,N,RR(%),p-value,MST,p-value,V325,2006,DCF,CF,103,105,38.7,23.2,.01,2,10.2m,8.5m,.00,6,4,Kang Y,2006,XP,FP,160,156,41,2,9,0.03,10.5m,9.3,m,0.27,S.Al-Batran,2006,FLO,FP,98,102,34,27,0.012,5.7(TTP),3.8,0.081,Wasaburo,2008,S-1+PDD,S-1,1,45,1,50,54,31,.002,13.0,m,11,.,0,m,.0,4,Cunningham 2008,ECF,E,CX,EOF,EOX,24,9,241,235,239,40.7,46.4,42.4,47.9,NS,9.9,m,9.9,m,9.3m,11,.2 m,NS,2021/1/5,5,胃癌规范治疗：,NCCN,指南作用,框架、原则,基本操作规程,循证医学原则,综合治疗理念,临床的复杂性,个体化问题,临床研究课题,学科发展和协作,倡导规范治疗,提出临床研究问题,2021/1/5,6,NCCN 2010.v.2,更新，引发新的讨论,转移性或局部进展期胃癌的化疗,DDP+,氟尿嘧啶类,(5-FU,或卡,培他滨,或替吉奥胶囊,),口服氟尿嘧啶类药物,(,卡培他滨,替吉奥胶囊,),术前,/,术后化疗,术前放化疗,最佳支持治疗,出血,梗阻,恶性腹水,治疗指南更要求细化，,并适合各期患者,2021/1/5,7,phase III Ramdomized 3-armed study of S-1,m,onotherapy versus S-1/CDDP,(SP),versus 5-FU/CDDP,(FP),in,patients with advanced gastric cancer,(AGC),(SC-101 study),Chinese patients;Ramdomized;Multicenter Comparison study,Peking University School of Oncology,2021/1/5,8,分层因素,:,KPS,转移器官数目,是否胃切除术,R,S-1,S-1:40,mg/m,2,bid(4 weeks on/2 weeks off),S-1+CDDP,CDDP:60 mg/m,2,iv(d8),S-1:40mg/m,2,bid (3 weeks on/2 weeks off,),5-FU+CDDP,CDDP:20mg/m,2,iv(d1-5),5FU:600mg/m,2,civ(d1-5)q4ws.,主要研究终点,:,RR,次要研究终点,:OS,TTF,不良事件,最终分析患者数,:,224,例,Evidence:SC-101,Jin et al.ASCO 2008#4533,入组患者：不可切除,/,复发性胃癌,If failed,can switch to S-1,2021/1/5,9,S-1,SP,FP,RR,24.7%,37.8%,19.2%,SP vs FP p=0.0021,有效率,FP,组,41,例患者进展后转入,S-1,组，又达到,1,4.6%,有效率,(S-1,作为二线化疗,),不良反应,(3/4),S-1,(%),SP,(%),FP,(%),中性粒细胞减少,3.8,17.1,16.2,白细胞减少,1.3,13.2,9.5,贫血,2.5,5.3,5.4,血小板减少,0,6.6,12.2,腹泻,3.8,6.6,0,呕吐,1.3,6.6,0,恶心,0,2.6,5.4,OS,结 论,S-1,及,SP,均安全有效,S-1+,DDP,可作为中国进展期胃癌一线治疗选择,2021/1/5,10,R,A,N,D,O,M,I,Z,E,CS,S-1,25 mg/m,2,PO BID for 21 days,every 4 wks,Cisplatin,75 mg/m,2,IV infusion on day 1,every 4 wks for max 6 cycles,CF,5-FU,1000 mg/m,2,/24 hrs,CI for 5 days,every 4 wks,Cisplatin,100 mg/m,2,IV infusion on day 1,every 4 wks for max 6 cycles,Stratification factors:,Type of disease(locally advanced;1 metastatic site;,2 metastatic sites),Prior adjuvant therapy(y/n),Measurable vs non-measurable disease,Center,Primary Endpoint:,Overall Survival,Secondary Endpoints:,Progression-Free Survival,Safety,Time to Treatment Failure,Overall Response Rate,ClinicalTrials.gov ID:,NCT00400179,FLAGS,Study Design,24 countries/146 centers/1053 patients/non asian trial,2021/1/5,11,Log-rank Test:p=0.1983,Hazard Ratio:0.92(95%CI:0.80,1.05),Median Overall Survival:,CS,:8.6 months,CF,:7.9 months,Overall Survival(FAS),2021/1/5,12,Evidence,：,phase III ML17032:XP vs FP,Kang YK Ann Oncol.2009 Jan 20.666-673,Superior ORR with XP vs.FP,Confirmed response%(95%CI),XP(n=160),FP(n=156),p-value,Overall response,41,(33,49),29,(2237),0.030,Superior PFS,with,XP vs FP,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,XP(n=139),FP(n=137),Median PFSmonths(95%CI),5.6(4.97.3),5.0(4.26.3),2021/1/5,13,2002.6-2004.8,纳入,141,例患者,(,中位年龄,Age:53.7ys),化疗方案,:,Cape 1000mg/m2 Bid d1-14,DDP 20mg/m2 iv d1-5 q3W,WHO,评价疗效,CTC v2.0,评价不良反应,有效率,CR 3(2.1%),PR 48(34.0%),SD 51(36.2%),PD 39(27.6%),mOS:12.0m,ORR:36.2%,安全性：,3/4 AE 2,?,从临床到基础,序贯,一线选择,2021/1/5,50,51,TAX-GC,DCF,对比,CF,一线治疗晚期胃癌的随机、开放、多中心,III,期注册临床研究,晚期,/,复发胃或胃食管结合部腺癌,未接受过化疗，或经新辅助、辅助化疗结束超过,6,个月出现进展,有可测量病灶,KPS70,重要脏器功能符合要求,多烯紫杉醇顺铂,/5-,氟尿嘧啶,顺铂,/5-,氟尿嘧啶,A,组,B,组,N=220,1:1,随机,研究终点：,TTP,OS,、,ORR,、安全性,DOC 60 mg/m2,，,CDDP 60mg/m2 d1,，,5-FU 600mg/m2 d1-5,CDDP 75 mg/m2 d1,，,5-FU 600 mg/m2 civ d1-5,21 days/cycle,2021/1/5,51,N,N,HN,F,O,O,O,HO,OH,O,HN,N,F,O,O,HO,OH,O,HN,N,H,F,O,O,TP,DPD,Anabolic,pathway,Tumor,5-DFUR,5-FU,TP:Thymidine phosphorylase,DPD:Dihydropyrimidine dehydrogenase,FUPA,FBAL,FUH,2,(inactive),Xeloda,Growth,inhibition,F,H,H,H,HN,N,H,O,O,Factors that affect Xeloda Efficacy,The efficacy of Capecitabine correlated with the ratio of TP/DPD.,DPD exists in various types of human cancers,2021/1/5,52,05101520,050100150200,*,(mg/kg),Exp.1,Control,Taxol,Taxotere,Vincristine,Vinblastine,Vindesine,Mitomycin C,Doxorubicin,CDDP,Exp.2,Control,Methotrexate,CPA,100,15,1.5,3,5,5,7.5,10,50,200,DPD,(pmol/mg protein/min),*,P 70,4-6cys RR+SD,Untill the patients intolerance or PD,Cape1000mg/m2 bid d1-14,PTX 80mg/m2 d1,8,Q3w,Cape1000mg/m2 bid d1-14,2021/1/5,54,Primary results-PTX+Cape sequenced with Cape,185 patiens,，,158 evaluated,CR 2 cases,，,PR 61 cases,(RR39.9%),SD 74cases,（,46.8%,）,PD 21cases,（,13.3,）,DCR 86.7%,同样是病理明确的胃腺癌，同样的分期，接受同样的药物、同样的剂量化疗，取得的疗效不同。,临床特点相同的个体，肿瘤分子生物学特性大不相同，导致治疗效果的差异,2021/1/5,55,tubulin III,表达对卡培他滨联合紫杉醇化疗,PFS,和,OS,的影响,2021/1/5,56,57,ML22697-III,期多中心、随机、对照研究,随机,1:1,紫杉醇卡培他滨,顺铂卡培他滨,4,周期,直到进展或,6,周期,卡培他滨,直到进展,A,组,B,组,晚期,/,复发胃或胃食管结合部腺癌,未接受过化疗，或经新辅助、辅助化疗结束超过,6,个月出现进展,N=320,2021/1/5,57,病例分享,2021/1/5,58,病例摘要,郭某，男，,68,岁，既往体健,主因“胃癌术后,2,年余，肝转移,1,月”于,2007-6-24,入院。,2005-5,因“呕血、黑便”查胃镜示贲门后壁占位，,22cm,，病理示腺癌,（外院）,2005-5-28,行贲门癌根治术，术中见肿瘤位于贲门，未侵出浆膜，与周围组织无粘连，无腹水及腹腔内转移结节,术后病理：溃疡型中高分化腺癌，侵及全层，切缘（,-,），淋巴结转移,2/11,，脉管癌栓及神经侵犯情况不详,2021/1/5,59,术后,10,天行腹腔化疗：,DDP 60mg,5-FU 500mg,共,3,次,同时开始行辅助化疗：,VP-16 0.1,，,D1-3,CF 0.5,，,D1-3,5-FU 0.75,，,D1-3,共,6,周期,末次化疗,2005-12-28,既往肿瘤标志物情况不详,病例摘要,-,既往治疗情况,2021/1/5,60,定期复查,2007-6,发现多发肝转移,(DFS 2Y),无不适，体重无明显变化,查体：,ECOG 0,分，腹部可见手术瘢痕，腹平软，无压痛，未及包块，移动性浊音阴性,肿瘤标志物：,CEA 7.29 ng/ml,CA199 51.17 U/ml,CA72.4,、,AFP,正常,腹部,CT,、盆腔,B,超等检查无其他远处转移,病例摘要,2021/1/5,61,MRI,（,2007-6,）,2021/1/5,62,病例特点,老年男性，一般状况较好,诊断：胃癌术后,（,pT3N1M0,）,多发肝转移,无病生存期 ：,2,年,辅助化疗方案：,VP-16+5-FU/CF,2021/1/5,63,治疗方案选择,化疗,介入,射频,手术,放疗、,刀,多学科综合治疗,2021/1/5,64,治疗方案,PTX+Xeloda,：,Xeloda 1000mg/m2,，,1500mg,，,bid,，,d1-14,PTX 80mg/m2,，,150mg,，,d1,、,8,周重复,3,2021/1/5,65,晚期胃癌的化疗,一线化疗：,5-FU,为主的联合方案,卡培他滨：口服,5-FU,类药物，生存获益略优，安全性好,紫杉类药物的疗效已得到公认（,V325,）,紫杉醇联合希罗达：两者之间有协同作用，毒性无重叠,2021/1/5,66,治疗过程,共,4,周期,2,周期评效,PR,，,4,周期确认,PR,消化道反应,II,度，骨髓抑制,II,度，肝损害,0,度,肿瘤标志物下降：,CEA 2.97 ng/ml,（,7.29 ng/ml,）,CA199 33.62U/ml,（,51.17 U/ml,）,2021/1/5,67,2007-6,2007-8,2007-10,2021/1/5,68,下一步治疗方案？,1,、化疗,2,、手术,3,、射频,4,、介入,一般状况较好,化疗有效,病灶局限,多学科讨论,2021/1/5,69,手术情况,(2007-10-27),术中所见：腹腔粘连，未见腹水，无腹腔转移结节,肝,S5,表面单发质硬肿物，直径,3cm,，肝,S4,表面不规则结节，直径,1cm,，术中超声探查未见其他转移病灶,行肝,S4,、,5,结节切除及周围,1cm,正常组织,2021/1/5,70,术后病理,中低分化腺癌，符合胃癌 肝转移,可见肿瘤细胞坏死，未见脉管癌栓,2021/1/5,71,术后肿瘤标志物进一步下降（,2007-12,）,CEA 1.83 ng/ml CA199 30.87U/ml,2021/1/5,72,1,、辅助化疗？,Yes or No,？,如果进行，方案？多长时间？,2,、定期复查？,3,、其他治疗？,后续治疗方案,2021/1/5,73,后续治疗方案,原方案有效，耐受性好，新辅助化疗,4,周期,辅助治疗持续时间？,再行原方案化疗,2,周期,口服单药希罗达,2,周期，末次化疗：,2008-1-22,化疗持续时间半年,定期复查,2021/1/5,74,2008-12,复查，无不适肿瘤标志物：,CEA 2.87 ng/ml CA199 26.36U/ml2009-4,随访：,CEA,升高（当地治疗）无病存活（,DFS-2,18m,）,2021/1/5,75,胃癌肝转移概述,发生率,10,50%,中位生存期,2,3,月,符合肝切除条件的仅有,0.4%,10%,手术死亡率为,2,7%,KEN SHIRABE,，,et al,，,HPB2006,2021/1/5,76,少量腹水，子宫肌瘤，左附件区肿物,胃癌卵巢转移的综合治疗,手术,+PTX+CAPE,CAPE,：,PFS 12,月（,9,个月时,CA199,升高，,12,月时腹膜后,LNM,）,2021/1/5,77,今后探索方向,优化一线,维持治疗：,结直肠癌,-OPTIMOX,肺癌,-Alimta,（,JMED,）,二线治疗：,如,EGF104578-lapatinib/PTX vs PTX,一线治疗：,靶向治疗,.,围手术期,vs,术后辅助，药物、方案优选,晚期胃癌多学科综合治疗等,2021/1/5,78,2021/1/5,79,Thank You For Your Attention!,2021/1/5,80,谢谢,