2014胰腺癌共识-晚期化疗.ppt

,CSCO,胰腺癌专家委员会,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,整理课件ppt,*,CSCO,胰腺癌专家委员会,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,整理课件ppt,*,CSCO,胰腺癌专家委员会,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,胰腺癌综合诊治中国专家共识,（,2014,年版）,晚期胰腺癌的化学治疗,1,整理课件ppt,不可切除局部晚期或转移性胰腺癌的治疗,健择单药成为一线标准,健择联合厄洛替尼统计学阳性,FOLFIRINOX,毒性控制,S-1,可作为标准治疗,GS,成为另一一线选择,健择联合白蛋白紫杉,1997,2005,2010,2013,5-FU vs.Gem,Burris/1997,Gem vs.Gem+Erlotinib,Moore/2005,Gem vs.Gem+nab-PTX,MPACT,，,Von Hoff/2013,Gem vs.FOLFIRINOX,Conroy/2010,Gem vs.S-1 vs.GS,GEST,，,Ioka/2011,2011,2,整理课件ppt,最初以,5-FU,为基础的化疗方案,胰腺癌化疗,META,分析：,5-FU,为基础的化疗生存期优于最佳支持治疗,J Clin Oncol.2007;25:2607-2615,3,整理课件ppt,晚期胰腺癌标准化疗方案的建立,健择,vs.5-FU,Burris HA,et al.,J Clin Oncol,1997;15(6):2403-13,4,整理课件ppt,晚期胰腺癌：健择,vs.5-FU,北美多中心随机化,期研究,5-FU(N=63),600mg/m,2,qw,健择,(N=63),1000mg/m,2,qw7,，休,1,周,此后,qw3,，休,1,周,入选标准：,n=160,病理确诊的局部晚期或转移性胰腺癌,既往未经化疗；可放疗，但不影响病灶疗效评价,KPS 50,足够的器官功能储备,至少满足以下条件之一：,基线,KPS 80,止痛剂用量,10mg/d,吗啡当量,MPAC,疼痛评分,20mm,治疗直至,PD,5,整理课件ppt,与,5-FU,相比，健择显著改善,CBR,临床受益反应,(CBR),：健择组是,5-FU,组的,近,5,倍,6,整理课件ppt,与,5-FU,相比，健择显著延长,OS,100,80,60,40,20,0,0,4,8,12,16,20,生存时间,(,月,),Log-rank P=0.025,OS(%),健择,(n=63),5-FU,(n=63),中位生存,(,月,),5.65,4.41,6,个月,OS(%),46,31,9,个月,OS(%),24,6,12,个月,OS(%),18,6,1,年生存率：健择组是,5-FU,组的,近,3,倍,7,整理课件ppt,与,5-FU,相比，健择显著延长,TTP,100,80,60,40,20,0,0,4,8,12,16,20,时间,(,月,),健择,(n=63),5-FU,(n=63),中位,TTP(,月,),2.33,0.92,6,个月,TTP(%),22,5,9,个月,TTP(%),9,5,12,个月,TTP(%),9,5,Log-rank P=0.0002,TTP(%),疾病进展时间,(TTP),：健择组是,5-FU,组的,近,3,倍,8,整理课件ppt,与,5-FU,相比，健择显著提高疾病控制率,疾病控制率,(DCR),：健择组达到,44.7%,开启晚期胰腺癌健择治疗时代,9,整理课件ppt,健择单药治疗方案,GEM 1000 mg/m,2,，每周一次，连续给药,7,周，休息,1,周，之后连续,3,周，休息一周，每,4,周重复（,Grade A,）,基于健择单药的证据，共识推荐,10,整理课件ppt,健择联合用药的多种尝试,健择,联合治疗,氟尿嘧啶类,5-FU,CAPE,铂类,CDDP,L-OHP,拓扑异构酶,I,抑制剂,CPT-11,11,整理课件ppt,健择为基础的其他联合化疗方案,研究者,患者人数,方案,OS,Berlin,et al.,322,健择,vs.,健择,+5-FU,5.4 vs.6.7 months(p=0.09),Colucci,et al.,107,健择,vs.,健择,+cisplatin,20 vs.30 weeks(p=0.48),Rocha Lima,et al.,342,健择,vs.,健择,+irinotecan,6.3 vs.6.6 months(p=0.79),Louvet,et al.,313,健择,vs.,健择,+oxaliplatin,7.1 vs.9.0 months(p=0.13),Oettle,et al.,565,健择,vs.,健择,+pemetrexed,6.3 vs.6.2 months(p=0.847),Heinemann,et al.,195,健择,vs.,健择,+cisplatin,6.0 vs.7.5 months(p=0.15),Stathopoulos,et al.,145,健择,vs.,健择,+irinotecan,6.4 vs.6.5 months(p=0.97),Abou-Alfa,et al.,349,健择,vs.,健择,+exatecan,6.2 vs.6.7 months(p=0.52),Hermann,et al.,319,健择,vs.,健择,+capecitabine,7.2 vs.8.4 months(p=0.234),Cunningham,et al.,533,健择,vs.,健择,+capecitabine,7.1 vs.6.2 months(p=0.08),Poplin,et al.,832,健择,vs.,健择,FDR vs.,健择,+oxaliplatin,4.9 vs.6.2(p=0.04)vs,5.7months(p=0.22),Colucci,et al.,400,健择,vs.,健择,+cisplatin,7.2 vs.8.2 months(p=0.38),2010,年前的各种联合方案的探索均未获得令人满意的结果,12,整理课件ppt,以上联合治疗方案与,GEM,单药相比，均未获得明显的生存获益，健择联合治疗是否已穷途末路？,新的联合治疗方案如何？,新的药物研发进展如何？,13,整理课件ppt,GEM+,白蛋白紫杉醇,为健择联合治疗带来新曙光,主要终点,:OS,次要终点,:PFS,Safety,入组人数,:861 pts,nab-P/GEM,nab-P 125 mg/m,2,followed by G 1000 mg/m,2,on days 1,8,and 15 every 4 w,R,GEM,Cycle 1:1,000 mg/m,2,weekly,Cycle 2:1,000 mg/m,2,on days 1,8,and 15 every 4 w,白蛋白紫杉醇联合健择对比健择单药用于转移性,胰腺癌化疗的随机,III,期临床研究（,MPACT,）,IV,期,;,既往未接受针对转移性疾病治疗；,KPS70,；可测量疾病,总胆红素,正常上限,14,整理课件ppt,MPACT,研究,获得了阳性结果,Gr.3/4 AEs,Gem,Gem+,nab,-P,Neutropenia,27%,38%,Thrombocytopenia,9%,13%,Fatigue,7%,17%,Peripheral neuropathy,1%,17%,Diarrhea,1%,6%,ORR,Safety,OS,15,整理课件ppt,MPACT,研究终结了,GEM,联合方案较,GEM,单药无生存获益的时代。基于,MPACT,结果，共识推荐：,健择,+,白蛋白结合型紫杉醇：,每周期的,d1,、,d8,和,d15,，,给予白蛋白结合型紫杉,125mg/m,2,，,GEM1000 mg/m,2,，,每,4,周重复一次,(Grade A),16,整理课件ppt,靶向药物：提供联合治疗又一新选择,n,mPFS,MST,p,值,REF,GEM,347,3.6 m,6.0 m,0.75,Van Cutsem EJCO 04,GEM/Tipifarnib,341,3.7 m,6.3 m,GEM,284,3.6 m,5.9 m,0.038,Moore MJ,JCO 07,GEM/Erlotinib,285,3.8 m,6.2 m,GEM,300,4.7 m,6.0 m,0.78,Kindler HL,JCO 10,GEM/Bev,302,4.9 m,5.7 m,GEM,369,3.0 m,5.9 m,0.14,Philip PA,JCO10 07,GEM/Cmab,366,3.5 m,6.4 m,GEM,316,4.4 m,8.3 m,0.5436,Spano,Lancet Oncol 11,GEM/Axitinib,316,4.4 m,8.5 m,统计学上,OS,获益药物只有,Erlotinib,17,整理课件ppt,健择厄洛替尼,局部晚期,/,转移性,胰腺癌,患者,化学疗法初治病例,Primary endpoint:OS,Secondary endpoint:PFS,RR,Response duration,Safety,QoL.,No.of patients:569 pts,GEM 1000mg/m,2,（,第,1,疗程,）,给药,7,周停药,1,周,（,第,2,疗程,）,给药,3,周停药,1,周,安慰剂,每天口服,GEM 1000mg/m2,（,第,1,疗程,）,给药,7,周停药,1,周,（,第,2,疗程,）,给药,3,周停药,1,周,erlotinib 100mg,每天口服,R,J Clin Oncol.2007;25:1960-1966,NCIC.PA.3 Study,18,整理课件ppt,NCIC.PA.3 Study,结果,【,生存期,】,【,无进展生存期,】,MST,、,PFS,有统计学差异,MST,差值为,10,天；,PFS,差值为,6,天,J Clin Oncol.2007;25:1960-1966,19,整理课件ppt,健择,+,厄洛替尼,GEM 1000mg/m2,，每周,1,次，连续给药,7,周，休息,1,周，为第,1,周期；第,2,周期开始，,d1,、,d8,和,d15,给药，每,4,周重复,厄洛替尼每日口服,100mg/d(Grade A),基于上述研究结果，共识推荐,20,整理课件ppt,GEST,研究：,*,根据体表面积（,BSA,）,:,BSA 1.25,；,1.25=BSA=1.5,S-1,(n=280),40,50,60mg,*,BID Day1-28,给药,4,周 停药,2,周,GEM,(n=277),1000mg/m,2,IV Day1,8,15,给药,3,周 停药,1,周,R,GEM+S-1,(n=277),GEM:1000mg/m,2,IV Day1,8,S-1:30,40,50mg,*,BID Day1-14,给药,2,周 停药,1,周,无法切除的晚期胰腺癌,（,n=834),层化因子,:,转移,vs,局部进展,中心,日本和中国台湾进行的,III,期临床：,GEST,研究,对比吉西他滨,(Gem),优效性：,GEM+S-1(GS),非劣效性：,S-1,首要研究终点：,总生存,(OS),次要研究终点：,PFS,；,RR,；,QOL,；毒性,21,整理课件ppt,S-1,成为首个,OS,非劣效健择的化疗药物,MST,GEM,:8.8 M(95%CI:8.0-9.7),S-1,:9.7 M(95%CI:7.6-10.8),HR=0.96(97.5%CI:0.78-,1.18,),P0.001,Bayesian posterior probability(HR1.15)=0.98,12-month overall survival rate,GEM,:35.4%,S-1,:38.7%,0.00,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,21,24,27,30,33,36,39,Months,Probability,GEM,S-1,n=277,n=280,277,280,184,186,97,104,41,45,12,18,3,5,0,1,GEM,S-1,At,risk,22,整理课件ppt,GS,方案获得了较好的总生存时间,0.00,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,21,24,27,30,33,36,39,MST,GEM,:8.8 M(95%CI:8.0-9.7),GS,:10.1 M(95%CI:9.0-11.2),HR=0.88(97.5%CI:0.71-1.08),p=0.15,12-month overall survival rate,GEM,:35.4%,GS,:40.7%,),Months,Probability,GEM,GS,n=277,n=275,277,275,184,209,97,108,41,42,12,19,3,3,GEM,GS,At,risk,23,整理课件ppt,GEST,：无进展生存（,PFS,）,S-1,非劣效于,GEM,，,GS,优效于,GEM,Months,0.00,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,21,24,27,30,33,36,39,Probability,m-PFS,GEM,:4.1M,S-1,:3.8M,GS,:5.7M,GEM vs.S-1,：,非劣效,HR=1.094(97.5%CI:0.900-,1.33,),p=0.02,GEM vs.GS,：,优效,HR=0.660(97.5%CI:0.541-,0.81,),p.0001,GEM,S-1,GS,277,280,275,82,73,130,25,19,55,10,6,21,3,3,3,0,2,0,0,1,0,At Risk,Gem,S-1,GS,24,整理课件ppt,GS,方案的反应率最高，,S-1,次之,GEM,S-1,GS,n,241,248,242,CR+PR,32,52,71,RR,13%,21%,29%,p=0.02,p20,岁，,ECOG PS 0-2,预期寿命,3,个月,可以口服药物,合适的器官功能,没有无法控制的感染、胃肠道出血、其他恶性疾病、同时化疗,R,Gem(n=53),Gem 1000mg/m2,30min,iv,d1,8,15,q4w,GS(n=53),Gem 1000mg/m2,30min,iv,d1,15;,S-1 40mg/m2,bid,d1-14,q4w,首要终点,PFS,次要终点,RR,DCR,OS,安全性,H.Isayama,et al.2011 ASCO abstr 4040,N=106,2011 ASCOGEMSAP,研究,H.Isayama,et al.2011 ASCO abstr 4040,GS,组较,Gem,组,PFS,延长；,但两组,OS,无统计学差异,29,整理课件ppt,除了以,S-1,为基础的化疗方案，其他非,GEM,化疗方案如何？,30,整理课件ppt,非,GEM,基础方案：,FOLFIRINOX,N Engl J Med 2011;364:1817-25.,Primary endpoint:OS Secondary endpoints:PFS,RR,Safety,QoL,Number of patients:342 pts,Patients:,转移性胰腺癌,化疗初治病例,PS0-1,GEM,1,000 mg/m2 IV weekly7,1 week rest,then weekly3q4w,oxaliplatin 85 mg/m2 day1,irinotecan 180 mg/m2 day1,LV 400 mg/m2 day1 followed by 5-FU 400 mg/m2 bolus day1,and 2,400 mg/m2 46h continuous infusion biweekly,R,FOLFIRINOX,Prodige 4-ACCORD 11 trial,31,整理课件ppt,FOLFIRINOX,方案改善生存期,MST,、,ORR,、,PFS,有统计学差异,MST,：,11.1,个月,MST,：,6.8,个月,N Engl J Med 2011;364:1817-25.,32,整理课件ppt,FOLFIRINOX,的安全性需予以关注,【,不良反应,Grade3/4】,不良事件（）,FOLFIRINOX,（,n=171,）,GEM,（,n=171,）,p,值,血液学毒性,嗜中性粒细胞减少,75/164(45.7),35/167(21.0),0.001,发热性嗜中性粒细胞减少,9/166(5.4),2/169(1.2),0.03,血小板減少,15/165(9.1),6/168(3.6),0.04,贫血,13/166(7.8),10/168(6.0),N.S.,非血液学毒性,疲劳,39/165(23.6),30/169(17.8),N.S.,呕吐,24/166(14.5),14/169(8.3),N.S.,腹泻,21/165(12.7),3/169(1.8),0.001,末梢神经异常,15/166(9.0),0/169,0.001,ALT,升高,12/165(7.3),35/168(20.8),0.001,血栓塞栓,11/166(6.6),7/169(4.1),N.S.,N Engl J Med 2011;364:1817-25.,33,整理课件ppt,FOLFIRINOX,方案,每周期,d1,，,静脉注射奥沙利铂,85 mg/m,2,，,伊立替康,180 mg/m,2,，,亚叶酸,400 mg/m,2,，,随后,5-FU 400 mg/m,2,静脉注射,，,之后,46,小时持续静脉输注,5-FU 2,400 mg/m,2,，,每,2,周重复,(Grade A),基于上述研究结果，共识推荐,34,整理课件ppt,2014,年中国专家共识推荐,对体能状况良好者，一线治疗方案：,（一）化疗方案：,健择,+,白蛋白结合型紫杉醇（,Grade A,）,FOLFIRINOX,方案（,Grade A,）,健择单药（,Grade A,）,健择,+S-1,（,Grade A,）,S-1,（,Grade A,）,35,整理课件ppt,2014,年中国专家共识推荐,对体能状况良好者，一线治疗方案：,（二）化疗联合靶向治疗方案：,健择,+,厄洛替尼（,Grade A,）,尼妥珠单抗,+GEM,36,整理课件ppt,2014,年中国专家共识推荐,对体能状况良好者，二线治疗方案：,首选参加临床研究,既往未接受过健择治疗的患者首选健择为基础的化疗,一线以健择为基础化疗的患者，二线治疗可选择以氟尿嘧啶类药物为基础的化疗方案，包括：,S-1,单药,卡培他滨单药,5-FU/LV/,奥沙利铂,S-1/,奥沙利铂,卡培他滨,/,奥沙利铂,对于术后发生远处转移者，若距离辅助治疗结束时间,6,个月，除选择原方案全身化疗外，也可选择替代性化疗方案,37,整理课件ppt,2014,年中国专家共识推荐,对体能状况较差者，不能耐受及不适合联合化疗者，,一线治疗方案：,健择单药,氟尿嘧啶类单药，,S-1,（,Grade A,），卡培他滨（,Grade B,）或持续灌注,5-FU,（,Grade B,）,38,整理课件ppt,2014,年中国专家共识推荐,对体能状况较差者，不能耐受及不适合联合化疗者，,二线治疗方案：,二线化疗比最佳支持治疗更有效（,Grade B,）,可选择健择或氟尿嘧啶为基础的单药化疗,最佳支持治疗,39,整理课件ppt,CSCO,胰腺癌专家委员会,谢 谢,40,整理课件ppt,