胰腺癌药物治疗现状及进展 _课件

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,*,胰腺癌药物治疗现状及进展,中国医学科学院肿瘤医院,林琳,概 述,胰腺癌的发病率国内逐年升高,由于早期诊断困难，手术率仅,15-20,，术后,5,年生存率,7%-25%,，中位生存期,15,19,个月。,手术切除的胰腺癌患者在,2,年内约,80%-95%,出现复发，包括局部和远处转移。,进展期胰腺癌患者的生存期, 6,月，,5,年生存率, 1,。,我国近年研究报道,:,回顾性研究,胰腺癌,128,例胰十二指肠切除术后,1,、,3,、,5,年生存率分别为,67.86,、,14.29,、,3.57,胰头癌根治性切除术,66,例患者,5,年生存率为,18.3%,，中位生存时间为,25,月。,5,3,例胰腺癌,根治性切除,后,1,3,5,年生存率分别为,44.71%, 14.98%, 9.99%; 1,、,2,期病人根治性切除术后,1,3,和,5,年生存率分别为,69.23%, 38.46%, 12.82%,河北四院,:,腹部外科,2008 21(2),四 川 大 学 华 西医 院 普 外 科,;:,华西医学,2007 22(4),浙大医院,:,中华肝胆外科杂志,2003,年,9(3),治疗,综合治疗,手术,唯一根治手段,放、化疗联合,RR 15-30,化疗,健择,-,标准一线方案,联合方案,?,靶向治疗,?,胰腺癌的辅助和新辅助治疗,CONKO-001:,三期临床试验最终结果：胰腺癌,R1/R0,术后,GEM,辅助化疗,- ASCO,GEM : 1g/m d 1, 8 , 15 Q4 w for,6 months,vs observation,N=368 pts ; ITT=354 pts,JAMA 2007,ASCO 2008 LBA4504,GEM,F-UP,p,mDFS,13.4 m,6.9m,p 0.001,3y DFS,23.5%,8.5%,5y DFS,16.0%,6.5%,mOS,22.8m,20.2m,p=0.005,3y OS,36.5%,19.5%,5y OS,21.0%,9.0%,问题,1,：辅助放化疗的必要性,?,研究,1,：来自,Johns Hopkins,的回顾性分析,Herman J, et al. J Clin Oncol 2008; 26: 3503,研究设计,目的：比较术后观察组和接受,5-FU,为基础的同期放化疗组的预后,入组时间：,1993-2005,年,入组人数：,616,例,入组标准：接受胰十二指肠切除术的胰腺癌,排除标准：术中发现远处转移；术后,60,天内死亡；接受了术前治疗；仅接受了单纯放疗或单纯化疗,Herman J, et al. J Clin Oncol 2008; 26: 3503,结 果,中位生存期,(,月,),5,年生存率,(%),观察组,放化疗组,观察组,放化疗组,所有患者,14.4,21.2,15.4,20.1,切缘状态,阴性,17.0,24.3,18.0,23.5,阳性,11.4,18.3,11.7,16.4,淋巴结状态,阴性,15.9,23.2,22.8,19.4,阳性,14.3,20.6,13.4,20.2,Herman J, et al. J Clin Oncol 2008; 26: 3503,共计,616,例,:,观察组,(345,例,),同期放化疗组,(271,例,),所有患者的生存曲线比较,Herman J, et al. J Clin Oncol 2008; 26: 3503,结 论,以,5-FU,为基础的同期放化疗作为辅助治疗方案能够改善胰腺癌患者的预后,术后辅助放化疗的优越性适用于各种高危人群,术后辅助放化疗与单纯辅助化疗的优劣性比较尚不明朗,Herman J, et al. J Clin Oncol 2008; 26: 3503,研究,2,：来自,Mayo Clinic,的回顾性分析,Corsini M, et al. J Clin Oncol 2008; 26: 3511,研究设计,目的：比较术后观察组和接受,5-FU,为基础的同期放化疗组的预后,入组时间：,1975-2005,年,入组人数：,466,例,(454,例进行疗效分析,),入组标准：接受胰腺癌,R0,根治术的患者,排除标准：术后,30,天内死亡；组织学类型为低度恶性肿瘤；手术切缘为阳性；仅接受了单纯化疗,Corsini M, et al. J Clin Oncol 2008; 26: 3511,患者的术后病理情况对比,治疗组预后更差,!,观察组,辅助治疗组,P,值,人数,%,人数,%,T,分期,0.02,T1-T2,98,54,119,43,T3,82,46,155,57,淋巴结分期,0.06,N0,104,58,133,49,N1,76,42,141,51,组织学分级,0.001,级,72,40,70,26,级,108,60,204,74,Corsini M, et al. J Clin Oncol 2008; 26: 3511,结 果,人数,中位生存期,(,月,),2,年生存率,(%),5,年生存率,(%),观察组,180,19.2,39,17,辅助放化疗,246,25.2,50,28,辅助放化疗,+,辅助化疗,28,34.8,61,34,Corsini M, et al. J Clin Oncol 2008; 26: 3511,亚组分析结果,中位生存期,(,月,),5,年生存率,(%),P,值,观察组,辅助治疗组,观察组,辅助治疗组,T,分期,T1-T2,21.6,31.2,23,33,0.13,T3,15.6,22.8,8,25, 0.001,淋巴结分期,N0,26.4,43.2,23,38,0.02,N1,14.4,20.4,7,20, 0.001,组织学分级,级,30.0,36.0,23,34,0.42,级,14.4,20.4,12,27, 0.001,Corsini M, et al. J Clin Oncol 2008; 26: 3511,CONKO-001:,三期临床试验最终结果：胰腺癌,R1/R0,术后,GEM,辅助化疗,- ASCO,GEM : 1g/m d 1, 8 , 15 Q4 w for,6 months,vs observation,N=368 pts ; ITT=354 pts,JAMA 2007,ASCO 2008 LBA4504,GEM,F-UP,p,mDFS,13.4 m,6.9m,p 0.001,3y DFS,23.5%,8.5%,5y DFS,16.0%,6.5%,mOS,22.8m,20.2m,p=0.005,3y OS,36.5%,19.5%,5y OS,21.0%,9.0%,ESPAC-3(v2): phase III trial of adjuvant 5-FU/FA vs GEM in patients with resected pancreatic ductal adenocarcinoma.,R0/R1 resection 8 weeks of surgery,5FU/FA vs GEM (1,000mg/m2 iv infusion 1d, 8d and 15d every 4 weeks) for 6 months.,1,030 patients were needed to detect a 10% difference in 2-year survival rates with 90% power.,Results:,1,088 patients from 16 countries were randomized from July 2000 to Jan 2007 (5FU/FA = 551, GEM = 537).,Median survival 5FU/FA was 23.0 months,；,GEM was 23.6 months.,no statistically significant difference in survival estimates between the treatment groups (p=0.39, HRGEM=0.94,）,Conclusions: No significant difference in survival between adjuvant 5FU/FA and adjuvant GEM.,J. Neoptolemos, ASCO 2009 (abstr LBA4505),A randomised phase III trial: Gemcitabine vs surgery-only in patients with resected PC,Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.,GEM:,1000 mg m(-2) over 30min d1, 8 and 15, Q4w x 3 cycles.,N=119,，,April 2002 - March 2005,GEM,（,58,）,vs Surgery-only,（,60,）：,mDFS, 11.4 vs 5.0 m; HR=0.60 (95% CI: 0.40-0.89); P=0.01,mOS, 22.3 vs 18.4 m; HR=0.77 (95% CI: 0.51-1.14); P=0.19,虽然,OS,无统计学差异，但可以看到,GEM,辅化的优势趋势,Ueno H,，,et al,：,Br J Cancer. 2009 Sep 15;101(6):908-15. Epub 2009 Aug 18,Fluorouracil vs gemcitabine before and after 5-FU-based chemoradiation following resection of PC,三期、随机临床试验,: RTOG9704-Trial,N=451,，,其中胰头癌，,388,例,，,July,1998 and July 2002 with follow-up through August 18, 2006,164 US and Canadian institutions,R,GEM 3w 5-FU/RT GEM 3m,5-FU 3w 5-FU/RT 5-FU 3m,20.5m,16.9m,mOS,3,年生存率,: 31%,与,EAPAC-1,、,CONKO-001,相似,(30%,、,34%),31%,22%,3Y OS,n = 230,，,250 mg/m2/ d;,n = 221, 1000 mg/m2 / week;,250 mg/m2/d +50.4 Gy.,HR 0.82 p=0.09,胰头癌，,388,例,The treatment effect was strengthened,on multivariate analysis,(HR 0.80, P = .05),Regine WF, JAMA. 2008 Mar 5;299(9):1019-26,结 论,以,5-FU,为基础的同期放化疗作为辅助治疗方案能够改善胰腺癌患者的预后,以,5-FU,为基础的同期放化疗结合,GEM,化疗能改善预后,术后辅助放化疗的优越性适用于各种高危人群,下一步的研究方向将结合新的药物,Corsini M, et al. J Clin Oncol 2008; 26: 3511,问题,2,：新辅助治疗的作用,?,新辅助治疗的潜在优越性,早期杀灭微小转移灶,增加,R0,手术切除率,降低局部复发率,有助于筛选出快速进展的患者，从而避免不必要的手术,研究,1,：以吉西他滨为基础的新辅助同期放化疗,Evans D, et al. J Clin Oncol 2008; 26: 3496,治疗方案,化疗：吉西他滨,400 mg/m,2,每周,1,次，连用,7,次,放疗：外照射,30 Gy/10,次,分割量,3 Gy/,次，第,2-3,周,Evans D, et al. J Clin Oncol 2008; 26: 3496,结 果,人数,中位无进展生存期,(,月,),中位总生存期,(,月,),5,年生存率,(%),所有患者,86,15.4,22.7,27,接受手术的患者,64,28.6,34,36,未接受手术的患者,22,-,7.1,0,Evans D, et al. J Clin Oncol 2008; 26: 3496,研究,2,：以吉西他滨为基础的新辅助化疗继以新辅助同期放化疗,Varadhachary G, et al. J Clin Oncol 2008; 26: 3487,治疗方案,新辅助化疗：吉西他滨,750 mg/m,2,每,2,周,1,次，连用,4,次,顺铂,30 mg/m,2,每,2,周,1,次，连用,4,次,新辅助放化疗：吉西他滨,400 mg/m,2,每周,1,次，连用,4,次,放疗,30 Gy/10,次,分割量,3 Gy/,次,Varadhachary G, et al. J Clin Oncol 2008; 26: 3487,结 果,人数,中位无进展生存期,(,月,),中位总生存期,(,月,),所有患者,90,13.2,17.4,接受完新辅助化疗的患者,79,-,18.7,未接受完新辅助化疗的患者,11,-,14.6,接受手术的患者,52,-,31.0,未接受手术的患者,27,-,10.5,Varadhachary G, et al. J Clin Oncol 2008; 26: 3487,结 论,以吉西他滨为基础的新辅助同期放化疗或联合新辅助化疗具有一定的血液学和非血液学毒性，但是可以耐受,与以吉西他滨为基础的辅助同期放化疗或术后辅助化疗研究相比较，新辅助化疗并没有增加疗效,但新辅助治疗获益并接受,R0,切除的患者其生存期延长,新辅助化疗和新辅助放化疗的优化组合仍有待于进一步研究,Varadhachary G, et al. J Clin Oncol 2008; 26: 3487,我国近年研究报道,:,回顾性研究,胰腺癌,128,例胰十二指肠切除术后,1,、,3,、,5,年生存率分别为,67.86,、,14.29,、,3.57,胰头癌根治性切除术,66,例患者,5,年生存率为,18.3%,，中位生存时间为,25,月。,5,3,例胰腺癌,根治性切除,后,1,3,5,年生存率分别为,44.71%, 14.98%, 9.99%; 1,、,2,期病人根治性切除术后,1,3,和,5,年生存率分别为,69.23%, 38.46%, 12.82%,河北四院,:,腹部外科,2008 21(2),四 川 大 学 华 西医 院 普 外 科,;:,华西医学,2007 22(4),浙大医院,:,中华肝胆外科杂志,2003,年,9(3),术后辅助化疗或联合放化疗有助于改善胰腺癌预后,推荐：,GEM,1g/m d 1, 8 , 15 Q4 w 6,月 或,5,FU,？,新辅助化疗或放化疗的作用尚待探索,胰腺癌的辅助和新辅助治疗总结,晚期胰腺癌药物治疗,ASCO 2007 - Heinemann V et al., Abstract # 4515,Bernhard J, et al: J Clin Oncol. 2008 Aug 1;26(22):3695-701,HR,p-value,Total Gem+X vs. Gem,0.91,0.004,Gem + platinum vs. Gem,0.85,0.01,Gem + fluoropyrimidine vs. Gem,0.90,0.03,Gem + other cytotoxic vs. Gem,0.99,ns,Gem + capecitabine vs. Gem,*,0.83,0.01,Poor KPS,1.08,ns,Good KPS,0.76,p0.001,*,no difference in CBR or QOL between GemCap and Gem.,16,个随机临床试验,Meta,分析,全组及各亜组生存结果,健择为基础联合化疗治疗晚期胰腺癌,Meta,分析,PS,好的病人从,GEM,和铂或氟嘧啶的联合中获益,Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer.,to evaluate randomized trials comparing GEM vs GEM+X (X = cytotoxic agent),15,个试验,4465,例入选,RESULTS: a,significant survival benefit,for GEM+X with HR 0.91 p = 0.004.,Platinum-based combinations indicated a HR of 0.85 p = 0.010,Fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 - 0.99, p = 0.030).,No risk reduction,was observed in the group of trials combining,GEM with irinotecan,pemetrexed (HR = 0.99).,A meta-analysis of the trials with adequate information on PS was performed in,5 trials with 1682 patients.,with a,good PS,had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 - 0.87;,p 0.0001,).,By contrast, combination chemotherapy to patients with poor PS appeared to be,ineffective,(HR = 1.08; 95% CI: 0.90 - 1.29, p = 0.40).,CONCLUSION: pancreatic cancer patients with a,good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a,poor PS seem to have no survival benefit from combination chemotherapy.,Heinemann V, et al: BMC Cancer. 2008 Mar 28;8:82.,一般状况良好的患者,（,90-100,）,可使用含健择的联合方案,健择单药,vs,健择联合,体力状况决定,KPS,评分较差患者（,70-80%,），健择单药的生存优势未被超越,Chemoradiotherapy with GEM and DDP with or without sequential chemotherapy with GEM/DDP vs chemoradiotherapy with 5-FU in patients with LAPC - a multi-centre randomised phase II study.,N=95,分组,用法,9m,生存率,mOS,RT-5-FU,50GY+5-FU350mg /m2 /d,58%,4.0m,RT-GC,50GY+GEM300mg /m2 +DDP30mg,D1,，,8,，,22,，,28,52%,5.6m,RT-GCGC,RT-GC GEM 1000 mg /m2 + DDP 50 mg /m2 Q2W,45%,6.0m,p,0.61,0.21,Wilkowski R, et al: Br J Cancer. 2009 Nov 10.,G,emcitabine,联合靶向药物治疗晚期胰腺癌,在,gemcitabine,治疗晚期胰腺癌的基础上 增加,VEGF,抑制剂,B,evacizumab,不,能改善生存,在,gemcitabine,治,疗晚期转移性胰腺癌的基础上增加,cetuximab,能很好耐受但对,PFS,没有明显的影响,评价,Sorafenib+Gemcitabine,联合治疗晚期胰腺癌的作用，疗效较低,目的未达到,中期分析后中止,GEM+Erlotinib in APC (PA.3),Phase III trial,加拿大国立癌症研究所临床试验小组,GEM+Erl,N=285,GEM,N=284,HR,p,用法,G EM,E 100mg qd,G,1g/m2 1/Wx7/8 -1/Wx3/4,OS,6.37,5.91,0.81,0.025,1Y,24%,17%,PFS,3.75m,3.55m,0.76,0.003,RR+SD,57.5%,49.2%,Moore MJ, et al, J Clin Oncol 2007; 25: 1960-1966.,厄洛替尼联合吉西他滨改善晚期胰腺癌患者的生存,厄洛替尼联合吉西他滨用于晚期胰腺癌的推荐剂量为,100 mg/d,Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.,N=301,GEM 1,000 mg/m(2)/week, erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks),vs,gemcitabine, erlotinib, and placebo,mOS was 7.1 and 6.0 months in the bevacizumab and placebo arms,，,HR 0.89; 95% CI, 0.74 to 1.07; P = .2087,Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95% CI, 0.61 to 0.86; P = .0002).,结论,:,加入贝伐仅改善,PFS,，但并未改善总生存,.,Van Cutsem E, et al,：,Clin Oncol. 2009 May 1;27(13):2231-7. Epub 2009 Mar 23,改变,GEM,为基础的药物治疗？,CAPE+Erlotinib vs GEM+Erlotinib,？,腹泻：,9% 7%,皮疹：,4% 12%,HFD,：,7% 0%,疗效？,其它：,oxa,？,Taxane,？,S-1,？,Boeck S, et al: Anticancer Drugs. 2009 Sep 18.,晚期胰腺癌药物治疗小结,胰腺癌的化疗效果较差，预后差。,健择为主的化疗方案对改善生活质量有益，仍是标准的一线选择。,健择为主的联合方案对,KPS,好者有益，否则选择单药，或参加临床试验,靶向药物在胰腺癌中的应用尚需继续探索。,二线治疗？,谢谢,