大肠癌标准课件（含胃癌和肺癌）科室会课件

PPT模板下载：/moban/,亿迈林(伊立替康) 持续治疗转移性结直肠癌的典范,亿迈林(伊立替康) 持续治疗转移性结直肠癌的典范,李云利,医学学士、MBA、经济学博士 医师、主管药师、国家执业药师、高级经济师 综合掌握医学、药学、经济、管理等知识 从业经历： 临床医生、产品管理、营销管理 特长和爱好： 英语、摄影、计算机、旅游,结直肠癌药物治疗的演进,1980,1985,1990,1995,2000,2005,治疗理念,Oxaliplatin 2002年,Cetuximab 2004年,Irinotecan 1996年,Panitumumab 2006年,分子靶向治疗,Capecitabin 2001年,Bevacizumab 2004年,S-1 1999年,5-Fu/CF 常用方案,欧洲(滴注)方案 AIO方案： 5-FU 23002600mg/m2/24h d2.29.36 CF 500mg/m2/2h d2.29.36 7w De Gramont(DGM)方案: 5-FU 400mg/m2/推注 600mg/m2/22h d1.2 CF 200mg/m2/2h d1.2/2W Modified de Gramont (MdG)方案: 5-FU 400mg/m2/推注 2800 mg/m2/CIV46 h CF175mg/m2/2h infusion day 1 before 5-FU d1.2/2W 美国(推注)方案 Mayo Clinic方案: 5-FU 425mg/m2/d d.5 低剂量CF 20mg/m2/d d.5 4W Rosewell Park方案: 5-FU 500mg/m 高剂量LV 500mg/m Weekly,强调5-FU持续静脉泵入,静滴5-FU明显提高RR，更小3/4级毒性，但中位生存期仍然是12个月,Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308.,6个随机分组研究的Meta分析 (N=1219),Response Rate,Survival (median),亿迈林(伊立替康)作用机制,伊立替康是喜树碱的半合成衍生物 体内活化成代谢物SN38，活性为喜树碱的10倍 拓扑异构酶 I 抑制剂 拓扑异构酶 I-DNA 的复合形式 抑制DNA单链断裂后的修复 双链断裂最后导致细胞死亡,Continuum of Care: Defining a Strategic Approach,The Treatment Continuum is a strategic framework Consideration of all available treatment options and regimen sequences across multiple lines of therapy Upfront planning for each patient to extend survival while minimizing side effects Flexibility to adjust the treatment plan Replacement of a strictly “treat-as-you-go” approach The Treatment Continuum concept is consistent with the current NCCN Guidelines for mCRC treatment and puts the guidelines in the context of patient benefits.,Advanced/mCRC Patients Can Tolerate Intensive Therapy,一线方案,二线方案,一线方案,二线方案,11,2012年版NCCN指南指出，无论在晚期一线还是二线治疗，FOLFIRI联合贝伐单抗均是推荐方案,FOLFIRI方案是贝伐单抗联合治疗的更优选择,FOLFOX联合西妥昔单抗全面退出NCCN指南,FOLFOX联合爱必妥全面退出指南，包括新辅助及晚期治疗,13,NCCN指南推荐晚期结直肠癌患者治疗的新选择,一线应用FOLFIRI方案，无论联合C-mab还是BV，在二线治疗中仍有更多的方案选择来改善病患的整体生存期,Treatment Selection Factors,Personalize treatment based on: Prior adjuvant therapy Ability to be resected Incorporation of targeted agents When to change regimens Patient condition Comorbidities QoL issues,一、二线化疗：我们知道了什么,Irinotecan and oxaliplatin are equivalent alternatives in first line treatment Xelox is equivalent to FOLFOX FOLFIRI is superior to IFL Initial therapy with fluoropyrimidines is proper in some patients,CPT-11 180 mg/m2 IV +简化的 LV5FU2,FOLFIRI,OXA 100 mg/m2 IV+简化的 LV5FU2,R,FOLFIRI,PD,PD,PD,A组,B组,PD,FOLFOX6,FOLFOX6,V308研究 -FOLFIRI还是FOLFOX6更好？,Phase III 序贯研究,Tournigang C, et al. J clin Oncol, 2004; 22: 229-37,V308研究:生存分析,Tournigang C, et al. J clin Oncol, 2004; 22: 229-37,一线治疗 FOLFIRIFOLFOX,二线治疗 FOLFIRIFOLFOX,V308研究:疗效分析,Tournigang C, et al. J clin Oncol, 2004; 22: 229-37,多项临床研究显示：一线应用FOLFIRI与FOLFOX腹泻发生率无明显差异,FOLFOX和FOLFIRI有何区别?,V308序贯试验:FOLFIRI一线的SOS优势,一线治疗更少的 级毒性反应 (53 vs 74%， P = .001 ) 没有蓄积性神经毒性 较低的毒性治疗中断率 (6% vs 11%) 临床显著体重增加 (35% vs 24%, P=0.05) 更多比例的患者提高生活质量,Safety安全,一、二线化疗：我们知道了什么,Irinotecan and oxaliplatin are equivalent alternatives in first line treatment Xelox is equivalent to Folfox Folfiri is superior to IFL 优化伊立替康为基础的化疗方案(从BICC-C到MEXICO) 4. Initial therapy with fluoropyrimidines is proper in some patients,Fuchs CS, et al. J Clin Oncol. 2007;25:4779.,BICC-C第一阶段：PFS和OS有效性 FOLFIRI vs mIFL vs CapeIRI,0,10,20,30,25,50,75,100,0,40,Months,PFS (%),FOLFIRI vs mIFL: P = .004,FOLFIRI vs Capelri: P = .015,mIFL vs Capelri: P = .46,FOLFIRI 7.6月,mIFL 6.0月,Capelri 5.8月,FOLFIRI vs mIFL: P = .09,FOLFIRI vs Capelri: P = .27,mIFL vs Capelri: P = .93,0,10,20,30,25,50,75,100,0,40,Months,Alive (%),FOLFIRI 23.1月,mIFL 17.6月,Capelri 18.9月,50,PFS,OS,Fuchs CS, et al. J Clin Oncol. 2007;25(30):4779-4786.,FOLFIRI + bevacizumab 11.2月,BICC-C第二阶段+贝伐单抗,0,10,20,25,25,50,75,100,0,Months,Progression Free (%),mIFL + bevacizumab 8.3月,P = .28,0,10,20,30,25,50,75,100,0,Months,Alive (%),FOLFIRI + bevacizumab 28月,mIFL + bevacizumab 19.2月,P = .007,PFS,OS,15,5,Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.,87%,61%,3-4 级不良事件,CapeIRI的3/4级腹泻、脱水、恶心呕吐、手足综合征发生率更高,一、二线化疗：我们知道了什么,Irinotecan and oxaliplatin are equivalent alternatives in first line treatment Xelox is equivalent to Folfox Folfiri is superior to IFL Initial therapy with fluoropyrimidines is proper in some patients,FOCUS = Fluorouracil, Oxaliplatin, and CPT-11: Use and Sequencing,FOCUS 试验(n=2100),13.9*,mOS(月),15.0,15.2,16.7,15.4,Seymour MT, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer MRC FOCUS: a randomised controlled trial. Lancet 2007;370:143152.),策略A OS明显要短 C(IRI) VS A P=0.043 HR=0.86 其他组OS无差异,All 3 Drugs与生存的关系 11个III期RCT, 5768名患者,0 10 20 30 40 50 60 70 80,Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 FOLFOXIRI CAIRO,22 21 20 19 18 17 16 15 14 13 12,中位生存期(月),应用三药患者比例 (%),P = .0001,一线治疗方案,2007,*3 drugs: 5-FU/LV, irinotecan, oxaliplatin. Grothey A, et al. J Clin Oncol. 2005;23:9441,在大肠癌的治疗中,我们需要这三种有效的药物,Saltz, ASCO, 2002,在不同治疗阶段,尽量给予转移性大肠癌使用这三药的机会,可有效延长患者生存期,Grothey JCO,2004,“5FU, CPT-11, OXA,结直肠癌的靶向治疗,有效率 (%),59,37,0,10,20,30,40,50,60,70,CRYSTAL (540例),OPUS (233例),43,61,FOLFIRI,FOLFOX,西妥昔 + FOLFIRI,西妥昔 + FOLF0X,CRYSTAL KRAS野生型: HR=0.68,p=0.017,进展风险降低32%,OPUS KRAS野生型: HR=0.57,p=0.016,进展风险降低43%,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,月,PFS,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,月,PFS,西妥昔单抗+化疗从K-ras野生型患者获益明显,1Bokemeyer C et al, Abst # 4000; Proc. ASCO 2008,CRYSTAL VS OPUS,CRYSTAL和OPUS试验结论,西妥昔单抗+ FOLFIRI or FOLFOX对KRAS野生型获益明显 PFS风险降低(32-43%) 提高RR 16-24% KRAS突变型患者不能从西妥昔单抗 + FOLFIRI或FOLFOX获益,FOLFIRI是与西妥昔单抗配伍的理想方案 (从CRYSTAL至OPUS),Historical improvements of Therapy in Advanced CRC,21.5,Van Cutsem/Hoff JCO 2000,Doulliard Lancet 2000,14.8,17.4,25.1,19.5,20.3,Saltz NEJM 2000,Douillard Lancet 2000,Saltz NEJM 2000,Goldberg JCO 2004,Hurwitz NEJM 2004,Hurwitz NEJM 2004,Douillard Lancet 2000,Tournigand JCO 2004,Months,Median overall survival (months),12.6,14.1,Supportive Care,5-FU bolus,5-FU infusion,Irinotecan/5-FU bolus,Irinotecan/5-FU infusion,Oxaliplatin + 5-FU infusion,Irinotecan/5-FU inf. followed by oxaliplatin/inf. 5-FU,Irinotecan/5-FU bolus/bevacizumab followed by oxaliplatin,Irinotecan/5-FU bolus/bevacizumab,Next Step: FOLFOX+Avastin , followed by Cetuximab (KRAS wild-type)?,结直肠癌肝转移新辅助化疗,结直肠癌患者合并肝转移，可切除或者潜在可切除，推荐术前化疗或化疗联合靶向药物治疗：西妥昔单抗（推荐用于K-ras基因状态野生型患者），或联合贝伐珠单抗。 化疗方案推荐FOLFOX，或FOLFIRI，或CapeOx。 建议治疗时限2-3个月。 治疗后必须重新评价，并考虑是否可行手术。,结直肠癌的诊疗规范（2010年版）,亿迈林推荐化疗方案,FOLFIRI,IFL,XELIRI,=,？,5-Fu持续滴注2.4-3.0 g/m2 CIV 46h,LV 200mg/m2 2h iv,伊立替康 180mg/m2 2h iv,5-Fu 推注 400mg/m2,第1天,第2天,FOLFIRI2 2周为一个疗程,2. Tournigand C,Andr T,Achille E,et al.FOLFIRI followed by FOLFOX6 or the renverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237.,亿迈林治疗晚期胃癌临床进展,V306: IF VS CF 一线治疗AGC 欧洲III期,IF (N=170) 伊立替康 80 mg/m2 IV 30min d1 CF 500 mg/m2 iv 2h d1; 5-FU 2000 mg/m2 CIV 22h 每周6周 q7w,CF (N=163) DDP 100 mg/m2 IV 1-3h d1 5-FU 1000 mg/m2 24h CIV d1-5 q4w,R,N=333,主要终点： TTP (优效性或非劣性) 次要终点： RR ,缓解持续时间， TTF (time to treatment failure) ,OS,Dank, M., J. Zaluski, C. Barone，et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol 2008；19(8): 1450-1457.,分层： 可测量或不可测量 是否肝转移 是否体重基线下降5% 是否手术 治疗中心,V306: IF VS CF结果,TTP : 从随机入组到PD或死亡的日期 TTF : 从随机入组到PD或死亡或治疗中断的日期,M.Dank et al: Annals of Oncology 19:14501457, 2008,V306: IF具有更好的安全性,IF具有更好的生活质量,Curran, D., C. Pozzo,J. Zaluski,et al. Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial. Qual Life Res 2009;published online,伊立替康+5-FU/CF在TTP/OS方面非劣于CF 处于非劣性检验边界 伊立替康+5-FU/CF TTF明显优于CF CF毒性反应中断化疗率是IF 2.2倍,P0.018 伊立替康+5-FU/CF 级毒性明显低于CF 伊立替康+5-FU/CF生活质量明显优于CF,V306: IF VS CF结论 一线非铂等效低毒方案的另一种选择,肺癌,伊立替康非小细胞肺癌 临床研究,Y. Ohe,et al. Annals of Oncology 2007； 18: 317323,DDP+IRI CBP+TAX DDP+GEM DDP+NVB Advanced NSCLC Randomized phase III study Japan -FACS Cooperative Group,Advanced NSCLC N=602,R,IP n=145 DDP 80 mg/m2 d1 Irinotecan 60 mg/m2 d1, 8, 15 q4w,TC n=145 CBP AUC 6 d1 Paclitaxel 200 mg/m2 d1 q3w,GP n=146 DDP 80 mg/m2 d1 GEM 1000 mg/m2 d1, 8 q3w,NP n=145 DDP 80 mg/m2 d1 NVB 25mg/m2 d1, 8 q3w,Y. Ohe,et al.Annals of Oncology 18: 317323, 2007,Patient characteristics and treatment delivery,Survival, TTP, TTTF, response rate, and response duration,IP VS TC,PFS,OS,IP VS GP,PFS,OS,IP VS NP,PFS,OS,Toxicity,Conclusion,相同的疗效 不同的毒性 IP / GP / NP / TC 方案均可一线用于晚期NSCLC化疗,伊立替康小细胞肺癌 临床研究,S0124: 伊立替康+顺铂(IP) vs VP-16+顺铂(EP)治疗广泛期小细胞肺癌(E-SCLC) 随机III期临床,R.B. Natale, P.N. Lara, K.Chansky, J.Crowley, J.R Jett, J.E. Carlton, J.P. Kuebler, H. Lenz, P. Mack, D.G. Gandara, SWOG, NCCTG, CALGB,背 景,VP-16 + 顺铂 (EP) 是近20年最为广泛接受SCLC标准化疗方案。 伊立替康，拓扑异构酶I抑制剂，单药或联合顺铂组成IP方案治疗SCLC有效。 IP vs EP一线治疗E-SCLC疗效如何？,ED-SCLC Japan and North American/Australia III phase :IP vs EP,伊立替康总剂量 520mg/m2,伊立替康总剂量 720mg/m2,ED-SCLC Japan and North American/Australia III phase :IP vs EP,伊立替康总剂量 520mg/m2,伊立替康总剂量 720mg/m2,疗效结果对比,* p = .02,* p = .002,JCOG 9511,N. American/Australian,生存期结果对比,IP,IP (n = 77) EP (n = 77),S0124: IP vs EP in E-SCLC 结论,以往日本IP方案治疗E-SCLC生存获益在北美大型III期临床中没有再现. 这种分歧的结论可能来自以下几个原因: 入组患者特征的明显不同 药物基因组学 日本JCOG 9511 III期临床过早结束 EP仍然是SCLC治疗的标准方案 IP方案不失为一种一线等效减毒方案或挽救治疗方案,IP vs EP一线治疗广泛期SCLC 的Meta-analysis.,J Clin Oncol 27:15s, 2009 (suppl; abstr 8105),IP:伊立替康+顺铂； EP：VP-16+D