晚期大肠癌化疗

1、晚期大肠癌化疗结直肠癌肝转移I期切除10-20%不可切除 80-90%绝大部分肝转移灶初期不能切除手术化疗/靶向药物治疗五年生存率30-40%5年生存率肝外转移/广泛转移II期切除10-20%目标提高结肠癌肝转移灶的切除率延长晚期结肠癌患者的生存期改善晚期结肠癌患者的生活质量1Therapy for Initially Resectable Liver MetastasesResults of liver surgeryfor metastatic CRC (N 100) N. of patients Operative mort 5-yr survivalAdson, 1984 (1)141

2、2.8%23%Hughes, 1988 (2) 859-33%Doci, 1991 (3) 1005%30%Scheele, 1991 (4) 2196%39%Rosen, 1992 (5) 2804%25%Nordlinger, 1992 (6) 18182.4%26%Gayowski, 1994 (7) 2040%32%Rees, 1997 (8) 1141%37%1 - MA. Adson et al., Arch. Surg., 1984; 119: 647-515 - CB. Rosen et al., Ann. Surg., 1992; 216: 493-5052 - KS. Hu

3、gues, Surgery, 1988; 103: 278-886 - B. Nordlinger et coll., Ed. Paris Springer-Verlag, 1992; 141-59 3 - R. Doci et al., Br. J. Surg., 1991; 78: 797-8017 - TJ. Gayowski et al., Surgery, 1994; 116: 703-11 4 - J. Scheele et al., Surgery, 1991; 110: 13-298 - M. Rees et al., Br. J. Surg., 1997; 84: 1136-

4、40 Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer Final efficacy results of the EORTC Intergroup phase III study 40983.B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O.Bechstein, J. Primrose, E.T. Walpole, T. Gr

5、uenbergerStatistical analysis L. ColletteFor the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCDALMCAO AGITGgTrial Design and ObjectivesRFOLFOX4 x 6 cyclesSurgeryFOLFOX4 x 6 cyclesSurgery 364 patients Potentially resectable (1-4) liver metastases Goal: Improve progression-free survival to demonstrate

6、a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%Progression-free survival in eligible patients; CI: 0.60-1.00, Periop CT28.1%36.2%+8.1%At 3 years (years)01234560102030405060708090100ONNumber of patients at risk :1251718357372281151711157443215Surgery onlyNCCN G

7、UIDELINES 2007“Patients who have completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy observation or a shortened course of chemotherapy is considered for patients who have completed neoadjuvant chemotherapy.”2Role of Neoadjuvant Systemic Chemotherapy for Live

8、r-only Metastases化疗对初始不能切除的肝转移患者的影响二次手术切除率ChemotherapyPts Surgery (%)5-yr OSOxaliplatin- based Adam, 2001 7011439%Giacchetti, 1999 1515150%Alberts, 2003 4236- Tournigand, 2004 11121- Adam, 2004 14391333%Irinotecan- based Pozzo, 2004 4033- Ducreux, 2003 5531- Tournigand, 2004 1099- 不可切除开始时不可切除开始时可切除乐

9、沙定为主化疗n=701 (80%)14%86%Adam R, et al. Ann Surg Oncol 2001; 14(Suppl 2): iii3iii6.患者数含乐沙定的化疗使结直肠癌肝转移患者获得二次手术机会法国Paul Brousse医院于19881996年收治的患者 (n=872)6069517101002003004005006007008009009536%64%可切除n=171+95=266肝转移一次切除及二次 (化疗后) 切除后生存率相似Adam R, Ann Oncol 2003;14: ii13-ii16 一次切除(n=425) 二次切除（初始时不可切除） (n=95

10、)生存(%)54%50%34%34%27%29%19%0 1 2 3 4 5 6 7 8 9 10 0 0.2 0.4 0.6 0.8 1.0 生存时间 (年)Collaboration : Oncologists - Surgeons For Non Resectable Metastases1- Current chemotherapy allows at least 20% of patients to be rescued by liver surgery2- The survival benefit of these patients is substantial (30% and

11、20% rate at 5 and 10 years)3- Resectability: a new end point for treatment strategy全球每年940,000 新发CRC病例50% 以上伴有肝转移470,000超过半数的晚期结直肠癌病人发生肝转移10%可切除47，00030% 以上可切除141，000目标提高结肠癌肝转移灶的切除率延长晚期结肠癌患者的生存期改善晚期结肠癌患者的生活质量结直肠癌治疗十年历程RR 20% TTP 56 months OS 1012 monthsFirst-line efficacyRR 50%+ TTP 9+ months OS 20+

12、 months5-FU5-FUOral fluoropyrimidinesIrinotecanOxaliplatin(Eloxatin)5-FUOral fluoropyrimidinesIrinotecanOxaliplatin(Eloxatin)CetuximabBevacizumabLow efficacy1995One option2000More options2005Many optionsRR 50% TTP 89 months OS 21 monthsIssuesOptimal regimensOptimal regimensCorrect sequencing1.关于联合化疗

13、III 期研究: 双药方案的比较IFLFOLFOXFOLFIRIIROXFOLFOX和FOLFIRI一线治疗mCRCStudyYearPatient numbersMedian PFS/TTPMedian OSFOLFIRIDouillard20001996.7 mo17.4 moTournigand20041138.5 mo20.9 moColucci20051647.0 mo14.0 moKohne20052148.5 mo20.1 moFOLFOX / XELOXde Gramont20002109.0 mo16.2 moGoldberg20042678.7 mo19.5 moTourn

14、igand20041118.0 mo21.5 moCassidy FOLFOX20063177.7 mo17.7 moCassidy XELOX20063177.3 mo18.8 moDucreux FOLFOX20071509.7 mo 18.4 moDucreux XELOX20071509.3 mo19.9 mo晚期结直肠癌的一线联合化疗N9741 研究设计Goldberg et al. J Clin Oncol. 2004;22:23-30. 随机795 例IFL: CPT-11+5-FU/LVCPT-11：125 mg/m2; 5FU: 500 mg/m2; LV: 20 mg/m2

15、d1,8,15,22，每6周重复FOLFOX: 乐沙定+5-FU/LVEloxatin: 85 mg/m2, d1; LV: 200 mg/m2，d1,2; 5FU: 400mg/m2 , bolus+600mg/m2 22小时iv，d1,每2周重复 IROX: 乐沙定+伊立替康Eloxatin: 85 mg/m2, d1; CPT-11: 200 mg/m2, d1;每3周重复含乐沙定的FOLFOX方案疗效更优IFL(n=264) FOLFOX4(n=267)IROX(n=264) 缓解率(%)314535(P=0.002 vs IFL)(P=0.034 vs IFL) 中位进展时间(M)6

16、.98.76.5(P=0.0014 vs IFL)(P0.05 vs IFL) 中位生存时间(M)1519.517.4(P=0.001 vs IFL)(P=0.004 vs IFL) *5年生存率(%)3.89.25.4（随访4.3年）（IFL vs FOLFOX: p0.002 11%24%19%22%7%IROX三度以上的毒副反应发生率Goldberg et al.J Clin Oncol. 2004;22:23-30.V 308 设计方案FOLFIRIFOLFOX6进展进展进展A组 B组进展Tournigand et al. J Clin Oncol. 2004;22:229-237R2

17、 hCF200 mg/m25FU CIV 2,400 to 3,000 mg/m2Irinotecan180 mg/m22 h46 hFOLFIRIFOLFOX6Bolus 5FU 400 mg/m22 hCF200 mg/m25FU CIV 2,400 to 3,000 mg/m2Eloxatin100 mg/m22 h46 hBolus 5FU 400 mg/m2FOLFOX6FOLFIRI序贯治疗获得20个月的生存期Arm AArm Bp valueFOLFIRIFOLFOXFOLFOXFOLFIRI(n=109)(n=81)(n=111)(n=69)中位疗程数（周期）13 (1-43)

18、8 (2-23)12 (1-38)6 (1-33)缓解率56%15%54%4%ns一线无进展生存期 (月)8.58.0 0.26二线无进展生存期(月)4.22.50.003总进展时间（月）14.211.80.64总生存期（月）21.520.60.99可切除率9%22%0.02Tournigand et al. J Clin Oncol. 2004;22:229-2373/4级毒性毒性FOLFIRI(n=110)*FOLFOX6(n=110)*P神经毒性0340.001腹泻1411NS中性粒细胞减少24440.003发热性中性粒细胞减少700.007血小板下降050.01贫血33NS呕吐1030

19、.027粘膜炎1010.003恶心1330.005皮肤21NS疲乏（3度）430.028Tournigand et al. J Clin Oncol. 2004;22:229-237是否有最佳的联合治疗方案 ?联合 = 最佳没有任何一个方案明显最佳，CRC一线治疗可选用5-FU/LV + 奥沙利铂或伊立替康IFL 和 IROX 不是最好的联合治疗方案采用含铂方案治疗，可明显提高二次手术切除率方案选择需考虑毒性 短肠: 奥沙利铂更好 治疗前已有的神经病: 伊立替康FOLFOX4 治疗老年结肠癌汇总分析 Goldberg R, et al. 2006 ASCO GIAndre T, et al.

20、N Engl J Med 2004;350:23432351.Goldberg R, et al. J Clin Oncol 2004;22:2330.de Gramont A, et al. J Clin Oncol 2000;18:29382947Rothenberg M, et al. J Clin Oncol 2003;21:20592069.研究名称研究方案设置患者数 (%)(n=3743)MOSAICFOLFOX4 vs5-FU/LV辅助2246 (60)GoldbergFOLFOX4 vs IFL一线进展期 546 (15)de GramontFOLFOX4 vs5-FU/LV一

21、线进展期420 (11)RothenbergFOLFOX4 vs5-FU/LV二线进展期531 (14)oxaliplatin 85 mg/m2FOLFOX4 治疗老年结肠癌汇总分析 Goldberg R, et al. 2006 ASCO GIGoldberg R, et al. ASCO 2006 Gastro-intestinal Cancers Symposium (Abstract 3502).27 moGroup: Mutant (n=78)Group: Wild Type (n=152)Benefit of Avastin is independent of k-RAS stat

22、usBevacizumab治疗VEGF 的表达 EGFHypoxiaPDGFIL-8bFGFCOX-2NOOncogenesVEGF releaseBinding and activationof VEGFRProliferationSurvivalMigrationANGIOGENESISPermeabilityIncreased expression(MMP, tPA, uPA, uPAr,eNOS, etc.) P PP P PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1IL-8 =

23、insulin-like growth factor 8IGF-1VEGF = vascular endothelial growth factormFOLFOX(n=50)FOLFOX+Bevacizumab一线治疗mCRC Phase IICapeOx(n=50)TREE-1(n=150)mFOLFOX +bevacizumab(n=75)bFOL +bevacizumab(n=70)CapeOx(dose reduced)+ bevacizumab (n=72)TREE-2(n=223)RbFOL(n=50)Nov 2002 Oct 2003Nov 2003 Apr 2004REffic

24、acy: TREE-1 and TREE-2FOLFOXbFOLCAPEOX- BEVN=49+ BEVN=71- BEVN=50+ BEVN=70- BEV N=48+ BEV N=72Conf. RR (%)*435322413548TTF (mo)6.55.84.95.54.45.5TTP (mo)8.79.96.98.35.910.3OS (mo)19.226.017.920.717.227.0Hochster et al., ASCO 2006*per protocol populationBevacizumab 联合治疗CRC一线治疗PFS的天花板效应PFS ( months)se

25、quential data5.56.27.48.67.68.75.93.74.41.90.82.31.24.4024681012Kabbinavar 5-FU/LVHurwitzIFLCassidy XELOXCassidy FOLFOXFuchsFOLFIRIHochsterFOLFOXHochsterXELOXPFS + BEVPFSIf we cannot increase 1st line PFS, why does OS increase?10 months17 months1st PFSOS 27 MonthsMore effective use of all active age

26、nts?Continuum of careUse of EGFR-mAbs?Use of bevacizumab beyond PD?Post-1st PD SurvivalBEV after 1st Progression in BEV-nave Patients - E3200FOLFOX + BEV(N=282)FOLFOX (N=279)BEV(N=228)OS (mos)12.910.810.2PFS (mos)7.34.72.7RR (%)22.78.63.3p=N/AB. Giantonio et al., JCO 2007BBP(n=642)No BBP(n=531)No Po

27、st-PD Treatment(n=253)Evaluablepatients(n=1953)1st Progression(n=1445)BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)BRiTE:Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo Grothey et al. ASCO 2007 #4036Physician decision - no randomizationBR

28、iTE: Patient Outcome Based on Treatment Post 1st PDBBP(n=642)No BBP(n=531)No Post-PD Treatment(n=253)# of deaths (%)168(66%)306(58%)260(41%)Median OS (mo)12.619.931.81yr OS rate (%)52.577.387.7OS after 1st PD (mo)3.69.519.2Grothey et al. ASCO 2007 #4036First suggestion of survival benefit associated

29、 with using BV beyond 1stPD (BBP)Improved OS appears to be due to an increase in survival beyond 1st PD in patients treated with BBPThese findings support the evaluation of BBP in the prospective, randomized phase III Intergroup trial S0600/iBET BRiTE: Conclusions评价5-氟尿嘧啶、亚叶酸和奥沙利铂（FOLFOX）或卡培他滨和奥沙利铂（

30、XELOX）联合Cediranib （AZD2171, RECENTINTM ）对照FOLFOX 或XELOX 联合安慰剂治疗初治转移性结直肠癌患者的疗效和安全性的一项随机、双盲、III 期临床研究xxxVEGFR TK InhibitorAZD2171AZD2171AZD2171AvastinxxLigand SequestrationAvastin (Genentech/Roche)PPPVEGF-AVEGF-BPlGF VEGF-AVEGF-CVEGF-DVEGF-CVEGF-DVEGFR-1 (Flt-1)VEGFR-2 (KDR)VEGFR-3 (Flt-4)Angiogenesis

31、LymphangiogenesisEndothelialCell MembraneCediranib：口服、高效的VEGFR阻断剂抑制VEGFR 抑制肿瘤新血管生成减少血管密度、直径和渗透性可以导致新进展肿瘤的毛细血管退化抑制肿瘤血管生成Cediranib作用机制研究设计FOLFOX (FOLFOX-4 OR mFOLFOX-6) 两周重复一次或 XELOX 三周重复一次Treatment A: AZD2171 30 mg/day + FOLFOX or XELOXaTreatment B: AZD2171 20 mg/day + FOLFOX or XELOXaTreatment C: FO

32、LFOX or XELOX + placebo to match AZD2171aRandomisation1：1：1目标提高结肠癌肝转移灶的切除率延长晚期结肠癌患者的生存期改善晚期结肠癌患者的生活质量“STOP and GO” 长期存活的需要治疗毒性和生活质量的平衡长期化疗易引起的耐药持续化疗对缓解率提高有限复发后再次使用相同的方案仍有效“Stop and Go”治疗进展期结直肠癌 提高耐受性停止 奥沙利铂累积应用已达预定剂量 或出现一定级别的感觉神经毒性 当感觉神经毒性已消退或 为阻止肿瘤进展必须应用奥沙利铂治疗继续 FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x 6 cyFOLFOX4 直到进展ABRTournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006Stop and Go in ACRCOPTIMOX 1间歇性FOLFOX伴维持治疗可保证疗效(%) FOLFOX4FOLFOX7缓解率 无进展生存期 总生存率 20.0 21.6 3/4级神经毒性 18.7 13.3Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006间歇性FOLFOX伴维持治疗可降低毒