大肠癌的内科治疗医学课件.ppt

1、大肠癌的内科治疗乙状结肠 12%-14%盲肠及升结肠 7%-9.5%降结肠 3.4%脾区 0.6%-3%横结肠 3%肝区 0.7%-2.7%结肠大 肠 癌 56%-70%直肠Parkin DM,CA Cancer J Clin.2005 Parkin DM,CA Cancer J Clin.2005 Lung&bronchus-1.35millionBreast-1.15millionColon&rectum-1.02millionStomach-934,000Liver-626,000Lung&bronchus-1.18millionStomach-700,000Liver-598,000C

2、olon&rectum 529,000Breast 411,000Parkin DM,CA Cancer J Clin.2005 男女性都包括在内男女性都包括在内Estimated Numbers of New Cancer Cases(Incidence)and Prevalent Cases(Five-year Survival)in 2002.Data shown in thousands by cancer site and sex.Parkin DM,CA Cancer J Clin.2005 第第4 4位位第第3 3位位第第3 3位位第第5 5位位 Estimated Number

3、s of New Cancer Cases(Incidence)and Deaths(Mortality)in 2002.Data shown in thousands for developing and developed countries by cancer site and sex.Parkin DM,CA Cancer J Clin.2005 第第2 2位位第第3 3位位第第3 3位位 第第2 2位位 第第3 3位位第第3 3位位第第2 2位位第第5 5位位第第7 7位位Parkin DM,CA Cancer J Clin.2005 1990-19921990-1992年我国抽样地

4、区年我国抽样地区男性男性肿瘤死亡率肿瘤死亡率(1/10(1/10万万)1990-19921990-1992年我国抽样地区年我国抽样地区女性女性肿瘤死亡率肿瘤死亡率(1/10(1/10万万)全国城市居民恶性肿瘤前全国城市居民恶性肿瘤前5 5位死因顺序为：位死因顺序为：肺癌、肝癌、胃癌、肺癌、肝癌、胃癌、结直肠癌结直肠癌、食管癌。、食管癌。卫生部信息统计中心卫生部信息统计中心20012001年资料年资料:*T4直接侵犯包括大肠癌的其他段,如盲肠癌侵及乙状结肠 TNM分期 (AJCC 2002)IIIA期期 T1 N1 M0 T2 N1 M0 IIIB期期 T3 N1 M0 T4 N1 M0IIIC

5、期期 任何任何 T N2 M0IIA期期 T3 N0 M0 IIB期期 T4 N0 M00期期 Tis N0 M I期期 T1 N0 M0 T2 N0 M0 IV 期期 任何任何T 任何N 临床分期 (AJCC2002)NCI guideline:Treatment decisions should be made with reference to the TNM classification,rather than the older Dukes or the Modified Astler-Coller(MAC)classification schema.大肠癌的内科治疗大肠癌的内科治疗

6、LV/5-FU规范给药方法nMayo Clinic:LV200mg/m2,I.V.2hr.5-FU 370mg/m2,bolus,5d,q4w LV20mg/m2,bolus,5-FU 425mg/m2,bolus,5d,q4wnde Gramont:LV 200mg/m2,I.V.2hr,5-FU 400mg/m2,bolus (LV5FU2)5-FU 600mg/m2,CIV 22hr,d1-2,q2wnAIO:LV500mg/m2,I.V.2hr,5-FU 2.6-3.0/m2,CIV,24hr,qw6,q8w影响预 多因素多因素 许多标记物的作用不清楚许多标记物的作用不清楚肿瘤完全切除

7、From DeVita 6th Ed,Lipincott;H Bleiberg colorectal cancer guide,2002,M Dunitz,and C Ribic,NEJM 2003,349,37个研究个研究;n=334125.Moertel CG,Fleming TR,Macdonald JS et al.Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/DukesB2 Colon Cancer.J Clin Oncol 1995;13:2936-2943.26.

8、International Multicentre Pooled Analysis of B2 Colon Cancer Trials(IMPACT B2)Investigators.Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer.J Clin Oncol 1999;17:1356-1363.21.Moore HCF,Haller DG.Adjuvant therapy of colon cancer.Semin Oncol 1999;26:545-555.27.Benson AB 3rd,Schrag

9、 D,Somerfield MR et al.American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer.J Clin Oncol 2004;22(16):3408-3419.28.Compton CC,Fielding LP,Burgart LJ et al.Prognostic factors in colorectal cancer.College of American Pathologists Consensus Statement 1

10、999.Arch Pathol Lab Med 2000;124(7):979-994.905 例病人例病人中位随访中位随访41个月个月两组两组DFS相似相似(127例例 vs 124例例,p=0.74)(3年无病生存年无病生存73%)死亡死亡:LV5FU2组组73例例 vs Mayo组组59例例,p=0.18LV5FU2组不良反应显著低于组不良反应显著低于Mayo组组(p0.001)RLV5FU2Mayo 静脉注射静脉注射 5FUAndr T et al.J Clin Oncol,2003,21,2896-2903新药方案在辅助MOSAICRLV5FU2FOLFOX4-LV5FU2+奥沙利铂

11、奥沙利铂 85mg/mn主要终点主要终点:无病生存无病生存(DFS)n次要终点次要终点:安全性安全性(包括长期毒性包括长期毒性)总生存总生存(OS)研究终点研究终点Andr T et al.N Engl J Med 2004;350:2343-51*Baxter LV5 infusors0,50,60,70,80,9101020304050ProbabilityDFS(months)24%risk reduction for stage III patients in the FOLFOX arm FOLFOX(n=672)71.8%LV5FU2(n=675)65.5%3-year0,50,6

12、0,70,80,9101020304050ProbabilityDFS(months)18%risk reduction for stage II patients in the FOLFOX armFOLFOX(n=451)86.6%LV5FU2(n=448)83.9%3-year无统计学差异无统计学差异无统计学差异无统计学差异ASCO 2005 LBA8Randomized Phase III Trial Comparing Infused Irinotecan/5-Fluorouracil(5-FU)/Folinic Acid(IF)versus 5-FU/FA(F)in Stage I

13、II Colon Cancer Patients(PETACC-3;V307)Eric Van Cutsem1,R.Labianca,D.Hossfeld,G.Bodoky,A.Roth,E.Aranda,B.Nordlinger,C.Barone,J.Tabernero,C.Topham,T.Andr,A.Sobrero,S.Assadourian,K.Wang,D.Cunningham on behalf of the PETACC-3 investigatorsUniv Hospital Gasthuisberg/Leuven,Leuven,Belgium1Stratification:

14、Stage II vs.III Center RANDOMIZATIONDay 1Day 2FA 200 mg/m25-FU bolus 400 mg/m25-FU CI 600 mg/m2Day 1Day 2Irinotecan 180 mg/m2LV5FU2LV5FU2 as aboveFIFRepeat q 2 weeksfor 12 Cycles210 pts treated with the AIO regimen irinotecan within given centers will be presented later.IFF0.0Probability0.50.60.70.8

15、0.91.0Duration(months)036912151821242730333639424548Duration(months)ProbabilityIFF0.00.50.60.70.80.91.00369121518212427303336394245480.0Probability0.50.60.70.80.91.0Duration(months)IFF036912151821242730333639424548ProbabilityDuration(months)IFF0.00.50.60.70.80.91.00369121518212427303336394245485-FU由

16、推注改为持续点滴与CF联合(生化调节)RR2030%,QOL 治疗现状100%074%62%43%13%7%其他tomOXACampto5-FU类ASCO，2002 治疗ACRC的常用药物dUMPCH2FH4TSdUMPTSdTMPDNA细胞繁殖CH2FH4FH2+TS5-FUFdUMPCH2FH4TSFdUMPTSdTMPDNA复制 受抑制CH2FH4三联复合物，可分离三联复合物稳定，不可分离CH2FH4细胞繁殖停止正常细胞代谢正常细胞代谢：-FU+CF治疗治疗:增效增效Results of the meta-analysis:5FU+Folinic Acid(FA)A significan

17、t increase in No survival advantage response rateP 10-711%5FU alonen=578Response rate%5FU5FU+FA%of patientsmonths Advanced CRC Meta-Analysis Project.JCO 199223%5FU+FAn=803Enhancing activity of 5-FU5-FU alone or 5-FU+FA?期短,约1020min2.氟尿嘧啶属于细胞周期特异性药物,只作用于细胞周期的S期,与癌细胞接接触时间短,抗癌效果差n氟尿嘧啶持续输注方法:1.肿瘤细胞暴露于氟尿嘧

18、啶的作用时间延长2.持续输注氟尿嘧啶的总剂量强度提高3.对胸苷酸合成酶(TS)抑制时间长,增加对DNA合成障碍.Six trials(1219 pts.)5-FU bolus5-FU CIpResponse rate(%)114220.0002Survival(months)111.312.10.04Toxicity:grade 3-4 neutropenia(%)23140.0001Hand-foot syndrome(%)213340.00015-FU bolus vs 5-FU CI meta-analysis1=Meta-analysis Group in Cancer,JCO 199

19、82=Meta-analysis Group in Cancer,JCO 1998Mayo,de Gramont,AIOMayo,de Gramont,AIO治疗治疗ACRCACRC比较比较Kohne(1998)New drugs inadvanced colorectal cancerXeloda5-DFCR5-DFUR5-DFCR5-DFUR5-FU肝脏CECYDCYDTP肿瘤组织5-DFCR：5-脱氧脱氧-5-氟胞苷氟胞苷5-DFUR：5-脱氧脱氧-5-氟尿苷氟尿苷CE:羧基酯酶羧基酯酶CYD:胞苷脱氨酶胞苷脱氨酶TP:胸腺嘧啶磷酸化酶胸腺嘧啶磷酸化酶1.Duguet M.,et al.

20、Medecine/sciences 1994;10:962-972.2.Pommier Y.Medecine/sciences 1994;10:953-955.3.Pommier Y.et al.CRC Press 1995.CPT-11联合LV/5-FU治疗大肠癌AIO 方案：Irinotecan5-FU 500leucovorinIFL(or Saltz)方案：开普拓开普拓+5-FU/LV vs 5-FU/LV一线一线治疗治疗ACRC III期随机研究期随机研究63转移性转移性结直肠癌结直肠癌的化疗的化疗 二线二线单药单药:RR 1:RR 11 1%,%,MST8-9MST8-9月月 5F

21、U/LV5FU/LV失败后二线联合失败后二线联合inf5FU/LVinf5FU/LV：RR 1RR 10-480-48%,%,MST10-18MST10-18月月 inf5FU/LV+CPT-11inf5FU/LV+CPT-11失败后二线联合失败后二线联合inf5FU/LVinf5FU/LV：RR RR 1 10-150-15%,%,MST9.8MST9.8月月 一线一线单药单药:RR:RR 10-2410-24%一线联合一线联合inf5FU/LV:inf5FU/LV:RR 40 54%,MST 16 RR 40 54%,MST 16 21.5 21.5 月月草酸铂64D15-FU bolus

22、5-FU bolusD2D15-FU bolus5-FU bolusD2ROXAFOLFOX4:LV5-FU2:de Gramont A,Figer A,Seymour M,et al.J Clin Oncol.2000 Aug;18(16):2938-47.研究设计结果分析结果分析de Gramont A,Figer A,Seymour M,et al.J Clin Oncol.2000 Aug;18(16):2938-47.Intergroup Study2nd line MCRC after failure to IFL(N=459)Randomized phase III studyM

23、.Rothenberg et al.,ASCO 2003External review of responses68V 308试验试验随机化随机化,多中心多中心,开放性开放性,前瞻性前瞻性,III期临床研究期临床研究L-OHP 100 mg/m2 IV+简化的简化的 LV5FU直至进展直至进展直至进展直至进展直至进展直至进展A组组B组组直至进展直至进展随机分组随机分组69中位中位至进展时间至进展时间 703563415FOLFOX6n=81二线二线404915个月时无进展个月时无进展0.921.520.4中位总生存期中位总生存期(月月)0.650.68p value11.514.4中位总中位总

24、TTP(月月)8179ORR+SD%54(5)56(3)ORR(CR)%FOLFOX6n=111一线一线FOLFIRIn=109一线一线A组组B组组FOLFIRIn=69二线二线7134061391*2095103117FOLFIRIn=68FOLFOX6n=82*+19%neurotoxicity gr.3 related to Folfox 1st line49 56*1 toxic death11031392434011141*644250.050.050.050.05nsns0.055374 0.001口腔炎口腔炎恶心恶心脱发脱发(gr.2)神经毒性神经毒性(gr.3)腹泻腹泻发热性中

25、性粒细胞减发热性中性粒细胞减少少中性粒细胞减少中性粒细胞减少FOLFOX6n=110FOLFIRIn=110 A组组 B组组 Specific modified Levy scale总体总体72治疗策略治疗策略:适合大多数病人适合大多数病人 取得了取得了20 个月以上的中位总生存期个月以上的中位总生存期这是迄今为止这是迄今为止转移性结直肠癌化疗史上所取得的转移性结直肠癌化疗史上所取得的最长中位总生存期最长中位总生存期7374tyrosine kinase domainN-terminus Downstream .signaling pathway:PmAb small molecule TKI

26、EGFR as therapeutic target in CRC MAPK,ras/raf,c-myc,.cell cycle:G1 S phase,75C225(cetuximab)C225(cetuximab)是针对EGFR的 IgG1 单抗 与EGFR结合，阻断信号传导、抑制增殖、抗血管生成和转移、刺激凋亡和分化 主要毒性是粉刺样皮疹，主要在治疗，不影响治疗的继续76C225单药二线治疗CPT-11耐药的mCRC*40%of pts received ErbituxTM as a 3rd or higher line treatment77Saltz et al 2001 Proc A

27、m Soc Clin Oncol 20:Abstract 7 C225单药二线治疗CPT-11耐药的mCRC78C225单药二线治疗CPT-11耐药的mCRCSaltz et al 2001 Proc Am Soc Clin Oncol 20:Abstract 7 79Erbitux plus irinotecan in irinotecan-refractory mCRC randomized BOND*studyCunningham,Van Cutsem et al 2003 Proc Am Soc Clin Oncol 22:Abstract 1012*Bowel Oncology wi

28、th cetuximab aNtiboDyRandomization Irinotecan+ErbituxTMn=218ErbituxTMn=111Patients with EGFR expressing mCRC failing onor within 3 mths of irinotecan-based therapyPDIrinotecan+ErbituxTMn=5480Efficacy of cetuximab in EGFR positive irinotecan resistant CRC60%of pts in BOND trial had prior treatment wi

29、th irinotecan and oxaliplatin*Significant differences81C225+CPT-11+5-FU/FA一线治疗82C225+FOLFOX4一线治疗62例病人，例病人，84%EGFR表达阳表达阳性性2005ASCO abstr353583Avastin(bevacizumab)Avastin(bevacizumab)是针对VEGF的 单抗 与VEGF结合，抑制血管生成84Kabbinavar.J et al ASCO 2004 Avastin in first-line CRC in subjects who are not suitable can

30、didates for first-line CPT-112.2 months4.7 monthsH.Hurwitz et al.,ASCO 2003*60 days mortality:IFL 4.9%,IFL/Bev 3.0%E32随随机机分分组组共共829例病人例病人至少曾用过至少曾用过5FU或或/和和CPT-11化疗后失败的病人化疗后失败的病人未用过未用过AvastinPS0-22005ASCO abstr22005ASCO abstr2PTKCONFI随随机机分分组组共共1168例病人例病人初治初治PS0-22005ASCO LBA3CONFIR2005ASCO LBA3CONFIR2005ASCO LBA3随随机机分分组组联合应用2005ASCO abstr 3508结2005ASCO abstr 35085-FU/LV5-FU/LVCetuximab(C225)Cetuximab(C225)Bevacizumab(BV)Bevacizumab(BV)开普拓开普拓新药联合的发展方向新药联合的发展方向草酸铂草酸铂氟尿嘧啶为基础的氟尿嘧啶为基础的“前药前药