大肠癌的内科治疗医学PPT课件.ppt

1、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 - 700,0

2、00Liver - 598,000Colon & 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 3位位第第5 5位位 Estimated Numbers 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

4、 J Clin. 2005 1990-19921990-1992年我国抽样地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 T

5、1 N1 M0 T2 N1 M0 IIIB期期 T3 N1 M0 T4 N1 M0IIIC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-Col

6、ler (MAC) classification schema. 大肠癌的内科治疗大肠癌的内科治疗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,

7、 5-FU 2.6-3.0/m2, CIV, 24hr, qw6,q8w 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 adjuvan

8、t therapy for stage II/ DukesB2 Colon Cancer. J Clin Oncol 1995;13:2936-2943.26. 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

9、DG. Adjuvant therapy of colon cancer. Semin Oncol 1999;26:545-555.27. Benson AB 3rd, Schrag 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

10、al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. 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

11、)RLV5FU2Mayo 静脉注射静脉注射 5FUAndr T et al. J Clin Oncol, 2003, 21, 2896 - 2903MOSAICRLV5FU2FOLFOX4 - LV5FU2 + 奥沙利铂奥沙利铂 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 infusors0,50,60,70,80,9101020304050ProbabilityDF

12、S (months)24% risk reduction for stage III patients in the FOLFOX arm FOLFOX (n=672) 71.8%LV5FU2 (n=675) 65.5% 3-year0,50,60,70,80,9101020304050ProbabilityDFS (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

13、 2005 LBA8Randomized Phase III Trial Comparing Infused Irinotecan/5-Fluorouracil (5-FU)/ Folinic Acid (IF) versus 5-FU/FA (F) in Stage III 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. Topha

14、m, T. Andr, A. Sobrero, S. Assadourian, K. Wang, D. Cunningham on behalf of the PETACC-3 investigatorsUniv Hospital Gasthuisberg/Leuven, Leuven, Belgium1Stratification: 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/m2LV5FU

15、2LV5FU2 as aboveFIFRepeat q 2 weeksfor 12 Cycles210 pts treated with the AIO regimen irinotecan within given centers will be presented later.IFF0.0Probability0.50.60.70.80.91.0Duration (months)036912151821242730333639424548Duration (months)ProbabilityIFF0.00.50.60.70.80.91.00369121518212427303336394

16、245480.0Probability0.50.60.70.80.91.0Duration (months)IFF036912151821242730333639424548ProbabilityDuration (months)IFF0.00.50.60.70.80.91.00369121518212427303336394245485-FU由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C

17、H2FH4FH2+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 significant increase in No survival advantage response rateP 10-711%5FU alonen=578Response rate %5FU5FU + FA% of patientsmonths Ad

18、vanced CRC Meta-Analysis Project. JCO 199223%5FU + FAn=803Enhancing activity of 5-FU5-FU alone or 5-FU + FA? 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

19、-FU CI meta-analysis1 = Meta-analysis Group in Cancer, JCO 19982 = 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

20、-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. 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： 63 Saltz Irinotecan5FU(b)/LV +

21、5FU(b)/LV Douillard Irinotecan5FU(i)/LV + 5FU(i)/LV Khne / Van Cutsem Irinotecan5FU/LV(AIO) +5FU/LV (AIO) RR% 21 39 23 41 31.5 54.2 TTP(mos) 4.7 6.7 4.4 6.4 (PFS) 6.4 8.5 OS(mos) 12.9 14.0 14.1 17.4 16.9 20.1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64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

22、 11 1%, %, MST8-9MST8-9月月 5FU/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

23、40 54%, MST 16 21.5 21.5 月月草酸铂D15-FU bolus5-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. Pat(N)RR (%)mTTP(months)mS(month

24、s) LV5FU215102.68.7 Oxaliplatin 1561.31.98.1 FOLFOX41529.9p0.00015.6p0.00019.8n.s.Intergroup Study2nd line MCRC after failure to IFL (N=459)Randomized phase III studyM. Rothenberg et al., ASCO 2003External review of responses69V 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 m

25、g/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70中位中位至进展时间至进展时间 713563415FOLFOX6n = 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723406

26、1391*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 modifi

27、ed Levy scale总体总体73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tyrosine kinase domainN-terminus Downstream . signaling pathway:PmAb small molecule TKIEGFR as therapeutic target in CRC MAPK, ras/ raf, c-myc, . cell cycle: G1 S pha

28、se, Tyrosine kinase (TK) inhibitorsGefitinib (Iressa)Erlotinib (Tarceva)EKB-569CI-1033编辑版编辑版ppt76C225 (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，不影响治疗的继续编辑版编辑版ppt77C225单药二线治疗CPT-11耐药的mCRC* 40% of pts received ErbituxTM as a 3rd or higher line

29、treatmentPtsRRDis ConmTTPmSSaltz 20025711%34%1.4 mths6.4 mthsCunningham 2003*11111%34%1.5 mths6.9 mths编辑版编辑版ppt78Efficacy resultsPR27 / 120 (23%)Disease control36 / 120 (30%)Median duration of response (MDR)6.2 mthsSaltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7 C225单药二线治疗CPT-11耐药的mCRC编辑版编辑版p

30、pt79Gr 3 4 toxicityIrinotecan + ErbituxTMDiarrhea22%Neutropenia14%Nausea9%Fatigue6%C225单药二线治疗CPT-11耐药的mCRCSaltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7 编辑版编辑版ppt80Erbitux plus irinotecan in irinotecan-refractory mCRC randomized BOND* studyCunningham, Van Cutsem et al 2003 Proc Am Soc Clin O

31、ncol 22: Abstract 1012* Bowel Oncology with cetuximab aNtiboDyRandomization Irinotecan + ErbituxTMn = 218ErbituxTMn = 111Patients with EGFR expressing mCRC failing onor within 3 mths of irinotecan-based therapyPDIrinotecan+ ErbituxTMn = 54编辑版编辑版ppt81 MonotherapyCombination withirinotecan IMCL0141BON

32、D trial (1:2)IMCL9923N pts57111218138PR (%)91123*22TTP (months)1.41.54.1*2.9OS (months)6.46.98.68.4Efficacy of cetuximab in EGFR positive irinotecan resistant CRC60% of pts in BOND trial had prior treatment with irinotecan and oxaliplatin * Significant differences编辑版编辑版ppt82C225 + CPT-11 + 5-FU/FA一线

33、治疗5-FU/FAResponseRRRosenberg 2002Bolus14 / 2948%Schffski 2002Lutz 2002AIO infus14 / 1974%Van Laethem 2003Biwkly infus11 / 2152%编辑版编辑版ppt83C225 + FOLFOX4一线治疗C225+FOLFOX4PR72%CRPR 9%63%SDPFS23%10.2月62例病人，例病人，84%EGFR表达阳表达阳性性2005ASCO abstr3535编辑版编辑版ppt84Avastin (bevacizumab) Avastin (bevacizumab) 是针对VEG

34、F的 单抗 与VEGF结合，抑制血管生成Kabbinavar.J et al ASCO 2004 Avastin in first-line CRC in subjects who are not suitable candidates for first-line CPT-112.2 months4.7 monthsH. Hurwitz et al., ASCO 2003* 60 days mortality: IFL 4.9%, IFL/Bev 3.0% 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Ava

35、stinPS0-22005ASCO abstr22005ASCO abstr2随随机机分分组组共共1168例病人例病人初治初治PS0-22005ASCO LBA3 FOLFOX + PTK/ZKFOLFOX + 安安慰剂慰剂HRp-value例数例数585583PFS (月）7.7 (7.7- 9.3) 7.5 (7.5- 7.7)0.830.0262005ASCO LBA32005ASCO LBA3随随机机分分组组2005ASCO abstr 3508Arm A (n= 40)Arm B（n=35）中位TTP5.8月4月PR14 (35%)8 (23%)SD17 (43%)19 (54%)PD7 (18%)6 (17%)尚未评价疗效尚未评价疗效1 (3%)2 (6%)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