大肠癌的内科治疗医学PPT

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,Epidemiology-worldwide,2002年新诊断癌症10.9million其中男性5.3million,女性4.7million2002年癌症死亡6.7million现患癌症病人24.6million,Parkin DM, CA Cancer J Clin. 2005,Parkin DM, CA Cancer J Clin. 2005,新发病数 死亡数,Lung & bronchus - 1.35millionBreast - 1.15millionColon & rectum - 1.02millionStomach - 934,000Liver - 626,000,Lung & bronchus - 1.18millionStomach - 700,000Liver - 598,000Colon & rectum 529,000Breast 411,000,Parkin DM, CA Cancer J Clin. 2005,Worldwide-2002,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4位,第3位,第3位,第5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2位,第3位,第3位,第2位,第3位,第3位,第2位,第5位,第7位,Parkin DM, CA Cancer J Clin. 2005,1990-1992年我国抽样地区男性肿瘤死亡率(1/10万),Epidemiology-China,Epidemiology-China,1990-1992年我国抽样地区女性肿瘤死亡率(1/10万),全国城市居民恶性肿瘤前5位死因顺序为：肺癌、肝癌、胃癌、结直肠癌、食管癌。,Epidemiology-China,卫生部信息统计中心,2001年资料:,TX 不能估价原发肿瘤 T0 未发现原发肿瘤 TiS 原位癌:位于粘膜层或侵犯固有膜 T1 肿瘤侵犯粘膜下层 T2 肿瘤侵犯肌层 T3 肿瘤侵透肌层达浆膜下,或侵犯结肠旁或直肠旁组织,但 未穿破腹膜 T4 肿瘤直接侵犯其他器官*或结构和/或穿破脏层腹膜,*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),T 原发肿瘤,NX 不能估价局部淋巴结 N0 无局部淋巴结 N1 13个局部淋巴结 N2 4个以上局部淋巴结 MX 不能估价远处转移 M0 无远处转移 M1 有远处转移,N 局部淋巴结,M 远处转移,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.,辅助化疗晚期大肠癌的治疗,大肠癌的内科治疗,LV/5-FU规范给药方法,Mayo Clinic: LV200mg/m2, I.V. 2hr. 5-FU 370mg/m2, bolus,5d, q4w LV20mg/m2, bolus, 5-FU 425mg/m2, bolus, 5d, q4wde Gramont: LV 200mg/m2, I.V. 2hr, 5-FU 400mg/m2, bolus (LV5FU2) 5-FU 600mg/m2, CIV 22hr, d1-2,q2wAIO: LV500mg/m2, I.V. 2hr, 5-FU 2.6-3.0/m2, CIV, 24hr, qw6,q8w,大肠癌辅助化疗,影响预后的因素?,树突状细胞计数,等位基因: CCND1 870ABRCA1 LOH,突变:p53K-rasMad2,侵袭: 深度 淋巴管 静脉 周围神经 浆膜,分化,侵袭性生长,DNA 倍体,CEA,手术技能,远端肠壁内播散,社会经济状况,受检淋巴结数目,多因素许多标记物的作用不清楚,穿孔梗阻,Watanabe T et al. NEJM 2001; 344: 1196-206,肿瘤完全切除病人的预后因素,From DeVita 6th Ed, Lipincott; H Bleiberg colorectal cancer guide, 2002, M Dunitz, and C Ribic, NEJM 2003, 349,3,结肠癌预后因素: II/III期,无病生存风险比p值阳性淋巴结142.10.000154.20.0001肿瘤浸润深度T31.20.2545T41.80.0033高分级1.30.0017年龄 60 yrs1.00.6447女性0.940.4130右侧结肠0.920.2537总生存风险比p值+年龄 60 yrs1.20有显著性,7个研究; n=3341,Gill S et al. J Clin Oncol 2004; 22:1797-1806,II期结直肠癌辅助治疗NCCN治疗指南,II期结肠癌患者术后不考虑辅助化疗作为标准治疗Intergroup 0035试验显示化疗与手术相比有降低复发率的倾向，但是结果没有生存受益25对B2结肠癌的国际多中心汇萃分析，包括1016例II期患者随机接受5-FU/LV或观察。无事件生存率分别为76%和73%（5年危险比0.83；90%可信区间，0.721.07）26。,25. 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. 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.,II期结直肠癌辅助治疗NCCN治疗指南,对于期高危患者，不良预后特征组织学分级差（34级的病灶）肿瘤周围的血管淋巴管侵犯肠梗阻肿瘤部位出现结肠穿孔不适当的淋巴结活检应考虑辅助化疗21，27，28,21. Moore HCF, Haller 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 al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124(7):979-994.,结肠癌辅助治疗主要进展-纵观,1990 - 1994 治疗(5-FU+LVor 左旋咪唑)优于不治疗1 19985-FU/LV 优于 5-FU/左旋咪唑219985-FU/LV治疗6个月与 12个月疗效相同31998左旋咪唑不必与 LV联用41998高剂量LV =低剂量LV51998每周给药方式= 每月给药方式 62001老年人 = “青年人”72002持续静脉滴注比静脉注射安全,References in comments,LV5FU2 用于结肠癌的辅助治疗,905 例病人中位随访41个月两组DFS相似(127例 vs 124例 , p= 0.74)(3年无病生存73%)死亡: LV5FU2组73例 vs Mayo组59例, p= 0.18LV5FU2组不良反应显著低于Mayo组 (p75 years : 56.4% 90.5% 5 年总生存率低于60% 由于手术和早期诊断技术的进步,总生 存已有所提高,治疗现状,与最佳支持治疗(BSC)相比延长生存 (至少6个月) 提高生活质量(QOL)早期治疗对患者有利延缓肿瘤相关症状的发生症状改善:PR的病人可改善90% ; SD的病人可改善65%似乎有利于老年病人 (适合化疗的老年病人)提高局部治疗的可能性(手术, 射频 .),晚期大肠癌的化疗,100%,0,74%,62%,43%,13%,7%,其他,tom,OXA,Campto,5-FU类,ASCO，2002,治疗ACRC的常用药物,大肠癌单药化疗疗效,大肠癌联合化疗疗效,生化反应调节剂使氟尿嘧啶增效,dUMP,CH2FH4,TS,dUMP,TS,dTMP,DNA,细胞繁殖,CH2FH4,FH2+TS,5-FU,FdUMP,CH2FH4,TS,FdUMP,TS,dTMP,DNA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：,-FU+CF治疗:,增效,Results of the meta-analysis: 5FU + Folinic Acid (FA),A significant increase in No survival advantage response rate,P 10-711%5FU alonen=578,Response rate %,100806040200,0812182430364248,5FU5FU + FA,% of patients,months,Advanced CRC Meta-Analysis Project. JCO 1992,23%5FU + FAn=803,Enhancing activity of 5-FU5-FU alone or 5-FU + FA?,氟尿嘧啶持续输注,氟尿嘧啶传统给药方法: 1.氟尿嘧啶的半衰期短,约1020min 2.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,抗癌效果差氟尿嘧啶持续输注方法: 1.肿瘤细胞暴露于氟尿嘧啶的作用时间延长 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.,De Gramont方案（）:,LV 200mg/m2 iv 2h d1、2 5FU 400mg/m2 iv bolus d1、2 5FU 600mg/m2 civ 22hr d1、2 2周重复,5-FU bolus vs 5-FU CI meta-analysis,1 = Meta-analysis Group in Cancer, JCO 19982 = Meta-analysis Group in Cancer, JCO 1998,Mayo, de Gramont, AIO治疗ACRC比较,Kohne(1998),New drugs inadvanced colorectal cancer,Xeloda,肠道,Xeloda5-DFCR5-DFUR,5-DFCR5-DFUR5-FU,肝脏,CE,CYD,CYD,TP,肿瘤组织,5-DFCR：5-脱氧-5-氟胞苷5-DFUR：5-脱氧-5-氟尿苷CE:羧基酯酶CYD:胞苷脱氨酶TP:胸腺嘧啶磷酸化酶,Xeloda,Xeloda对照5FU/CF(Mayo-clinic),Xeloda 5FU/CF P (n=603) (n=604) RR 22.4% 13.2% o.oo1 MST 12.9m 12.9m (12.0-14.0) (11.8-14),:作用机制,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.,是第一个特异性DNA拓扑异构酶I抑制剂，它通过与拓扑异构酶I和DNA形成的复合体的稳定结合，特异性抑制DNA重连步骤，引起DNA单链断裂。在细胞复制阶段这一断裂可使DNA产生不可逆的损伤，最终导致肿瘤细胞死亡。,DNA复制,剪切步骤,拓扑异构酶 I作用,重连步骤,对DNA复制阶段的抑制作用,松解,CPT-11,DNA的过度扭转,转移性结直肠癌的化疗,一线单药: RR 18-29%, MST12月二线单药: RR 11-17%, MST8-13月一线联合bolus5FU/LV: RR 29-39%, MST14.1-14.8月一线联合inf5FU/LV: RR 41 56%, MST 17.4 20.4 月,Douillard方案：,Irinotecan 180 mg/m2 d1 Leucovorin 200 mg/m2 d 1 2 5-FU 400 mg/m2 IV bolus, then 5-FU 600 mg/m2 CIV 22h d 1 2 q2w,CPT-11联合LV/5-FU治疗大肠癌,Irinotecan 100 mg/m2 d1; leucovorin 500 mg/m2 d1 5-FU 2.0 g/m2 IV 或 CIV 24h weekly x 4 every 6 weeks.,AIO 方案：,FOLFIRI 方案：,Irinotecan 180 mg/m2 d1leucovorin 400 mg/m2 d15-FU 400 mg/m2 IV d15-FU 2.4-3.0g/m2 CIV 46h q2w,Irinotecan 125 mg/m2 5-FU 500 mg/m2IV bolus leucovorin 20 mg/m2 IV bolus Weekly4 out of 6 weeks,IFL (or Saltz)方案：,开普拓+5-FU/LV vs 5-FU/LV一线治疗ACRC III期随机研究,转移性结直肠癌的化疗,二线单药: RR 11%, MST8-9月5FU/LV失败后二线联合inf5FU/LV： RR 10-48%, MST10-18月inf5FU/LV+CPT-11失败后二线联合inf5FU/LV： RR 10-15%, MST9.8月一线单药: RR 10-24%一线联合inf5FU/LV: RR 40 54%, MST 16 21.5 月,草酸铂,FOLFOX系列方案,OXA 85mg/m2 d1LV 200mg/m2 d1、25-FU 400mg/m2 iv d1、25-FU 600mg/m2 CIV 22h d1、2 q2W,FOLFOX4方案:,FOLFOX6方案:,OXA 100mg/m2 LV 400mg/m2 5-FU 400mg/m2 bolus5-FU 2.4-3.0g/m2 CIV 46h q2W,FOLFOX4 VS LV/5FU2一线治疗ACRC临床研究,D1,D1,R,OXA,FOLFOX4:,LV5-FU2:,de Gramont A, Figer A, Seymour M,et al .J Clin Oncol. 2000 Aug;18(16):2938-47.,研究设计,FOLFOX4 VS LV/5FU2一线治疗ACRC临床研究,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 study,M. Rothenberg et al., ASCO 2003,External review of responses,CPT-11 180 mg/m2 IV+ 简化的 LV5FU,V 308试验,随机化, 多中心, 开放性, 前瞻性, III期临床研究,FOLFIRI,FOLFOX6,L-OHP 100 mg/m2 IV+ 简化的 LV5FU,FOLFOX6,FOLFIRI,直至进展,直至进展,直至进展,A组,B组,直至进展,随机分组,V 308 疗效结果,FOLFIRI,FOLFOX,14.4 月,FOLFOX,FOLFIRI,11.5 月,中位至进展时间,主要终点,35,63,4,15,FOLFOX6n = 81二线,40,49,15个月时无进展,0.9,21.5,20.4,中位总生存期(月),0.65,0.68,p value,11.5,14.4,中位总TTP(月),81,79,ORR + SD %,54 (5),56 (3),ORR (CR) %,FOLFOX6n = 111一线,FOLFIRIn = 109一线,A组,B组,V 308 疗效结果,FOLFIRIn = 69二线,3,4,0,6,13,9,1*,20,9,5,1,0,31,17,FOLFIRIn = 68,FOLFOX6n = 82,* + 19% neurotoxicity gr. 3 related to Folfox 1st line,49,56,V 308 总体安全性 NCI-CTC 3-4度发生率,口腔炎,恶心,脱发 (gr. 2),神经毒性 (gr. 3),腹泻,发热性中性粒细胞减少,中性粒细胞减少,FOLFOX6n = 110,FOLFIRIn = 110,A组,B组, Specific modified Levy scale,总体,V 308 研究结论,FOLFIRI/FOLFOX治疗策略 : 适合大多数病人 取得了20 个月以上的中位总生存期,这是迄今为止转移性结直肠癌化疗史上所取得的最长中位总生存期,EGFR expression in solid tumors,Head&Neck (SCC),Colorectal cancer,Lung cancerNSCLC,tyrosine kinase domain,N-terminus,Downstream . signaling pathway:,P,Ligand,mAb,small molecule TKI,EGFR as therapeutic target in CRC,MAPK, ras/ raf, c-myc, . cell cycle: G1 S phase, ,C225 (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,C225单药二线治疗CPT-11耐药的mCRC,* 40% of pts received ErbituxTM as a 3rd or higher line treatment,Saltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7,C225单药二线治疗CPT-11耐药的mCRC,C225单药二线治疗CPT-11耐药的mCRC,Saltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7,Erbitux plus irinotecan in irinotecan-refractory mCRC randomized BOND* study,Cunningham, Van Cutsem et al 2003 Proc Am Soc Clin Oncol 22: Abstract 1012,* Bowel Oncology with cetuximab aNtiboDy,Randomization,Irinotecan + ErbituxTMn = 218,ErbituxTMn = 111,Patients with EGFR expressing mCRC failing onor within 3 mths of irinotecan-based therapy,PD,Irinotecan+ ErbituxTMn = 54,Efficacy of cetuximab in EGFR positive irinotecan resistant CRC,60% of pts in BOND trial had prior treatment with irinotecan and oxaliplatin * Significant differences,C225 + CPT-11 + 5-FU/FA一线治疗,C225 + FOLFOX4一线治疗,62例病人，84%EGFR表达阳性,2005ASCO abstr3535,Avastin (bevacizumab),Avastin (bevacizumab) 是针对VEGF的 单抗与VEGF结合，抑制血管生成,FU/LV/Placebo FU/LV/Avastin P-ValueRandomized 105 104Median survival(m0s) 12.9 16.6 0.159PFS(mos) 5.5 9.2 0.0002ORR(CR+PR) 15% 26% 0.0552Duration of response 6.8 9.2 0.1184GI perforations 0 2%Any thromboembolism 18.3% 18.0%Grade 3 proteinuria 0 1.0%Grade 3 hypertension 2.9% 16.0%,Kabbinavar.J et al ASCO 2004,Avastin in first-line CRC in subjects who are not suitable candidates for first-line CPT-11,Irinotecan-based combination t