癌症治疗进展PPT学习教案

1、会计学1癌症治疗进展癌症治疗进展ABC news、MedPage Today 2010第1页/共54页第2页/共54页嘌呤核苷酸嘧啶6巯基嘌呤硫鸟嘌呤脱氧核苷酸DNA RNA（tRNA、mRNA、核蛋白体） 蛋白质微管酶类抑制嘌呤合成抑制核苷酸转变氨甲喋呤抑制嘌呤合成抑制dTMP合成氟尿嘧啶阿糖胞苷抑制DNA聚合酶抑制RNA功能博莱霉素损伤DNA阻碍修复烷化剂、顺铂、丝裂霉素与DNA交叉联接三尖杉酯碱抑制蛋白质合成L门冬酰胺酶VP16、HCPT、ADM抑制TOPO酶或放线菌素D抑制RNA合成嵌入DNA长春碱类促使微管解聚紫杉类促使微管聚合羟基脲、脱氧胞苷抑制核苷酸还原酶 化疗作用机化疗作用机理

2、理4第3页/共54页5第4页/共54页 ErlotinibBevacizumabSunitinibSorafenibSorafenibChemotherapyPanitumumabCetuximabTemsirolimusInhibition of programmed cell death (apoptosis)Tumor cell proliferationTumor cell invasion metastasisDevelopment of tumor vasculature (angiogenesis)第5页/共54页第6页/共54页8第7页/共54页9第8页/共54页10第9页/共

3、54页Salomon (1995); Chow (1997)31-48%膀胱癌Salomon (1995); Watanabe (1996);Rieske (1998)40-63% 神经胶质瘤Bartlett (1996); Fischer-Colbrie (1997)35-70% 卵巢癌Klijn (1992); Bucci (1997);Walker (1999)14-91% 乳腺癌Salomon (1995); Yoshida (1997)50-90% 肾癌Fujino (1996); Fontanini (1998)40-90% 非小细胞肺癌Salomon (1995); Uegaki

4、 (1997)30-95% 胰腺癌Salomon (1995); Grandis (1996)95-100%头颈部肿瘤Salomon (1995); Messa (1998)72-82% 结直肠癌参考文献肿瘤的 EGFR 表达百分比肿瘤类型11第10页/共54页Neal (1985)差膀胱癌Sainsbury (1985)差乳腺癌Volm (1998)Veale (1993)Ohsaki (2000)Pavelic (1993)增加降低OS差差非小细胞肺癌Dong (1998)Yamanaka (1993)降低OS差胰腺癌Grandis (1998)Maurizi (1996)降低 DFS，降

5、低OS差头颈部癌Mayer (1993)Hemming (1992)增加差结直肠癌参考文献转移风险生存预后肿瘤类型DFS = disease-free survival; OS = overall survival; 12第11页/共54页Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.13第12页/共54页Baselga. Eur J Cancer 2001: 37 Suppl 4:S16-S22.14第13页/共54页Kinase inhibitorActivation of EGFR plays an essential role in cel

6、lular survival and proliferation programs第14页/共54页EGFTGF Amphiregulin -cellulinHB-EGFTyrosine - kinasedomainEGFR (ErbB) family and ligandsHeregulinsNRG2NRG3Heregulins -cellulinCysteine - richdomainserbB-1HER1EGFRerbB-2HER2neuerbB-3HER3erbB-4HER4C-Terminus10010010044823336592448792816第15页/共54页Erbitux

7、HerceptinerlotinibgefitinibSignalingCell Division/Tumor GrowthlapatinibErbituxHerceptin17第16页/共54页Adapted from Bergers G, et al. Nature 2002;3:40110小肿瘤小肿瘤 (12mm) 无血管无血管 休眠休眠大肿瘤大肿瘤 血管血管 转移潜能转移潜能18第17页/共54页19第18页/共54页Tumors Progressively Make More Angiogenesis StimulatorsRelf et al., Cancer Research,

8、57:953, 1997bFGFbFGFVEGFbFGFVEGFPDGFbFGFVEGFPDGFIL-8第19页/共54页VEGFR-3VEGFR-2VEGFR-1AngiogenesisAngiogenesisLymphangiogenesislymphangiogenesisPlGFVEGF-AVEGF-BVEGF-CVEGF-DNRP-1(neuropilin)Unclear but likely involved in tumor growth(Non-RTK)PlGF = Placental growth factor; RTK = Receptor tyrosine kinase.

9、Dvorak. J Clin Oncol. 2002; 20:4368; Ferrara et al. Nat Med. 2003; 9:669.Bevacizumab21第20页/共54页Wilhelm S, et al. Clin Cancer Res 2004;64:7099109Tumour cellEndothelial cell or pericyte (vascular)Angiogenesis:differentiationproliferationmigrationtubule formationRafVEGFR-2PDGFR- MEKApoptosisProliferati

10、onPDGFVEGFSurvivalRasNucleusRasERKRafMEKApoptosisERKPDGFVEGFParacrine stimulationSorafenibKIT/Flt-3/RETMitochondriaMitochondriaMcl-1HIFSorafenibSorafenibSorafenibNucleusHIF = hypoxia inducible factor; VEGF = vascular endothelial growth factor VEGFR = VEGF receptor; PDGF = platelet-derived growth fac

11、tor PDGFR = PDGF receptor; Mcl-1 = myeloid cell leukaemia-122第21页/共54页Kaelin WG. Nat Rev Cancer 2002;2:67382VHLHIF=VEGFREGFRPDGFRRafmTORErlotinibSorafenibSunitinibAG-013736SorafenibSorafenibTemsirolimusBevacizumabmTOR = mammalian target of rapamycinEGFR = endothelial growth factor receptorVEGFR = VE

12、GF receptor; PDGFR = PDGF receptorRafPDGFVEGF TGF- 23第22页/共54页第23页/共54页第24页/共54页第25页/共54页第26页/共54页第27页/共54页CetuximabBevacizumabZD6474LapatinibSorafenibRapamycinAntiCyclinD1?Anti Tumor stem cell?29第28页/共54页年年参考文献参考文献标准标准OS (月月)注注1976Hansen肺癌7SCLC, 腺癌2002SchillerNSCLC7.9铂类两药化疗2006Sandler非鳞癌NSCLC12.3贝伐

13、单抗2009Mok亚裔不/少吸烟，腺癌18.6吉非替尼2009Rosell西班牙EGFR 突变型NSCLC27厄洛替尼2009Mitsudomi日本EGFR突变型NSCLC30+吉非替尼第29页/共54页RR 15% 20-30% 2372% 40%1960s 1970-80s 1990s 20005-FUECF,LFEP5-FU+/-LV/PFAMTXEAP, ELFFUPFAMFAPUFTM紫杉类（泰索帝紫杉类（泰索帝 ）奥沙利铂（乐沙定奥沙利铂（乐沙定）卡培他滨卡培他滨, S-1伊立替康伊立替康,靶向药物靶向药物进展期胃癌的治疗历程进展期胃癌的治疗历程OS 4-5m 6-7m 6m 8

14、m 生生 物物 靶靶 向向 治治 疗疗 FAM = 5-FU, doxorubicin, mitomycin C; FAMTX = 5-FU, doxorubicin, methotrexate;ECF = epirubicin, cisplatin, 5-FU; CF = cisplatin, 5-FU1. Wagner A, et al. Cochrane Database Syst Rev 2005;2:CD004064. 2. Kim NK, et al. Cancer 1993;71:38133818.3. Ohtsu A, et al. J Clin Oncol 2003;21:5

15、459. 4. Wils JA, et al. J Clin Oncol 1991;9:827831. 5. Waters JS, et al. Br J Cancer 1999;80:269272.6. Vanhoefer U, et al. J Clin Oncol 2000;18:26482657. 7. Cocconi G, et al. Ann Oncol 2003;14:12581263.8. Ross P, et al. J Clin Oncol 2002;20:19962004. 9. Webb A, et al. J Clin Oncol 1997;15:261267.第30

16、页/共54页ITT, 治疗意向人群; wt, 野生型; LLD, 仅有肝转移患者1. Folprecht et al. ESMO 2008; 2. Van Cutsem et al. ESMO 2008; 3. Bokemeyer et al. ASCO 2008; 4. Van Cutsem et al. ASCO 2008; 5. Saltz et al. WCGIC 2007Tailored therapy new era in mCRC第31页/共54页1st-line (115,722)3rd-line (36,837)2nd-line (57,131)Cetuximab + iri

17、notecanEPIC / BONDPFSRRQoL Cetuximab + FOLFIRI/FOLFOXCRYSTAL / OPUSPFSRRCureCetuximab+/-irinotecanNCIC CO.17 / BONDPFSOSQoLStage IV mCRC patients in Europe: 209,690*IARC33第32页/共54页中位生存时间中位生存时间35302520151050Months5-FU最佳支持治疗最佳支持治疗依立替康依立替康卡培他滨卡培他滨奥沙利铂奥沙利铂 1980 1985 1990 1995 2000 2010安维汀安维汀第33页/共54页35第

18、34页/共54页p=0.0001Cumulative disease recurrence curvesSun JM. Cancer 2004;101:251622累计复发事件累计复发事件0020406080100月月HER2阳性患者平均风险曲线阳性患者平均风险曲线HER2 阴性患者平均风险曲线阴性患者平均风险曲线最低风险曲线最低风险曲线36第35页/共54页StudyTreatment armsnRRPFSOSE2100*PaclitaxelPaclitaxel + Bev35436821%37%5.9m11.8mnsAVADODocetaxelDocetaxel + lo

19、w dose BevDocetaxel + high-dose Bev24149546%55%64%8.2m9.0m10.1mnsRIBBON1Anthracyclines or Taxanes Anthracyclines or Taxanes + BevCapecitabineCapecitabine + Bev20741520640938%51%24%35%8.3m10.7m6.2m9.8mnsnsBevacizumab in HER2 negative MBC- First-line StudiesBevacizumab dose at 15mg/kg q3 weeks except

20、for low-dose arm in AVADOMiller et al. NEJM 2007, 357: 2666-76Miles et al. SABCS 2009Robert et al. ASCO 200937第36页/共54页SHARP亚太 sorafinib安慰剂sorafinib安慰剂OS11.5m8.5m6.5m4.2mHR0.69P=.000580.68P=.014OS延长44%47%TTP6m3m2.8m1.4mHR0.58P=.0000070.57P.001TTP延长73%74%38第37页/共54页第38页/共54页第39页/共54页昨天、今天昨天、今天 千篇一律的治

21、疗千篇一律的治疗敏感性敏感性 ( + )敏感性敏感性 ( - )抗抗肿肿瘤瘤药药物物有效者有效者生存生存获获益益无效者无效者毒性且无生存毒性且无生存获获益益有效治有效治疗疗延延误误第40页/共54页未来未来 度身定制的治疗度身定制的治疗分子学特征 1对正确的对正确的患者使用患者使用正确治疗正确治疗2有效者有效者生存生存获获益益无效者无效者毒性且无生存毒性且无生存获获益益有效治有效治疗疗延延误误敏感性敏感性 ( + )敏感性敏感性 ( - )第41页/共54页(n=132)(n=132)缓解率缓解率(%)(%)nEGFREGFR突变阳性突变阳性: :Odds ratio(95%CI) = 2.7

22、5 (1.65, Odds ratio(95%CI) = 2.75 (1.65, 4.60), p=0.00014.60), p=0.0001nEGFREGFR突变阴性突变阴性: :Odds ratio(95%CI) = 0.04 (0.01, Odds ratio(95%CI) = 0.04 (0.01, 0.27), p=0.00130.27), p=0.0013(n=129)(n=129)(n=85)(n=85)(n=91)(n=91)43第42页/共54页NSCLC-EGFR突变第43页/共54页45第44页/共54页46第45页/共54页野生型突变型野生型突变型folfiriC225+folfiriC225+folfoxC225+folfoxC225+n=176 n=176 n=87n=105 n=73n=61n=47n=52RR%4359403637614933P=0.0025P=0.46P=0.011P=0.106MPFS7.6HR0.681.07P=0.017P=0.7547第46页/共54页第47页/共54页第48页/共54页Heinrich et al. Hum Pathol. 2002