食管鳞癌的治疗课件.pptx

1、转移性食管鳞癌的治疗GLOBOCAN 2012GLOBOCAN 2012GLOBOCAN 2012GLOBOCAN 2012：ChinaChinaSurvival data：China 2010Annals of Translational Medicine,Vol 2,No 7 July Annals of Translational Medicine,Vol 2,No 7 July 20142014Work-up 体检，血常规体检，血常规/生化生化 CT:CT:胸腹部胸腹部 PET/CTPET/CT GIGI造影造影 腔镜腔镜+活检活检 EUSEUS EUS-FNAEUS-FNAClini

2、cal T stageCTCT 基础检查方法基础检查方法 CTCT正常食管壁正常食管壁3mm3mm 准确性低于准确性低于EUSEUS T3T3、T4T4准确性高准确性高 T4T4：与组织间的脂肪垫：与组织间的脂肪垫 与主动脉接触角度大于与主动脉接触角度大于9090度度 食管、主食管、主A A、椎体之间的、椎体之间的三角三角脂肪垫消失脂肪垫消失 气管支气管气管支气管侵犯侵犯EUSEUS 术前分期最准确术前分期最准确 准确性准确性90%90%敏感性敏感性81-90%81-90%特异性特异性99%99%缺点：缩窄型肿瘤缺点：缩窄型肿瘤Clinical N stage CTCT 根据淋巴结短径根据淋巴

3、结短径 胸胸腹腔腹腔10mm10mm，锁骨上，锁骨上5mm5mm，腹膜后，腹膜后6mm6mm MetaMeta：敏感性敏感性59%59%，特异性，特异性81%81%EUSEUS：准确性准确性7474%-90%-90%EUS/FNA:87EUS/FNA:87%-100%-100%PET,PET/CTPET,PET/CT 敏感性敏感性(33-37%)(33-37%)低于低于EUSEUS 特异性特异性高高(90%)(90%)7th TNM stageT stage TxTx:primary tumor can not be assessed primary tumor can not be asse

4、ssed TisTis Carcinoma Carcinoma in situ/in situ/High-grade High-grade dysplasiadysplasia T1:T1:lamina lamina propriapropria or or submucosasubmucosa T1a T1a lamina lamina propriapropria or or muscularismuscularis mucosae mucosae T1b submucosa T1b submucosa T2 T2 muscularismuscularis propriapropria T

5、3 T3 adventitia adventitia T4 adjacent T4 adjacent structuresstructures T4a T4a pleura,pleura,pericardium,diaphragmpericardium,diaphragm,or or adjacent peritoneumadjacent peritoneum T4b other adjacent T4b other adjacent structures,structures,e.g e.g.aorta,vertebral.aorta,vertebral body,tracheabody,t

6、racheaN stage Any Any periesophagealperiesophageal lymph node lymph node from cervical lymph nodes to from cervical lymph nodes to celiac celiac nodenode NxNx:Regional Regional lymph node lymph node can can not be not be assessedassessed N0:N0:No No regional lymph node regional lymph node metastases

7、metastases N1:N1:1 1 to 2 positive regional lymph to 2 positive regional lymph nodesnodes N2:N2:3 3 to 6 positive regional lymph to 6 positive regional lymph nodesnodes N3:N3:7 7 or more positive regional lymph or more positive regional lymph nodes nodes M stage Mx Distant metastasis cannot be assas

8、sed M0 No distant metastasis M1 Distant metastasisnonanatomical cancer characteristics HistopathologicHistopathologic cell type cell type Adenocarcinoma Adenocarcinoma Squamous Squamous cell cell carcinomacarcinoma Undifferentiated UndifferentiatedHistologic grade Histologic grade G1G1:Well differen

9、tiated:Well differentiated G2:Moderately differentiated G2:Moderately differentiated G3:Poorly differentiated G3:Poorly differentiated G4:Undifferentiated G4:Undifferentiated Stage Groupings of Squamous Cell Carcinoma stagestageT TN NM MG Glocationlocation0 0Tis(HGD)Tis(HGD)0 00 01 1anyanyIAIA1 10 0

10、0 01 1anyanyIBIB1 12-32-30 00 00 00 02-32-31 1AnyAnylowerlowerIIAIIA2-32-32-32-30 00 00 00 01 12-32-3Upper,middleUpper,middlelowerlowerIIBIIB2-32-31-21-20 01 10 00 02-32-3anyanyUpper,middleUpper,middleanyanyIIIAIIIA1-21-23 34a4a2 21 10 00 00 00 0AnyAnyAnyAnyanyanyAnyAnyAnyAnyanyanyIIIBIIIB3 32 20 0a

11、nyanyanyanyIIICIIIC4a4a4b4banyany1-21-2AnyAnyN3N30 00 00 0AnyAnyAnyAnyanyanyAnyAnyAnyAnyanyanyIVIVanyanyanyany1 1anyanyanyanyOverall survivalT.W.Rice,Worldwide esophageal cancer collaboration,Diseases of the Esophagus 2009;22:1-830 days 98%1 year 78%5 year 42%10 year 31%Survival of squamous cell car

12、cinomaProgression from 6th T stageT stage TisTis的定义：的定义：HPGHPG T4T4进一步分为：进一步分为：T4aT4a和和T4bT4b N stageN stage 根据转移数目根据转移数目 区域淋巴结区域淋巴结 M M stage stage 取消取消M1aM1a和和M1bM1b 组织分化纳入分期组织分化纳入分期 病理类型病理类型 解剖部位解剖部位limitations 数据库时间跨度太大，包括数据库时间跨度太大，包括R1R1及及R2R2切除病例切除病例 G4G4或未分化仅或未分化仅7 7例！例！TisTis内镜下切除和外科切除差别？内镜下

13、切除和外科切除差别？T1aT1a和和T1bT1b only surgery or pathologic stageonly surgery or pathologic stage？缺乏？缺乏临床临床分期！分期！Inoperative and advanced disease?Inoperative and advanced disease?分期对治疗的指导意义？分期对治疗的指导意义？颈颈段食管癌？段食管癌？8th？Stage 0 Stage 0 and Stage and Stage IVIV？Adding staging Adding staging classificationsclass

14、ifications Assessing other non-anatomic Assessing other non-anatomic tumor characteristics tumor characteristics that affect that affect survivalsurvival Adding non-Adding non-esophagectomyesophagectomy survival survival data endoscopic data endoscopic treatment in Stage 0,treatment in Stage 0,IA IA

15、，palliative palliative therapy in Stage IVtherapy in Stage IV.Adding cancer of the Adding cancer of the cervical esophaguscervical esophagus Construct validated models for Construct validated models for cancer recurrence and deathcancer recurrence and deathmESCCmESCC：治疗目的 姑息性治疗 缓解症状 减轻痛苦 延长生存时间有效化疗药

16、物 顺铂顺铂 卡铂卡铂 奥沙利铂奥沙利铂 奈达铂奈达铂 氟尿嘧啶类氟尿嘧啶类:5-FU,Cap,S-1,:5-FU,Cap,S-1,紫杉类紫杉类:PTX,DOC,ABX:PTX,DOC,ABX 吉西他滨吉西他滨 伊立替康伊立替康 长春瑞滨长春瑞滨 BLMBLM、MMCMMC、MTXMTX、ADMADM，VP-16VP-16Single agentANTICANCER RESEARCH 2007:2705Single agent:PTX文献药物（m2）病例数有效率PFS（个月）OS（个月）Semin Oncol.1994PTX 250mg q3wA30S1325%13%MDR 9周Ann Onc

17、ol 2007PTX 80mg qwS/A102一线15%二线5%5.79Cancer Chemother Pharmacol.2011PTX 100mg D1,8,15,22,29,36q7w二线S5244.2%MDR5.810.4Single agent：NVB、IRI文献药物（m2m2）病例数有效率PFSPFSOSOSJ J ClinClin OncolOncol.1996 1996 NVB 25mgNVB 25mg qwqwS46S46一线 3030二线161615%15%20%20%6%6%MDR 21MDR 21周DR 31DR 31周NANATumori.Tumori.2001

18、2001 NVB 30mgNVB 30mg q2wq2wS16S16(I/II(I/II线）25%25%Int J Colorectal Dis.2003 IRI 125mg IRI 125mg qwqw*4 4q6wq6w二线9 92/92/93.83.86.16.1mESCCmESCC的内科治疗：问题与思考 Q 01 Q 01：一线化疗能否获益 姑息性治疗 缓解症状 减轻痛苦 延长生存时间 缓解症状 吞咽困难 增加体重 改善恶液质 生存获益？S Afr Med J.1982;61(12):428-31.S Afr J Surg 1986；24:15-19,Eur J Surg.1998;1

19、64(11):849-57.RCTs of palliative chemotherapy vs BSC for advanced esophageal SCCRadiother Oncol Radiother Oncol 28:27,199328:27,1993Eur J Surg Eur J Surg 164:849,1998164:849,1998trialtrialarmarmN NRRRR（%）TTPTTPMSTMSTP valueP valueSchimid et Schimid et al.al.RadiotherRadiother OncolOncol ,19931993BSC

20、BSCRT 40GyRT 40GyCTCT46464141404022222020NANANANANANA15W15W13W13W11W11WNSNSLevardLevard et al.et al.Eur J Eur J SurgSurg,19981998BSCBSCCT(FP)CT(FP)84847272NANANANANANANANA12M12M12M12MNSNSStage Stage IVIV14 pts14 ptsQ02：standard care of 1st?Platin-based or non-platin-basedWhich paltin？DDP-based doubl

21、et：5-FU文献药物（/m2）病例数有效率PFS月OS月Jpn J Clin Oncol.1992DDP 70mg d15-FU 700mg d1-5，q21dS3935.9%平均缓解期3.5个月有效者 9.5其他者 6.5Eur J Cancer.1997;33:12165-FU 1g d1-5DDP 100mg d1 q21dVsDDP 100mg d1 q21dS8835%Vs19%MDR 32周Vs28周8.25Vs7.0Jpn J Clin Oncol.2001JCOG9407DDP 20mg d1-55-FU 800mg d1-5 CIV，q28dS3633.3%MDR 5.86

22、.7DDP-based doublet：other FU文献药物（/m2）病例数有效率PFS月OS月Cancer Chemother Pharmacol.2008;62(1):77DDP 60mg d1Xeloda 1250mg d1-14q21dS4557.8%TTP 4.711.2Oncology.2013;84(5):305-10S-12-3线S2025%3.311本组研究进行中部S-1/DDPSCC 4239.1%5.8MDDP-based Double：paclitaxel文献药物（/m2）病例数有效率PFS月OS月Semin Semin OncolOncol.1997 1997PT

23、X 200mg 24hPTX 200mg 24h，d1d1DDP 75mg d2,q3wDDP 75mg d2,q3wA27A27S10S1049%49%MDR 4m+for m MDR 4m+for m stagestageCancer J.Cancer J.2000 2000 PTX 200-250mg d1PTX 200-250mg d1DDP 75mgDDP 75mg d2 d2，q3wq3wA28A28S4S446%46%25%25%MDR 3.9MMDR 3.9M6.96.9Zhonghua Zhonghua ZhongZhong Liu Liu ZaZa ZhiZhi.2004

24、2004 PTX 175mg d1PTX 175mg d1DDP 40mg d2DDP 40mg d2、3 3，q3wq3wS27S2759.3%59.3%TTP 5.0TTP 5.09.79.7J Korean Med Sci.J Korean Med Sci.20052005PTX 90mg d1PTX 90mg d1DDP 50mg d1DDP 50mg d1 q2w q2wS32S3241%41%MDR 4.8MDR 4.87.07.0Med Med OncolOncol.2013 2013PTX 150mg d1PTX 150mg d1DDP 50mg d1DDP 50mg d1 q

25、2w q2wS46S4656.5%56.5%5.65.61717DDP-based Double：docetaxel文献药物（/m2）病例数有效率PFS月OS月Cancer Cancer ChemotherChemother PharmacolPharmacol.2010 2010DOC 70mg d1DOC 70mg d1DDP 70mgDDP 70mg d1 d1，q3wq3wS39S3933.3%33.3%5.05.08.38.3DDP-based Double：GEM文献药物（/m2）病例数有效率PFS月OS月Invest New Invest New DrugsDrugs 2004;

26、2004;GEM 1gGEM 1g，d1d1，8,158,15DDP 100mg d8,q4wDDP 100mg d8,q4wI/III/II线线A/CA/C 6464NANA7.37.3Ann Ann OncolOncol 2004;2004;GEM 800mg d2,9,16GEM 800mg d2,9,16DDPDDP 50mg d1,8 50mg d1,8，q4wq4w一线一线A24A24、S12S1241%41%9.89.8Br J Cancer 93:Br J Cancer 93:20052005GEM 1250mg d1,8GEM 1250mg d1,8DDPDDP 75mg d

27、1 75mg d1，q3wq3w一线一线A 28A 28，S14S1445%45%1111Chin Med J(Engl).2011;124:4012-7.GEM 1g d1,8GEM 1g d1,8DDPDDP 40mg d1,8 40mg d1,8，q3wq3w383842.1%42.1%4.14.11010DDP-based Double：NVB、IRI文献药物（m2m2）病例数有效率PFSPFSOSOSAnn Ann OncolOncol.2002 2002 NVBNVB 25mg d1,8 25mg d1,8DDP 80mg d1DDP 80mg d1，q3wq3wS71S71一线一

28、线33.8%33.8%PFSPFS 3.8 3.86.86.8文献药物（m2m2）病例数有效率PFSPFS（个月）（个月）OSOS（个月）Cancer Chemother Pharmacol.2008 Jan;61(1):83-8.IRI 100mg d1,8IRI 100mg d1,8DDPDDP 30mg d1,8 30mg d1,8，q3wq3w1 1ststSCC SCC 323231.3%31.3%4.44.49.69.6Other platin-based regimen文献药物（m2m2）病例数有效率PFSPFS（个月）个月）OSOS（个月）World J Gastroenter

29、ol.2013;19(35):5910-6PTX 175mg d1PTX 175mg d1NDPNDP 80mg d1 80mg d1q6wq6w1 1ststS36S3646.1%46.1%7.17.112.412.4Zhonghua Zhong Liu Za Zhi.2008TegafurTegafur 500mg d1-5 500mg d1-5 NDP 20mg d1-5NDP 20mg d1-5Q21dQ21d1 1ststS63S6360.3%60.3%TTPTTP：5.65.69.39.3Cancer Chemother Pharmacol.2013;71:905mFOLFOXmF

30、OLFOX1 1ststS56S5623.2%23.2%4.44.47.77.7Non-Platin-based regimen文献药物（/m2）病例数有效率PFS月OS月Med Oncol 20:1924,2003DOC 80mg d1DOC 80mg d1NVB 20mg d1NVB 20mg d1S20S2060%60%MDR 7MMDR 7M10.510.5BMC Cancer.2011;11:385PTX 80mg d1,8PTX 80mg d1,8Cap 900mg bidCap 900mg bid d1-14d1-14I/III/II线线S32S321 1线线 75%75%2 2

31、线线 45%45%5.25.2个月个月AllAll 11.7 11.71 1线线 14.314.32 2线线 8.48.4Med Oncol.2013;30(4):746DOC 60mg d1DOC 60mg d1Cap 825mg bid d1-14Cap 825mg bid d1-14II II线线S30S3023.3%23.3%TTP 3.0TTP 3.08.38.3World J Gastroenterol.2015;21(14):4268DOC 35mg d1,8DOC 35mg d1,8GEMGEM 1g FDR d1,8 1g FDR d1,8II II线线S33S3330%30

32、%4.04.08.88.8platin or not?Cap 1000mg/m2 bid d1-14PTX 80mg/m2 d1,8 N=48 Q 3 weeksx4-6mESCC180 PtsCap 1000mg/m2 bid d1-14DDP 75mg/m2 d1 N=46 Q 3 weeksx4-6RRRRPFSPFSMSTMST58%6.7M13.2M57%5.1M10.5MBMC Cancer.2015 A02：standard care of 1st?Platin-based or non-platin-basedWhich paltin？Chemotherapy Chemothe

33、rapy mESCCmESCC,like,like squamous cell malignancies in squamous cell malignancies in general,is based on cisplatingeneral,is based on cisplatin none of the chemotherapy none of the chemotherapy regimens currently approved by regimens currently approved by the FDA or EMA,SFDA.the FDA or EMA,SFDA.Q 0

34、3 Platin-based doubleTaxane or fluorouracil？缺乏RCT 同期化放疗、术前化疗的RCT，DP优于FP 回顾性研究显示含Taxane、GEM优于传统方案一项比较顺铂联合紫杉醇方案或顺铂联合替吉奥方案一线治疗转移性食管鳞癌的II II期临床研究研究负责单位：复旦大学附属肿瘤医院参 加 单 位：中山大学附属肿瘤医院内科 河南省肿瘤医院内科 复旦大学附属肿瘤医院闵行分院肿瘤内科 无锡市第四人民医院肿瘤内科 常州市第四人民医院研究负责人：常建华 教授研究设计DDP 75mg/m2 d1PTX 175mg/m2 d1 Q 3 weeksx4-6mESCC180 P

35、tsDDP 75mg/m2 d1S-1 S1.5者50mg bid，1.5者60mg bid 口服 d1-14 Q 3 weeksx4-6mESCC：Q 04Platin-based double or tripleDDP-based:triple文献文献药物药物(/m2)(/m2)病例数病例数有效率有效率PFSPFSOSOSJ Clin Oncol.1998 PTX 175mg d1PTX 175mg d1DDP 20mg d1-5DDP 20mg d1-55-FU 1g5-FU 1g d1-5 q4w d1-5 q4wA30A30S30S3046%46%50%50%MDR5.7MDR5.7

36、月月10.810.8个月个月Anticancer Anticancer Drugs.Drugs.2007 2007 PTX 35 mg d1PTX 35 mg d1、4 4、8 8、1111DDP 20mg d2DDP 20mg d2、5 5、9 9、1212FU 2g d5FU 2g d5、1212CF 300mg d5CF 300mg d5、1212，q3wq3wS41S4139%39%6.36.38.98.9Dis Esophagus.Dis Esophagus.2010 2010 ADM 30mg d1ADM 30mg d1DDP 14mg d1-5DDP 14mg d1-5FU 70

37、0mg d1-5FU 700mg d1-5S41S4143.9%43.9%NANA1010DDP-based:triple文献文献药物药物(/m2)(/m2)病例数病例数有效率有效率PFSPFSOSOSJ J ThoracThorac OncolOncol.2010 2010DOCDOC 50mg d1 50mg d1DDPDDPFU FU S39S3966.6%66.6%7 71313Cancer Chemother Pharmacol.2010;66(6):1159-65DOC 35mg d1DOC 35mg d1DDP 40mg d1DDP 40mg d15-FU 400mg d1-55

38、-FU 400mg d1-5，q2wq2wS18S1888.9%88.9%NANANANAAnticancer Res.2011;31(2):633-8.DOC 60mg d1DOC 60mg d1DDP 60mg d1DDP 60mg d15-FU 800mg d1-55-FU 800mg d1-5，q3-4wq3-4wS30S3072%72%NANA9 9Oncology.2011;80(5-6):307-13DOC 70mg d1DOC 70mg d1DDP 70mg d1DDP 70mg d15-FU 700mg d1-55-FU 700mg d1-5，q3-4wq3-4wS46S46

39、LA/MELA/MESCCSCC72.5%72.5%1414mESCC：Q 05 二线治疗二线治疗 单药或联合单药或联合 铂类？铂类？二线治疗能否获益？治疗前后显示症状改善治疗前后显示症状改善 Retrospective study platinum-refractory mESCC disease 66 and 45 pts were determined to receive docetaxel and BSC The median PPS was 5.4 in the docetaxel group and 3.3 months in the BSC group(P=0.005)Dis

40、Esophagus.Dis Esophagus.2014 2014Salvage chemotherapy versus best supportive care in patients with mESCC Retrospective study refractory or intolerable to fluorouracil,platinum,and refractory or intolerable to fluorouracil,platinum,and taxanetaxane.147 received BSC(BSC group)147 received BSC(BSC grou

41、p)138 did 138 did CTxCTx(CTxCTx group:PT containing regimen 38;investigational drugs 29;group:PT containing regimen 38;investigational drugs 29;irinotecanirinotecan containing regimen 26;containing regimen 26;taxanestaxanes 25;FU 16;others 4).25;FU 16;others 4).MST was 4.2 and 7.8 months in BSC grou

42、p and MST was 4.2 and 7.8 months in BSC group and CTxCTx group groupJ Clin Oncol 33,2015(suppl;abstr e15101)Multivariate analysis for OSHR(95%CI)PCTx0.46(0.32 0.66).001Metastasis other than lymph node,lung,liver,or bone1.54(1.03 2.32).038CRP 1.0 mg/dL1.57(1.09 2.25).015Sum of diameter of targetlesio

43、ns 50 mm1.50(1.10 2.04).011Taxane for salvage therapy for mESCC retrospective study PF-based pretreated chemotherapy Docetaxel was administered 3-weekly at 70 mg/m(2)Paclitaxel was administered at 100 mg/m(2)weekly for 6 weeks,with 1 weeks rest.NPFSOSDOC1322.35.3PTX312.36.1Cancer Chemother Pharmacol

44、.2014Re-challenge of platin？Phase II DDP/FU pretreated Docetaxel(70 mg/m)d1 cisplatin (75 mg/m)d1 35 pts The overall response rate was 34.2%The median PFS and overall survival times were 4.5 months and 7.4 months Pts with cisplatin-pretreated refractory DOC 30mg d1 NDP 50mg d1 q2w 48pts RR 27.1%PFS

45、3.1 M MST 5.9 MAm J Clin Oncol.2010;33(6):624-8.J Thorac Oncol.2009 Aug;4(8):1017-mESCC：Q 06 Role of targeted therapyRole of targeted therapy？mESCC Q 06:Role of targeted therapyRole of targeted therapyTargeted EGFRTargeted EGFRCetuximabCetuximabNimotuzumabNimotuzumabIcoIcotinibtinibImmunotherapy:Imm

46、unotherapy:PembrolizumabAnti Anti angiogenesangiogenes:endostarendostar Phase II RCT：cetuximab剂量（/m2)NRRDCRPFS（月）OS（月）CF组DDP 100mg d15-FU 1000mg d1-5 CIVQ28d*63013%57%3.65.5CET-CF组CF+Cetuximab 400mg d1，250mg weekly3219%75%5.99.5Ann Oncol.Ann Oncol.2009;20(10):1667 2009;20(10):1667CetuximabCetuximab

47、plus plus pemetrexedpemetrexed as as 2 2ndnd therapy therapy 29pts Twelve patients(41.4%)presented PR,ten(34.5%)had SD,and seven(24.1%)had PD.The response rate was 41.4%.The median PFS was 4.5 months,and the median OS was 9.4 months.Cancer Chemother Pharmacol.2015 NimotuzumabNimotuzumab plus plus CT

48、CT nimotuzumab 200 mg weekly,paclitaxel 175 mg/m(2)on day 1 and cisplatin 30 mg/m(2)on d1,2;q3w*6cycles.56 pts Overall RR was 51.8%and DCR was 92.9%.PFS for pts with metastatic disease and local-regional advanced disease to 8.2 months and more than 23 months,respectively.The OS for patients with met

49、astatic disease was 14.0 monthsCancer Sci.Cancer Sci.2016 2016;107(4;107(4):486-90):486-90dacomitinibdacomitinib in recurrent and/or in recurrent and/or metastatic ESCCmetastatic ESCC Pan her inhibitor dacomitinib 45 mg/day 48pts 6(12.5%)achieved PR and 29(60.4%)had SD.The median response duration w

50、as 7.1 months.The median PFS and OS was 3.3 and 6.4 months.Upregulation of ERBB signaling pathway was significantly associated with longer PFS(5.0 vs.2.9 months,P=0.016)and OS(10.0 vs.4.8 months,P=0.022).Oncotarget.2015 Dec 29;6(42):44971-84second-line icotinib treatment in advanced esophageal cance