晚期胃癌化疗策略培训ppt课件

晚期胃癌化晚期胃癌化疗策略策略晚期胃癌化疗策略1 1晚期胃癌治疗现状晚期胃癌治疗现状n n局部进展期治愈：手术与化疗的结合局部进展期治愈：手术与化疗的结合局部进展期治愈：手术与化疗的结合局部进展期治愈：手术与化疗的结合n n复发或转移不能治愈：化疗为主的综合治疗，复发或转移不能治愈：化疗为主的综合治疗，复发或转移不能治愈：化疗为主的综合治疗，复发或转移不能治愈：化疗为主的综合治疗，但手术或其它局部治疗手段的作用加强但手术或其它局部治疗手段的作用加强但手术或其它局部治疗手段的作用加强但手术或其它局部治疗手段的作用加强n n化疗：新药、新方案高效低毒，近期疗效增加而化疗：新药、新方案高效低毒，近期疗效增加而化疗：新药、新方案高效低毒，近期疗效增加而化疗：新药、新方案高效低毒，近期疗效增加而生存期延长不满意，但近生存期延长不满意，但近生存期延长不满意，但近生存期延长不满意，但近3 3年进展迅速年进展迅速年进展迅速年进展迅速 晚期胃癌化疗策略2晚期胃癌治疗现状局部进展期治愈：手术与化疗的结合晚期胃癌胃癌化疗胃癌化疗n n新辅助化疗新辅助化疗新辅助化疗新辅助化疗n n辅助化疗辅助化疗辅助化疗辅助化疗n n晚期胃癌的化疗晚期胃癌的化疗晚期胃癌的化疗晚期胃癌的化疗生存目标生存目标新辅化新辅化辅化辅化根治、延长根治、延长PFS手术手术姑息化疗姑息化疗手手术术化化疗疗化化疗疗延长生存期延长生存期改善生活质量改善生活质量化疗化疗 手术手术局部治疗局部治疗晚期胃癌化疗策略3胃癌化疗新辅助化疗生存目标新辅化辅化根治、延长PFS手术姑息晚期胃癌化疗临床问题晚期胃癌化疗临床问题n n药物、方案的选择药物、方案的选择n n疗程及后续治疗n n化疗与手术或局部治疗的合理应用（新辅助化疗）n n手术后辅助化疗晚期胃癌化疗策略4晚期胃癌化疗临床问题药物、方案的选择晚期胃癌化疗策略4 药物、方案的选择药物、方案的选择所有的选择所有的选择所有的选择所有的选择:1.1.1.1.5FU5FU5FU5FU/CAPECAPECAPECAPE/S-1S-1S-1S-12.2.2.2.DDP+5FUDDP+5FUDDP+5FUDDP+5FU3.3.3.3.ECF/LFEPECF/LFEPECF/LFEPECF/LFEP4.4.4.4.多西紫杉醇多西紫杉醇多西紫杉醇多西紫杉醇/紫杉醇紫杉醇紫杉醇紫杉醇CAPE/CAPE/CAPE/CAPE/DDP+5FUDDP+5FUDDP+5FUDDP+5FU5.5.5.5.OXAOXAOXAOXA+CAPECAPECAPECAPE/5FU/5FU/5FU/5FU6.6.6.6.CPT-11CPT-11CPT-11CPT-11+5FU/5FU/5FU/5FU/CAPE/S-1CAPE/S-1CAPE/S-1CAPE/S-17.7.7.7.分子靶点药物分子靶点药物分子靶点药物分子靶点药物晚期胃癌化疗策略5 药物、方案的选择所有的选择:晚期胃癌化疗策略5Randomized Phase III Study:1990-2000StudyStudyRegimenRegimenN NRR RR(%)(%)p-p-valuevalueMSTMSTp-p-valuevalueEORTCEORTC19911991FAMFAMFAMTXFAMTX1031031051059 94141.00015%)inPrior 3 Months CentersResponse assessment every 8 weeks independent of treatment schedule Cisplatin 100 mg/m2 IV D1Cycles repeated every 4 weeksDocetaxel 75 mg/m2 IV D1Cisplatin 75 mg/m2 IV D15-FU 750 mg/m2 CIV D1-5Cycles repeated every 3 weeks5-FU 1000 mg/m2 CIV D1-5vs 晚期胃癌化疗策略11Docetaxel,5-FU and Cisplatin:胃癌III期临床-TAX 325随访结果n n TCF vs CF p N 227 230RR 37%25%0.0106 TTP 5.6m 3.7m 0.00042Y 18%9%0.0201G3/4 81%75%2005 ASCO，abs 4002晚期胃癌化疗策略12胃癌III期临床-TAX 325随访结果 TAX325:increased febrile neutropenia with TCF%patients with grade 3/4NeutropeniaAnemiaPlateletsFebrile neutro-penia,infection020406080100TCFFPMoiseyenko VM et al.Proc Am Soc Clin Oncol 2005;(Abst 4002).82573014晚期胃癌化疗策略13TAX325:increased febrile neutTAX 325 研究结果研究结果n nTCF(TCF(多西紫杉醇、顺铂、多西紫杉醇、顺铂、多西紫杉醇、顺铂、多西紫杉醇、顺铂、5FU)5FU)是用于预后较好的患者的是用于预后较好的患者的是用于预后较好的患者的是用于预后较好的患者的一项新的治疗选择一项新的治疗选择一项新的治疗选择一项新的治疗选择Moiseyenko et al,ASCO 2005,Abstract 4002例数例数例数例数总体缓解总体缓解总体缓解总体缓解疾病进展时间疾病进展时间疾病进展时间疾病进展时间（月）（月）（月）（月）总生存期总生存期总生存期总生存期（月）（月）（月）（月）3434级毒性级毒性级毒性级毒性TCFTCF221/227221/22737%37%5.65.69.29.2腹泻，感染，腹泻，感染，腹泻，感染，腹泻，感染，中性粒细胞减中性粒细胞减中性粒细胞减中性粒细胞减少症少症少症少症*p=0.01p=0.01p=0.0004p=0.0004p=0.02p=0.02CFCF224/230224/23025%25%3.73.78.68.6胃炎，肾毒性胃炎，肾毒性胃炎，肾毒性胃炎，肾毒性*34级毒性包括：级毒性包括：81的非血液学毒性反应，的非血液学毒性反应，75的血液学毒性反应中的血液学毒性反应中30伴有中性粒细胞减少性发热伴有中性粒细胞减少性发热晚期胃癌化疗策略14TAX 325 研究结果TCF(多西紫杉醇、顺铂、5FU)是CPT-11 for AGC期多中心临床期多中心临床研究研究（2003 ASCO）FFCD 9803 法国法国Bouche O et al.J Clin Oncol2004;22:431927Bouche O et al.J Clin Oncol2004;22:431927例例例例 数数数数RRRRmTTPmTTPmOSmOSLV5FU2 LV5FU2 454513%13%3.2m3.2m6.8m6.8mLV5FU2-LV5FU2-DDPDDP444427%27%4.9m4.9m9.5m9.5mLV5FU2-LV5FU2-CPT-11CPT-11454540%40%6.7m6.7m11.3m11.3m晚期胃癌化疗策略15CPT-11 for AGC期多中心临床研究（200CPT-11联合5-FU治疗AGC-III期临床试验（2005 ASCO）N=170CPT-11 80mg/m2CF 500mg/m25FU 2000mg/m2 civ1/W x 6w N=163CDDP 100mg/m2 d15FU 1000mg/m2/d d1-5Q4WN=333 AGCRR 5454（31.8%31.8%）42 42（25.8%25.8%）TTP 5.0m 4.2m (p=0.088)TTF 4.0m 3.4m (p=0.002)OS 9.0m 8.7m p0.53M.Dank 2005 ASCO abs 4003晚期胃癌化疗策略16CPT-11联合5-FU治疗AGC-III期临床试验新世纪初的选择：问题！新世纪初的选择：问题！n n多西紫杉醇（多西紫杉醇（多西紫杉醇（多西紫杉醇（DocetaxelDocetaxel）联合）联合）联合）联合DDP/5-FUDDP/5-FU：高效！生存期延长！不良反应性大！高效！生存期延长！不良反应性大！高效！生存期延长！不良反应性大！高效！生存期延长！不良反应性大！n nCPT-11CPT-11联合联合联合联合5-FU/CF:RR5-FU/CF:RR改善、安全性提高、改善、安全性提高、改善、安全性提高、改善、安全性提高、TTFTTF延长延长延长延长,OSOS无延长无延长无延长无延长n n如何改变？更合理的选择？如何改变？更合理的选择？如何改变？更合理的选择？如何改变？更合理的选择？晚期胃癌化疗策略17新世纪初的选择：问题！多西紫杉醇（Docetaxel）联合新的探索和循证医学证据新的探索和循证医学证据n nOXA DDPn nCAPE5-FUn n重新设定剂量强度或改变剂量密度重新设定剂量强度或改变剂量密度n n增、减药物联合增、减药物联合n n续惯。续惯。晚期胃癌化疗策略18新的探索和循证医学证据OXA DDP晚期胃癌化疗策略18REAL 2randomised multicentre phase III study comparing capecitabine with 5-FU and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancerD CunninghamD Cunningham et al.et al.2006 ASCO 2006 ASCO Abstract LBA 4017Abstract LBA 4017晚期胃癌化疗策略19REAL 2randomised multicentre REAL-2:randomized,phase III trial in gastric and GEJ cancer Epirubicin Cisplatin5-FUEpirubicinCisplatinXeloda Epirubicin Eloxatin5-FUEpirubicinEloxatin Xeloda21-day cyclePlanned duration of treatment:24 weeks(8 cycles)Target randomizationn=600Eloxatin 130mg/m2 day 1CAPE 625 mg/m2 twice daily days 121Eprirubucin 50mg/m2 day 1;Cisplatin 60 mg/m2 day1;5-FU 200 mg/m2/day晚期胃癌化疗策略20REAL-2:randomized,phase III REAL 2:研究目标研究目标n nPrimary endpoint of non-inferiority in overall survivaln nXeloda vs.5-FUXeloda vs.5-FUn noxaliplatin vs.cisplatinoxaliplatin vs.cisplatinn nSecondary endpointsn nORR and response durationORR and response durationn nPFSPFSn nsafetysafetyn nQoLQoLSumpter K et al.Br J Cancer 2005;92:197683.晚期胃癌化疗策略21REAL 2:研究目标Primary endpoint oREAL 2 interim analysis:good response with oxali-vs.cisplatin%Cisplatin armsECF&ECX(n=94)Oxaliplatin armsEOF&EOX(n=102)ORR3343CR54PR2839SD3330D.Cunningham Md ASCO 2006晚期胃癌化疗策略22REAL 2 interim analysis:good 1-year S 1-year S(%)(%)Median OSMedian OS(months)(months)HRHR2x2 comparisons2x2 comparisons5-FU:ECF+EOF5-FU:ECF+EOF39.439.49.69.61 1Capecitabine:ECX+EOXCapecitabine:ECX+EOX44.644.610.910.90.860.86Cisplatin:ECF+ECXCisplatin:ECF+ECX40.140.110.110.11 1Oxaliplatin:EOX+EOFOxaliplatin:EOX+EOF43.943.910.410.40.920.92REAL 2:survival outcomes晚期胃癌化疗策略231-year S Median OSHR2x2 comparUpdated results for four regimens1 year OS(95%1 year OS(95%CI)CI)Median Median OSOSHR(95%CI)HR(95%CI)ECF ECF n=263n=26337.7%(31.8-37.7%(31.8-43.6)43.6)9.9 mths9.9 mths1 1EOF EOF n=245n=24540.4%(34.2-40.4%(34.2-46.5)46.5)9.3 mths9.3 mths0.95(0.79-0.95(0.79-1.15)1.15)ECX ECX n=250n=25040.8%(34.7-40.8%(34.7-46.9)46.9)9.9 mths9.9 mths0.92(0.76-0.92(0.76-1.11)1.11)EOX EOX n=244n=24446.8%(40.4-46.8%(40.4-52.9)52.9)11.2 mths11.2 mths0.80(0.65-0.80(0.65-0.97)0.97)D.Cunningham Md ASCO 2006晚期胃癌化疗策略24Updated results for four regimECFECFEOFEOFECXECXEOXEOXGrade 3/4 non-Grade 3/4 non-haematological toxicity,haematological toxicity,%3636424233334545Grade 3/4 neutropenia,Grade 3/4 neutropenia,%4242303051512828p-valuep-value0.0080.0080.0080.0080.00430.00430.0010.001REAL 2:safety outcomesn nThere was less neutropenia in the Eloxatin-There was less neutropenia in the Eloxatin-containing arms compared with the cisplatin-containing arms compared with the cisplatin-containing armscontaining arms晚期胃癌化疗策略25ECFEOFECXEOXGrade 3/4 non-haemREAL 2:conclusionsn nThe primary objective of the trial was met:The primary objective of the trial was met:n nCapecitabine is not inferior to 5-FUCapecitabine is not inferior to 5-FUn nOxaliplatin is not inferior to cisplatinOxaliplatin is not inferior to cisplatinn nIn these triplet regimens In these triplet regimens n nCapecitabine could replace 5-FU Capecitabine could replace 5-FU n nOxaliplatin could replace cisplatin Oxaliplatin could replace cisplatin n nThe use ofThe use of EOX EOX is associated with improved is associated with improved efficacy over ECFefficacy over ECF以以EPIEPI为基基础的三的三药联合可行！合可行！EOXEOX有明有明显生存生存优势！晚期胃癌化疗策略26REAL 2:conclusionsThe primaryOxaliplatin联合EPI、5-FU/CF治疗晚期胃癌的临床多中心研究 china用药方法用药方法乐乐乐乐沙沙沙沙定定定定 100mg/m100mg/m100mg/m100mg/m2 2 2 2 d d d d1 1 1 1EPI 50mg/mEPI 50mg/mEPI 50mg/mEPI 50mg/m2 2 2 2 d d d d1 1 1 1CF 200mg/mCF 200mg/mCF 200mg/mCF 200mg/m2 2 2 2 d d d d1-31-31-31-35-FU 500mg/m5-FU 500mg/m5-FU 500mg/m5-FU 500mg/m2 2 2 2 CIV d CIV d CIV d CIV d1-31-31-31-3每每每每3 3周周周周重重重重复复复复，治治治治疗疗疗疗至至至至少少少少3 3个个个个周周周周期期期期评价疗效及毒性反应评价疗效及毒性反应评价疗效及毒性反应评价疗效及毒性反应CR 2CR 2例（例（5.6%5.6%）PR 13PR 13例（例（36.1%36.1%）SD 17SD 17例（例（47.2%47.2%）总有效率总有效率41.7%。其中初治患者其中初治患者9/209/20（45%45%）复治患者复治患者6/166/16（37.5%37.5%）主要不良反应主要不良反应：骨髓抑制：骨髓抑制：-O OANC7/36ANC7/36（19.4%19.4%），），O OPLT3/36PLT3/36（8.3%8.3%），），O O HbHb4/364/36（11.1%11.1%），），O O神经末梢毒性神经末梢毒性 4/364/36（11.1%11.1%），），晚期胃癌化疗策略27Oxaliplatin联合EPI、5-FU/CF治疗晚期胃first-line chemotherapy with fluorouracil,leucovorin and oxaliplatin(FLO)versus fluorouracil,leucovorin and cisplatin(FLP)FLOF 2600mg/m2 24h infusion,L 200mg/m2,oxaliplatin 85mg/m2 q2wFLPF 2000mg/m2 24h infusion,qwL 200mg/m2,qw cisplatin 50mg/m2,q2w.Total 220 pts Median age 64 yrs Advanced and/ormetastatic gastric cancer(AGC)RANDO MIZATIONS.Al-Batran,J.Hartmann,ASCO 2006晚期胃癌化疗策略28first-line chemotherapy with fSuperior Performance with FLO vs.FLPConfirmed Confirmed responseresponse%(95%CI)%(95%CI)FLOFLO(N=98)(N=98)FLPFLP(n=102)(n=102)p-valuep-valueOverall responseOverall response34%34%27%27%0.012 0.012 TTPTTP5.75.73.83.80.0810.081TTFTTF5.35.33.13.10.0280.028S.Al-Batran,J.Hartmann,ASCO 2006晚期胃癌化疗策略29Superior Performance with FLO 奥沙利铂5FU作为一线治疗1.De Vita et al.Br J Cancer 2005;92:164449.2.Al-Batran et al.J Clin Oncol 2004;22:65863.3.Al-Batram et al,ASCO 2005,Abstract 4014.方案方案方案方案例数例数例数例数缓解率缓解率缓解率缓解率疾病进展疾病进展疾病进展疾病进展时间时间时间时间/总总总总生存期生存期生存期生存期3-43-4度的度的度的度的神经病神经病神经病神经病变变变变FOLFOX4FOLFOX41 1616138%38%7.1/11.27.1/11.25%5%FOLFOX6FOLFOX62 2414143%43%-/9.6-/9.60 0改良的改良的改良的改良的FOLFOX6 FOLFOX6 vsvs5-Fu(AIO)5-Fu(AIO)顺铂顺铂顺铂顺铂3 3105105（8080例可评价）例可评价）例可评价）例可评价）39.1%39.1%24.2%24.2%-54.5%54.5%19.4%19.4%晚期胃癌化疗策略30奥沙利铂5FU作为一线治疗1.De Vita et alOxaliplatin/CF/5-FU vs paclitaxel/CF/5-FU in pats with advanced gastric cancerA phase II clinical trialA phase II clinical trial T.Lin ASCO2006 Abstr 14014armA FOLFOX6armA FOLFOX6armB FOLFPaarmB FOLFPa PTX 80 mg/m2PTX 80 mg/m2病例数病例数病例数病例数46464343CR+PRCR+PR37.0%37.0%47.2%47.2%CR+PR+SDCR+PR+SD76.1%76.1%69.4%69.4%TTPTTP6.0 m6.0 m3.2 m3.2 m?OSOS13.4 m13.4 m13.8 m13.8 m晚期胃癌化疗策略31Oxaliplatin/CF/5-FU vs paclitaPhase II multicenter trial of docetaxel+oxaliplatin in stage IV gastroesophageal and/or stomach cancerPATIENT PROFILE:Median age=59.4 years72%male patients,76%whiteECOG PS scores:0(45%);1(49%);2(6%)32.8%of patients had distal gastric cancerN=71Eligibility:Patients with metastatic(Stage IV)AGEJ/SENDPOINTS:Primary:ORR,Secondary:time to response,duration of response,TTP,toxicity,1-and 2-year survivalDocetaxel60 mg/m2 1h IV D1;q3wOxaliplatin130 mg/m2 2h IV D1;q3w+Richards DARichards DA et al.et al.2006 ASCO 2006 ASCO Abstract 4071Abstract 4071晚期胃癌化疗策略32Phase II multicenter trial of Results:efficacyNN%Best responseBest responsePartial responsePartial response25 25 3 38 8Stable disease(SD 6 months;3 Stable disease(SD 6 months;3 patients)patients)34345 52 2Progressive diseaseProgressive disease7 71 11 1Clinical benefit rateClinical benefit rate28284 42 2Time to response(months)Time to response(months)Median Median 1.3 1.3 Range Range 1.14.4 1.14.4Duration of response(months)Duration of response(months)Median Median 4.6 4.6 Range Range 2.718.3 2.718.3Estimated overall survival rateEstimated overall survival rate Media survival time 95%CI Media survival time 95%CI 9.2 months 6.5 9.2 months 6.511.211.2RR of 38%similar to TAX 325;OS of 9.2 months similar to TAX 325晚期胃癌化疗策略33Results:efficacyN%Best responAdverse events(Grade 3/4)Adverse events(Grade 3/4)Total(%)Total(%)HaematologicalHaematological Leukopenia Leukopenia Neutropenia Neutropenia Thrombocytopenia Thrombocytopenia Febrile neutropenia Febrile neutropenia171770707 77 7Non-haematologicalNon-haematological Dehydration Dehydration Diarrhoea Diarrhoea Fatigue Fatigue Nausea Nausea Vomiting Vomiting13131313131316161717Results:toxicity晚期胃癌化疗策略34Adverse events(Grade 3/4)TotML17032:CAPE vs 5-FU trial designFPCisplatin80 mg/m2 3-hour i.v.infusion5-FU c.i.800 mg/m2/day;d15 q3wXPCisplatin80 mg/m2 3-hour i.v.infusionCapecitabine 1000 mg/m2 twice daily;d114 q3wKPS 70%1875 yearsAdvanced and/ormetastatic gastric cancer(AGC)1 measurable lesionNo prior treatment for AGCRANDO MIZATION晚期胃癌化疗策略35ML17032:CAPE vs 5-FU trial Superior response rate with XP vs.FPConfirmed Confirmed responseresponse%(95%CI)%(95%CI)XPXP(n=160)(n=160)FPFP(n=156)(n=156)p-valuep-valueOverall responseOverall response41 41(33(33 49)49)29 29(2237)(2237)0.0300.030Complete Complete responseresponse2 23 30.6680.668Partial responsePartial response393926260.0190.019Progressive Progressive diseasedisease101018180.0410.041晚期胃癌化疗策略36Superior response rate with XPML17032:XP vs FPprogression-free survival HR 0.81 Estimated probabilityHR=0.81(95%CI:0.631.04)Compared to HR upper limit 1.25,p=0.00080Months24681012141618202224261.00.80.60.40.20.0Per protocol analysisXP(n=139)FP(n=137)Median PFSmonths(95%CI)5.6(4.97.3)5.0(4.26.3)晚期胃癌化疗策略37ML17032:XP vs FPprogressionSimilar all-grades hematologic adverse events:XP vs.FP%of patients%of patientsXPXP(n=1(n=15656)FPFP(n=(n=155155)NeutropeniaNeutropenia33333030Leukopenia Leukopenia 14141717AnemiaAnemia12125 5ThrombocytopeniaThrombocytopenia6 66 6晚期胃癌化疗策略38Similar all-grades hematologA Phase II Trial of Capecitabine and DDP in AGCChina2002.6-2003.5,N=145,2002.6-2003.5,N=145,Cape 1000mg/m2 Bid d1-Cape 1000mg/m2 Bid d1-1414 DDP 20mg/m2 iv d1-5 DDP 20mg/m2 iv d1-5 q3W q3W130pts evaluable:98M/32F 130pts evaluable:98M/32F Age:53.7ys Age:53.7ysResultsCR 10(8%)PR 48(37%)SD 51(39%)PD 21(16%)OS 12mSafety：grade 3-4 adverse event 5%-2005,2006 ASCO晚期胃癌化疗策略39A Phase II Trial of CapecitabiSummary of Combination Chemotherapy with CAPE in AGCRegimenXXPTX DXDX(weekly)ECXDXPN4442 45 42555440RR(%)3455 49 60405968TTP(mo)3.26.3 5.7 5.24.56.07.8OS(mo)9.510.1 11.4 10.512.09.616.9Neut(%)G3/4032 47 15*366063NeutFever(%)000791910TxDeath-11X;Xeloda,P;Cisplatin,T;Taxol,D;Docetaxel,E;Epirubicin,C;Cisplatin*not based on weekly CBC 晚期胃癌化疗策略40Summary of Combination ChemothCAPE vs 5-FU in doublet regimens for AGCStudiesStudiesn nRR(%)RR(%)PFS/TTPPFS/TTPmonthsmonthsOSOSmonthsmonthsOxaliplatin+5-FUOxaliplatin+5-FU1 1Oxaliplatin+XOxaliplatin+X2 244442020404065655.85.87.57.59.39.3too earlytoo earlyIrinotecan+5-FUIrinotecan+5-FU3 3Irinotecan+XIrinotecan+X4 41721723838323246465.05.05.15.19.09.08.68.6Paclitaxel+5-FUPaclitaxel+5-FU5 5Paclitaxel+XPaclitaxel+X6 638384040424250504.34.36.86.89.99.913.613.6Docetaxel+5-FUDocetaxel+5-FU7 7Docetaxel+XDocetaxel+X8 84343383838386060 5.55.55.25.29.59.510.510.51.Al-Batran S Proc Am Soc Clin Oncol 2005;(Abst 4015);2.Park Y Br J Cancer 2006;94:95963;3.Dank M Proc Am Soc Clin Oncol 2005;(Abst 4003);4.Baek J Br J Cancer 2006 Apr 25;5.Park S.Anticancer Drugs 2006;17:2259;6.Kang.H.Proc Am Soc Clin Oncol 2004;(Abst 4051,poster update);7.Thuss-Patience P J Clin Oncol 2005;23:494501;8.Park Y Br J Cancer 2004;90:132933 晚期胃癌化疗策略41CAPE vs 5-FU in doublet regime新的探索和循证医学证据新的探索和循证医学证据n nCAPE5-FUn nOXA DDPn n重新设定剂量强度或改变剂量密度重新设定剂量强度或改变剂量密度n n增、减药物联合增、减药物联合n n续惯。续惯。晚期胃癌化疗策略42新的探索和循证医学证据CAPE5-FU晚期胃癌化疗策略42 irinotecan plus capecitabine in patients with AGC n nN=38/40/41 N=38/40/41，n nCape 1000 mg/m2 BID day 1-14 Cape 1000 mg/m2 BID day 1-14 irinotecan 100 mg/m2 d 1 irinotecan 100 mg/m2 d 1，8 8 Q3W Q3Wn nRR 46.3%.TTP 5.1 RR 46.3%.TTP 5.1 OS 8.6 mOS 8.6 m,n n Grade 3/4 neutropenia in 4 pats Grade 3/4 neutropenia in 4 pats grade 3 febrile neutropenia in 2 pats.grade 3 febrile neutropenia in 2 pats.grade 3 diarrhea grade 3 diarrhea grade 2 HFS in 6 patients grade 2 HFS in 6 patients J.Baek ASCO2006，ABSTR14037 n nIri 80 mg/m2 on d1,8,and 15 Iri 80 mg/m2 on d1,8,and 15 n ncape 625 mg/m2 BID D1-14;cape 625 mg/m2 BID D1-14;Q 4 wQ 4 w n n29/31 pts were evaluable for 29/31 pts were evaluable for responseresponsen nPR 38.5%.SD29%,PR 38.5%.SD29%,n nTTP 5.8 months TTP 5.8 months n n OS 10.5 monthsOS 10.5 monthsn nno grade III-IV toxicityno grade III-IV toxicity F.Farhat ASCO2006 Abstr 14030 晚期胃癌化疗策略45 irinotecan plus capecitabine n nN=45/48N=45/48 irinotecan 150 mg/m2 d1 irinotecan 150 mg/m2 d1 oxaliplatin 85 mg/m2 d1 oxaliplatin 85 mg/m2 d1 lv 100 mg/m2/d lv 100 mg/m2/d 5-FU 2000 mg/m2 48-h ci d1,Q 2 w 5-FU 2000 mg/m2 48-h ci d1,Q 2 wn nRR 73.3%RR 73.3%（2 CRs and 31 PR2 CRs and 31 PR）.SD 9%PD 18%.SD 9%PD 18%n nestimated estimated mOS 14.0 m estimated mTTP 8.9 mmOS 14.0 m estimated mTTP 8.9 mn ngrade 3/4 toxicities were neutropenia(11%of all grade 3/4 toxicities were neutropenia(11%of all cycles)and emesis(12%)cycles)and emesis(12%)FOLFOXIRI combination chemotherapy in metastatic or recurrent gastric cancerJ.Lee ASCO2006 Abstr 4076晚期胃癌化疗策略47N=45/48FOLFOXIRI combination cCapecitabine and docetaxel for advanced gastric cancer n npart I part I：Docetaxel 75 mg/m2 d1,capecitabine Docetaxel 75 mg/m2 d1,capecitabine 2000 mg/m2 d1-14,q3w.2000 mg/m2 d1-14,q3w.CR 2.6%,PR 52.6%,NC 36.8%,PD 7.9%,CR 2.6%,PR 52.6%,NC 36.8%,PD 7.9%,RR:55.3%RR:55.3%n nIn part II In part II：further improve tolerability further improve tolerability：reduced the dose of docetaxel to reduced the dose of docetaxel to 60 mg/m260 mg/m2 and and capecitabine to capecitabine to 1600 mg/m21600 mg/m2 to toP.C.Thuss-Patience,2006ASCO Abstr:4068晚期胃癌化疗策略49Capecitabine and docetaxel forTaxanes+5-FU或CDDP二联治疗AGC方法：PCT 175mg/m2/3w,DCT 75-85mg/m2/3w5-FU 750mg/m2 civ,d1-5/3w或 200-300mg/m2/3w civ2w/3wCDDP 20mg/m2 I.V.d1-5/3w或75mg/m2 I.V./d1/3w晚期胃癌化疗策略50Taxanes+5-FU或CDDP二联治疗AGC方法：A phase I/II study of oxaliplatin,docetaxel,and capecitabine in advanced carcinoma of the esophagus and stomach.DLT：Grade 3/4 diarrhea,nausea,and febrile neutropenia RD：Oxaliplatin 50 mg/m2 and docetaxel 35 mg/m2 day 1 and 8 capecitabine 750mg/m2 BID 10 days Q21 day D.L.Evans ASCO2006 Abstr 14046晚期胃癌化疗策略51A phase I/II study of oxaliplaA phase II study of alternating chemotherapy with CDDP/5FU/FA and epirubicin(E)/docetaxel(T)(CF-ET regimen)as first line therapy for pts with MGC n nN=34 N=34 CDDP 35 mg/m2 d1,2,15 and 16,CDDP 35 mg/m2 d1,2,15 and 16,5FU 2000 mg/m2 ci d 1,8,15 and 22,5FU 2000 mg/m2 ci d 1,8,15 and 22,FA 200 mg/m2 iv d 1,8,15 and 22 FA 200 mg/m2 iv d 1,8,15 and 22 E 60 mg/m2 d 29 and 43,E 60 mg/m2 d 29 and 43,T 60 mg/m2 d 29 and 43 q 8WT 60 mg/m2 d 29 and 43 q 8Wn n RR 64.5%.The median response duration was RR 64.5%.The median response duration was 6.1 months.OS 11.4 months 6.1 months.OS 11.4 months。n n Grade 3/4 toxicities Grade 3/4 toxicities：leukopenia 41/37.5%,leukopenia 41/37.5%,neutropenia 16/82%,thrombocytopenia neutropenia 16/82%,thrombocytopenia 23.2/0%,23.2/0%,H.H.Kirchner ASCO2006 Abstr 14021续贯续贯晚期胃癌化疗策略52A phase II study of alternatin靶向治疗靶向治疗靶点靶点靶点靶点期期期期Her-2Her-2HerceptinHerceptinVEGFVEGFBevacizumab(AvastinBevacizumab(Avastin)EGFREGFR西妥昔单抗（西妥昔单抗（西妥昔单抗（西妥昔单抗（C225C225）多靶点多靶点多靶点多靶点Sutent(Sunitinib)Sutent(Sunitinib)晚期胃癌化疗策略53靶向治疗靶点期Her-2HerceptinVEGFBeVEGFRn nBevacizumab抑制抑制VEGFRn n在转移性病变中顺铂和伊立替康在转移性病变中顺铂和伊立替康在转移性病变中顺铂和伊立替康在转移性病变中顺铂和伊立替康（MSKCCMSKCC）n n辅助辅助辅助辅助ECFECF方案（方案（方案（方案（MAGIC-2MAGIC-2实验）实验）实验）实验）晚期胃癌化疗策略55VEGFRBevacizumab抑制VEGFR晚期胃癌化疗策胃癌靶向治疗胃癌靶向治疗Bevacizumab（BEV）联合）联合PT-11+DDP一线治疗一线治疗AGC-II期临床试验（ASCO 2005）BEV 15mg/kg d1CPT 65mg/m2 d1，8DDP 30mg/m2 d1，8q3wN=24 3m PFS 89%6m PFS 76%16例可评价近期疗效例可评价近期疗效 PR（12/16）75%MR 3，SD 1不良反应（不良反应（24例）：例）：级白细胞减少、恶心呕吐、腹泻级白细胞减少、恶心呕吐、腹泻 8%血栓（血栓（4肺和肺和2深静脉）：深静脉）：6例（例（20%）；）；2例胃穿孔，例胃穿孔，2例几近穿孔（肿瘤部位）例几近穿孔（肿瘤部位）M.A.ShAh et al:ASCO 2005 abstr 4025晚期胃癌化疗策略56胃癌靶向治疗Bevacizumab（BEV）联合PT-11+CPT-11、DDPBevacizumabin AGCn n仅进行了初步的治探索仅进行了初步的治探索n n正在进行或准备之中正在进行或准备之中n n早期的效果令人鼓舞早期的效果令人鼓舞n n但需要注意一些确定的潜在毒性（如血栓但需要注意一些确定的潜在毒性（如血栓形成、穿孔）形成、穿孔）Shah MA et al,ASCO 2005.晚期胃癌化疗策略57CPT-11、DDPBevacizumabin AGC仅新药新方案的选择小结新药新方案的选择小结新世纪的选择趋向新世纪的选择趋向n n紫杉烷类紫杉烷类紫杉烷类紫杉烷类(DOC)(DOC)顺铂顺铂顺铂顺铂+5-Fu+5-Fu /CAPE/S-1CAPE/S-1n nCAPECAPEOXA/DDPOXA/DDPn nOXAOXAEPI+CAPE EPI+CAPE/5-Fu/5-Fu n n伊立替康伊立替康伊立替康伊立替康5-Fu/5-Fu/CAPE/S-1CAPE/S-1/DDP/DDPn n分子靶点药物分子靶点药物分子靶点药物分子靶点药物晚期胃癌化疗策略58新药新方案的选择小结新世纪的选择趋向紫杉烷类(DOC)OXA治疗胃癌：治疗胃癌：n n与与与与5 5FUFU联合高效、安全！生存期延长尚不理想联合高效、安全！生存期延长尚不理想联合高效、安全！生存期延长尚不理想联合高效、安全！生存期延长尚不理想n nCAPECAPE替代替代替代替代5 5FUFU与之联合有望延长生存期与之联合有望延长生存期与之联合有望延长生存期与之联合有望延长生存期n n作为三药联合取代作为三药联合取代作为三药联合取代作为三药联合取代DDPDDP，疗效、安全性及生存期，疗效、安全性及生存期，疗效、安全性及生存期，疗效、安全性及生存期改善改善改善改善n n或或或或CPT/TAX+CAPE/FUCPT/TAX+CAPE/FU，以期进一步提高疗效，以期进一步提高疗效，以期进一步提高疗效，以期进一步提高疗效延长生存延长生存延长生存延长生存XELOX;EOF vs FOLFOX;DOX vs DCF-需进一步临床试验证实！需进一步临床试验证实！晚期胃癌化疗策略59OXA治疗胃癌：与5FU联合高效、安全！生存期延长尚不理想Taxanes在胃癌中应用的关键在胃癌中应用的关键减毒减毒通过通过改变改变剂量或方案剂量或方案n n疗效不减低疗效不减低疗效不减低疗效不减低n n不良反应减少不良反应减少不良反应减少不良反应减少n n疗效明确疗效明确疗效明确疗效明确n n从三药联合改为两药：减去从三药联合改为两药：减去从三药联合改为两药：减去从三药联合改为两药：减去DDPDDPn nCAPE 5-FU CAPE 5-FU n nOXA DDP OXA DDP n nDOCDOC改为周给药方法改为周给药方法改为周给药方法改为周给药方法n