消化道肿瘤ESMO.ppt

The title goes here Arial 24pt,First level(Arial 20 pt),Second level(Arial 18 pt),Third level(Arial 16 pt),Fourth level(Arial 14 pt),*,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,The title goes here Arial 24pt,First level(Arial 20 pt),Second level(Arial 18 pt),Third level(Arial 16 pt),Fourth level(Arial 14 pt),文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,The title goes here Arial 24pt,First level(Arial 20 pt),Second level(Arial 18 pt),Third level(Arial 16 pt),Fourth level(Arial 14 pt),文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,ESPAC-3,PANCREAS,LIVER/BILIARYNETs,GASTRIC,GIP-1ABC-02PROMIDTOGA,AIO-PK0104EACH,A6181111AVAGAST,Prodige IV-Accord 11RADIANT-1,AIO(2nd line),NCT00219557,Conko-4/FRAGEM,VEGFR polymorphisms,ADVANCED,ADJUVANT,Pancreatic cancer background,Adjuvant:,Both FU and gemcitabine shown to improve OS,Role of RT controversial,Advanced:,Gemcitabine monotherapy=standard for 10 years,Clinical benefit in 20-30%of pts;median OS 6-8 m;1-y S 20-30%,Controversial improvement adding a second cytotoxic(fluoropyrimidines,platinum derivatives:positive meta-analysis but negative single studies),Small improvement(clinical relevance questioned)adding erlotinib;no improvement with other biologics(cetuximab,bevacizumab),Oxaliplatin/FU/LV:best option after gemcitabine failure(2nd line),High incidence of venous thromboembolism(17-30%),Resected pancreatic ductal adenocarcinoma,FU/LV vs Gemcitabine(ESPAC-3),Neoptolemos et al.ASCO 2009;Abstract LBA4505,No difference in efficacy,B,etter toxicity profile with gemcitabine(more myelotoxicity but less stomatitis and diarrhea;less tx related SAEs overall),Global QL scores no difference-ESPAC-4:GEM+/-capecitabine,Survival by treatment,PFS by treatment,Survival(%),12,24,36,48,60,0,25,50,75,100,Months from resection,X,2,LR,=0.74,p=0.39,HR,GEM VS SFU/FA,=0.94(95%CI:0.81,1.08),0,Median S(t)=23.0 months(95%CI:21.1,25.0),Median S(t)=23.6 months(95%CI:21.4,26.4),5FU FA,GEM,No.at risk,5FU FA5514132491093615,GEM5374152511034213,PFS(%),12,24,36,48,60,0,25,50,75,100,Months from resection,X,2,LR,=0.59,p=0.44,HR,GEM VS SFU/FA,=0.95(95%CI:0.83,1.09),0,Median PFS(t)=14.1 months(95%CI:12.5,15.3),Median PFS(t)=14.3 months(95%CI:13.5,15.7),5FU FA,GEM,No.at risk,5FU FA551296160642311,GEM537319152682211,Advanced pancreatic cancerGemcitabine+/-cisplatin(GIP-1),Additional negative randomized study on a gemcitabine doublet compared to gemcitabine alone(previous meta-analysis not confirmed),Colucci et al.ASCO 2009:Abstract 4504;Colucci et al.J Clin Oncol 2010;28:1645-1651,n,mOSmonths,mPF,months,RR,%,Gemitabine,199,8.3,3.9 m,10.1,Gem/cisplatin,201,7.2,3.8 m,12.9,p,0.38,0.80,0.37,Advanced pancreatic cancerAIO-PK0104,Boeck et al.ASCO 2010;Abstract LBA4011,Similar OS and overall TTF with either sequence.Gemcitabine more active(response rate and TTF)than capecitabine(both as 1st and 2nd line),AA placebo,Overall survival,TTF after 2nd line(1ry endpoint),Gemcitabine+Erlotinib,-Capecitabine,Capecitabine+Erlotinib-Gemcitabine,R,(n=281),Metastatic,pancreatic cancer,Gemcitabine vs FOLFIRINOX,(Prodige IV-Accord 11 study)n=342(ECOG PS 0-1;2/3 body and tail),Conroy et al.ASCO 2010;Abstract 4010,Progression-free survival,Overall survival(1ry endpoint),HR=0.47:95%CI 0.37-0.59,p0.0001,HR=0.57:95%CI 0.45-0.73,p0.0001,mPFS:6.4 vs 3.3 mo,mOS:11.1 vs 6.8 mo,First study to show a superior outcome(OS,PFS,and RR)compared with gemcitabine.New treatment option for metastatic pancreatic cancer but toxicity limits routine application(grade 3-4 neutropenia:46%;grade 3-4 fatigue:25%).Adjuvant study planned,Probability,Months,Months,0.00,0.25,0.50,0.75,1.00,Probability,0,3,6,9,15,18,21,24,27,30,33,36,12,0.00,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,21,24,27,30,33,36,FOLFIRINOX,FOLFIRINOX,Advanced pancreatic cancer,Gemcitabine+/-Axitinib(NCT 00219557),Additional negative randomized study of a VEGF inhibitor combined with gemcitabine compared to gemcitabine alone,Kindler et al.ECCO-ESMO 2009;Abstract O-6502,Overall survival,Months,Probability,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,0.0,0.20,0.40,0.60,0.80,1.00,Axitinib+gemcitabine8.5 months(95%CI:6.9-9.5),Placebo+gemcitabine,8.3 months(95%CI:6.9-10.3),HR=1.014(95%CI:0.786-1.309),1-sided p=0.5436,Median survival,Bevacizumab,Placebo,AA genotype,AC genotype,CC genotype,Advanced pancreatic cancer,Lambrechts et al.ECCO-ESMO 2009;Abstract 16LBA,OS(overall population),Analysis of VEGFR-1 polymorphisms may help identify a subset deriving benefit from bevacizumab,Retrospective analysis of VEGF polymorphisms in the AVITA trial,OS by genotype,Metastatic pancreatic cancer(n=607),Gemcitabine+erlotinib+placebo(n=301),Gemcitabine+erlotinib+bevacizumab(n=306),Survival(%),0,0.4,0.6,0.8,1.0,0,0.2,Time(months),3,6,9,12,15,18,21,24,Median OS,Gemcitabine+erlotinib+bevacizumab:7.1 Months,Gemcitabine+erlotinib+placebo:6.0 months,p=0.2087;HR=0.89(95%CI:0.74-1.07),0,0.4,0.6,0.8,0,0.2,Time on study(days),200,400,600,800,1.0,AA beva,AA placebo,Advanced pancreatic cancerRole of low molecular weight heparin,Prophylactic LMWH concomitant to chemotherapy(at least 3 months)significantly reduces the rate of thromboembolic events(,but does not improve survival),FRAGEM STUDY,CONKO-4 1st-line chemo+/-enoxaparin,FRAGEM,1st-,line chemo+/-dalteparin,VTE(first 3 months),p0.01,%,Riess ASCO 2009-2010;Pelzer ECCO-ESMO 2009,Maraveyas ECCO-ESMO 2009,%,0.00,4.00,6.00,8.00,10.00,2.00,Observation,Enoxaparin,9.9%,1.3%,VTE profile,Control,LMWH,0,10,20,25,35,5,RR=0.38,p0.02,RR=0.138,p0.002,RR=0.046,p0.001,RR=0.083,p0.028,AllOverall,100D,ClinicalVTE 100D,LethalVTE new reference treatment,Bridgewater et al.ECCO-ESMO 2009;Abstract 6500;Valle et al.ASCO 2009;Abstract 4503,PFS,OS,n=410,Well-differentiated GI neuroendocrine tumors background,Rare tumors but incidence is increasing,Site of primary affects prognosis(mid-gut better than pancreas),Limited treatment options if unresectable:,Debulking surgery,regional therapies(radiofrequency,chemo-embolization),and targeted radiotherapy provide some palliation,Somatostatin analogs primarily relieve symptoms(limited and controversial data on control of tumor growth),Cytotoxic chemotherapy has limited efficacy,Well-developed vasculature/expression of several angiogenic proteins-potential target for anti-angiogenic agents(promising activity of multiple anti-vascular agents in phase II studies supports the hypothesis),Well-differentiated untreated mid-gut NETs,Octreotide LAR vs placebo,PROMID,Arnold et al.ASCO 200;Abstract 4508:Rinke et al.J Clin Oncol 2009;27:4656-4663,Significant,TTP improvement independent of functional and CgA status -support an anti-proliferative effect of octreotide LAR,HR:0.33 95%CI:0.19-0.55 p=0.000017,0.00,0.50,0.75,1.00,0.25,0,12,24,36,48,Time(months),54,66,78,90,Proportion without progression,Octreotide LAR:42 patients/27 eventsMedian 15.6 months 95%CI:11.0-29.4,Placebo:43 patients/41 eventsMedian 5.9 months 95%CI:5.5-9.1,6,18,30,42,60,72,84,Progressing,well-differentiated pancreatic NETs,Sunitinib vs placebo*,Study A 6181111,*With BSC.Somatostatin analogs were permitted,Raoul et al.ECCO-ESMO 2009:Abstract O-6501;Raymond et al.ASCO 2010;Abstract 4031,PFS(primary endpoint),Early termination due to difference in efficacy at interim analysis(154 of 340 pts randomized),Strong support for clinical use(1ry endpoint met/initial effect on survival observed/efficacy maintained across different subtypes in subgroup analysis),VEGF confirmed to be a crucial target in NETs,Overall survival,0,0.6,0.8,1.0,0.4,0,5,10,Time(months),15,20,25,HR=0.418(95%CI 0.263,0.662)p=0.0001,Sunitinib,Placebo,Median PFS,11.4 months(95%CI 7.4,19.8),5.5 months(95%CI 3.6,7.4),Proportion of patients,0.2,0,0.6,0.8,1.0,0.4,0,5,10,Time(months),15,20,25,HR=0.409(95%CI 0.187,0.894)p=0.0204,Sunitinib,Placebo,Proportion of patients,0.2,Pancreatic NETs progressing after 1st-line Tx,Oral everolimus,Pavel et al.ECCO-ESMO 2009:Abstract PD-6514;Yao et al.J Clin Oncol 2010;28:69-76,Stratum 1Stratum 2,RR,%9.64.4,mPFS,m9.716.7,mOS,m24.9not reached,CgA reponse,%50.760.0,RADIANT-1(,PHASE II STUDY),Daily everolimus has anti-tumor activity in pre-treated pancreatic NETs(consistent with previous data on untreated NETs),Stratum 1,not being treated with octreotide LAR at study entry(n=115),Stratum 2,on octreotide LARsince,3 months at study entry(n=45),Gastric cancer background,Early:,Peri-operative CT:13%5-y survival improvement,Post-op chemoradiation:10%3-y survival improvement,Post-op chemotherapy:5%5-y survival improvement,Advanced:,Palliative chemotherapy improves survival and QoL,Combination chemo better than single agent(but three drug regimens not clearly better than platinum/FU doublets):,CF(CI FU+cisplatinum),RR:20-30%;mOS:8-9 months,Capecitabine may replace CI FU,ECF(CI FU+cisplatinum+epidoxorubicin),RR:40-45%;mOS:9 months,Capecitabine may replace CI FU;oxaliplatin may replace cisplatinum,DCF(CI FU+cisplatinum+docetaxel),RR:36%;mOS:9 months,Toxicity is an issue,Van Cutsem et al.ASCO 2009;Abstract LBA4509:Van Cutsem et al.ECCO-ESMO 2009;Abstract 7BA,Trastuzumab significantly improves the efficacy and activity of chemotherapy in HER-2+advanced gastric cancer(greater benefit in pts with higher immunoreactivity in exploratory analysis)-standard option in this group of patients,Advanced gastric cancer,ToGA trial,0,0.6,0.8,1.0,0.4,0,4,12,Time(months),20,24,32,HR=0.71(95%CI 0.59,0.85)p=0.0002,0.2,8,16,28,PFS,5.5,6.7,0,0.6,0.8,1.0,0.4,0,Time(months),HR=0.74(95%CI 0.60,0.91)p=0.0046,0.2,OS(1ry endpoint),11.1,13.8,3807 patients screened810 HER-2 positive(22.1%),HER-2 positive advanced GC(n=584),R,5-FU or capecitabine+cisplatin(n=290),5-FU or capecitabine+cisplatin+trastuzumab(n=294),34,30,26,22,18,14,10,6,2,0,4,12,20,24,32,8,16,28,34,30,26,22,18,14,10,6,2,36,Advanced gastric cancer,Kang et al.ASCO 2010;Abstract LBA4007,Cape/CDDP+/-bevacizumab(AVAGAST),Use of bevacizumab in advanced gastric adenocarcinoma not supported(1ry end-point OS not met-negative study).,The(modest)effect on RR and PFS(and OS)and the apparent heterogeneity in efficacy results across geographic regions may warrant further studies,n,mOS,mPF,RR,%,Cape/CDDP,387,10.1,5.3 m,37,Cape/CDDP/beva,387,21.1,6.7 m,46,HR,0.87,0.80,p,0.10,0.004,0.03,Thuss-Patience et al.ECCO-ESMO 2009;Abstract O-6504,Irinotecan significantly prolongs overall survival compared with BSC in pre-treated advanced gastric carcinoma(first randomized study showing a benefit for 2nd-line chemo in advanced gastric cancer),Advanced gastric cancer,Irinotecan vs BSC(2nd-line treatment),GASTRIC,PANCREAS,LIVER/BILIARY,NETs,Gem as effective as FU with a more favorable toxicity profile,Single-agent gem remains standard(but not necessarily the backbone for combos),FOLFIRINOX=option for selected patients,Role of concomitant prophylactic LMWH,VEGF polymorphisms may identify subsets benefiting from bevacizumab(research purposes),Cisplatinum+gemcitabine=new reference treatment,for advanced biliary cancer,FOLFOX is active in HCC,Octreotide LAR=treatment option forwell-differentiatedmid-gut NETs(with or w/o syndrome),Strong support for sunitinib use in well-differentiated pancreatic NETs,Everolimus has activity in chemo-pretreated patients(preliminary),Trastuzumab+CDDP/FU=standard for HER-2+patients,No support for use of bevacizumab(but activity not completely ruled out-further studies may be warranted),Phase III support for 2nd-line chemo,ADJUVANT,ADVANCED,