转移性结直肠癌治疗的新进展-.ppt

转移性结直肠癌化疗的新进转移性结直肠癌化疗的新进展展中山大学肿瘤医院 内科何友兼 教授结结 直直 肠肠 癌癌l西方国家中，结 直肠癌占癌症死亡第二位（10%-12%）。l发病率每年递增4.2%。l外科手术五年生存率：期90%、期70%-75%、期35%-50%、期 推注lFOLFOX 的疗效大致与 FOLFIRI相当,但毒性各异l三药方案(FOLFOXIRI)疗效和生存比二药略佳l合用靶向药可提高疗效,改善生存l用足三药(5FU.L-OHP.IRI)者中位生存可超过2年l维持治疗或间歇休息(treatment holiday)应个体化处理效力和毒性效力和毒性:FOLFIRI vs FOLFOXEfficacy/Toxicity5FU/LVIrinotecan OxaliplatinRR(first line)56%54%OS(mo)21.5 20.4G3/4 neutropenia 24%44%G3/4 febrile neutr.7%0%G3/4 mucositis 10%1%G2/3 neurological 0%71%G3/4 diarrhea 14%11%Tournigand et al.JCO 2004.22:229-237III 期试验期试验:FOLFOXIRI vs FOLFIRI作者作者作者作者RR,%RR,%Median Median TTP/PFS,TTP/PFS,MosMedian OS,Median OS,MosSouglakos(n=283)43.0 vs 33.68.4 vs 6.921.5 vs 19.5FalconeFalcone(n=(n=244)244)60 vs 34*60 vs 34*9.8 vs 6.9*9.8 vs 6.9*22.6 vs 16.7*22.6 vs 16.7*Souglakos J,et al.Br J Cancer.2006;94:798-805.Falcone A,et al.J Clin Oncol.2007;25:1670-1676.*Statistically significant difference.用足三药用足三药.改善生存改善生存:Update 200511 Phase III Trials,5768 PatientsOS(mos)=13.2+(%3drugs x 0.1),R2=0.85Grothey&Sargent,JCO 20050 10 20 30 40 50 60 70 80Infusional 5-FU/LV+irinotecanInfusional 5-FU/LV+oxaliplatinBolus 5-FU/LV+irinotecanIrinotecan+oxaliplatinBolus 5-FU/LV LV5FU22221201918171615141312Median OS(mo)Patients with 3 drugs(%)P=.0001First-Line TherapyMultivariate analysis:Effect on OSPFirst-line doublet0.69All 3 drugs0.005 mCRC:一线治疗的中位生存一线治疗的中位生存lBSC06121824Median OS(Mos)4-6 mos12-14 mos 15-16 mos20.3 mos19-20 mos5-FU/LVFOLFOX4 or CAPEOXIFL+BevacizumabIFL or FOLFIRI21.5 mosFOLFOX6FOLFIRI+Bevacizumab24 mos Gallagher DJ,et al.Oncology.2010;78:237-248.mCRC:主要的一线化疗效果主要的一线化疗效果比较方案比较方案中位中位 PFS,Mos中位中位 OS,MosIFL vs FOLFOX vs IROX16.9 vs 8.7 vs 6.515.0 vs 19.5 vs 17.4FOLFIRI vs FOLFOX4FOLFIRI vs FOLFOX4227.0 vs 7.07.0 vs 7.014.0 vs 15.014.0 vs 15.0XELOX(CapeOx)vs FOLFOX43,47.3 vs 7.719.0 vs 18.9FOLFIRI vs mIFL vs FOLFIRI vs mIFL vs CapeIRICapeIRI557.6 vs 5.9 vs 7.6 vs 5.9 vs 5.85.823.1 vs 17.6 vs 23.1 vs 17.6 vs 18.918.91.Goldberg RM,et al.J Clin Oncol.2004;22:23-30.2.Colucci G,et al.J Clin Oncol.2005;23:4866-4875.3.Cassidy J,et al.J Clin Oncol.2008;26:2006-2012.4.Cassidy J,et al.Br J Cancer.2011;105:58-64.5.Fuchs CS,et al.J Clin Oncol.2007;25:4779-4786.mCRC:分子靶点药分子靶点药分子靶点分子靶点药结构构靶点靶点临床床应用用CetuximabCetuximab单单抗抗抗抗EGFREGFR化化化化疗疗抗抗抗抗药药二二二二线线表达表达表达表达EGFREGFREGFREGFR后用后用后用后用化化化化疗疗20%20%20%20%.三三三三线单药线单药10%10%10%10%，皮疹腹泻皮疹腹泻皮疹腹泻皮疹腹泻(Erbitux,C225)(Erbitux,C225)(erbB-1)(erbB-1)PanitumumabPanitumumab全人单抗全人单抗全人单抗全人单抗EGFREGFRCet.Cet.无效时可用无效时可用无效时可用无效时可用,同上同上同上同上BevacizumabBevacizumab单单抗抗抗抗VEGF-AVEGF-A一一一一线线合用化合用化合用化合用化疗疗，疗疗效提高效提高效提高效提高10%10%，生存延，生存延，生存延，生存延长长5 5个月个月个月个月(Avastin)(Avastin)分子靶药物分子靶药物(in CRC):以往临床研究结以往临床研究结果果lCet(Pan),Bev与化疗联合均可增效.延长生存,可用于各线(一.二.三)的治疗lCet(Pan)单药有效,Bev必须与化疗联合使用,两个单抗合用不增效lBev.在一线进展后用仍可获生存效益lCet(Pan)只能用于K-RAS野生型或G13d突变的病人,Bev.的使用不须测靶l首次皮疹程度反映Cet(Pan)的疗效,与K-RAS无关lCet(Pan),Bev 用于术后辅助治疗均未证实有效 VEGF 和和 VEGF-受体家族受体家族VEGF regulates angiogenesis via interaction with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1VEGFR-1(Flt-1)VEGF-AReceptorisoformsLigandisoformsVEGFR-2(KDR)VEGF-BVEGFR-1sAngiogenesisVEGF-E VEGF-CVEGF-DVEGFR-3(Flt-4)Lymph angiogenesistumor metastasesExtracellularIntracellularVEGF-A 165NRP-1PlGFShinkaruk S,et al.Curr Med Chem Anti-Canc Agents.2003;3:95-117.Luttun A,et al.Ann N Y Acad Sci.2002;979:80-93.mCRC:一线化疗一线化疗/贝伐单抗贝伐单抗Comparative Comparative Regimens,MosRegimens,MosPFSPFSOSOSIFL/Bev vs IFL110.6 vs 6.220.3 vs 15.6FOLFOX4/XELOX/Bev vs FOLFOX4/XELOX/Bev vs FOLFOX4/XELOXFOLFOX4/XELOX229.4 vs 8.09.4 vs 8.021.3 vs 19.921.3 vs 19.9FOLFOX/Bev vs FOLFIRI/Bev310.3 vs 10.223.7 vs 25.51.Hurwitz H,et al.N Engl J Med.2004;350:2335-2342.2.Saltz LB,et al.J Clin Oncol.2008;26:2013-2019.3.Bendell JC,et al.Oncologist.2012;17:1486-1495.1.Bevacizumab package insert.South San Francisco,CA:Genentech;2011.2.Nalluri SR,et al.JAMA.2008;300;2277-2285.3.Hurwitz H,et al.J Clin Oncol.2011;29:1757-1764.Adverse EventIncidence With Bev Across Indications,1%CommentsGrade 3 ATE2.6nRisk of ATE increased in pts 65 yrs of age or older or with ATE historyGrade 3/4 HTNGrade 3/4 HTN5-18*5-18*n nPatients should receive otherwise standard CV Patients should receive otherwise standard CV prophylaxis and have BP monitored and managedprophylaxis and have BP monitored and managedGI perforations0.3-2.4Grade 3 Grade 3 hemorrhagic hemorrhagic eventevent1.2-4.61.2-4.6 n nBev not recommended for pts with serious Bev not recommended for pts with serious hemorrhage or recent hemoptysishemorrhage or recent hemoptysisn nRisk of major bleeding does not appear to be Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx increased in pts receiving full-dose anticoagulation tx without other risk factors without other risk factors Wound complications15nDiscontinue 4-8 wks before surgery;resume 6-8 wks postsurgeryPotential for increased VTE risk controversial;increased risk noted in 1 study but not in others.2,3*Predominantly grade 3.May apply more to NSCLC.When surgery conducted during bev therapy.贝伐单抗贝伐单抗:相关毒性相关毒性TrialTrialComparative RegimensComparative RegimensMedian PFS,Median PFS,MosMosMedian OS,Median OS,MosMosCRYSTAL1FOLFIRI/Cetux vs FOLFIRI9.9 vs 8.423.5 vs 20.0OPUSOPUS22FOLFOX4/Cetux vs FOLFOX4FOLFOX4/Cetux vs FOLFOX48.3 vs 7.28.3 vs 7.222.8 vs 18.522.8 vs 18.5PRIME3-5FOLFOX4/Pmab vs FOLFOX49.6 vs 8.023.8 vs 19.4FOLFOX4/Pmab vs FOLFOX4(KRAS/NRAS WT)10.1 vs 7.926.0 vs 20.2COINCOIN66FOLFOX/XELOX/Cetux vs FOLFOX/XELOX/Cetux vs FOLFOX/XELOXFOLFOX/XELOX8.6 vs 8.68.6 vs 8.617.0 vs 17.917.0 vs 17.9KRAS WT mCRC:一线一线EGFR-靶向药靶向药lWorse PFS outcome with panitumumab+FOLFOX4 in mutant KRAS disease31.Van Cutsem E,et al.J Clin Oncol.2011;29:2011-2019.2.Bokemeyer C,et al.Ann Oncol.2010;22:1535-1546.3.Douillard JY,et al.J Clin Oncol.2010;28:4697-4705.4.Douillard JY,et al.ASCO 2013.Abstract 3620.5.Douillard JY,et al.N Engl J Med.2013;369:1023-1034.6.Maughan TS,et al.Lancet.2011;377:2103-2114.mCRC:个体化治疗应考虑个体化治疗应考虑l病变范围l治疗目的(姑息 vs 可能根治)l活动能力l年龄l合并疾病 l以往一年内的辅助治疗l分子标记l器官(肝肾,造血)功能l毒性风险:活动性出血,蛋白尿,伤口不愈,神经病变,过敏,l是否方便l花费/资源l病人意愿mCRC:化疗有关的选择化疗有关的选择可能切除可能切除不能切除不能切除治疗目的治疗目的治疗目的治疗目的 争取治愈争取治愈,延长生延长生存存 延长生存延长生存,改善改善QoLQoL方案选择方案选择方案选择方案选择 二联、三联二联、三联 二联、单药二联、单药序贯序贯序贯序贯/联合联合联合联合 联合联合 联合，也可序贯联合，也可序贯加入靶向药加入靶向药加入靶向药加入靶向药 有条件尽早加入有条件尽早加入 必要时后续加入必要时后续加入维持与否维持与否维持与否维持与否 维持维持 CFI CFI或间断或间断mCRC：化疗选择临床依据：化疗选择临床依据u 无病间歇（DFI),缓解期u PS（01，2）u 年龄（70，70）u 肿瘤分子生物学标记 (TS.DDP.UGT.KRAS.NRAS.BRAF)u 化疗目的(新辅助,辅助)u 患者取舍mCRC:临床处理程序临床处理程序确定治疗目的确定治疗目的选择治疗策略选择治疗策略决定治疗强度决定治疗强度病人是否需要病人是否需要(渇望渇望)积极治疗积极治疗Yes85%No15%KRAS无法检测无法检测野生型野生型突变型突变型5FU/CAPECITABINE+/-Bevacizumab二联化疗二联化疗+Bevacizumab二联二联+Cet二联二联+Bev二联化疗二联化疗+BevacizumabKRAS WT mCRC:一线一线EGFR vs VEGF单抗单抗lThe primary endpoint of ORR was not significantly different between treatment arms in the FIRE-3 study(62%vs 58%;P=.183)21.Schwartzberg LS,et al.ASCO GI 2013.Abstract 446.2.Heinemann V,et al.ASCO 2013.Abstract LBA3506.*Statistically significant difference.TrialTrialComparative Comparative RegimensRegimensPFS,PFS,MosMosOS,MosOS,MosPEAK1(N=285)mFOLFOX6/Pmab vs mFOLFOX6/Bev10.9 vs 10.1NR vs 25.4FIRE-32(N=592)FOLFIRI/Cetux vs FOLFIRI/Bev10.0 vs 10.328.7 vs 25.0*mCRC:其它的生物标志物其它的生物标志物lKRAS G13D1综合有关预测和预后的资料大型随机研究抗EGFR治疗无价值lBRAF2,3预后结局很差未见综合 一线治疗有关预测资料lExpanded RAS analysis4,5 10%of KRAS 12/13 野生型肿瘤有其它 RAS 突变lKRAS exons 3,4lNRAS exons 2,3,4抗-EGFR 单抗无效1.Peeters M,et al.J Clin Oncol.2013;31:759-765.2.Richman SD,et al.J Clin Oncol.2009;27:5931-5937.3.Van Custem E,et al.J Clin Oncol.2011;29:2011-2019 4.Peeters M,et al.Clin Cancer Res.2013;19:1902-1912.5.Douillard JY,et al.N Engl J Med.2013;369:1023-1034.III期期 80405 试验试验:一线化疗一线化疗 Either Cetux or Bev in KRAS-WT mCRClPrimary endpoint:OSlSecondary endpoints:ORR,PFS,TTF,duration of responsePatients with mCRC and KRAS WT,ECOG PS 0/1(N=2900)FOLFOX or FOLFIRI+Bevacizumab q2w ClinicalTrials.gov.NCT00265850.FOLFOX or FOLFIRI+Cetuximab q1wA third arm with CT+bevacizumab+cetuximab was closed to accrual in September 2009延续治疗策略上的考虑延续治疗策略上的考虑 l增加病变得到长时间良好控制病人的数目l大多数新治疗研究到病人病变进展或毒性受限而终止l对病变得到良好控制病人的策略:继续治疗到病变进展或毒性而终止维持治疗治疗停息(Treatment holidays)OPTIMOX:维持维持 or 间歇休息间歇休息OPTIMOX11 Maintenance therapy(n=620)FOLFOX 4 until progressionFOLFOX 7FOLFOX 7sLV5FU2OPTIMOX22 Chemotherapy-free interval(n=202)mFOLFOX 7mFOLFOX 7sLV5FU2mFOLFOX 7mFOLFOX 7Chemotherapy-Free Interval 1.Tournigand C,et al.J Clin Oncol.2006;24:394-400.2.Chibaudel B,et al.J Clin Oncol.2009;27:5727-5733.OPTIMOX:研究结果研究结果lOPTIMOX1(维持 vs 继续治疗)l疾控期,PFS,or OS 无明显差异lOPTIMOX2(治疗休息 vs 维持治疗)l维持治疗的疾控期,PFS 明显为好l但 OS 无差异 Tournigand C,et al.J Clin Oncol.2006;24:394-400.Chibaudel B,et al.J Clin Oncol.2009;27:5727-5733.维持贝伐单抗维持贝伐单抗:MACRO TrialCapecitabine+Oxaliplatin+Bevacizumabx 6 cycles q3w(n=241)Bevacizumabuntil progression Capecitabine+Oxaliplatin+Bevacizumabx 6 cycles q3w(n=239)Capecitabine+Oxaliplatin+Bevacizumabuntil progression Patients with newly diagnosedmCRC and ECOG PS 2 Diaz-Rubio E,et al.Oncologist.2012;17:15-25.MACRO:OS(ITT)XELOX-XELOX-BevBevBevBevPatients,nPatients,n239239241241Events,n Events,n(%)(%)175(73)175(73)174(7%)174(7%)Censored,n Censored,n(%)(%)64(27)64(27)67(28)67(28)Median(95%Median(95%CI)CI)23.2 23.2(19.79,-(19.79,-26.01)26.01)19.99 19.99(17.98-(17.98-23.25)23.25)MosXELOX-BevBevPatients at Risk,n 241 239Survival Probability00.250.500.751.00002391913332623303940275460247785211011201813214615159170121931919210208622622738636BevXELOX-Bev Diaz-Rubio E,et al.Oncologist.2012;17:15-25.HR:1.05(95%CI:0.851-1.295)间歇休息间歇休息:GISCAD TrialCR,PR,SDPreviously untreated mCRCRANDOM I ZAT I ONFOLFIRI x 2 mos2:1FOLFIRI x 2 mosEVALUATEProgression:Off TrialBreak x 2 mos then FOLFIRI x 2 mosFOLFIRI x 4 mos Labianca R,et al.Ann Oncol.2011;22:1236-1242.146147757025271091461479510139431013Pts at Risk,nContinuousIntermittentMos0Patients(%)061218Mos100806040200Patients(%)6121824303613012460681929 Labianca R,et al.Ann Oncol.2011;22:1236-1242.OSPFS100806040200间歇休息间歇休息:GISCAD TrialContinuous armIntermittent armEvents145143Totals146147Continuous armIntermittent armEvents145143Totals146147Arm CBevacizumab(n=243)Arm AFOLFOX4+Bevacizumab(n=286)Arm BFOLFOX4(n=291)Patients with previously treated mCRC;no previous bevacizumab(N=820)FOLFOX4Oxaliplatin 85 mg/m2 on Day 1 q2w5-FU 400 bolus/600 mg/m2 IV on Days 1 and 2 q2wLV 200 mg/m2 on Days 1 and 2 q2wBevacizumab10 mg/kg on Day 1 q2wGiantonio BJ,et al.J Clin Oncol.2007;25:1539-1544.Stratified by ECOG performance score 0 vs 1 or 2;previous XRTE3200:二二线用贝伐单抗线用贝伐单抗 for mCRCAlive,nDead,nMedian,MosTotal,nA:FOLFOX4+bevacizumab2862543212.9B:FOLFOX42912642710.8C:Bevacizumab2432192410.2Giantonio BJ,et al.J Clin Oncol.2007;25:1539-1544.E3200:在以前治疗过的在以前治疗过的 mCRC FOLFOX+Bev 改善改善 OSOS(Mos)Probability00.200.40.60.81.061218243036HR:0.76A vs B:P=.0018B vs C:P=.95ML18147(TML):进展后继续用贝伐单抗进展后继续用贝伐单抗lA randomized,open-label phase III intergroup studyStandard second-line CT(oxaliplatin or irinotecan based)until PD(n=411)BEV 2.5 mg/kg/wk+standard second-line CT(oxaliplatin or irinotecan-based)until PD(n=409)Progressive mCRC after BEV+standard first-line CT(either oxaliplatin oririnotecan based)(n=820)Bennouna J,et al.Lancet Oncol.2013;14:29-37.Stratified by first-line CT(oxaliplatin or irinotecan based),first-line PFS(9 or 9 mos),time from last BEV dose(42 or 42 days),ECOG PS at baseline(0/1 or 2)Primary endpoint:OSML18147(TML):改善改善 OS(ITT)OS(%)MosCT(n=410)BEV+CT(n=409)1008060402000 6 12 18 24 30 36 42 489.8 mos9.8 mos11.2 mos11.2 mosUnstratified*HR:0.81(95%CI:0.69-0.94;log-rank P=.0062)Stratified HR:0.83(95%CI:0.71-0.97;log-rank P=.0211)*Primary analysis method.Stratified by first-line CT(oxaliplatin based,irinotecan based),first-line PFS(9 mos,9 mos),time from last dose of BEV(42 days,42 days),ECOG PS at baseline(0,1).Bennouna J,et al.Lancet Oncol.2013;14:29-37.100806040200PFS(%)0 6 12 18 24 30 36 42MosUnstratified*HR:0.68(95%CI:0.59-0.78;log-rank P .0001)Stratified HR:0.67(95%CI:0.58-0.78;log-rank P .0001)4.1 mo4.1 mo5.7 mo5.7 mo一线治疗后继续用血管生成抑制剂一线治疗后继续用血管生成抑制剂?lBevacizumablziv-aflibercept(阿帕西普)(阿帕西普阿帕西普)III期期 VELOUR 研究研究:FOLFIRI ziv-Aflibercept 二线治疗二线治疗 mCRClPrimary endpoint:OSlSecondary endpoints:PFS,ORR,safety,immunogenicitylNo correlativesPatients with mCRC progressing on first-line oxaliplatin-based chemotherapy*(planned N=1226)FOLFIRI+ziv-Aflibercept 4 mg/kg q2w(n=612)FOLFIRI+Placebo q2w(n=614)*30%had previous bevacizumab.Stratified by previous bevacizumab(yes vs no),ECOG PS(0 vs 1 vs 2)Van Cutsem E,et al.J Clin Oncol.2012;30:3499-3506.ClinicalTrials.gov.NCT00561470.(阿帕西普阿帕西普)VELOUR 研究研究:生存结果生存结果 Van Cutsem E,et al.J Clin Oncol.2012;30:3499-3506.OS(%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39Stratified HR:0.817(95.34%CI:0.713-0.937;log-rank P=.0032)Placebo/FOLFIRIMedian:12.06 mosAflibercept/FOLFIRIMedian:13.50 mosPFS(%)100806040200Mos036912151821 2427 30Stratified HR:0.758(95%CI:0.661-0.869;log-rank P .0001)Placebo/FOLFIRIMedian:4.67 mosAflibercept/FOLFIRIMedian:6.90 mos(阿帕西普阿帕西普)(阿帕西普阿帕西普)VELOUR 研究研究:按贝伐单抗分层按贝伐单抗分层OS Tabernero J,et al.Eur J Cancer.2013;Epub ahead of print.OS(%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR:0.862(95.34%CI:0.673-1.104)Placebo/FOLFIRIMedian:11.7 mosAflibercept/FOLFIRIMedian:12.5 mosPts at Risk,n PlaceboAFL18718617017813815011512181895459373622221313Previous BevacizumabOS(%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR:0.788(95.34%CI:0.699-0.927)Placebo/FOLFIRIMedian:12.4 mosAflibercept/FOLFIRIMedian:13.9 mosPts at Risk,n PlaceboAFL4274264033883473482862952052221391579411265823862No Previous Bevacizumab(阿帕西普阿帕西普)(阿帕西普阿帕西普)ziv-Aflibercept(阿帕西普阿帕西普):毒性毒性Increased Grade 3/4 AEs in Aflibercept Arm,%FOLFIRI+Aflibercept(n=611)FOLFIRI+Placebo(n=605)Any83.562.5Diarrhea19.37.8Asthenia16.910.6Stomatitis/ulceration13.75.0Infection12.36.9Palmar-plantar erythrodysesthesia2.80.5Anti-VEGFassociated eventsAnti-VEGFassociated eventsHypertensionHypertension19.319.31.51.5HemorrhageHemorrhage2.92.91.71.7Arterial thromboembolic eventsArterial thromboembolic events1.81.80.50.5Venous thromboembolic eventsVenous thromboembolic events7.97.96.36.3Neutropenia36.729.5Complicated neutropeniaComplicated neutropenia5.75.72.82.8Thrombocytopenia3.31.7 Van Cutsem E,et al.J Clin Oncol.2012;30:3499-3506.(阿帕西普阿帕西普)mCRC:二线二线EGFR 单抗治疗单抗治疗TrialTrialComparative Comparative RegimensRegimensPFS,PFS,MosMosOS,MosOS,MosEPIC1Irinotecan/Cetux vs Irinotecan4.0 vs 2.6*10.7 vs 10.018118122FOLFIRI/Pmab vs FOLFIRI/Pmab vs FOLFIRIFOLFIRI5.9 vs 5.9 vs 3.9*3.9*14.5 vs 14.5 vs 12.512.5SPIRITT3FOLFIRI/Pmab vs FOLFIRI/Bev7.7 vs 9.218.0 vs 21.41.Sobrero AF,et al.J Clin Oncol.2008;26:2311-2319.2.Peeters M,et al.J Clin Oncol.2010;28:4706-4713.3.Hecht JR,et al.ASCO 2013.Abstract 335.*Statistically significant difference.(瑞格非尼瑞格非尼)CORRECT:所有治疗肠癌方案失效后用所有治疗肠癌方案失效后用Regorafenib(瑞格非尼瑞格非尼)lPrimary endpoint:OSlApproximately 50%of patients with 4 systemic therapiesAll patients had received bevacizumabPatients with progression after all available standard therapy(N=760)Arm A:Regorafenib 160 mg PO QD+BSC3 wks on,1 wk off(n=505)Arm B:Placebo+BSC3 wks on,1 wk off(n=255)2:1 Grothey A,et al.Lancet.2013;381:303-312.CORRECT:Overall SurvivalPrimary endpoint me