前列腺癌的化療及新型藥物治療

前列腺癌的化療

及新型藥物治療目錄前列腺癌化療的歷史mCRPC的化療mHSPC的化療高危前列腺癌術(shù)后輔助化療前列腺癌的新型藥物治療目錄前列腺癌化療的歷史mCRPC的化療mHSPC的化療高危前列腺癌術(shù)后輔助化療前列腺癌的新型藥物治療前列腺癌化療的歷史2010年5月中國(guó)批準(zhǔn)多西他賽治療轉(zhuǎn)移性去勢(shì)抵抗性前列腺癌2014mHSPC199620042011Estramustine

·Ancienthistory1981Mitoxantrone+prednisone

·ReductioninpaincomparedwithprednisoneDocetaxel+prednisone

·Prolongedoverallsurvivalcomparedwithmitoxantrone+prednisoneCabazitaxel+prednisone（AfterD.P.）

·Prolongedoverallsurvivalcomparedwithmitoxantrone+prednisone目錄前列腺癌化療的歷史mCRPC的化療mHSPC的化療高危前列腺癌術(shù)后輔助化療前列腺癌的新型藥物治療NEnglJMed.2004Oct7;351(15):1502-12TAX327研究TAX-327研究設(shè)計(jì)多西他賽（75mg/m2）q3w×10周期

+潑尼松（5mgbid）（n=335）米托蒽醌（12mg/m2）q3w×10周期+潑尼松（5mgbid）（n=337）

隨機(jī)多西他賽（30mg/m2）q1w5of6wks×5周期

+潑尼松（5mgbid）（n=334）mCRPCN=1,006D3PD1PMPTX327主要終點(diǎn)：OS比較JClinOncol.2008Jan10;26(2):242-5TX327次要終點(diǎn)的比較MPD1PD3PP值PSA反應(yīng)（至少下降50%）32%48%45%

0.001疼痛緩解22%31%35%0.01生活質(zhì)量改善13%23%22%0.009TROPIC研究卡巴他賽-Cabazitaxel(Jevtana?)均源于歐洲紫杉樹(shù)針葉XYXYDocetaxelCabazitaxel-OH-OCH3-OCH3-OCCH3O99thAACRannualmeeting,SanDiego,April2008(abstract#3227)TROPIC:PhaseIIIregistrationstudy146Sitesin26CountriesPrimaryendpoint:

OverallSurvivalSecondaryendpoints:Progression-free

survival(PFS),responserate,andsafetyInclusion:PatientswithmeasurablediseasemusthaveprogressedbyRECIST;otherwisemusthavehadnewlesionsorPSAprogressioncabazitaxel25mg/m2q3wk

+prednisone*for10cycles(n=378)mitoxantrone12mg/m2q3wk

+prednisone*for10cycles(n=377)*Oralprednisone/prednisolone:10mgdaily.StratificationfactorsECOGPS(0,1vs.2)?Measurablevs.non-measurablediseasemCRPCpatientswhoprogressedduringandaftertreatmentwithadocetaxel-basedregimen(N=755)DeBonoJetal.Lancet,2010,376:1147-54TROPIC：OSDeBonoetal.Lancet,2010,376:1147-5430%reductionintheriskofdeathMPCBZPMedianOS(months)12.715.1Hazardratio0.7095%CI0.59–0.83Pvalue<0.0001ProportionofOS(%)100806040200

MitoxantroneCabazitaxel061218243028%17%Time(months)PFS：25%reductioninriskofprogressionMPCBZPMedianPFS(months)1.42.8Hazardratio0.7495%CI0.64–0.86P-value<0.0001PFScompositeendpoint:PSAprogressionORpainprogressionORtumorprogressionORsymptomdeteriorationORdeath.DeBonoetal.Lancet,2010,376:1147-54

ProportionofPFS(%)100806040200Time(months)061218213915

MitoxantroneCabazitaxel目錄前列腺癌化療的歷史mCRPC的化療mHSPC的化療高危前列腺癌術(shù)后輔助化療前列腺癌的新型藥物治療E3805(CHAARTED)研究2015年8月發(fā)表于新英格蘭雜志GETUG15研究2013年1月發(fā)表于柳葉刀雜志STAMPEDE研究部分結(jié)果2015年12月發(fā)表于柳葉刀雜志<br/><br/>E3805<br/>CHAARTED:ChemoHormonalTherapyversusAndrogenAblationRandomizedTrialforExtensiveDiseaseinProstateCancerPresentedByChristopherSweeneyat2014ASCOAnnualMeetingE3805–CHAARTEDTreatmentPresentedByChristopherSweeneyat2014ASCOAnnualMeetingHV:visceralmetastasesand/or4ormorebonemetastasesStudyEndpointsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingPatientcharacteristicsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingPatientcharacteristicsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingPatientcharacteristicsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingPrimaryendpoint:OverallsurvivalPresentedByChristopherSweeneyat2014ASCOAnnualMeetingOSbyextentofmetastaticdiseaseatstartofADTPresentedByChristopherSweeneyat2014ASCOAnnualMeetingADT+DocetaxelbenefitedallsubgroupsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingSecondaryEndpointsPresentedByChristopherSweeneyat2014ASCOAnnualMeetingTherapybeyondprogressionPresentedByChristopherSweeneyat2014ASCOAnnualMeetingChemotherapyDosesGivenPresentedByChristopherSweeneyat2014ASCOAnnualMeetingNon-HematologicToxicity(%)PresentedByChristopherSweeneyat2014ASCOAnnualMeetingHematologicToxicity(%)PresentedByChristopherSweeneyat2014ASCOAnnualMeetingPatrick-MillerLJ,etal.2016ASCOAbstract5004.CHAARTED研究生活質(zhì)量(QoL)分析——轉(zhuǎn)移性激素敏感性前列腺癌化療聯(lián)合ADT的隨機(jī)研究(E3805)A組和B組之間的差異估值SEP值基線-1.001.280.433個(gè)月-3.091.320.026個(gè)月0.901.340.509個(gè)月0.291.370.8412個(gè)月2.851.390.04FACT-PADT+多西他賽1.201.141.161.18036912時(shí)間(月)總體FACT-P僅ADTP=0.02N=706P<0.01N=548ADT+多西他賽vs僅ADT在3個(gè)月時(shí)總體QoL較差(90%RR)在6個(gè)月時(shí)無(wú)差異在12個(gè)月時(shí)更優(yōu)(69%RR)總體QoL：FACT-P(癌癥治療功能評(píng)價(jià)-前列腺癌)：總體及疾病特異性生活質(zhì)量的自我報(bào)告評(píng)估。分?jǐn)?shù)越高，說(shuō)明QoL越好。

5個(gè)分量表如下身體方面：軀體癥狀社會(huì)方面：家庭及朋友關(guān)系情感方面：抑郁、焦慮及應(yīng)對(duì)方式功能狀況：做想要做的事的能力針對(duì)前列腺癌的特定擔(dān)憂：失禁、男性特征研究結(jié)果：總體QoL（主要終點(diǎn)）Patrick-MillerLJ,etal.2016ASCOAbstract5004.*校準(zhǔn)年齡(≤59vs.60-69vs.≥70)、疾病嚴(yán)重程度(高vs.低)、局部治療(是vs.否)、ECOGPS(0vs.1/2)、基線身體狀況(≤20vs.20~25vs.>25)及基線疼痛評(píng)分(0/1vs.2/3vs.≥4)FACT-F(乏力)FACT-紫杉類(lèi)情感狀況疼痛結(jié)果證實(shí)接受ADT+多西他賽治療的患者多項(xiàng)生活質(zhì)量指標(biāo)（情感狀況，乏力）在12個(gè)月以后優(yōu)于僅接受ADT患者Patrick-MillerLJ,etal.2016ASCOAbstract5004.研究結(jié)果：次要終點(diǎn)小結(jié)多西他賽聯(lián)合ADT治療轉(zhuǎn)移性激素敏感性前列腺癌可較單用ADT延長(zhǎng)總生存13.6個(gè)月；對(duì)于高瘤負(fù)荷患者可以提高OS17個(gè)月接受ADT+多西他賽治療的患者總體QoL(FACT-P)會(huì)暫時(shí)下降，但在治療過(guò)程中逐漸恢復(fù)到基線水平，且在12個(gè)月以后優(yōu)于僅接受ADT患者Patrick-MillerLJ,etal.2016ASCOAbstract5004.Slide1PresentedByNicholasJamesat2015ASCOAnnualMeetingInclusioncriteriaPresentedByNicholasJamesat2015ASCOAnnualMeetingOutcomemeasuresPresentedByNicholasJamesat2015ASCOAnnualMeetingAccrualPresentedByNicholasJamesat2015ASCOAnnualMeetingDocetaxel:Failure-freesurvivalPresentedByNicholasJamesat2015ASCOAnnualMeetingDocetaxel:SurvivalPresentedByNicholasJamesat2015ASCOAnnualMeetingZoledronicacid+docetaxel:Failure-freesurvivalPresentedByNicholasJamesat2015ASCOAnnualMeetingZoledronicacid+docetaxel:SurvivalPresentedByNicholasJamesat2015ASCOAnnualMeetingTreatmenteffectbymetastaticstatus:FFSPresentedByNicholasJamesat2015ASCOAnnualMeetingTreatmenteffectbymetastaticstatus:OverallsurvivalPresentedByNicholasJamesat2015ASCOAnnualMeetingDocetaxel:Survival–M1PatientsPresentedByNicholasJamesat2015ASCOAnnualMeetingGrade3+adverseeventsat1yearPresentedByNicholasJamesat2015ASCOAnnualMeetingConclusionsPresentedByNicholasJamesat2015ASCOAnnualMeeting2016NCCN:轉(zhuǎn)移性激素敏感性晚期前列腺癌的治療選擇目錄前列腺癌化療的歷史mCRPC的化療mHSPC的化療高危前列腺癌術(shù)后輔助化療前列腺癌的新型藥物治療AhlgrenG,etal.2016ASCOAbstract5001.SPCG12研究：高危前列腺癌患者前列腺癌根治術(shù)后輔助多西他賽vs.監(jiān)測(cè)的隨機(jī)III期研究SPCG12研究設(shè)計(jì)AhlgrenG,etal.2016ASCOAbstract5001.入組條件：>18~≤70歲男性患者WHO/ECOGPS0-1組織學(xué)證實(shí)的前列腺腺癌以下任一條：pT2，Gleason評(píng)分4+3或8-10，前列腺癌根治術(shù)后切緣陽(yáng)性或任何pT3腫瘤，Gleason評(píng)分4+3或更高或任何分級(jí)的pT3b腫瘤任何N+腫瘤，若Gleason評(píng)分≥4(pT2-3)如術(shù)前PSA≥10.0ng/ml，應(yīng)行淋巴結(jié)清掃但不強(qiáng)制術(shù)后PSA≤0.5ng/ml研究開(kāi)始前骨掃描陰性根治性前列腺切除術(shù)隨機(jī)分組A組：多西他賽75mg/m2i.v.q3wx6未連續(xù)使用皮質(zhì)類(lèi)固醇B組：監(jiān)測(cè)直至達(dá)到終點(diǎn)研究開(kāi)始高風(fēng)險(xiǎn)患者終點(diǎn)：間隔1周的兩次PSA>0.5ng/ml達(dá)到終點(diǎn)后允許使用內(nèi)分泌治療和放療估計(jì)患者數(shù)：396隨機(jī)化預(yù)后因素(患者基線特征)AhlgrenG,etal.2016ASCOAbstract5001.因素A組B組年齡(歲)61.862.7PSA(RP之前)12.211.9PSA(隨機(jī)分組之前)0.1570.155pT分期pT2-3a/pT3b60.7/39.360.7/39.3Gleason≤7/8-1062.1/37.962.9/37.1手術(shù)切緣陽(yáng)性%57.860.7淋巴結(jié)轉(zhuǎn)移%16.918.9多西他賽治療周期及相關(guān)SAE(n=55)AhlgrenG,etal.2016ASCOAbstract5001.治療周期數(shù)頻率百分比累積百分比0125.25.2193.99.1262.611.7352.213.9452.216.15114.820.9618279.1100.0總體230100.0發(fā)熱性中性粒細(xì)胞減少39(70.9%)心臟手術(shù)下肢水腫無(wú)np感染中性粒細(xì)胞減少血栓栓塞皮炎/脫皮胸痛前列腺癌根治術(shù)后患者基本都能耐受并完成6個(gè)周期的多西他賽治療，且主要不良反應(yīng)為發(fā)熱性中性粒細(xì)胞減少。1.00.80.60.40.20.00102030405060累積生存率多西他賽組監(jiān)測(cè)組P=0.078分析時(shí)間(月)AhlgrenG,etal.2016ASCOAbstract5001.60個(gè)月內(nèi)進(jìn)展