美罗华在DLBCL老年患者中使用

利妥昔单抗注射液在老年DLBCL患者中应用摘要：大部分DLBCL患者都是65岁以上的老年人群，这些老年患者大多合并有其他疾病，有些严重患者，甚至影响到他们接受标准治疗的能力。我们回顾所有潜在的困难，如并发症的评估，功能状态和合并症影响预后，潜在并发症多等等，针对老年患者这些特点，我们提出解决方案。作为标准方案RCHOP，能使绝大多数患者获得治愈，因此，RCHOP也是作为老年患者的首选方案，从而尽可能让老年患者能获得像年轻患者一样的完全缓解。减少剂量强度只能是适应于超高龄或不适合足剂量蒽环类药物的患者。对于一个医生来说，最关键的问题是为什么这些患者不能够给予标准治疗，即RCHOP。关键词：老年；DLBCL；利妥昔单抗；年龄；标准典型的老年患者是指65岁以上的老年患者，在发达国家，在过去一个世纪，平均寿命快速增长，预计到2030年，女性平均寿命可达到85岁，男性在80岁ChristensenK,DoblhammerG,RauR,VaupelJ.Ageingpopulations:thechallengesahead..Lancet2009;374:1196-208。65岁以上的人口很快会超过全球人口的20%KennedB.Agingangcancer.Oncology2000;14:1731-3，同样在我国，人口老龄化越来越明显。年龄将成为癌症的主要危险因素之一。到2020年，所有肿瘤的70%可能发生在超过65岁的老年人BalducciL.Geriatriconcology:challengesforthenewcentury.EurJCancer2000;36:1741–54.，NHL是男性第5大最常见癌症，女性第6。DLBCL是最常见的NHL、ChristensenK,DoblhammerG,RauR,VaupelJ.Ageingpopulations:thechallengesahead..Lancet2009;374:1196-208KennedB.Agingangcancer.Oncology2000;14:1731-3BalducciL.Geriatriconcology:challengesforthenewcentury.EurJCancer2000;36:1741–54.ThieblemontC,CoiffierB.Lymphomainolderpatients.JClinOncol2007;25:1916–23.SiegelR,DesantisC,VirgoK,SteinK,MariottoA,SmithT,etal.Cancertreatmentandsurvivorshipstatistics,2012.CACancerJClin年龄与一些合并症息息相关，因此一直是预后的一个主要因素TheInternationalNon-Hodgkin'sLymphomaPrognosticFactorsProject.Apredictivemodelforaggressivenon-Hodgkin''slymphoma.NEnglJMed1993;329:987–94.。然而，正常的超过80岁女性老年患者平均还可以有8年寿命，男性可达9年寿命AriasE,RostronB,Tejada-VeraB.UnitedStateslifetables,2005.NatlVitalStatRep2010;58:1–132.。因此对于哪些没有合并症年龄超过70岁的老年患者还是可以争取达到年轻患者一样的治疗效果TheInternationalNon-Hodgkin'sLymphomaPrognosticFactorsProject.Apredictivemodelforaggressivenon-Hodgkin''slymphoma.NEnglJMed1993;329:987–94.AriasE,RostronB,Tejada-VeraB.UnitedStateslifetables,2005.NatlVitalStatRep2010;58:1–132.BastionYB,BlayJY,DivineM,BriceP,BordessouleD,SebbanC,etal.Elderlypatientswithaggressivenon-Hodgkin'slymphoma:diseasepresentation,responsetotreatment,andsurvival–aGrouped'EtudedesLymphomesdel'Adultestudyon453patientsolderthan69years.JClinOncol1997;15:2945–53.DixonDO,NeilanB,JonesSE,LipschitzDA,MillerTP,GrozeaPN,etal.Effectofageontherapeuticoutcomeinadvanceddiffusehistiocyticlymphoma:theSouthwestOncologyGroupexperience.JClinOncol1986;4:295–305.DrozJP,AaproM,BalducciL.Overcomingchallengesassociatedwithchemotherapytreatmentinthesenioradultpopulation.CritRevOncolHematol2008;68Suppl1:S1–8.1形态学差异DLBCL患者从基因遗传学上分为3中表型：GCB、ABC以及间变大B细胞型。这些表型的分布随年龄发生变化。老年患者ABC偏多RosenwaldA,WrightG,ChanWC,ConnorsJM,CampoE,FisherRI,etal.TheuseofmolecularproRosenwaldA,WrightG,ChanWC,ConnorsJM,CampoE,FisherRI,etal.Theuseofmolecularprofilingtopredictsurvivalafterchemotherapyfordiffuselarge-B-celllymphoma.NEnglJMed2002;346:1937–47.MareschalS,LanicH,RuminyP,BastardC,TillyH,JardinF.TheproportionofactivatedB-celllikesubtypeamongdenovodiffuselargeB-celllymphomaincreaseswithage.Haematologica2011;96:1888–90.2初步评估老年患者和年轻患者之间表现相似的临床症状ThieblemontC,GrossoeuvreA,HouotR,Broussais-GuillaumontF,ThieblemontC,GrossoeuvreA,HouotR,Broussais-GuillaumontF,SallesG,TraulleC,etal.Non-Hodgkin'slymphomainveryelderlypatientsover80years.Adescriptiveanalysisofclinicalpresentationandoutcome.AnnOncol2008;19:774–9.老年患者有合并症（如其他癌症，糖年病，心脏或肺部疾病，肾功能不全等等）很普遍情况。DLBCL合并症患者有更高的治疗毒性和死亡风险。造血储备能力随年龄增长而受损严重，标准剂量的骨髓毒性在老年人中表现更严重。查尔森指数，疾病累计评估表通常被用于评估这些合并症CharlsonME,PompeiP,AlesKL,MacKenzieCR.AnewmethodofCharlsonME,PompeiP,AlesKL,MacKenzieCR.Anewmethodofclassifyingprognosticcomorbidityinlongitudinalstudies:developmentandvalidation.JChronicDis1987;40:373–83.评估患者的体能状态依然依赖的是东部合作肿瘤(ECOG)状态评分进行评估AaldriksAA,MaartenseE,leCessieS,GiltayEJ,VerlaanHA,vanderAaldriksAA,MaartenseE,leCessieS,GiltayEJ,VerlaanHA,vanderGeestLG,etal.Predictivevalueofgeriatricassessmentforpatientsolderthan70years,treatedwithchemotherapy.CritRevOncolHematol2011;79:205–12.3预后指数针对HL的Annarbor分期系统对NHL预后不理想，国际NHL预后因子项目组1993年在NEJM杂志提出国际预后指数IPI，有五个风险因子：年龄，血清乳酸脱氢酶升高，体能状态，疾病分期以及结外侵犯位点的数量，用于NHL的预后评估。后经过改良和简化，经年龄调整aaIPI应运而生，人群以60岁为区分，风险因子减少至3个，包括：疾病分期，血清LDH，体能状态。广泛用于预测生存以及制定治疗方案，aaIPI不仅用于老年患者，亦用于年轻患者SehnLH,BerryB,ChhanabhaiM,FitzgeraldC,GillK,HoskinsP,etal.SehnLH,BerryB,ChhanabhaiM,FitzgeraldC,GillK,HoskinsP,etal.TherevisedInternationalPrognosticIndex(R-IPI)isabetterpredictorofoutcomethanthestandardIPIforpatientswithdiffuselargeB-celllymphomatreatedwithR-CHOP.Blood2007;109:1857–61.4治疗相对较大年龄DLBCL患者与较低CR,较短PFS，较短OS有较大相关性。老年患者治疗方案选择主要基于aaIPI评分和合并症。许多老年患者一般状况良好可以接受标准方案进行治疗，相反，一般状况差的老年患者可能会面临显著的副作用并需要调整治疗方案。不幸的是，由于没有科学根据，年龄似乎成为降低化疗剂量的唯一理由deSchansSA,WymengaAN,vanSpronsenDJ,SchoutenHC,CoeberghJW,Janssen-HeijnenML.Twosidesofthemedallion:poordeSchansSA,WymengaAN,vanSpronsenDJ,SchoutenHC,CoeberghJW,Janssen-HeijnenML.Twosidesofthemedallion:poortreatmenttolerancebutbettersurvivalbystandardchemotherapyinelderlypatientswithadvanced-stagediffuselargeB-celllymphoma.AnnOncol2012;23:1280–6.4.1老年DLBCL（aaIPI=0伴局部肿块）治疗GELA做了一随机对照试验，比较4CHOP与4CHOP+RtBonnetC,FilletG,MounierN,GanemG,MolinaTJ,ThieblemontC,etal.CHOPalonecomparedwithCHOPplusradiotherapyforlocalizedaggressivelymphomainelderlypatients:astudybytheGrouped'EtudedesLymphomesdel'Adulte.JClinOncol2007;25:787–92.，入组的患者都是60岁以上，I/II期患者，但最终结果显示CHOP+Rt并不优于单纯CHOPBonnetC,FilletG,MounierN,GanemG,MolinaTJ,ThieblemontC,etal.CHOPalonecomparedwithCHOPplusradiotherapyforlocalizedaggressivelymphomainelderlypatients:astudybytheGrouped'EtudedesLymphomesdel'Adulte.JClinOncol2007;25:787–92.ReyesF,LepageE,GanemG,MolinaTJ,BriceP,CoiffierB,etal.ChemotherapyalonewiththeintensifiedACVBPplussequentialconsolidationregimencomparedwiththreecyclesofstandardCHOPplusinvolvedfieldradiotherapyforlowrisklocalizedaggressivelymphomainpatientslessthan60yearsofage.NEnglJMed2005;352:1197–205.PfreundschuhM,SchubertJ,ZiepertM,SchmitsR,MohrenM,LengfelderE,etal.Sixversuseightcyclesofbi-weeklyCHOP-14withorwithoutrituximabinelderlypatientswithaggressiveCD20þB-celllymphomas:arandomisedcontrolledtrial(RICOVER-60).LancetOncol2008;9:105–16.4.2老年低危患者治疗研究证明老年患者单纯CHOP治疗获得CR40-50%，3年总生存30%的结果是不理想的PetersFPJ,LalisangRI,FickersMMF,ErdkampFLG,WilsJ,HoubenSGJ,etal.Treatmentofelderlypatientswithintermediate-andhighgradenon-Hodgkin'slymphoma:aretrospectivepopulation-basedstudy.AnnHematol2001;80:155–9.PetersFPJ,LalisangRI,FickersMMF,ErdkampFLG,WilsJ,HoubenSGJ,etal.Treatmentofelderlypatientswithintermediate-andhighgradenon-Hodgkin'slymphoma:aretrospectivepopulation-basedstudy.AnnHematol2001;80:155–9.HaiounC,LepageE,GisselbrechtC,SallesG,CoiffierB,BriceP,etal.Survivalbenefitofhigh-dosetherapyinpoor-riskaggressivenon-Hodgkin'slymphoma:finalanalysisoftheprospectiveLNH87-2pro-tocol–agrouped'etudedeslymphomesdel'Adultestudy.JClinOncol2000;18:3025–30.PfreundschuhM,TrumperL,KloessM,SchmitsR,FellerAC,RubeC,etal.Two-weeklyor3-weeklyCHOPchemotherapywithorwithoutetoposideforthetreatmentofelderlypatientswithaggressivelymphomas:resultsoftheNHL-B2trialoftheDSHNHL.Blood2004;104:634–41.SonneveldP,DeridderM,VanderlelieH,NieuwenhuisK,SchoutenHL,MulderA,etal.Comparisonofdoxorubicinandmitoxantroneinthetreatmentofelderlypatientswithadvanceddiffusenon-Hodgkin'slymphomausingCHOPversusCNOPchemotherapy.JClinOncol1995;13:2530–9.直到1998年，GELA做了首个在老年DLBCL中比较8RCHOP21与8CHOP21III期随机对照研究，入组的都是II-IV期患者，随访时间10年CoiffierB,LepageE,BriereJ,HerbrechtR,TillyH,BouabdallahR,etal.CHOPchemotherapyplusrituximabcomparedwithCHOPaloneinelderlypatientswithdiffuselarge-B-celllymphoma.NEnglJMedCoiffierB,LepageE,BriereJ,HerbrechtR,TillyH,BouabdallahR,etal.CHOPchemotherapyplusrituximabcomparedwithCHOPaloneinelderlypatientswithdiffuselarge-B-celllymphoma.NEnglJMed2002;346:235–242.CoiffierB,ThieblemontC,VanDenNesteE,LepeuG,PlantierI,CastaigneS,etal.Long-termoutcomeofpatientsintheLNH-98.5trial,thefirstrandomizedstudycomparingrituximab-CHOPtostandardCHOPchemotherapyinDLBCLpatients:astudybytheGrouped'EtudesdesLymphomesdel'Adulte.Blood2010;116:2040–5.ReyesF,LepageE,GanemG,MolinaTJ,BriceP,CoiffierB,etal.ChemotherapyalonewiththeintensifiedACVBPplussequentialconsolidationregimencomparedwiththreecyclesofstandardCHOPplusinvolvedfieldradiotherapyforlowrisklocalizedaggressivelymphomainpatientslessthan60yearsofage.NEnglJMed2005;352:1197–205.CunninghamD,SmithP,MounceyP,QianW,PocockC,ArdeshnaK,etal.AphaseIIItrialcomparingR-CHOP14andR-CHOP21forthetreatmentofpatientswithnewlydiagnoseddiffuselargeB-cellnon-Hodgkin'slymphoma.JClinOncol27:15s,2009(suppl;abstr8506).DelarueR,TillyH,SallesG,GisselbrechtC,MounierN,FournierM,etal.R-CHOP14ComparedtoR-CHOP21inelderlypatientswithdiffuselargeB-celllymphoma:resultsoftheInterimAnalysisoftheLNH03-6BGELAStudy[abstract].In:Proceedingsofthe51stAnnualMeetingandExposition;2009Dec5–8;NewOrleans,LA.Washington,DC:ASH;2009.Abstractnr406.4.3超高龄患者治疗（大于80岁）R-CHOP方案大部分临床研究是在年轻或是60-80岁患者中开展，对于超过80岁超高龄患者很少有前瞻性试验。GELA研究组针对80岁以上DLBCL做了II期临床研究PeyradeF,JardinF,ThieblemontC,ThyssA,EmileJF,CastaigneS,etal.Attenuatedimmunochemotherapyregimen(R-miniCHOP)inelderlypatientsolderthan80yearswithdiffuselargeB-celllymphoma:amulticentre,single-arm,phase2trial.LancetOncol2011;12:460–8.，共入组150例患者，使用降低毒副作用的R-miniCHOP方案，结果显示2年OS达59%，PFS达47%。耐受性良好，72%患者完成了整个计划方案，在多变量分析中，血清白蛋白水平是唯一的影响生存因素(>35g/L或更少)，它强调这些病人营养状况的相关性。58例死亡数中，33例与淋巴瘤相关，12例与治疗毒性相关。总之，该研究证实，R-miniCHOP给超老龄患者提供一种生存获益并伴随良好疗效和安全性。瑞典在1997年到2009年做了一个回顾性研究证实PeyradeF,JardinF,ThieblemontC,ThyssA,EmileJF,CastaigneS,etal.Attenuatedimmunochemotherapyregimen(R-miniCHOP)inelderlypatientsolderthan80yearswithdiffuselargeB-celllymphoma:amulticentre,single-arm,phase2trial.LancetOncol2011;12:460–8.HasselblomS,StensonM,WerleniusO,SenderM,LewerinC,HanssonU,etal.ImprovedoutcomeforveryelderlypatientswithdiffuselargeB-celllymphomaintheimmunochemotherapyera.LeukLymphoma2012;53:394–9.5预防5.1对蒽环类药物禁忌患者综所周知，毒性是蒽环类药物主要不良事件HershmanDL,McBrideRB,EisenbergerA,TsaiWY,GrannVR,JacobsonJS.Doxorubicin,cardiacriskfactors,andcardiactoxicityinelderlypatientswithdiffuseB-cellnon-Hodgkin'slymphoma.JClinOncol2008;26:3159–65.。患者心脏功能改变无法接受阿霉素或其它蒽环类药物治疗。由于潜在的先前存在的心脏疾病，老年患者比年轻患者更容易出现心脏副作用SwainSM,WhaleyFS,EwerMS.Congestiveheartfailureinpatientstreatedwithdoxorubicin:aretrospectiveanalysisofthreetrials.Cancer2003;97:2869–79.。然而，不含阿霉素方案对淋巴瘤患者来书意味着更短生存以及更高死亡率PetersFPJ,LalisangRI,FickersMMF,ErdkampFLG,WilsJ,HoubenHershmanDL,McBrideRB,EisenbergerA,TsaiWY,GrannVR,JacobsonJS.Doxorubicin,cardiacriskfactors,andcardiactoxicityinelderlypatientswithdiffuseB-cellnon-Hodgkin'slymphoma.JClinOncol2008;26:3159–65.SwainSM,WhaleyFS,EwerMS.Congestiveheartfailureinpatientstreatedwithdoxorubicin:aretrospectiveanalysisofthreetrials.Cancer2003;97:2869–79.PetersFPJ,LalisangRI,FickersMMF,ErdkampFLG,WilsJ,HoubenSGJ,etal.Treatmentofelderlypatientswithintermediate-andhigh-gradenon-Hodgkin'slymphoma:aretrospectivepopulation-basedstudy.AnnHematol2001;80:155–9.MocciaA,SchaffK,HoskinsP,KlasaR,SavageK,ShenkierT,etal.R-CHOPwithEtoposideSubstitutedforDoxorubicin(R-CEOP):ExcellentOutcomeinDiffuseLargeBCellLymphomaforPatientswithaContraindicationtoAnthracyclines.Blood2009;114:408.脂质体阿霉素能提供最大安全并确保疗效，最新意大利一项II期临床研究将RCHOP方案里阿霉素用脂质体阿霉素替代，以此评估脂质体阿霉素的活性和安全性LuminariS,MontaniniA,CaballeroD,BolognaS,NotterM,DyerMJ,etal.Nonpegylatedliposomaldoxorubicin(MyocetTM)combination(R-COMP)chemotherapyinelderlypatientswithdiffuselargeB-celllymphoma(DLBCL):resultsfromthephaseIIEUR018trial.AnnOncol2010;21:1492–9.。该研究中，CR达到57%，3年OS，FFS，PFS分别达到72%，39%，72%。然而，心脏毒性上出现21%心脏事件，3-4级心脏毒性为4%。另一项研究入选了35例虚弱的老年患者，使用减量脂质体（30mg/m2)LuminariS,MontaniniA,CaballeroD,BolognaS,NotterM,DyerMJ,etal.Nonpegylatedliposomaldoxorubicin(MyocetTM)combination(R-COMP)chemotherapyinelderlypatientswithdiffuselargeB-celllymphoma(DLBCL):resultsfromthephaseIIEUR018trial.AnnOncol2010;21:1492–9.GimenoE,Sanchez-GonzalezB,Alvarez-LarranA,PedroC,AbellaE,CominJ,etal.Intermediatedoseofnonpegylatedliposomaldoxorubicincombination(R-CMyOP)asfirstlinechemotherapyforfrailelderlypatientswithaggressivelymphoma.LeukRes2011;35:358–62.5.2发热性中性粒细胞减少预防有研究证明中性粒细胞减少和感染在老年患者中发生率更高PettengellR,JohnsonHE,LugtenburgPJ,SilvestreAS,DuhrsenU,RossiFG,etal.ImpactoffebrileneutropeniaonR-CHOPchemotherapydeliveryandhospitalizationsamongpatientswithdiffuselargeB-celllymphoma.SupportCareCancer2012;20:647–52.，40%老年患者可能受影响（而年轻患者18%），并导致较高的住院和死亡率。老年DLBCL在治疗和改善生存期间使用G-CSF预防能否降低死亡率仍然存在争议DoorduijnJK,vanderHoltB,vanImhoffGW,vanderHemKG,KramerPettengellR,JohnsonHE,LugtenburgPJ,SilvestreAS,DuhrsenU,RossiFG,etal.ImpactoffebrileneutropeniaonR-CHOPchemotherapydeliveryandhospitalizationsamongpatientswithdiffuselargeB-celllymphoma.SupportCareCancer2012;20:647–52.DoorduijnJK,vanderHoltB,vanImhoffGW,vanderHemKG,KramerMHH,vanOersMHJ,etal.CHOPcomparedwithCHOPplusgranulocytecolony-stimulatingfactorinelderlypatientswithaggressivenon-Hod