sre2-肺癌骨轉(zhuǎn)移患者的發(fā)生率

腸癌LungCancer67(2010)CoreyLangera,Vera降低生活質(zhì)量（QOLNSCLC患者骨轉(zhuǎn)移的診斷與治療的規(guī)范卻比較少。NSCLC患者的骨疾病發(fā)生率、骨轉(zhuǎn)移的診斷與治療的數(shù)據(jù)。結(jié)果：NSCLCNSCLC患者會發(fā)生≥1SRE。隨著新的治療方法對生存期的改善，SREs的患病率可能增加。每個(gè)后才被診斷出來，但早期治療能夠延遲SREs的發(fā)生。在NSCLC（n=773，與安慰劑相比，唑來膦酸（ZOL；4mg1531次）能夠?qū)ⅲ≒=0.009SREs32%（P=0.016結(jié)論：NSCLCSREs（QOL移相比，惡性骨病對細(xì)胞物治療不敏感。（SRE，（HCM不管是否存在骨損害的放射學(xué)表（如溶骨性或成骨性【10-12骨相關(guān)都可能發(fā)生；【15SRE時(shí)才被診斷【4SREs的（如骨痛、活動(dòng)度降低）可能在患者生存期間持續(xù)存在。因此，在SRE發(fā)生前QOL及功能自立性，并可能有助于維持患者、二膦酸鹽是破骨細(xì)胞介導(dǎo)的骨質(zhì)溶解的抑制劑，已證實(shí)該類藥物能夠預(yù)防骨轉(zhuǎn)移患者的SREs的發(fā)生【10，16。唑來膦酸能夠顯著延遲伴有骨轉(zhuǎn)移的癌、肺癌及多種實(shí)體瘤患者【15，17-19】的SREs發(fā)生，降低骨疾病進(jìn)展和SREs發(fā)生的。唑來膦酸是唯一批準(zhǔn)用于治療除以外的實(shí)體腫瘤骨轉(zhuǎn)移的二膦酸鹽。、存。對于骨轉(zhuǎn)移患者，二膦酸鹽已經(jīng)成為治療的一部分，以延遲病理性骨折及其他方法的應(yīng)用使激素耐受的癌患者的生存提高最近的指南推薦應(yīng)用唑來膦酸預(yù)防骨轉(zhuǎn)（成骨作用在沒有合適的診斷檢測的情況下，NSCLC的骨轉(zhuǎn)移容易被忽略。骨轉(zhuǎn)移的經(jīng)典檢測是患者進(jìn)行全身骨掃描；在有骨疼痛或符合早期骨損害的檢測值的11名患者中，有目前臨床腫瘤學(xué)會（ASCO）指南建議對臨床評價(jià)異常的NSCLC患者進(jìn)行骨掃描骨掃描發(fā)現(xiàn)的可疑骨損害一般需進(jìn)一步X線檢查、計(jì)算機(jī)體層攝影、磁成像、代謝標(biāo)際上，氟-18脫氧葡萄糖（FDG）-PETNSCLC骨轉(zhuǎn)移的檢測的特異性高于骨掃描90%vs70%6%vs39%蹤成像后，F(xiàn)DG-PETNSCLC骨轉(zhuǎn)移診斷的敏感性是旗鼓相當(dāng)?shù)摹?9，30關(guān)于骨轉(zhuǎn)移疾病負(fù)荷的情況見于近期一些安慰劑與二膦酸鹽對照的試驗(yàn)。對不同2SREsSREs（1【15，32-35NSCLC骨轉(zhuǎn)移患者中，安慰劑組的大多5SRE，較安慰劑組的中位生存時(shí)間短【6DeleaNSCLCSRE4個(gè)月。因此不管組織學(xué)如何骨轉(zhuǎn)移的病理生理學(xué)機(jī)制導(dǎo)致骨骼疾病發(fā)生即使是侵襲強(qiáng)的、生存期較短的也具備骨轉(zhuǎn)移所致SREs發(fā)生的時(shí)間。1.合并有骨損害的不同腫瘤的骨疾病的平均發(fā)生率（SREs發(fā)生數(shù)。數(shù)據(jù)來源：對照組*來自Liptonetal【32Rosenetal【15Berensonetal【33§Saadetal【34患者接受進(jìn)一步治療所必需的合格標(biāo)準(zhǔn)，預(yù)防SREs能夠有助于防止體力狀態(tài)。除了對患者的健康、生活質(zhì)量、體力狀態(tài)的影響以外，SREs與醫(yī)療費(fèi)用增加相關(guān)。在一項(xiàng)回顧性分析中，534NSCLC295SREs有關(guān)的醫(yī)SRE的急性處理相關(guān)（HCM的治（P<0.001Ras信號傳導(dǎo)，從而誘導(dǎo)凋亡【45、、在人類腫瘤的動(dòng)物模型系統(tǒng)中，包括多發(fā)性骨髓瘤癌二膦酸鹽能夠、、0.1uM時(shí)幾乎完全抑制了法呢基二膦酸合5-40倍【432002。對包括激素耐受的癌及NSCLC在內(nèi)的其他實(shí)體腫瘤的治療獲益延長批準(zhǔn)唑來膦酸用于治療實(shí)體腫瘤基于一項(xiàng)隨機(jī)、安慰劑對照的III期試驗(yàn)，在該試驗(yàn)中，除及1SRE的患者的比例（HCM；39%vs48%安慰劑組；p=0.0392p=0.012天；p=0.00931%（相對風(fēng)險(xiǎn)【RR】=0.693；p=0.003。2.SRE的比例（21個(gè)月的研究。*HCM。數(shù)據(jù)Rosenetal【15SREs發(fā)生時(shí)才被診斷為骨轉(zhuǎn)移。但是，預(yù)先存在的骨疾病并不妨礙隨后治療的獲益。實(shí)際上，已經(jīng)發(fā)生SRE的患者以后發(fā)生的風(fēng)險(xiǎn)格外高。例如，41%（p=0.03631%（p=0.009p=0.030SRE4個(gè)月（215vs106【19SRE的患者也顯示治療獲益，但未達(dá)到顯著統(tǒng)計(jì)學(xué)意義。該SREs61%在接受安慰劑或4mg唑來膦酸（15分鐘靜脈輸注）的每組患者中，發(fā)生3或4級肌酐水平升高的患者為1.8%，兩組的嚴(yán)重不良的發(fā)生沒有顯著差異。在唑來膦酸與安慰劑的試驗(yàn)過程中最常見的不良反應(yīng)為骨疼（分別為48%與58%）分別為47%與32%30%膦酸減少SRE發(fā)生或鎮(zhèn)痛的效應(yīng)。兩組間的鎮(zhèn)痛評分沒有顯著差異，做來磷酸組的性骨放療較安慰劑組沒有顯著減【6在NSCLC患者中沒有發(fā)生4級肌酐水平升高見但可能嚴(yán)重的不良【49，50。由于所有靜脈給藥的二膦酸鹽通過腎清除，因此應(yīng)該在每次靜脈給前檢測腎功能和水化狀態(tài)以確保腎臟的安全性腎功能正常的患者可能出ONJ的標(biāo)準(zhǔn)的定義。ONJ的發(fā)生率，包括預(yù)防性牙科處ONJ【58（n=238中的水平與骨生成標(biāo)志BALP在中的水平【59。與基線NTX低（＜100nmol/mmol肌3（RR=3.03；p＜0.001，、圖3.NSCLC或其他實(shí)體腫瘤伴有骨轉(zhuǎn)移患者的SREs、疾病進(jìn)展的相對風(fēng)險(xiǎn)。根據(jù)基（ANTx（B）BALP基線水平低者（＜46IU/LBrownetal【59、45%（18.8%vs66.7%p=0.001（n=204n=14435（RR=0.65p=0.024SRE速度減低或直接的抗腫瘤作用。越來越多的臨床前表明二膦酸鹽能夠抑制多種人類腫瘤細(xì)胞系的增殖誘導(dǎo)其凋亡【43，64。體外試驗(yàn)顯示，唑來膦酸抑制來源于人類腫瘤細(xì)胞系的生長，包括12種小細(xì)胞肺癌細(xì)胞系，50%有效抑制濃度（IC50）1330mM【6516NSCLC唑來膦酸能夠阻斷其中3種高的細(xì)胞系的【67。與順鉑單藥相比，100uM唑來膦70（p=0.007（p<0.05骨肉瘤肺轉(zhuǎn)移的鼠模型上，經(jīng)唑來膦酸（0.1mg/kg25次）的小鼠未發(fā)生肺轉(zhuǎn)移，（p=0.036道【71CD40，CD80，CD83化γδT細(xì)胞的溶細(xì)胞活性，并可能因此提高抗腫瘤免疫反應(yīng)【73NSCLC患者（n=150）II期研究評估了多西他塞（75mg/m2）+卡16612個(gè)月【74的中位總生存期輕度延長（266天vs206天。總的來說，唑來膦酸與化療的聯(lián)合具有良好的（AEs（41.8%vs28.8%（16.3%vs5.7%究終點(diǎn)的差異的檢驗(yàn)效價(jià)不夠，兩組均有很多患者在治療3周期后由于疾病進(jìn)展而停止了NSCLC患者的疾病進(jìn)展和生存影響的隨機(jī)研已證實(shí)對早期女性患者而言與單獨(dú)的內(nèi)分泌治療相比唑來膦酸聯(lián)合內(nèi)分泌治76NSCLC患者疾病進(jìn)展時(shí)間效用的研究提供了理論NSCLC患者的研究評價(jià)了唑來膦酸預(yù)防骨轉(zhuǎn)移的有效性，在其的入組并將把隨機(jī)分入唑來膦（4mg/3-4周或無唑來膦酸治療組為期2【774mg組接受治療。主要研究終點(diǎn)是評價(jià)疾病進(jìn)展（如骨疾病的進(jìn)展20094個(gè)月內(nèi)完成。一項(xiàng)公開的對IIIB或IV期不伴有骨轉(zhuǎn)移的NSCLC患者的抗腫瘤試驗(yàn)（Z-PACT）已完成了的入組【78。患者接受化療，并被隨機(jī)分入唑來膦酸4mg組或無唑來膦酸治6周期或疾病進(jìn)展。對治療反應(yīng)的唑來膦酸組患者將進(jìn)一步被隨機(jī)分入唑來4mg12QOL及連續(xù)治療過程中的醫(yī)療費(fèi)用已變得越來越重要。早期治療可能特別有利于維持患者NSCLC骨轉(zhuǎn)移患者骨疾病發(fā)生風(fēng)險(xiǎn)的二膦酸鹽。此外，NSCLC患者，唑來膦酸可能提高其生存獲益，這可能是通過預(yù)防影響的SREs的發(fā)生或通過阻斷生長因子自骨基質(zhì)的釋放而NSCLC患者骨轉(zhuǎn)移發(fā)生的臨床試驗(yàn)正在進(jìn)行中，二膦酸鹽對肺癌的治療作用將不斷發(fā)展。有必要確認(rèn)NSCLC患者的骨轉(zhuǎn)移，從而優(yōu)SREs的發(fā)生。GiacconeG,GallegosRuizM,LeChevalierT,etal.Erlotinibforfrontlineofadvancednon-smallcelllungcancer:aphaseIIstudy.ClinCancerResSandlerA,GrayR,PerryMC,etal.Paaxel-carbotinaloneorwithfornon-small-celllungcancer.NEnglJMedColemanRE.Metastaticbonedisease:clinicalfeatures,pathophysiologyandtreatmentstrategies.CancerTreatRev2001;27:165–76.IordanidouL,TrivizakiE,SarantiS,etal.Istherearoleofwholebodybonescaninearlystagesofnonsmallcelllungcancerpatients.JBUONShahamD,BreuerR,CopelL,etal.Computedtomographyscreeningforlungcancer:applicabilityofaninternationalprotocolinasingle-institutionClinLungCancerRosenLS,GordonD,TchekmedyianS,etal.Zoledronicacidversuscebothetreatmentofskeletalmetastasesinpatientswithlungcancerandothersolidtumors:aphaseIII,double-blind,randomizedtrial—theZoledronicAcidLungCancerandOtherSolidTumorsStudyGroup.JClinOncol2003;21:FukuokaM,YanoS,GiacconeG,etal.Multi-institutionalrandomizedphasetrialofgefitinibforpreviouslytreatedpatientswithadvancednon-small-celllungcancer(theIDEAL1trial).JClinOncol2003;21:2237–46[corrected].BerensonJR,RajdevL,BroderM.ManagingbonecomplicationsofsolidCancerBiolTherColemanRE.Managementofbonemetastases.OncologistColemanRE.Bisphosphonates:clinicalexperience.Oncologist2004;9(suppl.KakonenSM,MundyGR.Mechanismsofosteolyticbonemetastasesinbreastcarcinoma.Cancer2003;97(suppl.):834–9.GuiseTA,mmadKS,ClinesG,etal.Basicmechanismsresponsibleforosteolyticandosteoblasticbonemetastases.ClinCancerResGoltzmanD,KaraplisAC,KremerR,RabbaniSA.Molecularbasisoftheofskeletalcomplicationsofneosia.CancerKoizumiM,YamadaY,TakiguchiT,etal.Bonemetabolicmarkersinbonemetastases.JCancerResClinOncol1995;121:542–8.RosenLS,GordonD,TchekmedyianNS,etal.Long-termefficacyandsafetyofzoledronicacidinthetreatmentofskeletalmetastasesinpatientswithnonsmallcelllungcarcinomaandothersolidtumors:arandomized,phaseIII,double-blind,cebo-controlledtrial.Cancer2004;100:2613–21.LiptonA.Pathophysiologyofbonemetastases:howthisknowledgemayleadtotherapeuticintervention.JSupportOncol2004;2:205–13[discussionfollows].RosenLS,GordonD,KaminskiM,etal.Long-termefficacyandsafetyofacidcomparedwithpamidronatedisodiuminthetreatmentofskeletalcomplicationsinpatientswithadvancedmultiplemyelomaorbreastcarcinoma:arandomized,double-blind,multicenter,comparativetrial.CancerSaadF,GleasonDM,MurrayR,etal.Long-termefficacyofzoledronicacidthepreventionofskeletalcomplicationsinpatientswithmetastaticprostatecancer.JNatlCancerInstHirshV,TchekmedyianNS,RosenLS,ZhengM,HeiYJ.Clinicalbenefitofacidinpatientswithlungcancerandothersolidtumors:ysisbasedonhistoryofskeletalcomplications.ClinLungCancer2004;6:170–4.HillnerBE,IngleJN,ChlebowskiRT,etal.AmericanSocietyofClinical2003updateontheroleofbisphosphonatesandbonehealthissuesinwomenwithbreastcancer.JClinOncol2003;21:4042–57.NationalComprehensiveCancerNetwork. clinicalpracticeguidelinesoncology:prostatecancer. .org/professionals/physiciangls/PDF/prostate.pdf.AccessedSeptember17,2008.MundyGR.Mechanismsofbonemetastasis.CancerSaadF,SchulmanCC.Roleofbisphosphonatesinprostatecancer.EurUrolSabinoMA,MantyhPW.Pathophysiologyofbonecancerpain.JSupportOncolPfisterDG,JohnsonDH,AzzoliCG,etal.AmericanSocietyofClinicaltreatmentofunresectablenon-small-celllungcancerguideline:update2003.JClinOncol2004;22:330–53.BaumRP,wigD,MezzettiM.Positionofnuclearmedicinemodalitiesindiagnosticworkupofcancerpatients:lungcancer.QJNuclMedMolImagingSilvestriGA,TanoueLT,MargolisML,BarkerJ,DetterbeckF.Thestagingofnon-smallcelllungcancer:theguidelines.ChestNationalComprehensiveCancerNetwork. clinicalpracticeguidelinesinoncology:non-smallcelllungcancer. physiciangls/PDF/nscl.pdf.AccessedSeptember17,2008.BuryT,BarretoA,DaenenF,etal.Fluorine-18deoxyglucosepositrontomographyforthedetectionofbonemetastasesinpatientswithnon-smallcelllungcancer.EurJNuclMed1998;25:1244–7.GayedI,VuT,JohnsonM,MacapinlacH,PodoloffD.Comparisonofboneand2-deoxy-2-[18F]fluoro-D-glucosepositronemissiontomographyintheevaluationofbonymetastasesinlungcancer.MolImagingBiol2003;5:HetzelM,ArslandemirC,KonigHH,etal.F-18NaFPETfordetectionofmetastasesinlungcancer:accuracy,cost-effectiveness,andimpactonpatientmanagement.JBoneMinerRes2003;18:2206–14.LiptonA,TheriaultRL,HortobagyiGN,etal.Pamidronatepreventscomplicationsandiseffectivepalliativetreatmentinwomenwithbreastandosteolyticbonemetastases:longtermfollow-upoftworandomized,cebo-controlledtrials.Cancer2000;88:1082–90.BerensonJR,LichtensteinA,PorterL,etal.Long-termpamidronatetreatmentofadvancedmultiplemyelomapatientsreducesskeletalevents.MyelomaArediaStudyGroup.JClinOncol1998;16:593–602.SaadF.Clinicalbenefitofzoledronicacidforthepreventionofskeletalinadvancedprostatecancer.ClinProstateCancerLiptonA.Bisphosphonatetherapyintheoncologysetting.ExpertOpinDrugsDeleaT,McKiernanJ,LissM,etal.Costofskeletalcomplicationsinwithbonemetastasesoflungcancer[ ].LungCancer2003;41(suppl.2):S7[ DeleaT,LangerC,McKiernanJ,etal.Thecostoftreatmentofeventsinpatientswithbonemetastasesfromlungcancer.OncologySabaN,KhuriF.Theroleofbisphosphonatesinthemanagementofadvancedcancerwithafocusonnon-small-celllungcancer.Part2:Clinicalstudiesandeconomicyses.Oncology2005;68:18–22.RipamontiC,FulfaroF.Malignantbonepain:pathophysiologyandCurrRevPainSaadF,LiptonA,CookR,etal.Pathologicfracturescorrelatewithsurvivalinpatientswithmalignantbonedisease.CancerWeinfurtKP,LiY,CasLD,etal.Thesignificanceofskeletal-relatedeventsforthehealth-relatedqualityoflifeofpatientswithmetastaticprostatecancer.AnnOncol2005;16:579–84.DeleaTE,McKiernanJ,BrandmanJ,etal.Impactofskeletalcomplicationstotalmedicalcarecostsamongpatientswithbonemetastasesoflungcancer.JThoracOncol2006;1:571–6.GreenJR.Preclinicalprofileandanticancerpotentialofzoledronicacid.BirchEV,editor.Trendsinbonecancerresearch,24.NewYork:NovaSciencePublishers,Inc;2006.p.217–45.FleischH.Developmentofbisphosphonates.BreastCancerResGreenJR.Bisphosphonates:preclinicalreview.Oncologist2004;9(suppl.GreenJ.Zoledronate:thepreclinicalpharmacology.BrJClinPractSuppl1996;87:16–8[discussionfollows].GreenJR,MullerK,JaeggiKA.PreclinicalpharmacologyofCGP42’446,anew,potent,heterocyclicbisphosphonatecompound.JBoneMinerResBukowskiR,RosenL,GordonD,etal.Long-termtherapywithzoledroniciseffectiveandsafeinreducingtheriskofskeletalcomplicationsinwithbonemetastasesfromnon-smallcelllungcancer(NSCLC)[poster].In:10thWorldConferenceonLungCancer.2003[ ConteP,GuarneriV.Safetyofintravenousandoralbisphosphonatesandwithdosingregimens.Oncologist2004;9(suppl.WeitzmanR,SauterN,EriksenEF,etal.Criticalreview:updatedfortheprevention,diagnosis,andtreatmentofofthejawincancerpatients—May2006.CritRevOncolHematol2007;62:Zometa[packageinsert].EastHanover,NJ:NovartisPharmaceuticalsDurieBG,KatzM,CrowleyJ.Osteonecrosisofthejawandbisphosphonates.EnglJMed2005;353:99–102[discussionHoffAO,TothBB,AltundagK,etal.FrequencyandriskfactorsassociatedosteonecrosisofthejawincancerpatientstreatedwithintravenousJBoneMinerResPozziS,MarcheselliR,SacchiS,etal.Bisphosphonate-associatedofthejaw:areviewof35casesandanevaluationofitsfrequencyinmultiplemyelomapatients.LeukLymphoma2007;48:56–64.DimopoulosMA,KastritisE,BamiaC,etal.Reductionofosteonecrosisofthejaw(ONJ)afterimplementationofpreventivemeasuresinpatientswithmultiplemyelomatreatedwithzoledronicacid.AnnOncol2009;20:MontefuscoV,GayF,SpinaF,etal.Antibioticprophylaxisbeforedentalproceduresmayreducetheincidenceofosteonecrosisofthejawinpatientswithmultiplemyelomatreatedwithbisphosphonates.LeukLymphomaRipamontiCI,ManiezzoM,CampaT,etal.Decreasedoccurrenceofofthejawafterimplementationofdentalpreventivemeasuressolidtumourpatientswithbonemetastasestreatedwithbisphosphonates.TheexperienceoftheNationalCancerInstituteofMilan.AnnOncolRipamontiC,ManiezzoM,GhiringiR,etal.Medicalozoneoilapplicationshealosteonecrosisofthejaw(ONJ)inpatientstreatedwith(BPs):preliminaryresultsofasingleinstitutionprotocol[poster].In:PrimaryTherapyofEarlyBreastCancer11thInternationalConference.2009[Poster194].BrownJE,CookRJ,MajorP,etal.Boneturnovermarkersaspredictorsofcomplicationsinprostatecancer,lungcancer,andothersolidtumors.JNatlCancerInst2005;97:59–69. idesD,NikolaouM,FarmakisD,etal.Clinicalvalueofbonemarkersinpatientswithbonemetastasestreatedwithzoledronicacid.AnticancerRes2005;25:1457–63.ColemanRE,MajorP,LiptonA,etal.Predictivevalueofboneresorptionformationmarkersincancerpatientswithbonemetastasesreceivingthezoledronicacid.JClinOncolLiptonA,CookR,SaadF,etal.Normalizationofbonemarkerswithimprovedsurvivalinpatientswithbonemetastasesfromsolidtumorsandelevatedboneresorptionreceivingzoledronicacid.Cancer2008;113:HirshV,MajorPP,LiptonA,etal.Zoledronicacidandsurvivalinpatientswithmetastaticbonediseasefromlungcancerandelevatedmarkersofosteoclastactivity.JThoracOncol2008;3:228–36.GreenJR.Antitumoreffectsofbisphosphonates.CancerMatsumotoS,KimuraS,SegawaH,etal.Efficacyofcombiningthethirdbisphosphonate,zoledronatewithimatinibmesylateinsmallcelllungcancercelllineproliferation[ ].ProcAmSocClin2003;22(suppl.):684 BergerW,KubistaB,ElblingL,SutterlutyH,MickscheM.TheN-containingbisphosphonatezoledronicacidexertspotentanticanceractivityagainstcelllungcancercellsbyinhibitionofproteingeranylgeranylation ].ProcAmAssocCancerRes2005;46[ OzturkOH,BozcukH,BurgucuD,etal.CistincytotoxicityisenhancedzoledronicacidinA549lungcancercellline:preliminaryresultsofaninstudy.CellBiolIntGjyreziA,O’BrateA,Chanel-VosC,GiannakakouP.ZoledronicacidwithTaxolinanHDAC6-dependentmanner:novelmechanisticimplicationsforcombinationanticancertherapywithtaxanes[ ].ProcAmAssocCancerRes2007[ LiYY,ChangJW,ChouWC,etal.Zoledronicacidisunabletoinducebutslowstumorgrowthandprolongssurvivalfornon-small-celllungcancers.LungCancer2008;59:180–91.OryB,HeymannMF,KamijoA,etal.Zoledronicacidsuppresseslungand