sre2-肺癌骨转移患者的发生率

肠癌LungCancer67(2010)CoreyLangera,Vera降低生活质量（QOLNSCLC患者骨转移的诊断与治疗的规范却比较少。NSCLC患者的骨疾病发生率、骨转移的诊断与治疗的数据。结果：NSCLCNSCLC患者会发生≥1SRE。随着新的治疗方法对生存期的改善，SREs的患病率可能增加。每个后才被诊断出来，但早期治疗能够延迟SREs的发生。在NSCLC（n=773，与安慰剂相比，唑来膦酸（ZOL；4mg1531次）能够将（P=0.009SREs32%（P=0.016结论：NSCLCSREs（QOL移相比，恶性骨病对细胞物治疗不敏感。（SRE，（HCM不管是否存在骨损害的放射学表（如溶骨性或成骨性【10-12骨相关都可能发生；【15SRE时才被诊断【4SREs的（如骨痛、活动度降低）可能在患者生存期间持续存在。因此，在SRE发生前QOL及功能自立性，并可能有助于维持患者、二膦酸盐是破骨细胞介导的骨质溶解的抑制剂，已证实该类药物能够预防骨转移患者的SREs的发生【10，16。唑来膦酸能够显著延迟伴有骨转移的癌、肺癌及多种实体瘤患者【15，17-19】的SREs发生，降低骨疾病进展和SREs发生的。唑来膦酸是唯一批准用于治疗除以外的实体肿瘤骨转移的二膦酸盐。、存。对于骨转移患者，二膦酸盐已经成为治疗的一部分，以延迟病理性骨折及其他方法的应用使激素耐受的癌患者的生存提高最近的指南推荐应用唑来膦酸预防骨转（成骨作用在没有合适的诊断检测的情况下，NSCLC的骨转移容易被忽略。骨转移的经典检测是患者进行全身骨扫描；在有骨疼痛或符合早期骨损害的检测值的11名患者中，有目前临床肿瘤学会（ASCO）指南建议对临床评价异常的NSCLC患者进行骨扫描骨扫描发现的可疑骨损害一般需进一步X线检查、计算机体层摄影、磁成像、代谢标际上，氟-18脱氧葡萄糖（FDG）-PETNSCLC骨转移的检测的特异性高于骨扫描90%vs70%6%vs39%踪成像后，FDG-PETNSCLC骨转移诊断的敏感性是旗鼓相当的【29，30关于骨转移疾病负荷的情况见于近期一些安慰剂与二膦酸盐对照的试验。对不同2SREsSREs（1【15，32-35NSCLC骨转移患者中，安慰剂组的大多5SRE，较安慰剂组的中位生存时间短【6DeleaNSCLCSRE4个月。因此不管组织学如何骨转移的病理生理学机制导致骨骼疾病发生即使是侵袭强的、生存期较短的也具备骨转移所致SREs发生的时间。1.合并有骨损害的不同肿瘤的骨疾病的平均发生率（SREs发生数。数据来源：对照组*来自Liptonetal【32Rosenetal【15Berensonetal【33§Saadetal【34患者接受进一步治疗所必需的合格标准，预防SREs能够有助于防止体力状态。除了对患者的健康、生活质量、体力状态的影响以外，SREs与医疗费用增加相关。在一项回顾性分析中，534NSCLC295SREs有关的医SRE的急性处理相关（HCM的治（P<0.001Ras信号传导，从而诱导凋亡【45、、在人类肿瘤的动物模型系统中，包括多发性骨髓瘤癌二膦酸盐能够、、0.1uM时几乎完全抑制了法呢基二膦酸合5-40倍【432002。对包括激素耐受的癌及NSCLC在内的其他实体肿瘤的治疗获益延长批准唑来膦酸用于治疗实体肿瘤基于一项随机、安慰剂对照的III期试验，在该试验中，除及1SRE的患者的比例（HCM；39%vs48%安慰剂组；p=0.0392p=0.012天；p=0.00931%（相对风险【RR】=0.693；p=0.003。2.SRE的比例（21个月的研究。*HCM。数据Rosenetal【15SREs发生时才被诊断为骨转移。但是，预先存在的骨疾病并不妨碍随后治疗的获益。实际上，已经发生SRE的患者以后发生的风险格外高。例如，41%（p=0.03631%（p=0.009p=0.030SRE4个月（215vs106【19SRE的患者也显示治疗获益，但未达到显著统计学意义。该SREs61%在接受安慰剂或4mg唑来膦酸（15分钟静脉输注）的每组患者中，发生3或4级肌酐水平升高的患者为1.8%，两组的严重不良的发生没有显著差异。在唑来膦酸与安慰剂的试验过程中最常见的不良反应为骨疼（分别为48%与58%）分别为47%与32%30%膦酸减少SRE发生或镇痛的效应。两组间的镇痛评分没有显著差异，做来磷酸组的性骨放疗较安慰剂组没有显著减【6在NSCLC患者中没有发生4级肌酐水平升高见但可能严重的不良【49，50。由于所有静脉给药的二膦酸盐通过肾清除，因此应该在每次静脉给前检测肾功能和水化状态以确保肾脏的安全性肾功能正常的患者可能出ONJ的标准的定义。ONJ的发生率，包括预防性牙科处ONJ【58（n=238中的水平与骨生成标志BALP在中的水平【59。与基线NTX低（＜100nmol/mmol肌3（RR=3.03；p＜0.001，、图3.NSCLC或其他实体肿瘤伴有骨转移患者的SREs、疾病进展的相对风险。根据基（ANTx（B）BALP基线水平低者（＜46IU/LBrownetal【59、45%（18.8%vs66.7%p=0.001（n=204n=14435（RR=0.65p=0.024SRE速度减低或直接的抗肿瘤作用。越来越多的临床前表明二膦酸盐能够抑制多种人类肿瘤细胞系的增殖诱导其凋亡【43，64。体外试验显示，唑来膦酸抑制来源于人类肿瘤细胞系的生长，包括12种小细胞肺癌细胞系，50%有效抑制浓度（IC50）1330mM【6516NSCLC唑来膦酸能够阻断其中3种高的细胞系的【67。与顺铂单药相比，100uM唑来膦70（p=0.007（p<0.05骨肉瘤肺转移的鼠模型上，经唑来膦酸（0.1mg/kg25次）的小鼠未发生肺转移，（p=0.036道【71CD40，CD80，CD83化γδT细胞的溶细胞活性，并可能因此提高抗肿瘤免疫反应【73NSCLC患者（n=150）II期研究评估了多西他塞（75mg/m2）+卡16612个月【74的中位总生存期轻度延长（266天vs206天。总的来说，唑来膦酸与化疗的联合具有良好的（AEs（41.8%vs28.8%（16.3%vs5.7%究终点的差异的检验效价不够，两组均有很多患者在治疗3周期后由于疾病进展而停止了NSCLC患者的疾病进展和生存影响的随机研已证实对早期女性患者而言与单独的内分泌治疗相比唑来膦酸联合内分泌治76NSCLC患者疾病进展时间效用的研究提供了理论NSCLC患者的研究评价了唑来膦酸预防骨转移的有效性，在其的入组并将把随机分入唑来膦（4mg/3-4周或无唑来膦酸治疗组为期2【774mg组接受治疗。主要研究终点是评价疾病进展（如骨疾病的进展20094个月内完成。一项公开的对IIIB或IV期不伴有骨转移的NSCLC患者的抗肿瘤试验（Z-PACT）已完成了的入组【78。患者接受化疗，并被随机分入唑来膦酸4mg组或无唑来膦酸治6周期或疾病进展。对治疗反应的唑来膦酸组患者将进一步被随机分入唑来4mg12QOL及连续治疗过程中的医疗费用已变得越来越重要。早期治疗可能特别有利于维持患者NSCLC骨转移患者骨疾病发生风险的二膦酸盐。此外，NSCLC患者，唑来膦酸可能提高其生存获益，这可能是通过预防影响的SREs的发生或通过阻断生长因子自骨基质的释放而NSCLC患者骨转移发生的临床试验正在进行中，二膦酸盐对肺癌的治疗作用将不断发展。有必要确认NSCLC患者的骨转移，从而优SREs的发生。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;100:2613–2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