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時才被診斷【4SREs的（如骨痛、活動度降低）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、二膦酸鹽是破骨細胞介導(dǎo)的骨質(zhì)溶解的抑制劑，已證實該類藥物能夠預(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、肺癌及多種實體瘤患者【15，17-19】的SREs發(fā)生，降低骨疾病進展和SREs發(fā)生的。唑來膦酸是唯一批準用于治療除以外的實體腫瘤骨轉(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異常的NSCLC患者進行骨掃描骨掃描發(fā)現(xiàn)的可疑骨損害一般需進一步X線檢查、計算機體層攝影、磁成像、代謝標際上，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?shù)摹?9，30關(guān)于骨轉(zhuǎn)移疾病負荷的情況見于近期一些安慰劑與二膦酸鹽對照的試驗。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間短【6DeleaNSCLCSRE4個月。因此不管組織學(xué)如何骨轉(zhuǎn)移的病理生理學(xué)機制導(dǎo)致骨骼疾病發(fā)生即使是侵襲強的、生存期較短的也具備骨轉(zhuǎn)移所致SREs發(fā)生的時間。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患者接受進一步治療所必需的合格標準，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)療費用增加相關(guān)。在一項回顧性分析中，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)的其他實體腫瘤的治療獲益延長批準唑來膦酸用于治療實體腫瘤基于一項隨機、安慰劑對照的III期試驗，在該試驗中，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【RR】=0.693；p=0.003。2.SRE的比例（21個月的研究。*HCM。數(shù)據(jù)Rosenetal【15SREs發(fā)生時才被診斷為骨轉(zhuǎn)移。但是，預(yù)先存在的骨疾病并不妨礙隨后治療的獲益。實際上，已經(jīng)發(fā)生SRE的患者以后發(fā)生的風(fēng)險格外高。例如，41%（p=0.03631%（p=0.009p=0.030SRE4個月（215vs106【19SRE的患者也顯示治療獲益，但未達到顯著統(tǒng)計學(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的標準的定義。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或其他實體腫瘤伴有骨轉(zhuǎn)移患者的SREs、疾病進展的相對風(fēng)險。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胞系的增殖誘導(dǎo)其凋亡【43，64。體外試驗顯示，唑來膦酸抑制來源于人類腫瘤細胞系的生長，包括12種小細胞肺癌細胞系，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細胞的溶細胞活性，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%究終點的差異的檢驗效價不夠，兩組均有很多患者在治療3周期后由于疾病進展而停止了NSCLC患者的疾病進展和生存影響的隨機研已證實對早期女性患者而言與單獨的內(nèi)分泌治療相比唑來膦酸聯(lián)合內(nèi)分泌治76NSCLC患者疾病進展時間效用的研究提供了理論NSCLC患者的研究評價了唑來膦酸預(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。主要研究終點是評價疾病進展（如骨疾病的進展20094個月內(nèi)完成。一項公開的對IIIB或IV期不伴有骨轉(zhuǎn)移的NSCLC患者的抗腫瘤試驗（Z-PACT）已完成了的入組【78?；颊呓邮芑煟⒈浑S機分入唑來膦酸4mg組或無唑來膦酸治6周期或疾病進展。對治療反應(yīng)的唑來膦酸組患者將進一步被隨機分入唑來4mg12QOL及連續(xù)治療過程中的醫(yī)療費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)生的臨床試驗正在進行中，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;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