肿瘤核素靶内照射治疗-中山大学肿瘤防治中心

肿瘤核素靶向内照射治疗中山大学肿瘤医院樊卫fanwei@主要内容肿瘤核素靶向治疗概述临床应用现状甲状腺癌；B细胞淋巴瘤神经内分泌瘤；前列腺癌乳腺癌肿瘤核素靶向治疗面临的问题3肿瘤核素靶向治疗以肿瘤细胞表面特异性靶点（如受体、转运体、或抗原决定簇及特异性基因片断等）作为治疗靶，以对应的配基（配体）或单克隆抗体等作为载体，通过血液循环将含有放射性核素的特异性载体与细胞靶点结合，利用核素发出的射线（shortrangebetaparticle,alphaparticleorelectronemissions）杀灭肿瘤细胞的治疗方法神经内分泌瘤PET图像与分子病理学213Bi-DOTATOC治疗后，68Ga-DOTATOCPET评价疗效基于药代分析（蛋白质水平）的指导靶向治疗的方法，从治疗角度看，优于基因水平的作用，更优于体外检测的价值。45/F,18F-FESFESPredictsBreastCaResponsetoHormonalTherapy

Case1•Recurrentsternallesion•ER+primary•RecurrentDzstronglyFES+Pre-RxPost-RxExcellentresponseafter6wksLetrozole

Case2•NewlyDx’dbreastcancer•ER+primary•FES-negativebonemets Mankoff,U.WashingtonFESFDGFDGNoresponseseveraldifferenthormonalRxPMSA-617radiolabeledGa-68,orLu-177分化型甲状腺癌概述甲状腺癌分化型甲状腺癌(DTC)甲状腺乳头状癌(PTC)甲状腺滤泡状癌(FTC)甲状腺髓样癌（MTC）未分化癌（ATC）DTC治疗问题DTC激素抑制131I内照射手术治疗DTC最优综合治疗方案“手术+131I+TSH抑制”模式“手术+131I+TSH抑制”方案Note:TNM预测的仅是死亡危险度，而非复发危险度；DTC生存期长，需复发危险度分层DTC细胞摄碘机制DTC诊治指南（2012ATA）推荐的复发危险度分层I-活化和合成T3、T4关键酶--甲状腺过氧化物酶(TPO)+131I2单碘酪氨酸二碘酪氨酸T3T4David.S,etal.Antithyroiddrug.NEnglJMed.2005;35:905-917TPO催化酪氨酸残基-甲状腺球蛋白131I-碘-131物理特性131碘衰变时主要释放β射线(占98.89%)和γ射线(占1%)。131碘在衰变时产生6种不同能量β射线，且各有概率，β衰变中还拌有19种不同能量γ射线。碘-131衰变纲图：ICRP30出版物：131I口服后属于快速吸收F类化合物，f值是1即100%吸收入血，但从血液到甲状腺的量取决于甲状腺的机能状态。一般正常状态：131I到甲状腺的量约为摄入量的30-34%，其它进入体内的131I都经肾排泄掉了。ICRP30规定：甲状腺生物半排期为120天，而甲状腺以外器官的生物半排期为12天左右。碘的放射毒理学131I治疗DTC转移获CR淋巴结转移68%肺转移46%骨转移7%META分析数据131I治疗无疗效淋巴结转移12%肺转移24%骨转移54%META分析数据131I治疗肺转移X线胸片未发现，131I显像有肺部弥散摄取的患者易获CRX线胸片能发现，131I显像有肺部弥散摄取的患者很难获CR肺部转移灶大于1cm，疗效差131I治疗未131I治疗5年存活率（%）74.927.110年存活率（%）60.812.2DTC肺转移患者存活率牟达、匡安仁等，放射性131I治疗DTC肺转移的疗效及其主要预后因素的系统评价。中华内分泌代谢杂志2009：250~254系统评价Schlumbergeretal1976年以后诊断的DTC远处转移的患者10年生存率，比1960-1976诊断者提高30%比1960以前诊断者提高140%近期副作用1、唾液腺损伤（主要是腮腺）2、白细胞或血小板降低3、放射性咽喉炎4、放射性胃炎远期副作用致癌作用？对生育的影响？流行病学调查发现电离辐射本底高的地区与低的地区肿瘤发病率无差异成人接受低于100mSv，儿童接受低于50mSv,肿瘤发病率无增高既有实验结果，也有临床观察结果，支持低剂量照射防癌作用LNT模型在100mSv以下受到严峻挑战TherapeuticNuclearMedicine,2014,836P作者资料来源随访时间甲状腺癌确诊年龄研究人数累积剂量继发肿瘤时间继发肿瘤总发病率Brown（2008）北美中位8.6年0.2-29.7中位42岁4-10030278未登记中位数8.1年7.1%Rubino（2003）欧洲平均13年（2-55）平均44岁（2-91）68416.0GBq0.2~55.5平均数15年8.4%甲状腺癌继发肿瘤的两项多中心研究资料总的来说，放射性碘治疗仅产生较轻微的短期副作用，远期放射性损害发生几率非常小，因此即使儿童也可安全使用。DTC131I治疗实体瘤RR1.19/GBq白血病RR2.50/GBqOccupationLLE(days)Unemployment500Agriculture320Construction227Mines167Transportation160Government60Medicalradiationworker(5mSvperyearoverworkinglife)42Manufacturing40Trade27Services27Medicalradiationworker(2mSvperyearoverworkinglife)17Comparisonofvariousoccupationintermsoflossoflifeexpectancy(LLE)NakedantibodyRadiolabeledantibody放射免疫治疗机制Evenwhennotallthecellsarereachedbytheantibody,theradioactivelabelsoftheantibodyirradiatethesurroundingcellsAlltumorcellsneedtobeboundbyantibodiesPatient’simmunemechanismsmaynotbesufficientlyintacttointeractwiththeantibodyTumorcellsmayberesistanttodirectanti-tumormechanismsaswellasimmunemechanismsoftheantibodyRIT与靶向治疗区别AdvantagesGoodkillingeffectGoodeffectivepenetrationContinuouslyactingLimitationsNon-specificeffect(toxic)RequirestargetedlocalizationUnwantedeffectwhilecirculatingAdvantagesTheoreticallyaspecificeffectDoesnotrequiretargetedlocalizationLimitationsPoorpenetrationPoorkillingeffectBoneMarrowBlood,LymphCD20Press.SeminOncol.1999;26:5(suppl14):58.PluripotentstemcellLymphoidstemcellPre-BcellBcellActivatedBcellPlasmacell骨髓干细胞和浆细胞不表达CD20Tositumomab-131Iodine:Bexxar™Mouse；（

2003,6,FDA）TositumomabunlabeledIbritumomabTituxetan-90Yttrium:Zevalin™Mouse（2002,4,FDA批准）IbritumomabTiuxetan111Indium:Zevalin™?MouseRituximabunlabeled:Rituxan™ChimericAnti-CD20靶向放射性药物RITofB-celllymphomaisgenerallybutnotalwaysdirectedattheCD20antigen90Y-ibritumomabtituxetan(Zevalin,90Y-Mabothera)，02年4月FDA批准上市131Itositumomab(Bexxar，AntiCD-20Antibody)2003,6,FDA标准上市Zevalin在欧洲适应指针由2004年用于复发或难治CD20阳性滤泡型淋巴瘤或转化B细胞NHL，到2008年被欧盟人用药品委员会（CHMP）批准作为滤泡型淋巴瘤一线强化疗法。Rituximab250mg/m2Followedby90YZevalin™

(0.4or0.3mCi/kg*;

maxdose32mCi)治疗方法ororFollowedby111Inibritumomabtiuxetan5mCiRituximab250mg/m2剂量计算123456789DayIDECPharmaceuticalsCorp.Zevalin™PrescribingInformation.2002.

Zevalin™

治疗方案*0.4mCi/kginpatientswithaplateletcount150,000cells/Lor0.3mCi/kgwithaplateletcount100,000–149,000cells/L2–24hours90–120hours(optional)48–72hoursDay02infusions:450mgofTositumomab35mgofTositumomabwith5mCiIodine-131Scan#1Day2,3,or4

Scan#2Day6or7

Scan#3剂量计算步骤OneDayBetweenDay7-Day142infusions450mgofTositumomab35mgofTositumomabwithindividualizeddoseofradioactivity(Iodine-131)togive75cGytotalbodydoseofradiation治疗步骤BEXXAR治疗方案Thyroprotection:Day-1continuingthrough14dayspost-therapeuticstepTimetoProgressionTimefromTreatment(months)223Ra治疗骨转移瘤现状Thetargetpopulationispatientswithprogressive

symptomatic

CRPC,withatleasttwoskeletalmetastasesonbonescanandnovisceralmetastases.SpecificallythetargetpopulationisSubjects

whohavereceiveddocetaxelSubjects

whoarenotfitenoughtoreceivedocetaxelSubjects

notwillingtoreceivedocetaxel,SubjectsreceivingBSoCandnotincludingtheuseofcytotoxictherapy,radioisotopes,orhemibodyexternalradiotherapy(PA1)Patientspopulation③①②⑤④⑥223Ra物理特性背景：骨转移瘤核素治疗现状TreatmenttobeadministeredRadium-223dichloride:

50kBq/kgbw

AdministeredasaslowbolusIntravenous(IV)injection

At4weekintervalsforupto6doses223Ra治疗前列腺癌骨转移现状M36(PA1)M16M24M12M0Radium-223*

50kBq/kgM28M6M20M30M8M10Primaryobjective:SafetyandEfficacy(Overallsurvival[OS])Secondaryobjectives:tALPchange/normalization/timetoprogressionPSAchange/timetoprogressionSREfreesurvival/timetofirstSRETimetostartofanyotheranti-cancertreatmentTimetofirstdeteriorationofECOGPerformanceStatusQualityoflife(QoL)Exploratoryobjectives:BonemetastasesassessmentPharmacokineticanalysis(PA1)FOLLOW-UP(maximum3years)TREATMENTPERIOD

6injectionsat

4-weekintervalsConfirmedsymptomaticCRPCProgressive≥2bonemetastasesNoknownvisceralmetastasesPost-docetaxelordocetaxelineligibleN=230(PA1)ASingle-arm,international,prospective,interventional,open-label,multicenterstudyofRadium-223dichlorideinthetreatmentofpatientswithCastration-ResistantProstateCancer(CRPC)withBoneMetastasis.*Plusbeststandardofcare. AssessmentsMonthALSYMPCA

AdverseEventsofInterest–inASCO2012AllGradesGrades3or4Rad