大剂量化疗后迟发型肺毒性Word格式文档下载.docx
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大剂量化疗后迟发型肺毒性Word格式文档下载.docx
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STEPHENW.WILCZYNSKI,JEREMYJ.ERASMUS,WILLIAMP.PETROS,JAMESJ.VREDENBURGH,andRODNEYJ.FOLZ
DepartmentsofMedicine,Radiology,andCellBiology,DukeUniversityMedicalCenter,Durham,NorthCarolina
ABSTRACT
Wehaveintenselyfollowed45consecutivewomenwhounderwenthigh-dosechemotherapy(cyclophosphamide/cisplatin/BCNU)andautologousbonemarrowtransplant(HDC/ABMT)forprimarybreastcancerwithpulmonaryfunctiontestingandcomputedtomographyatregularintervalsupto126wk(medianfollow-up,72wk).Ourresultsshowahighincidenceofinterstitialpneumonitisrequiringsteroids(64%),butnodeathsduetopulmonarytoxicity.TheDLCOreachesanadirof58.2±
SEM3.4(expressedasapercentofbaselinevalue)15-18wkfollowingHDC/ABMT,andmarginallyimproveswithtime.Toamuchlesserextent,vitalcapacityisreducedwithaparalleldropinFEV1,suggestingmildrestrictivechangeswithoutsignificantobstruction.PatientswhodeveloppulmonarysymptomsofcoughordyspneahaveacorrespondingsignificantlygreaterandearlierdeclineinDLCO.Chestcomputedtomographywasneithersensitivenorspecificfordiagnosingpulmonarytoxicity.Forpatientswhoreceivedsteroidsforpulmonarytoxicity,therewasasubsequentimprovementinDLCOof17.1%(p=0.0001).Becauseourpatientsdonotfitwiththerecentdefinitionofidiopathicpulmonarysyndrome(IPS),weproposethetermdelayedpulmonarytoxicitysyndrome(DPTS)tobetterdescribethemilderformoflungtoxicityseeninourpatientpopulation.WewereunabletocorrelatetheseverityofDPTSwithage,tobaccouse,baselinepulmonaryfunction,orsystemicexposuretoBCNU,cyclophosphamide,orcisplatin.Thesedatasuggestthatfactor(s)otherthan,orinadditionto,chemotherapysystemicexposurecancontributetoDPTS.Furthermore,earlyidentificationandinstitutionofsystemiccorticosteroidsmayimprovelungfunction.
INTRODUCTION
Anumberofchemotherapeuticagentshavebeenassociatedwiththedevelopmentofadrug-inducedinterstitialpneumonitis.Interstitialpneumonitishasbeencommonlyreportedinthesettingofbothautologousandallogeneicbonemarrowtransplantation.Theclinicalsymptomscanincludeadrycough,dyspneaonexertionoratrest,andfever.Idiopathicpneumoniasyndrome(IPS),adiffuseandseverelunginjurywithoutevidenceofinfection,isaseriouscomplicationofbonemarrowtransplant
(1).Mortalitycanreach65%
(2).Steroidsareoftenusedtotreattheinterstitialpneumonitis,thoughtheefficacyofsuchtreatmentisnotproven.Followingautologousbonemarrowtransplantation(ABMT),agentsthathavebeenassociatedwiththedevelopmentofIPSincludecarmustine(BCNU)(1,3)andcyclophosphamide(CPA)(1,3,4,6,7).Followingallogeneicbonemarrowtransplants,thedevelopmentofIPSmayberelatedtoseveralfactors,includingthepresenceofseveregraft-versus-hostdisease(GVHD),useofmethotrexatetopreventGVHD,highdosesofirradiation,olderage,poorerperformanceratingsbeforetransplantation,andinfectionwithcytomegalovirus(CMV)(8,9).InadditiontoIPS,anacutealveolarpulmonaryhemorrhagehasbeendescribedinpatientsreceivingautologousandallogeneicmarrow(10).InABMT,thisusuallyoccursearlierthanIPS,typicallywithinthefirst2wkfollowingtransplant(10).Idiopathicpneumoniasyndrome,bycontrast,ismoretypicallydelayedbyseveralweekstomonthsfollowingABMT
(1).
Carmustine-baseddose-intensivechemotherapyregimenswithABMTforcellularsupporthavebeenshowntoimproveoverallsurvivalandprogression-freesurvivalinpatientswithmetastaticbreastcanceraswellasthosewithextensiveaxillarynodeinvolvement(13).Theoccurrenceofpulmonarydrugtoxicitywiththisregimenisvariableandhasbeenreportedtorangefrom39-53%(5).Wesoughttofurthercharacterizetheincidenceandseverityofpulmonarytoxicityinconsecutivebreastcancerpatientstreatedwithhigh-doseCPA/cDDP/BCNUandABMT.Inparticular,wewantedtodescribetheincidenceofsymptoms,associatedabnormalitiesinpulmonaryfunctiontesting,andassociationwithradiologicabnormalitiesnotedonCTscans.Wealsosoughttodeterminepredictorsforthedevelopmentofpulmonarytoxicityaswellastheresponsetocorticosteroidtherapy.
Overall,wefoundahighincidenceofpulmonarytoxicity,thoughtherewasnorelatedmortalityduetolunginjury.Theseresultshaveledustocointhetermdelayedpulmonarytoxicitysyndrome(DPTS)tobetterdescribethepost-transplantnoninfectiouscomplicationseeninourpatientpopulation.Delayedpulmonarytoxicitysyndromecaninvolvethedevelopmentofcough,dyspnea,andfever,andshouldincludeasignificantdeclineinsingle-breathdiffusingcapacity(DLCO).Delayedpulmonarytoxicitysyndrome,whichappearstorespondtosteroidtreatment,istobedistinguishedfromIPS,whichcarriessignificantmortalityrisk.
METHODS
StudyDesign
Weperformedaretrospectivechartreviewof45consecutivepatientswhounderwenthigh-dosechemotherapyandautologousbonemarrowtransplant(HDC/ABMT)forprimarybreastcancerwithinvolvementoffourtoninelymphnodes.AllpatientsweretreatedonresearchprotocolapprovedbytheDukeUniversityInstitutionalReviewBoard(DORIS#92094)andgaveinformedconsent.Eligibilitycriteriaforthistreatmentprotocolincludedthefollowing:
operable,histologicallyconfirmedstageII/IIAbreastcancerwithfourtonineinvolvedlymphnodesatresection,lessthan8wkfromlastsurgery,Karnofskyperformancestatus80-100%,nopriorchemotherapyorradiationtherapy,noothermalignancyorcomorbiddisease,pulmonaryfunctiontest(PFT)demonstratingDLCO,FEV1,FVC,andtotallungcapacity(TLC),toallbe>
60%predicted,andnegativebonemarrowbiopsies.
Chemotherapy/BoneMarrowTransplantProtocol
Patientsreceivedinductionchemotherapywithadriamycin(80mg/m2)and5-fluorouracil(800mg/m2)givenevery2wkforthreecycles.Patientsthenreceivedrecombinantgranulocytecolony-stimulatingfactor(G-CSF)(filgrastim)for5dtoprimeperipheralprogenitorcells(PBPC)forleukopheresis.Inductionchemotherapywasfollowedbyhigh-dosechemotherapywithcyclophosphamide(CPA)(1,875mg/m2intravenouslyasadaily1-hinfusionfor3d),cisplatin(cDDP)(165mg/m2continuousintravenousinfusionover72h)givenonDays
6,
5,
4,andBCNU(600mg/m2intravenouslyasaone-timeinfusionover2h)givenonDay
3.BloodsamplesformeasurementofBCNUeliminationweretakenateighttimepoints:
oneduringandsevenfollowinginfusionupto210minfromthestartoftheinfusion.High-dosechemotherapywasfollowedbyABMTatDay+1,andPBPCreinfusionsonDays
1,0,and+1.Theareaunderthedrugeliminationcurve(AUC)foreachofthechemotherapeuticagentswasdeterminedfromserialbloodlevelsutilizinghighperformanceliquidchromatography(HPLC)accordingtopreviouslypublishedmethods(7,17).Thetreatmentprotocolcallsforstandardlocalregionalradiotherapytobedeliveredtothechestwallandipsilateralsupraclavicularandinternalmammarynodesataminimumof50.4Gy,followedbya10Gyboosttothemastectomyscar.Thisisbegungenerally6wkfollowingABMT,butmaybedelayedbycytopeniasorpulmonarytoxicity.
PatientFollow-up
Patientshadregularfollow-upattheDukeUniversityBoneMarrowTransplantClinic.Theywerefollowedcloselyforthedevelopmentofpulmonarytoxicitybyregularlyscheduledpulmonaryfunctiontestingdoneevery6wkforthefirst24wkandevery12wkthereafter.AdditionalPFTsweredonewhenpatientsdevelopedpulmonarycomplaints.Ifsignsand/orsymptomsoftoxicitydeveloped,thepatientsreceivedprednisoneataninitialdoseof60mg/dfor2wkfollowedbyagradualtaperoverthefollowing6wk.
ThecliniciansinourBoneMarrowTransplantClinicusedthefollowingguidelinesfordiagnosingDPTSandinitiatingprednisonetherapy:
(1)developmentoftypicalsymptoms(nonproductivecough,dyspnea,withorwithoutfeveroccurringseveralweekstomonthsfollowingABMT)andfallinDLCOtolessthan60%predicted;
or
(2)declineinDLCOtolessthan50%predictedwithorwithoutsymptoms;
(3)forasymptomaticpatientswithDLCO50-60%predicted,treatmentwaslefttothediscretionofthetreatingphysician.Patientstreatedwithprednisonealsoreceivedconcurrentpneumocystisprophylaxiswithtrimethoprim/sulfamethoxasole.Clinicalfeaturesofthesepatientswererecorded,includingage,smokinghistory,historyorpriorlungdisease,CMVimmunestatus,pulmonarysymptoms,anddatarelatingtoprednisonetreatmentandradiationtherapy(XRT).
PulmonaryFunctionTests
Pulmonaryfunctiontestingwasdonebeforeinductionchemotherapy(baseline)andatregularintervalsafterHDC/AMBT,asnotedabove.Pulmonaryfunctiontestsincludedspirometry,lungvolumes,anddiffusioncapacities(DLCO),andwereperformedaccordingtoAmericanThoracicSocietystandards(18,19).TheDLCOwascorrectedforhemoglobinusingtheformula:
(1.7×
hemoglobin)/(9.38+hemoglobin)(19).Toassesschangesinpulmonaryfunction,valuesforDLCO,FEV1,FVC,andTCLwerenormalizedbyexpressingthemasapercentoftheirbaselinevalues(%BL).BaselinespirometryandDLCOwereavailableforallpatients,butTLCwasavailableatbaselineinonly34patients.Weconsideredadeclinefrombaselinevalueof15%forFEV1,FVC,andTLCand20%forDLCOtobesignificant(19,20).CompleterecoveryofPFTsafterdevelopmentofpulmonarytoxicitywasdefinedasimprovementto85%ofbaseline
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- 关 键 词:
- 剂量 化疗 发型 毒性