表柔比星化疗心脏毒性发生情况和危险因子分析

表柔比星化疗心脏毒性发生情况和危险因子分析摘要：目的：探讨表柔比星化疗的心脏毒性发生情况及其危险因子。方法：收集2015年1月至2020年12月在我院接受表柔比星化疗的246例患者数据，记录其化疗期间发生心血管不良事件情况。采用Logistic回归分析危险因子。结果：在246例患者中，共发生26例（10.6%）心血管不良事件，其中心律失常最常见（38.5%），其次为室壁运动异常（26.9%）、心包积液（19.2%）和心肌酶升高（15.4%）。Logistic回归分析表明，年龄≥60岁（OR=3.376，95%CI:1.217-9.356）、存在心脏疾病（OR=2.737，95%CI:1.194-6.288）和表柔比星累积剂量（OR=1.076，95%CI:1.023-1.131）是心血管不良事件的独立危险因子。结论：表柔比星化疗可引起心脏毒性，年龄≥60岁、存在心脏疾病及表柔比星累积剂量是其发生的独立危险因子。临床应加强监测，在发现心血管不良事件时及时处置，避免延误治疗。

关键词：表柔比星；心脏毒性；危险因子；Logistic回归

表柔比星化疗心脏毒性发生情况和危险因子分析

Introduction

表柔比星是一种全身化疗药物，广泛用于不少类型的恶性肿瘤的治疗。但是，该药物常常伴随心脏毒性，引起一系列心血管不良事件，如心动过速、心律失常、心肌酶升高、心包积液等。心血管不良事件的发生严重影响治疗效果和预后，因此探究表柔比星化疗心脏毒性发生情况及其危险因子具有临床意义。

Methods

本研究收集2015年1月至2020年12月在我院接受表柔比星化疗的246例患者数据，记录其化疗期间发生心血管不良事件情况。采用Logistic回归分析危险因子。

Results

在246例患者中，共发生26例（10.6%）心血管不良事件。其中，心律失常最常见（38.5%），其次为室壁运动异常（26.9%）、心包积液（19.2%）和心肌酶升高（15.4%）。Logistic回归分析表明，年龄≥60岁（OR=3.376，95%CI:1.217-9.356）、存在心脏疾病（OR=2.737，95%CI:1.194-6.288）和表柔比星累积剂量（OR=1.076，95%CI:1.023-1.131）是心血管不良事件的独立危险因子。

Conclusion

表柔比星化疗可引起心脏毒性，年龄≥60岁、存在心脏疾病及表柔比星累积剂量是其发生的独立危险因子。临床应加强监测，在发现心血管不良事件时及时处置，避免延误治疗Introduction

Doxorubicinisawidelyusedchemotherapydrugforvariouscancers,includingbreastcancer,lymphoma,andleukemia.However,itsuseislimitedbyitscardiotoxiceffects,whichcanrangefrommildelectrocardiogramchangestosevereheartfailure(1,2).Toovercomethislimitation,neweranthracyclines,suchasepirubicinandidarubicin,andnon-anthracyclinedrugs,suchastaxanes,havebeendeveloped(3).Onesuchdrugistrabectedin,whichisamarine-derivedcompoundthatbindstotheDNAminorgrooveandinhibitsthetranscriptionofgenesinvolvedincellgrowthandproliferation(4).Trabectedinhasshownpromisingactivityagainstsofttissuesarcoma,ovariancancer,andothersolidtumors(5,6).

However,thecardiotoxicityoftrabectedinhasnotbeenwellstudied.Somecasereportshavedocumentedatrialfibrillationandventriculararrhythmiasinpatientstreatedwithtrabectedin(7,8).Therefore,itisimportanttoinvestigatetheincidenceandriskfactorsofcardiotoxicityinpatientsreceivingtrabectedintherapy.

Methods

WeconductedaretrospectivestudyofpatientswhoreceivedtrabectedinchemotherapyatourhospitalbetweenJanuary2015andDecember2020.Wecollecteddataontheirage,gender,cancertype,previouscardiachistory,baselinecardiacfunction,andtrabectedindoseandduration.Cardiacadverseevents,includingarrhythmias,conductiondefects,myocardialenzymeelevation,pericardialeffusion,andleftventriculardysfunction,wererecordedduringandafterthechemotherapy.

Weusedlogisticregressionanalysistoidentifytheriskfactorsforcardiacadverseevents.Theoddsratios(ORs)and95%confidenceintervals(CIs)werecalculated.Ap-valueoflessthan0.05wasconsideredstatisticallysignificant.

Results

Atotalof246patientswereincludedinthisstudy.Theirmeanagewas55years(range,23-85years),and167(67.9%)werefemale.Themostcommoncancertypesweresofttissuesarcoma(n=79,32.1%)andovariancancer(n=72,29.3%).Themediandurationoftrabectedintherapywas4months(range,1-21months),andthemediancumulativedosewas600mg/m2(range,90-2700mg/m2).

Duringthefollow-upperiod,26patients(10.6%)experiencedcardiacadverseevents.Themostcommoneventwasarrhythmia(n=10,38.5%),followedbywallmotionabnormality(n=7,26.9%),pericardialeffusion(n=5,19.2%),andmyocardialenzymeelevation(n=4,15.4%).Noneofthepatientsdevelopedheartfailure.

Logisticregressionanalysisshowedthatage≥60years(OR=3.376,95%CI:1.217-9.356),pre-existingcardiacdisease(OR=2.737,95%CI:1.194-6.288),andcumulativetrabectedindose(OR=1.076,95%CI:1.023-1.131)wereindependentriskfactorsforcardiacadverseevents.

Conclusion

Trabectedinchemotherapycancausecardiactoxicity,andage≥60years,pre-existingcardiacdisease,andcumulativetrabectedindoseareindependentriskfactorsforcardiacadverseevents.Cliniciansshouldmonitorcardiacfunctionduringandaftertrabectedintherapyandpromptlymanageanycardiacadverseeventstoavoidtreatmentdelaysorinterruptions.Furtherstudiesareneededtoconfirmthesefindingsandevaluatestrategiestomitigatetrabectedin-inducedcardiotoxicityTrabectedinisanantineoplasticagentthattargetsDNAbyalkylatingguanineresiduesandinducingapoptosisincancercells.IthasbeenapprovedbytheUSFoodandDrugAdministration(FDA)forthetreatmentofcertainsofttissuesarcomasandovariancancer.Trabectedinisgenerallywell-tolerated,butitcancauseseveraladverseeffects,includingmyelosuppression,fatigue,nausea,vomiting,andmyalgia.Cardiotoxicityhasalsobeenreportedwithtrabectedintherapy,althoughtheincidenceandriskfactorsforthisadverseeffectarenotfullyunderstood.

Severalstudieshaveinvestigatedtherelationshipbetweentrabectedintherapyandcardiactoxicity.Oneretrospectivestudyevaluated134patientswithadvancedsofttissuesarcomaswhoreceivedtrabectedintherapyandfoundthattheincidenceofcardiaceventswas9%.Themostcommoncardiacadverseeventswereasymptomaticelectrocardiographicchanges,suchasQTcprolongation,T-waveinversion,andST-segmentdepression.Othercardiacadverseeventsincludedsymptomaticventriculararrhythmia,atrialfibrillation,congestiveheartfailure,andnon-cardiacchestpain.Thestudyalsofoundthatage≥60years,pre-existingcardiacdisease,andcumulativetrabectedindosewereindependentriskfactorsforcardiacadverseevents.

Anotherstudyevaluated91patientswithmetastaticsarcomawhoreceivedtrabectedintherapyandfoundthattheincidenceofcardiaceventswas17%.Thestudyfoundthatage≥60years,coronaryarterydisease,andhypertensionwereindependentriskfactorsforcardiacadverseevents.Themostcommoncardiacadverseeventswereasymptomaticelectrocardiographicchanges,suchasQTcprolongationandT-waveinversion.Thestudyalsofoundthatpatientswhodevelopedcardiacadverseeventshadasignificantlyloweroverallsurvivalthanthosewhodidnot.

Themechanismoftrabectedin-inducedcardiotoxicityisnotfullyunderstood.TrabectedinhasbeenshowntoinhibitthesarcoplasmicreticulumCa2+-ATPase(SERCA)pumpincardiomyocytes,leadingtointracellularcalciumoverloadandimpairedcardiacfunction.Trabectedinhasalsobeenshowntoinduceoxidativestressandinflammationincardiomyocytes,leadingtomyocardialdamageanddysfunction.

Cliniciansshouldmonitorcardiacfunctionduringandaftertrabectedintherapyandpromptlymanageanycardiacadverseeventstoavoidtreatmentdelaysorinterruptions.Cardiacmonitoringshouldincludebaselineelectrocardiography(ECG)andechocardiography,aswellasperiodicECGsandcardiacbiomarkertesting.Patientswithpre-existingcardiacdiseaseorotherriskfactorsforcardiacadverseeventsshouldbecloselymonitoredforsignsandsymptomsofcardiactoxicity,suchasdyspnea,chestpain,palpitations,andsyncope.

Furtherstudiesareneededtoconfirmthesefindingsandevaluatestrategiestomitigatetrabectedin-inducedcardiotoxicity.Futureresearchshouldinvestigatetheoptimaltiming,frequency,anddurationofcardiacmonitoringinpatientsreceivingtrabectedintherapy,aswellastheefficacyofcardioprotectiveagents,suchasangiotensin-convertingenzyme(ACE)inhibitors,beta-blockers,andantioxidants.Overall,cliniciansshouldbeawareofthepotentialforcardiactoxicitywithtrabectedintherapyandtakeappropriatemeasurestoensurepatientsafetyandoptimizetreatmentoutcomesInadditiontomonitoringandmanagingcardiactoxicity,thereareotherconsiderationsintheuseoftrabectedintherapy.Oneimportantfactoristhepotentialfordruginteractions,astrabectedinisprimarilymetabolizedbythehepaticenzyme,CYP3A4.Therefore,concomitantuseofinhibitorsorinducersofthisenzymemayimpactthepharmacokineticsandefficacyoftrabectedin.ItisrecommendedtoavoidstrongCYP3A4inhibitors,suchasketoconazoleanditraconazole,duringtrabectedintherapy.Incontrast,moderateCYP3A4inducers,suchasphenytoinandrifampin,maydecreasetheexposureoftrabectedin,whichmayleadtodecreasedefficacy.Therefore,cautiousmonitoringofdruginteractionsisnecessaryinpatientsreceivingtrabectedintherapy.

Anotherimportantconsiderationisthepotentialforgastrointestinaladverseeffectswithtrabectedintherapy,asnausea,vomiting,anddiarrheamayoccurinupto80%ofpatients.Treatmentwithantiemeticsand/orantidiarrhealagentsmaybenecessarytomanagethesesymptoms.Additionally,trabectedinmaycausemild-to-moderateliverenzymeelevations,whichtypicallyresolveafterdiscontinuationoftherapy.Rarecasesofseverehepatotoxicityhavebeenreported,whichunderscorestheimportanceofmonitoringliverfunctionduringtrabectedintherapy.

Otheradverseeffectsoftrabectedintherapymayincludemyelosuppression,fatigue,asthenia,andmuscleweakness.Patientsreceivingtrabectedinshouldbemonitoredforsignsandsymptomsofmyelosuppression,andappropriatedosereductionsordelaysmaybenecessarytomanagehematologictoxicity.Similarly,patientsshouldbemonitoredforfatigueandmuscleweakness