Higher efficacy and reduced adverse reactions in neoadjuvant ...

The present study aimed to investigate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in preoperative neoadjuvant ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature scientificreports articles article Higherefficacyandreducedadversereactionsinneoadjuvantchemotherapyforbreastcancerbyusingpegylatedliposomaldoxorubicincomparedwithpirarubicin DownloadPDF Subjects BreastcancerToxicology AbstractThepresentstudyaimedtoinvestigatetheefficacyandtoxicityofpegylatedliposomaldoxorubicin(PLD)inpreoperativeneoadjuvantchemotherapyforpatientswithbreastcancerbycomparingwithconventionalanthracycline.Thisstudyisanon-randomizedcontrolledtrial.Prospectiveanalysiswasconductedaftermatchingasrequired.Atotalof146patientswithconfirmeddiagnosisofbreastcancerbyhistopathologicalexaminationswereenrolledintotheobservationgroupandcontrolgroupin1:1ratio.Eachofthecasesintheobservationgroupwasrequiredtocorrespondtoanotherinthecontrolgroupaccordingtotherequirementsincludingage,molecularsubtype,axillarynodestatus,andregimenofthepreoperativeneoadjuvantchemotherapy.Thechemotherapywasbasedonregimensconsistingofanthracyclines,paclitaxelordocetaxel,and/orplatinum.PLDwasusedatleasttwiceintheobservationgroup,withtraditionalanthracyclineasacontrastinthecontrolgroup.Clinicalresponsesaswellascardiacsideeffectsandotheradversereactionswereevaluatedbyclinicalandimagingexaminationssuchaselectrocardiogram(ECG)andcolorDopplerultrasoundduringthechemotherapy.Pathologicexaminationswereperformedfollowingthesurgeriesafterpreoperativeneoadjuvantchemotherapy.Allthepatientsinbothgroupscompletedthepreoperativeneoadjuvant chemotherapyaccordingtotheiroriginalregimens.Thepostoperativepathologicalevaluationrevealedahigherpathologiccompleteresponse(PCR)rateandsignificantlymorepatientsofgradeVoftheMiller-Paynegradingsystemintheobservationgroupascomparedtothecontrolgroup(p = 0.047).Inaddition,theobservationgrouprecordedanevidentlyloweroccurrenceoftheadversecardiacevents(p = 0.014),ECGchanges(p = 0.048),andtherelativelysevereadversereactionssuchasmyelosuppression.Comparedwithconventionalanthracyclinedrugs,PLDhasabetterpathologicresponseandsafetyperformance,aswellasasimilarclinicaleffectivenessinpreoperativeneoadjuvantchemotherapyforbreastcancer. 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IntroductionBreastcancerisoneofthemostcommonmalignanttumorsinwomenworldwide,withamortalityrateonlylowerthanthatoflungcanceramongallthemalignancies.Everyyear,morethan1.3millionwomenintheworldarenewlydiagnosedwithbreastcancer,andabout500,000casesdieofthislife-threateningdisease1.Breastcancermanagementtowardsafavorableprognosisrequirescomprehensivemeasures,amongwhichchemotherapyhasalwaysbeenusedasakeypartduetoitssubstantialclinicaleffectsindiseasecontrol.Neoadjuvanttherapyistypicallyusedforthemanagementoflocalmalignanttumorspriortosurgeryandothertreatment2.Therearethreetypesofneoadjuvanttherapyforbreastcancer—preoperativeneoadjuvantchemotherapy,targetedtherapyandendocrinetherapy.Anumberofclinicaltrialsshowedthat80%ofthepatientswithbreastcancerachievedasignificantreductionintumorsize,andabout10–20%obtainedpathologiccompleteresponse(PCR)bypreoperativeneoadjuvantchemotherapy3.NationalComprehensiveCancerNetwork(NCCN)guidelinesalsorecommendpreoperativeneoadjuvantchemotherapyasaroutineforstageIIandpartofstageIIIbreastcancer4.However,avarietyofsideeffects,eventoxicresponsesconcomitantwithchemotherapyhaveputalimittotheclinicalapplicationoftheantineoplastics,resultingintherestricteduseofsomepotentchemotherapeuticdrugsdespiteoftheirpromisingfutureinimprovingthesurvivalrateforpatientswithbreastcancer.Toxicreactionscausedbychemotherapyvarieswiththeagents,butmostcommonlynausea,vomiting,myelosuppression,andevensomeseverersideeffectsthatmaydiscontinuethetreatment.Cardiotoxicityofadrugisusuallyconfirmedwhencongestiveheartfailureoccursaccompaniedbyrelevantclinicalsymptomsaftertreatment,orleftventricularejectionfraction(LVEF)islessthan55%ordecreasesbymorethan10%comparedwiththereferencevaluealthoughabsentofclinicalsymptoms5,6.Theclinicalsymptomssuggestingcongestiveheartfailureincludebutnotlimitedtolungmoistrale,pretibialedemaofbothlegs,andcyanosisoflipormouth.Therearemanykindsofantineoplasticsusedforchemotherapy.Anthracyclines,taxanesandtargeteddrugsarefrequentlyemployedasadjuvantdrugsinbreastcancertreatment.Anthracyclines,forinstance,hasbeenconstantlyplayinganirreplaceableroleinchemotherapy,particularlyforthepatientswithlocallyadvancedbreastcancer7.Alargenumberofclinicalstudieshavealsoconfirmedthatanthracyclinesarecurrentlyaroutinebycombiningwithtaxusinpreoperativeneoadjuvantchemotherapy8.However,thecardiotoxicitycausedbyanthracyclineagentsisstillconsideredbypractitionersasagreatchallengetotheirclinicalapplication,particularlyforelderlypatientsandthosereceivinganthracycline-basedmulti-coursechemotherapyowingtothepotentialriskofheartfailure9,10.Fortunately,theprogressinpharmaceuticaltechnologyovertherecentyearshascontributedtothedevelopmentofalargenumberofnovelagentstotackletheseproblems.Pegylatedliposomaldoxorubicin(PLD),anewdosageformofdoxorubicinwhichisencapsulatedbyliposome,canformastablethree-dimensionalstructure(stealthliposome)bypegylationonthesurfaceofliposome.Inthetreatmentofmetastaticbreastcancer,PLDshowedasimilarefficacyasdoxorubicin,butalowerincidenceofnausea,vomiting,andcardiotoxicity11.Therefore,inthepresentstudy,weaimedtoevaluatetheefficacy,cardiotoxicityandothersideeffectsofPLDinpreoperativeneoadjuvantchemotherapyforbreastcancerbycomparingwithtraditionalanthracyclineagents.ClinicalTrials.govID:NCT02953184(01/11/2016)andUniqueProtocolID:2016yx238.MaterialsandmethodsPatientsFromSeptember2016toDecember2019,atotalof146patientswithbreastcancerwererecruitedintheDepartmentofBreastSurgery,theFirstHospitalofJilinUniversity.Theadmissioncriteriawereasfollows:(1)femalepatientsof18 yearsoldorabove,withaninitialdiagnosisofstageI–IIIbreastcancerconfirmedbyhistopathologicalexaminations;(2)tolerableforpreoperativeneoadjuvantchemotherapy;(3)EasternCooperativeOncologyGroup(ECOG)physicalscore0–1,LVEF ≥ 55%,andnoabnormalityobservedinECG.(4)Othernecessarybloodtestswerealsocarriedoutwiththeresultsmeetingtherequirementsforchemotherapy—whitebloodcellsrangingfrom3.5 × 109to9.5 × 109;aspartateaminotransferase13.0–35.0(U/L);andalanineaminotransferase7.0–40.0(U/L).Theexclusioncriteriawere:(1)patientswithseveresystemicinfectionordiseases;(2)allergicorintoleranttochemotherapydrugsortheirexcipients;(3)patientsofchild-bearingagewhorefusedtotakeappropriatecontraceptivemeasuresduringthetreatmentandoneyearthereafter;(4)patientswithconditionsnotsuitableforthisstudyaccordingtothejudgmentoftheresearchers,suchaspotentialmentalillness,poorcompliance,orresidentialaddressfarawayfromtheresearchcenter.InNSABPB27,2411patientswereenrolled,ofwhichthePCRrateofAC-Tprotocol(anthracyclinescombinedwithcyclophosphamidefollowedbysequentialTaxus)was26.1%12.InapreoperativeneoadjuvantchemotherapyphaseIIclinicalstudy,35patientswereenrolled,withtheresultshowingthePCRrateof17%intheschemeofpegylatedliposomeadriamycinpluscyclophosphamidefollowedbysequentialTaxus.Inthisstudy,βerrorwas0.2,andαerrorwas0.05,withaboundaryvalue(δ)of0.1.Accordingtothedataofrescuetreatment,assumingtheoveralleffectiverateoftreatmentwasobtainedatapowerof80%andavarianceof2,andtheminimumsamplesizewascalculatedaccordingto1:1matching,thereforethenumberofenrolledpatientswassetas80foreachofthegroups,ofwhich10%ofthepatientswereallowedtofalloffduringthetreatment.TreatmentplanThechemotherapyschemesforbothgroupswerebasedonasimilarcombinationuseoftheagentssuchasanthracyclines,paclitaxelordocetaxel,platinumandmoleculartargeteddrugs,specifically,AC-Tprotocol,anthracyclinescombinedwithcyclophosphamidefollowedbysequentialTaxusandtrastuzumab(AC-TH),anthracyclinescombinedwithTaxusandcyclophosphamide(TAC),aswellasanthracyclinescombinedwithTaxus(TA).68.5%(50cases),17.8%(13cases),5.5%(4cases)and8.2%(6cases)ofthepatientsintheobservationgroupreceivedAC-T,AC-TH,TAC/TAorplatinum,respectively,correspondingto74%(54cases),15.1%(11cases),2.7%(2cases)and8.2%(6cases)inthecontrolgroup.Inaddition,PLDwasintravenouslyadministratedtothepatientsintheobservationgroup,35 mg/m2,atleasttwiceforeachone,whilepirarubicin,arepresentativeagentoftraditionalanthracyclines,wasinfusedintravenouslyat60 mg/m2asthecontrolforthoseinthecontrolgroup.Dextrineandothernecessarymeasureswereallowedinthisstudyforheartprotectionandpreventionfrompotentialmyocardialinjury.Symptomatictreatmentsuchasantidiarrheals,antiemetics,analgesics,granulocytestimulatingfactorsandothersupportivetreatmentcouldalsobeusedifnecessary.ForcaseswithevidencesuggestingcardiotoxicityattributedtoPLDorpirarubicinformorethan3 weeksafterthestartofthenextcycle,thesubjectsshouldquitthestudyiftheexaminationsdidn’tshowafullrecoveryfromthecardiotoxicity.Forthepatientsfailedtocompletetheestablishedchemotherapyregimens,aprotocolwithoutanthracyclinesshouldbeusedtoreplacetheoriginalonetillthecompletionofthetreatment,orthetreatmentshouldbediscontinuedbasedonthejudgementoftheoncologists.Thepatientsinbothoftheobservationgroupandcontrolgroupunderwentsurgicaltreatmentafterpreoperativeneoadjuvantchemotherapy,includingmodifiedradicalmastectomy[51cases(69.9%)vs.57cases(78.1%)],breastconservingsurgery[11cases(15.1%)vs.6cases(8.2%)],breastcancersimpleresectionplussentinellymphnodebiopsy[7cases(9.6%)vs.10cases(13.7%)],andbreastcancerprosthesisimplantation[4cases(5.5%)vs.0cases(0%)].AllthepatientsachievedR0resection.EfficacyandpathologicalassessmentThetumorwasevaluatedevery3 weeksuntilthediseaseprogressed.Theclinicalevaluationwasperformedafter6–8roundsofpreoperativeneoadjuvantchemotherapybutbeforesurgeries.Besides,theobjectiveremissionrateoftumorwasevaluatedbycolorDopplerultrasoundbeforeeachcycleofchemotherapy.TheclinicaleffectofthechemotherapyisassessedinaccordancewiththeResponseEvaluationCriteriaInSolidTumors(RECIST)13:Completeresponse(CR)thebreastandarmpitontheaffectedsidearenottouchedwithobviousmassesandenlargedlymphnodes;Partialresponse(PR)thesumofthelargestdiametersofthetargetedlesionsdecreasesby ≥ 30%ascomparedtothebaselinesumdiameters;Stabledisease(SD)thesumofthemaximumdiametersofthetargetedlesionsdecreasesby