The Role of Propranolol in the Treatment of Infantile Hemangioma

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

www.revportcardiol.org

ORIGINAL

ARTICLE

The

role

of

propranolol

in

the

treatment

of

infantile

hemangioma

Sérgio

Laranjo

,

Glória

Costa,

Filipa

Paramés,

Isabel

Freitas,

José

Diogo

Martins,

Conceic

¸ão

Trigo,

Fátima

F.

Pinto

Servic¸odeCardiologiaPediátrica,HospitaldeSantaMarta,CentroHospitalarLisboaCentral,EPE,Lisboa,Portugal

Received15April2013;accepted19October2013 Availableonline4June2014

KEYWORDS Infantile hemangioma; Propranolol

Abstract

Introduction:Infantilehemangioma(IH)isoneofthemostcommonchildhoodtumors.There arevariousmedicalorsurgicaltherapeuticoptions,allwithsuboptimalresults.Recently,the successful useofpropranololfor involutionofIH wasdescribed.We reporttheresultsofa single-centerexperiencewiththistherapeuticoption.

Objective: Toprospectivelyassesstheefficacyandsafetyofpropranololinchildrenwith infan-tilehemangioma.

Methods:WeperformedaprospectiveanalysisofclinicaldataofallpatientswithIHreferred to apediatriccardiologycenterfor baseline cardiovascularassessmentprior topropranolol therapy.Propranololwasgivenatastartingdoseof1mg/kg/dayandtitratedtoatargetdose of2---3mg/kg/dayaccordingtoclinicalresponse.Efficacywasassessedthrougha photograph-basedseverityscoringscale.Safetywasassessedbycollectingdataregardingsignificantside effects.

Results:Starting in2010, 30 patients (15 female) were referred for propranololtreatment ofIH,atamedianageofsixmonths (1---63months).Themeantargetpropranololdosewas 2.8mg/kg/day,withameandurationoftherapyof12months.Allpatientsexperienced signif-icantreductionofIHsizeandvolume.Therewerenosideeffects.

Conclusions: Inourexperiencepropranololappearstobeausefulandsafetreatmentoptionfor severeorcomplicatedIH,achievingarapidandsignificantreductionintheirsize.Noadverse effects were observed, although until larger clinical trials are completed, potential adverseeventsshouldbeborneinmindandconsultationwithlocalspecialistsisrecommended priortoinitiatingtreatment.

© 2013 SociedadePortuguesa de Cardiologia. Published by Elsevier España, S.L. All rights reserved.

∗_{Correspondingauthor.}

E-mailaddress:sergiolaranjo@gmail.com(S.Laranjo).

http://dx.doi.org/10.1016/j.repc.2013.10.018

PALAVRAS-CHAVE Hemangiomainfantil; Propranolol

Opapeldopropranololnotratamentodoshemangiomasemidadepediátrica

Resumo

Introduc¸ão:Oshemangiomassãoalesãotumoralcutâneamaisfrequenteemidadepediátrica. Atéao momentotodasasopc¸ões terapêuticas(tantomédicascomo cirúrgicas)têm resulta-dossub-ótimos.Recentemente,foidescritaautilizac¸ãodepropranololparatratamentodos hemangiomas.Relatamososresultadosdanossaexperiênciacomestaopc¸ãoterapêutica.

Objetivo:Avaliac¸ãoprospetivadaeficáciaeseguranc¸adepropranololemcrianc¸ascom heman-giomainfantil.

Métodos: Avaliac¸ão prospetiva de todos os doentes com hemangioma referenciados para avaliac¸ão cardiovascularprévia ao iníciode terapêuticacompropranolol. Opropranololfoi administradonumadoseinicialde1mg/kg/diaetituladaparaumadosealvode2---3mg/kg/dia, deacordocomarespostaclínica.Aeficáciafoiavaliadaatravésdeumaescala fotográfica. Aseguranc¸afoiavaliadaatravésdarecolhadedadossobreosefeitossecundáriossignificativos.

Resultados: Desde2010,30crianc¸as(15dosexofeminino)comhemangiomasforam referenci-adosparaavaliac¸ãocardiovascularpréviaaoiníciodeterapêuticabeta-bloqueante,comuma idademédiade6meses(1-63meses).A dosealvo médiaatingidafoi de2,8mg/kg/dia, comumadurac¸ãomédiadetratamentode12 meses.Emtodososdoentesseverificouuma reduc¸ãosignificativadasdimensõesevolumedoshemangiomas.Nãoforamobservadosefeitos colaterais.

Conclusões:Nanossaexperiência,opropranololéumaopc¸ãoeficazeseguraparaotratamento dehemangiomasextensosoucomplicados,obtendo-seumareduc¸ãorápidaesignificativadas suasdimensões.Nãoforamobservados efeitosadversoscontudo,recomenda-se aavaliac¸ão cardiovascularsistemática,préviaaoiníciodeterapêuticacompropranolol.

© 2013 SociedadePortuguesa de Cardiologia. Publicado por Elsevier España, S.L.Todos os direitosreservados.

Introduction

Infantile hemangiomasare the most common benign vas-culartumorsininfancy,affecting5---10%ofthepopulation. Femalesareaffectedmoreoften thanmales,witha ratio of3:1.1_{Typicallytheypresentshortlyafterbirth,undergo}

a period of rapid proliferation, and then slowly involute overmanyyears.2,3_{Althoughmostaresmallcutaneous}

vas-cular malformationsof the face,4 _{theycan alsobe large,}

disfiguringlesionswithseriouscomplications.Infants with largehemangiomas,especiallythosewithasegmental dis-tribution or hemangiomatosis, are at particular risk for extracutaneous complications. They may also be associ-atedwithothercongenitalmalformations,suchasPHACE,5

PELVIS4_{orSACRALsyndrome.}6,7

In mostcases only parentaleducationand reassurance arerequired.Although85---90%ofallinfantilehemangiomas eventuallyundergospontaneousinvolution,aminoritycan stillcausedisfigurementandseriouscomplications, depend-ing on their location (obstruction of airways and vision), size, and speed of regression, which can be associated with painful ulcerations and hemorrhage or even high-outputheartfailure.4,8,9_{Hemangiomaswiththepotentialto}

threatenachild’slifeorvitalfunctionsandthosethat ulcer-ateorcausesubstantialdisfigurementwarranttreatment,10

which may be medical or surgical, or a combination of both.11

Atpresentthereisnogoldstandardmedicaltreatment. Unfortunately,currenttherapeuticapproacheshavelimited

success and significant adverse effects that limit their use.12---16 _{Since Léauté-Labrèze’s accidental observation}17

of the anti-proliferative effect of propranolol on infan-tile hemangiomas, propranolol has become increasingly popular18,19 _{asasuccessfultherapeuticoption,withfewer}

sideeffectsthanothertreatments.

Wepresentasingle-centerstudydescribingtheefficacy andsafetyofpropranololinchildrenwithinfantile heman-giomas.

Methods

Inclusionandexclusioncriteria

Allpatientswerereferredbytheirpediatricdermatologist or pediatric surgeontoapediatric cardiology department forbaselinecardiovascularassessmentpriortopropranolol therapy,andcardiovascularassessmentduringtherapy.

Patients with infantile hemangiomas were considered for propranolol treatment if they met the following cri-teria: eyelid involvement withrisk of ocular occlusionor compression;airwayobstruction;orlargehemangiomawith significant disfigurement orulceration. Patientspreviously treated with other therapeutic modalities were also con-sidered candidatesfor inclusion iftheprevious treatment had failed. Exclusioncriteria included cardiac anomalies, centralnervoussystemvascularanomaliesasinPHACE syn-drome,hypoglycemia,asthmaorbronchospasm.Whilethe

study focused on infants, patients over one year of age wereenrollediftheirhemangiomasshowedsignsof contin-uedproliferationorhadshownnosignsofresolutionsince infancy.

Treatmentprotocol

All patients underwent full cardiac examination before treatment,whichincludedclinicalexamination,heartrate andbloodpressuremeasurements,electrocardiogram,and echocardiogram.Abaselinefingerstickblood glucoselevel wasobtained.Furthermonitoringduringthestudyincluded a weekly re-evaluationwhile thedose wasbeing titrated toits maximum target dose, at weeks1---4. Parents were instructed to look for signs of lethargy, poor feeding or wheezing. After the first month, monthly follow-up visits werescheduled until theend of the treatment for sever-ity scoring of the hemangiomas, physical assessment and monitoringforadverseeffects.

Dosageandduration

Propranololwasgivenatastartingdoseof1mg/kg/day,in twoorthreedivideddoses,andtitratedtoatargetdoseof 2---3mg/kgperdayaccordingtoclinicalresponse.

Severityscoringsystem

Aphotograph-basedseverityscoringscalewasused.Frontal and lateral pictures of every patient were taken before treatmentandateveryfollow-upvisit.

Results

Startingin2010thirtypatientswereincludedinthisstudy, of whom 15 (50%) were female; none were born prema-turely.Superficialhemangiomawasthepredominanttype, observed in 25 (83%) patients, whereas in three (10%) the hemangiomas had a segmental distribution (Table 1). The mostfrequent locationwasfacial-cervical(70%). Pro-pranolol was started at a median age of six months (1---63months);theoldestpatientwasfiveyearsold.Themean target propranolol dose was 2.8 mg/kg/day (range 2.5---3.2 mg/kg/day). The mean duration of therapy was 12 months.Allpatientsexperiencedimmediatecolorchanges and effects on the rate of hemangioma growth; in all patients a reduction of its size and volume was seen (Figures1---3).Noadverseeffectswereidentifiedorreported by the patients or their parents. Propranolol was discon-tinuedin fivepatientswhentheresiduallesionsceasedto respondtotherapy;onehadaslightrelapsebutitwasnot necessarytore-startpropranolol.

In this groupof patients propranolol therapy had simi-lareffectivenessregardlessofageatinitiationoftreatment (beforeoraftersixmonthsofage).Itwasequallyeffective in hemangiomas considered to be beyond the prolifera-tivephase.Also,segmentalandnonsegmental,superficial, mixed, and deepinfantile hemangiomas showeda similar responsetopropranolol(Figures1---3).

Table1 Summaryofpatientcharacteristics. n=30 Female:maleratio 1:1 Typeofhemangioma Superficial 25 Deep 5 Distributionofhemangioma Head 8 Periocular/eyelidinvolvement 9 Peribuccualinvolvement 4 Thoracicinvolvement 5 Limbinvolvement 4

Baselineassessment(bloodpressure,fastingblood glucose,heartrate)

Normal All Electrocardiogrampre-treatment Normal All Echocardiogrampre-treatment Normal 24 Abnormal 6

Discussion

Inourexperiencepropranololappearstobeauseful treat-ment for severe or complicated infantile hemangiomas, achieving a rapid and significant reduction in size. This reductionwasmainlyachievedduringthefirst20weeksof treatment,andfurthertreatmentinduced alessdramatic therapeutic effect. In this series of patients propranolol wasequallyeffectiveinbothsegmentalandnonsegmental infantilehemangiomasandinthosebeyondtheproliferative phase.

Infantile hemangiomas have a predictable natural history.4,20_{Themajorityarenotpresentatbirth.Ahallmark}

ofinfantilehemangiomaisitsdramaticgrowthafterbirth, bydiffuseproliferationofimmature endothelialcells, fol-lowedbyspontaneousregression.Themajorityofchildren with infantile hemangiomas require no treatment as the lesionsregressovertimeandproducenolong-termscarring; regressionis completein50%offive-year-oldpatientsand 90%ofnine-year-olds.16_{Inapproximately10%ofcasesthere}

canbeseriousor life-threatening hemangiomas,requiring treatment.10

Current treatment options for complicated heman-giomas include various medical or surgical modalities. Until recently, the mainstay of treatment for infantile hemangiomaswascorticosteroidsin variousforms, includ-ingtopical, intralesional,and oral formulations,the most commonbeingoralprednisolone.12 _{Onlyin complicatedor}

refractoryhemangiomacaseshaveothertreatment modal-ities been considered, such as chemotherapeutic agents (vincristine, interferon-alpha), laser therapy, surgery or a combination of these, and, most recently, propranolol. Each treatment option has limited therapeutic benefit, withits own side effects and risks. However,in the past three years there have been more than 120 reports of theefficacy of oral beta-blockers, usually propranolol, as

Figure1 Afour-month-oldgirlwhopresentedwithalargehemangiomaontheleftuppereyelid,showingcompleteinvolutionof thelesionsafterfivemonthsoforalpropranolol.M:months.

Figure2 Atwo-month-oldboywhopresentedwithhemangiomaontheleftthigh,showingcompleteinvolutionofthelesionon

thighandscrotumaftereightmonthsoftherapy.M:months.

ahighly effective therapeuticoption for infantile heman-gioma and its complications.18,21---23 _{Furthermore, it has}

beendemonstratedthatpropranolol therapyissuperiorto oral corticosteroid treatment, the former standard ther-apy for infantile hemangioma, and should be considered the first-line agent given its safety and efficacy.24

Possi-bleexplanationsfor the therapeuticeffectof propranolol onhemangiomasincludevasoconstrictionbydecreasingthe releaseof nitric oxide, which is immediately visible asa

change incolor,associatedwithpalpabletissuesoftening. Othersuggestionsaredown-regulationofproangiogenic sig-nalssuchasVEGF,bFGF, MMP-9andHBMEC,andinduction ofapoptosisinproliferatingcapillaryendothelialcells.25,26

A large international randomized clinical trial is under-way,butmanyarealreadyadvocatingitsuseasafirst-line treatment for infantile hemangiomas, in terms of both safety and efficacy.21,27 _{Its effects were first discovered}

by chanceby Léauté-Labrèzeetal.in2008.17 _Subsequent

Figure3 Aten-month-oldboywithhemangiomaontherightpatellaandupperrightleg,showingafairresponseafter18months

Infan

til e he

mang

ioma

The

prop

rano

lol

algo

rithm

- risk of ulceration - risk of organ dysfunction - risk of disfiguration Exclude - PHACE syndrome - diffuse hemangiomatosis - PELVIS syndrome Cardiovascular assessment - Physical examination - Heart rate, blood pressure - Blood glucose - Electrocardiogram - Echocardiogram Contraindications - Bradycardia - Bronchospasm - Hypotension - Hypoglycemia Dosage

- Start with 1 mg/kg/day

- Titrate up to 3 mg/kg/day weekly

Adverse reactions - Bradycardia - Bronchospasm - Hypotension - Hypoglycemia Follow-up

- Clinical assessment every three months - Photograph lesions at each assessment - If complete regression or plateau:

start progressive weaning – reduce dosage by 1 mg/kg/day weekly - If rebound:

return to previous dosage - If adverse reactions or no regression:

stop proranolol

Figure4 Flowchartshowingproposedwork-upandtreatmentprotocol.

reportshaveemphasizedpropranolol’srolenotonlyin halt-inghemangiomagrowthbutalsoindiminishingtheirsize.21

Most groups have used a maximum target dose of 1---3 mg/kg/day.9,11,17,18,21,22,28---37 _{However, there are no}

estab-lishedconsistentprotocols,particularlyregardingthetiming oftreatmenttaperinganddiscontinuation.9,11,17---19,21,22,28---37

Thereisalsonoconsensusregardingtherelapserateafter discontinuation,withsomestudiesshowingnorelapses,30---32

while others reportminor recurrences.17,18,36 _{In our short}

series only one of the patients in whom propranolol was tapered showeda slight,non-significant, relapse,withno needtore-starttreatment.

Until recently,themostcommonapproachforpatients withinfantilehemangiomasinthepost-proliferativephase was ‘‘active non-intervention’’.38 _{In our series,}

propra-nolol improved esthetics in all patients, giving scope for more conservative surgical intervention in the future if

necessary.Thesefindingsareconsistentwiththosereported by Zvulunov et al.,39 _{Schupp et al.}36 _{and Celik et al.,}21

whoreportedtheresultsofpropranololtherapyfor heman-giomasbeyondtheproliferativephase,andimplythatoral propranolol therapy may be warranted in children with lateresidual infantilehemangiomas, prior toany surgical intervention.21_{Still,themostimpressiveresponsesoccurred}

inthe youngest patients, afindingthat is consistent with thenaturalhistoryofhemangioma,inwhich80%ofitssize isreachedbysixmonthsofage,andjustifiesreferringsuch casesearlierforoptimaltherapeuticresponse.

The appropriate monitoring protocol for assessment of adverse effects in infants with infantile hemangiomas, before and during propranolol treatment, has not been established.18,19_{Thepotentialsideeffectsofbeta-blockers,}

which are well known and include bradycardia, hypoten-sion,andhypoglycemia,11,18,33,40---44_{must beborneinmind.}

Propranolol is also contraindicated in patients with asthma, and it is not recommended during episodes of bronchiolitis.18,45 _{Notwithstanding, propranolol appears to}

be a safe drug when correctly administered. No adverse effectswere observed in ourseries; none of ourpatients had symptoms of hypoglycemia or hypotension. However, untillargerclinicaltrialsarecompleted,potentialadverse eventsshouldbeborneinmindandconsultationwithlocal specialistssuchaspediatric cardiologists isrecommended priortoinitiatingtreatment.PatientswithPHACEsyndrome andseverecerebrovasculardiseaseare,atleastintheory,at riskforbrainischemiaevenwiththerelativelymild hypoten-sioninducedbybeta-blockers.19_{Therisksandbenefitsinthis}

subsetofpatientsmustbeweighedcarefully.Figure4 sum-marizesourtreatmentalgorithmbasedonourexperience.

Inconclusion,abetterunderstandingofthemechanisms ofpropranolol-inducedregressionofinfantilehemangiomas will provide opportunities to design even more success-ful therapies. Meanwhile, propranolol appears to be a uniquely effective and safe therapy for infantile heman-giomas,includinginthepost-proliferativephase,andshould beconsideredthefirst-linetherapyinthissetting.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethat the proceduresfollowed were in accordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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