Scalp cooling to prevent chemotherapy-induced alopecia,

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Anais

Brasileiros

de

Dermatologia

www.anaisdedermatologia.org.br

REVIEW

Scalp

cooling

to

prevent

chemotherapy-induced

alopecia

夽,夽夽

Giselle

de

Barros

Silva

a,∗

_,

_Kathryn

_Ciccolini

b

_,

_Aline

_Donati

c

_,

Corina

van

den

Hurk

d

a_Center_of_Oncology,_Hospital_Alemão_Oswaldo_Cruz,_São_Paulo,_SP,_Brazil

b_Department_of_{Hematology/Oncology,}_Mount_Sinai_Hospital,_New_York,_NY,_United_States_of_America c_Department_of_Dermatology,_Hospital_do_Servidor_Público_Municipal_de_São_Paulo,_São_Paulo,_SP,_Brazil d_R_&_D_Department,_Netherlands_{Comprehensive}_Cancer_{Organisation,}_Utrecht,_The_Netherlands

Received29August2019;accepted20March2020 Availableonline16June2020

KEYWORDS Alopecia; Antineoplastic combined chemotherapy protocols; Cooling; Drugtherapy; Preventionand mitigation

Abstract Chemotherapy-inducedalopeciacausesanimportantimpactoncancerpatientsand itsriskofpersistenceiscurrentlyaconsiderableissueincancersurvivors.Ofthevarious inter-ventions proposed for the prevention ofchemotherapy-induced alopecia, scalp cooling has emergedasaneffective andsafe strategy.Thispaperaimstoprovideanoverviewonscalp coolingandchemotherapy-inducedalopeciaprevention.

夽 _How_to_cite_this_article:_Silva_GB,_Ciccolini_K,_Donati_A,_Hurk_C.

Scalpcoolingtopreventchemotherapy-inducedalopecia.AnBras Dermatol.2020;95:631---7.

夽夽_Study_conducted _at_the _Hospital_Alemão_Oswaldo_Cruz, _São

Paulo,SP,Brazil.

∗_{Corresponding}_author.

E-mail:gisellebarros@yahoo.com.br(G.B.Silva).

Introduction

Chemotherapy-induced alopecia (CIA) is one of the most reportedunpredictableadverseevents(AEs)experiencedby cancerpatientsandsurvivors,1_with_an_overall_incidence_of

65%.2_It_has_been_reported_as_the_most_disturbing_condition

ofcancertreatmentbymost(88%)womenreceiving periop-erativechemotherapy.1_Patients_may_decline_{life-prolonging}

chemotherapy to avoid developing alopecia.1,3,4

Further-more,CIAstrongly inﬂuences howothersperceive cancer patients,thevisibilityofdisease,socialrelationships,and

https://doi.org/10.1016/j.abd.2020.03.005

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sexuality.1,3,5_In_addition_to_physical_and_psychosocial

impair-ment, CIA can also be ﬁnancially detrimental due to expensivecosmeticproductssuchaswigsandhairregrowth treatments.6

ManystrategieshavebeentestedtominimizeCIA,among whichscalpcoolinghasproventobethemosteffective.7,8

Since recent publications on its efﬁcacy and safety as a preventivemethodagainstCIA,7---9 _this_procedure_has_been

increasinglyemployedinBrazilandworldwide.TheNational Comprehensive Cancer Network (NCCN) Clinical Practice GuidelinesinOncologyhaverecentlyaddeda recommenda-tionofscalpcoolingtreatmentforCIAprevention(category 2A)forbreastcancerpatients.10

The presentarticle aimstoprovidean overviewof CIA andscalpcoolingsothatdermatologistscanbecome famil-iarwiththesetopics,whichhavebecomemorecommonin clinicalpractice.

Understanding

chemotherapy-induced

alopecia

Most chemotherapeutic agents are cytotoxic drugs that affectproliferatingcancercells.Othernormally proliferat-ingcells, e.g.,thehair matrix cells(in anagenphase90% of the time) and bone marrow, are unintentional targets of chemotherapy. Patientsreceiving --- among other drugs --- anthracyclines(i.e.,doxorubicinandepirubicin),taxanes (i.e.,docetaxelandpaclitaxel),oretoposidedevelop alope-cia,oftenreferredtoasanagenefﬂuvium(Fig.1).8,11---14

Clinically,alopeciaismostnoticeableonthescalp,which hasthehighestdensity ofterminalhairfolliclesinanagen phase,andtypicallyappearswithindaystoweeksafter ini-tiationoftreatmentwithmanychemotherapeuticagents.14

Theinterruptionofhairfolliclemitoticactivitycontributes tothefragilityoftheproximalportionofthehairshaft,and consequentlybreakagewithinthehaircanal.2_After

cessa-tionofchemotherapy,inmostcases,regrowthbeginswithin 1---3months;however, itcanpresent withchangesin tex-ture,color,and/orthickness.13---15 _Depending_on_the_degree

Figure 1 Chemotherapy-induced alopecia. Breast cancer patientattheendofthetreatmentwithfourcyclesof doxoru-bicinandcyclophosphamide (PhotocourtesyofLíviaNicoletti Ariano).

ofhair-folliclestem-celldamage,regrowthgenerallytakes uptosixmonthsaftercessationofchemotherapy.8,14

The trichoscopic findingsof CIA show thechanges suf-fered by thehair shaftthroughout chemotherapy, varying accordingtothephaseofthetreatment.Brokenhairs,black dots,flamehairs,andPohl-Pinkusconstrictionsmaybeseen inthe firstmonthsofchemotherapy. Additionally, regrow-ing hairs,rare terminal hairs,and circlehairs areusually observedattheendofthetreatment(Fig.2).16

Consideringthetypeofthechemotherapeuticagent,the incidenceofCIAmayrangefrom60%to100%with topoiso-meraseinhibitors(i.e.,irinotecan,etoposide,doxorubicin), >80% with taxanes (i.e., docetaxel, paclitaxel), and >60% withalkylatingagents(i.e.;cyclophosphamide,ifosfamide), whereas antimetabolites (i.e.; 5FU, methotrexate, gemc-itabine)presentalowerrisk.17,18

Besidesthechemotherapydrugtype,commonrisk fac-tors for CIA include dose, pharmacokinetic proﬁle, and combination regimens with various concurrent cytotoxic agents.14 _The _degree _of _hair _loss _can _also _vary_with _age,

comorbidities,andnutritional/hormonalstatus.14

Persistentchemotherapy-inducedalopecia:an increasingconcern

In some instances,hair loss may bepersistent (persistent chemotherapy-inducedalopecia,PCIA),whichisdeﬁnedas theabsenceorsuboptimalhairgrowthpersistingbeyondsix monthsaftercessationofchemotherapy.13_The_incidence_of

PCIAcanrangefrom14%inchildhoodcancersurvivorsto30% inbreastcancersurvivors.19_In_the_1990s,_the_ﬁrst_reported

casesof PCIAoccurredafterhigh-dosechemotherapy reg-imens (busulfan and cyclophosphamide) received before bonemarrowtransplantation.20_Radiation_and_taxane-based

chemotherapyregimenshavealsobeen involvedinPCIA.21

In a recent cohort ofAsian breastcancer patients,about 42% had PCIA afterthree yearsof chemotherapy comple-tion,withhigherriskusingtaxanes,whichappeartobemore cytotoxicto hair-follicle stem cells.15 _Relevant _impact_on

self-imagewasreportedinthosepatients.15,22

Figure2 Trichoscopyofchemotherapy-inducedalopecia. Tri-choscopicﬁndingsintheregionofthevertexofthescalpofthe patientinﬁg.1:multipleblackdots,circularhair,andgrowing hair.Rareterminalhairs,someshowingpointsofconstriction (Pohl-Pinkus)intheirextension,referringtopreviouscyclesof chemotherapy(PhotocourtesyofLíviaNicolettiAriano).

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Strategiesforchemotherapy-inducedalopecia prevention

Considering the impactof CIA in cancer patients, several medications and procedures have been tested to reduce or preventCIA. A large numberof studies have used ani-mal models, with variable and not yet clinically proven results.23---28 _A_few_products_have_been_tested_in_humans_in

small studies with positive results, but more evidence is lacking, exceptforscalpcooling, whosesafetyand effec-tiveness have been frequently described in recent years (Table1).Sometopicals,suchasminoxidilorbimatoprost, havebeen showneffectivein stimulationofhairregrowth afterchemotherapy,withnopreventiveeffectonCIA.29---44

Sincethe1970s,avarietyofscalpcoolingtechniques ---such as cryogel bags, cold caps, and cooling machines ---havebeen usedfor CIAprevention.12,25---28 _Cold_caps_(e.g.,

Elasto-gel,Penguin)andelectroniccoolingmachines(e.g., Paxman,Dignitana)arethemostusedworldwide.

InBrazil,threedeviceshaveapprovalfromtheBrazilian Health Regulatory Agency(Agência Nacional de Vigilância Sanitária[ANVISA])forscalpcoolingduringchemotherapy: Elasto-gel,PaxmanandCapelli.Thelatterisadevicemade inBrazil,usingcoldair,whosestudiesregardingitsefﬁcacy areabouttobepublished.

Workingmechanism

The beneﬁcial effects of scalp cooling are caused by vasoconstriction in the scalp skin, decreased intrafollicu-larmetabolic rate,anddecreasedfollicular drugsuptake, whichintheoryreducefollicularexposuretoharmful cyto-toxiceffectsattheirpeakplasmaconcentrations.3,11,45---48 Efﬁcacy

Theefﬁcacyofscalpcoolingwasrecentlyconﬁrmedby Nan-giaetal.inarandomized-controlledtrialwithearly-stage breast cancer patients that received at least four cycles of taxane- and/or anthracycline-based chemotherapy, in which the experimental group used a Paxman device for scalp cooling,started 30min prior chemotherapy infusion

and maintained throughout infusion and for 90min after infusion.Inthescalpcoolinggroup,successwasreportedin 50.5%ofwomen(50.5%;95%CI40.7---60.4%)comparedto0% inthecontrolgroup(0%;95%CI0---7.6%).9_Rugo_et_al.,_in_a

recentsystematicreviewandmeta-analysiswhichincluded tenrandomizedcontrolledtrials(twowithaPaxmandevice and the others with cryogel caps or bag), endorsed the positiveeffectof scalpcooling inreducingCIAinpatients withsolidtumors (RR=0.54; 95%CI 0.46---0.63; I2¼=11%;

p<0.00001).7_Shah_et_al._analyzed_controlled_and

random-izedclinical trials (CCTand RCT, respectively) evaluating scalp hypothermia for CIA prevention, with reduction in theincidence of CIA by 2.7 (in CCT) to3.9 fold (in RCT) in scalp-cooled patients. There were 18 trials included in the review, with different scalp cooling techniques ---rangingfromolderandlesscomplexcoolingcapstodigitally controlledmachines.49_Scalp_cooling_machines_from_Paxman

andDignitana have been approved by the Food and Drug Administration(FDA),andhavebeenincorporatedintothe NCCNguidelinesforbreastcancerpatients.

Pre-coolingtimeandpost-infusioncoolingtime

Theduration ofscalp coolingappears tobean inﬂuential factor in hair preservation.50 _Cooling _is _generally _started

30minbeforeinfusion(pre-coolingtime[PCT])sothatthe scalpskin temperaturehasreacheditslowestpeakatthe momentthedrugentershairfollicles. Intradermalor sub-cutaneousscalptemperatureduringscalpcoolingtendsto beon average around 22◦C,the target temperature sug-gestedbyGregoryetal.51_However,_low_scalp_temperature

rangemayvaryfromone patienttoanother for unknown reasons.Itmaybeduetodifferencesintheinsulatingaction ofscalpstructures(hair,dermis,andsubcutaneoustissue), heatdissipation,skullanatomy,andreﬂexthermalreaction tovasoconstriction.Those withintradermal scalp temper-aturelowerthan18◦Caremorelikelytohave betterhair protectionwithscalpcooling.49,52

The cooling procedure is maintained during the chemotherapyinfusion andkeptforaperiodoftimeafter itsend(post-infusioncoolingtime[PICT]),dependingonthe chemotherapyregimen.

Table1 Preventivestrategiesforchemotherapy-inducedalopecia(CIA)inanimalmodelsandinhumantrials Studiedinanimalmodels Studiedinhumantrials:not

effective

Studiedinhumantrials:effective

Anti-doxorubicin29 _Topical_minoxidil23 _AS101a30

Topicalepinephrineandnorepinephrine31 _Parathyroid_hormone_receptor (PPR)ligands32

Scalpcooling9,33,34 Topicaln-acetylcysteine35 _Scalp_tourniquet36

Topicalantioxidants(resveratrol,aminothiol)31 _Topical_calcitriol37 TopicalcyclosporineA38 _DHL-HisZnNA39 Immunomodulators(Il-1,40_imuvert41₎

AcidFGF,EGF40 CDK2inhibitors42 Caspase-3inhibitors43

Multi-targetironchelatorM3044

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Some studies involving cold caps reported they were unabletomaintainlow temperaturesfor theentire dura-tionoftheplannedtreatmenttime.Ithas,however,been suggested that the caps shouldbe changed three tofour times,or every25min, duringthe chemotherapy infusion andPICT,toensureastabletemperature.48_However,

cool-ingmachines with thermostatmanagement keep a stable temperatureandrequirefewernursinginterventions.18

To date, the precise durationof thePICT is yet tobe estimated. Ideally, the PICT should consider the pharma-cokinetics of exposure to the cytotoxic agent and/or its activemetabolites, whichcorrespondtopeakplasma con-centrations,drug half-life, and potential interactions.28,50

Consideringpatientstreatedwithdocetaxelregimens,PICTs of90’and45’hadsimilarresultspreventinghairloss(79%

vs.95% of patientswith success,respectively; p=0.04).53

Komenetal.studiedPICTsof20’and45’,alsoinpatients taking docetaxel, with comparable rates of hair reten-tion (73% vs. 79% of patients with success, respectively;

p=0.5).54_In_{anthracycline}_regimens,_PICTs_of_90’_or_greater

areoftenused;however,prolongingPICTshowedno reduc-tionin theneed for scalp coverage.55 _Further _studies _are

needed to determine the most effective PICT for each chemotherapyregimen.

Hairlossassessmentandscalpcoolingresults

The Common Terminology Criteria for Adverse Events (CTCAE) is largely used in oncology to systematize the adverseeventsofcancertreatment.AccordingtotheCTCAE v.5.0,alopeciagrade1correspondstolessthan50%ofhair loss,notrequiringtheuseofawigoraheadcover;in alope-ciagrade2,hairlossismorethan50%,andawigorascarf isnecessary.56 _A_modiﬁed _Dean’s_scale _for_hair _loss_is _also

usedtoquantifytheseverityofCIA(grade0:nohairloss; grade1:0to≤25%hairloss;grade2:>25%to≤50%hairloss; grade3:>50to≤75%hairloss;grade4:>75%hairloss).In theliterature,scalpcoolingisgenerallyconsidered success-fulwhenalopeciaislessthan50%(CTCAEv.5.0grade0or 1;modiﬁedDean’sscalegrade0.1or2).9,34,57

Factorsinﬂuencingscalpcoolingsuccess

The success of scalp cooling may vary according to the chemotherapeutic drug, dose, and combination, and also depends on the scalp temperature achieved, duration of cooling,andproper ﬁtting of thecap.33,48,58 _In _the

litera-ture,thereisvariabilityinthesuccessratesofscalpcooling forthesamechemotherapyregimenanddose.Consideration shouldbegiventothestudydesign,population character-istics, applied technique, PCT/PICT, hair loss assessment scale,andtheselectedsuccesscriteria.InaDutchregistry studywith1411patients(scalpcoolingperformedwith Pax-mandevices),regimenswithlow-dosedocetaxel(75mg/m2₎

andpaclitaxel (70---90mg/m2₎_showed_better _rates_of

suc-cesswithscalpcooling(94%and81%,respectively)whereas amongpatientstakinganthracyclineandcyclophosphamide, 39%weresuccessful.33_Rugo_et_al._reported_success_in_66.3%

of patientsreceiving taxanes withscalp coolingwith Dig-nitanadevices.34 _Nangia_et _al._reported_that _scalp-cooled

patientsusingPaxmandevicesundertaxane-basedregimens

aremorelikelytohavehigherratesofhairpreservation(59% success;paclitaxelusedweeklyismoreeffectivethan doc-etaxel used every three weeks) than anthracycline-based chemotherapy(16%success).9

Scalpcoolingandcutaneousscalpskinmetastases

Since the ﬁrst reports of scalp cooling studies, safety concerns have been raised regarding the possibility that chemotherapy doesnotsufﬁcientlytreat pre-existing sub-clinicalscalpskinmetastases.59_The_incidence_of_metastases

in scalp-cooled breast cancer patients appears to be less than1.1%,whichiswithintherates(0.03---3%)reportedin breastcancerpatientstreatedwithoutscalpcooling.46,60_In

astudyinvolving442patientsusingacoldcap,theoverall incidenceofscalpskinmetastaseswas0.45%(2/442), occur-ringin0.88%(2/227)ofbreastcancerpatients.59_Similar_low

ratesofscalpskinmetastases(7/640,1.1%)werealsonoted inaretrospectivecohortstudyofwomenwithbreast can-cer, wherein the majority (86.4%) had been offeredscalp coolingatsomepointduringtheirtreatment.Itis notewor-thy that in neithercase didscalpmetastases manifest as theﬁrstisolatedsiteofrecurrence---womenwhohadahigh riskofbreastcancerrecurrence,suchasthoseinstageIII, weremorelikelytohavemetastasesinthescalp,inaddition tootherorgans.61_Although_additional_research_with_longer

follow-up is needed to establish a clear association, data availableindicatethatthereis noincreasedriskofapoor outcomewithscalpcoolinginbreastcancerpatients.7,62

However, regression of scalp skin metastases, despite scalpcooling,hasalsobeenreported(twocases),suggesting thatthedistributionofchemotherapyatthesesitesisnot completely prevented.59,63 _{Nevertheless,} _in _patients _with

bloodcancerspresentingwithcancercellsalloverthebody (e.g. leukemia,lymphoma), scalpcooling is currently not recommended.46,64_Witman_et_al._reported_a_case_of_mycosis

fungoidesthatdisappeared withconsolidation chemother-apybutrecurredonthescalp.64_Another_instance_of_relapse

wasdescribedina17-year-oldboywhoseacutemyeloblastic leukemiamanifestedwithseveralsubcutaneous scalp nod-ules but withnoevidenceof hematologicalrelapse seven yearsaftertheuseofscalpcoolingduringhistwocourses ofchemotherapy.65

Adverseeventsandcontraindicationsforscalp cooling

Scalpcoolinghasbeenshowntobeawell-tolerated support-ivecare.49,66 _The _most_commonly _reported_AEs_with_scalp

coolingarelow-gradeandincludeheadaches,nausea, dizzi-ness,complaintsofcoldness,andclaustrophobia.Frostbite wasreportedinafewcaseswithcoldcaps,whichare usu-allybelow−25◦Cbeforebeingappliedtothepatient’shead; nonehasbeenreportedwithcoolingmachines.9,33,50,58,67,68

Hairlessareas(e.g.,forehead,ears,scalpalopecia)should beprotectedduringscalpcooling,usingasimplebandage.

Scalp cooling is not indicated for patients with cold agglutinin disease, cryoglobulinemia, cryoﬁbrinogenemia, orcoldsensitivity.50_It_is_not_recommended_for_patients_with

hematologic tumors,whoareat higherrisk for cutaneous metastases.

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Scalpcoolingandimpactonqualityoflifeand well-being

Althoughtheuse ofscalpcoolinghasbecomeincreasingly widespreadtopreventCIA,studieshaveshowninconsistent evidenceofimprovementinpatients’qualityoflife(QoL), reportedlyduetononspeciﬁcQoLassessments(most stud-iesusedEORTCQLQ-C30and-BR23),differencesinmethods andoutcomesreportingQoLandoverallcostandﬁnancial burdenofscalpcooling.47_When_scalp_cooling_does_not_work

asexpected,theimpactonQoLisworsewhencomparedto controls,i.e.,patientsnotusingscalpcooling.33_Therefore,

anappropriateQoLinstrumentisstillsought.Inoneofthe ﬁrstmulti-centeredprospectivestudiesdesignedto inves-tigatethe impactonwell-being in breastcancer patients receivingscalp cooling(98/266), 52% of thepatients who experienced effective scalp cooling reportedbetter well-being when compared to patients in whom this was not achieved.69

Final

considerations

Scalpcooling is an approved and generallywell-tolerated option to prevent CIA and can minimize the burden of cancer treatment and potential impairments in patients’ health-relatedQoLandpsychosocialwell-being.Whilethe type of scalp cooling method might not be decisive, maintaining stable low scalp skin temperatures is cru-cial.Patientsreceivinganthracycline-basedregimenshave lower rates of hair retention compared to taxane-based chemotherapies.Patientswithhematologicalmalignancies and cold-precipitated diseases should not undergo scalp-coolingtherapy.Scalpcoolingdoesnotappeartoincrease theriskofcutaneousscalpmetastasesinearly-stagebreast cancerpatients,nordoes itappeartocompromisecancer outcome,althoughlong-termfollow-upstudiesareneeded.

Financial

support

Nonedeclared.

Authors’

contributions

Giselle de Barros Silva: Approval of ﬁnal version of the manuscript; conception and planning of the study; draft-ingandeditingofthemanuscript;collection,analysis,and interpretationofdata;participationinstudydesign;critical reviewoftheliterature;criticalreviewofthemanuscript.

KathrynCiccoliniHernandez:Approvalofﬁnalversionof themanuscript;draftingandeditingofthemanuscript; par-ticipationinstudydesign;criticalreviewofthemanuscript. AlineDonati:Approvalofﬁnalversionofthemanuscript; criticalreviewofthemanuscript.

Corina van den Hurk: Approval of ﬁnal version of the manuscript;criticalreviewofthemanuscript.

Conﬂicts

of

interest

Nonedeclared.

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