Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
REVIEW
Management
of
dermatologic
adverse
events
from
cancer
therapies:
recommendations
of
an
expert
panel
夽,夽夽
Jade
Cury-Martins
a,∗,
Adriana
Pessoa
Mendes
Eris
b,c,
Cristina
Martinez
Zugaib
Abdalla
d,
Giselle
de
Barros
Silva
e,
Veronica
Paula
Torel
de
Moura
f,
Jose
Antonio
Sanches
aaDepartmentofDermatology,HospitaldasClínicas,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil bDermatologyClinic,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
cSkinCancerUnit,A.C.CamargoCancerCenter,SãoPaulo,SP,Brazil dDermatologyUnit,HospitalSírio-Libanês,SãoPaulo,SP,Brazil eDermatologyUnit,CentroPaulistadeOncologia,SãoPaulo,SP,Brazil
fOncologyCenter,HospitalBeneficênciaPortuguesadeSãoPaulo,SãoPaulo,SP,Brazil
Received13January2019;accepted12January2020
Availableonline15February2020
KEYWORDS Antineoplastic agents; Antineoplastic agents, immunological; Dermatology; Drug-relatedside effectsandadverse reactions;
Medicaloncology; Moleculartargeted therapy
Abstract Withthedevelopmentofnewcancertherapies,systemictoxicityprofileandeffects
on survivalachieved animportant improvement. However, aconstellation oftoxicities has
emerged,evenmoreremarkably,cutaneousadverseevents.Thisreport,developedbyaboard
ofBrazilian expertsinoncodermatology,aimstoestablishaguidelineforthedermatological
careofoncologicpatients.Whenpossible,evidence-basedrecommendationsweremade,but
inmanycases,whenstrongevidencewasnotavailable,aconsensuswas reached,basedon
somedatasupportingtherapiescombinedwithpersonalexperiences.
©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan
openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
夽 Howtocitethisarticle:Cury-MartinsJ,ErisAPM,AbdallaCMZ,SilvaGB,MouraVPT,SanchesJA.Managementofdermatologicadverse eventsfromcancertherapies:recommendationsofanexpertpanel.AnBrasDermatol.2020;95:221---37.
夽夽StudyconductedattheFaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil. ∗Correspondingauthor.
E-mail:[email protected](J.Cury-Martins).
https://doi.org/10.1016/j.abd.2020.01.001
0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
Withtheadvanceofcancertreatment, systemictoxicities andsurvivalfacedanimportantimprovement.However,its useisoftenrelatedtodermatologicadverseevents(DAE), whichhaveahigh frequency,areoftensymptomatic,may be disfiguring, and might cause an important impact on patient’squalityoflife(QoL).Anotherimportantissuerelies onthe fact that those skin toxicities might lead to dose reductionsorevendiscontinuationofcancertherapy,with impact on the disease outcome. For those reasons, it is important for dermatologists to know the most common typesofreactions inordertobeabletohelppatientsand oncologists on the prevention and management of those toxicities.1,2
Amultidisciplinaryteamwithagoodinteractionbetween thedifferentspecialists(e.g.:oncologists,dermatologists, nurses) is fundamental for the best supportive care for cancerpatients andtheirfamilies.Differentsocietiesand associations are dedicated to the research, support and education in all aspects of cancer treatment, such as theMultinationalAssociationofSupportive Carein Cancer (MASCC),theAmericanSocietyofClinicalOncology(ASCO), theOncologyNurse Society (ONS),and theNational Com-prehensiveCancerNetwork(NCCN).
The aim of this paper was to establish a guideline to helpprofessionalsonthedermatologicalcareofoncologic patients.Whenpossible,evidence-basedrecommendations weremade, but whenstrong evidencewasnot available, a consensus was reached based on some data supporting therapies combined with personal experiences. Levels of evidencearedefinedbellowandarereportedforeach treat-mentintables1---3.
Categoriesofevidencebasedontypesofstudies3:
IA --- Evidence frommeta-analysis of Randomized Con-trolledTrials(RCT);
IB---EvidencefromatleastoneRandomizedControlled Trial(RCT);
IIA---Evidencefromatleastonecontrolledstudywithout randomization;
IIB---Evidencefromatleastoneothertypeof experimen-talstudy;
III---Evidencefromnon-experimentaldescriptivestudies, suchascomparativestudies,correlation studiesand case-controlstudies;
IV---Evidencefromexpert committeereports, opinions orclinicalexperienceofrespectedauthorities,orboth.
Categories
of
agents
Conventionalchemotherapeuticdrugs
Conventionalcytotoxicchemotherapystillplaysan impor-tantroleincancertreatment.Itworksprimarilythroughthe inhibitionofcelldivision.Itisassociatedwithmanyadverse events(AE),especiallyinsomesystemsthatsharewiththe tumorthepropertyofrapidcellproliferationandtherefore ahigh rateofcelldivision,suchasthehematopoieticand gastrointestinalsystems,andtheskin.2,4Examplesof
com-moneffectsareemesis,cytopenias,alopecia,mucositisand nailchanges.Theyareassociatedwithdose,typeofdrug,
timeofinfusion andareinmostcasesreversiblewiththe endofchemotherapycycles.
Belonging to this class of drugs are agents such as antimetabolites (e.g. capecitabine, fludarabine, cladrib-ine, gemcitabine, 5-fluoracil), alkylating agents (e.g. cyclophosphamide,platins), topoisomeraseinhibitors(e.g. irinotecan,topotecan,etoposide),anthracyclines(e.g. dox-orubicin,daunorubicin),bleomycin,antimicrotubuleagents (e.g. taxanes andvinca alkaloids).The related cutaneous adverse eventstothisclass,mostfrequentcausing agents andmanagement(withlevel ofevidence)aresummarized intable1.
Targetedtherapiesandimmunomodulatoryagents
(‘‘checkpoint’’inhibitors)
Inthelastdecadean enormousdevelopmentononcologic treatmentshave occurred,withtheemergence of numer-oustargetedagentsandimmunecheckpointrelatedagents. Withthosenewmechanismsofactionatotallynewscopeof adversereactionshasarisen,andprofessionalsmaynotbe familiarwiththespectrumofdermatologicaltoxicities.5---8In
onehand,thosetherapieswerecrucialfortheimprovement of survival. On the other hand, theycreated anew chal-lenge:withthecontinuousandprolongeduseofthesedrugs, patients and professionals have to deal with the chronic aspectsof thetoxicities,notanymore relatedwitha spe-cificnumberofchemotherapycycles,butlastingformonths toyears,withanimportantimpactonqualityoflife.
Targeted therapies inhibit specific molecules involved in tumordevelopmentandgrowth,havingamore specific action thanconventional chemotherapy,withgreater effi-cacyandlesstoxicity.Manyofthosemoleculesaremutated oroverexpressedontumors,butarealsopresentinnormal tissuessuchastheskin.Thisjustifies thecommon derma-tological sideeffects relatedto thisclass.They might be monoclonal antibodies, largemolecules that target extra-cellularcomponents;orsmallmoleculeinhibitors,thatcan enter cells, block receptor signaling, and interfere with downstreamintracellular molecules (theywill bereferred as Tyrosine Kinase Inhibitors --- TKI).9 The main agents on
thisclassareEpidermalGrowthFactorReceptorInhibitors ---EGFRi(e.g.cetuximab,panitumumab,gefitinib,erlotinib, lapatinib); antiangiogenic agents, inhibitors of Vascular Endothelial Growth FactorReceptor --- VEGFRi (e.g. beva-cizumab, sorafenib); inhibitors of the Mitogen-Activated Protein Kinase (MAPK)pathway, suchas RAFi (e.g. vemu-rafenib, dabrafenib), MEKi(e.g. cobimetinib, trametinib); mTOR inhibitors (e.g. everolimus); multikinase inhibitors (e.g.vandetanib,pazopanib,sunitinib);andHedgehog path-way inhibitors (vismodegib). Related cutaneous adverse events totheagents onthisclass,their managementand levelsofevidencearesummarizedintable2.
Morerecently,thecomprehensionoftheregulatory pro-cessesinvolved in therestrictionof theimmune response tocancer,ledtothedevelopmentofanewpromisinggroup ofagents,the‘‘immunecheckpoint’’targetedagents,also knownasimmunotherapy.They havethegoalof releasing theimmunesystemagainsttumorcells,blockinginhibitory receptors expressedonT-cellssuch asProgrammedDeath 1 (PD-1) or Cytotoxic T Lymphocyte-associated Antigen 4
Table1 Dermatologicadverseeventsofconventionalchemotherapeuticagents. Dermatologic
toxicity
Mostfrequentagents Management Levelof
evidence
Hyperpigmentation -Photoprotectivemeasures
-Bleachingagents
IV IV
Diffuse Busulfan(‘‘tan’’appearance);
methotrexate;procarbazine,
capecitabine
Flagellate Bleomycin
Serpentine supravenous
5-FU,docetaxel,vincristine,
vinorelbine
Areasofpressure,
flexural,under
occlusivedressings
Ifosfamide,thiotepa,hydroxyurea,
cisplatin,docetaxel
Palmsandsoles Hydroxyurea,doxorubicin,
capecitabine
Palmarcreases Ifosfamide,cyclophosphamide
bleomycin,busulfan,doxorubicin
Mucous membranes
Cyclophosphamide(gingiva),
busulfan,doxorubicin,cisplatin,
capecitabine
Nailchanges Generalmeasurestoallpatients:reductionof
contacttowater,useofcottonglovesbeneath
plasticorrubberglovesforanywetwork,avoidance
ofanydamagingprocedure(e.g.:aggressive
manicuring),andhydrationwiththickemollients
IV
Onycholysis Taxanes,cyclophosphamide
doxorubicin,capecitabine,etoposide
Prevention:frozenglovesandsocksduringinfusion
(dependingontheagentandtypeofinfusion)
IIA
Treatment:
-Avoidingtraumas(e.g.:keepingnailsshort)and
humidity
IV
-Ifgreendiscoloration:topicalantibiotic(tobramycin
orciprofloxacineyedrops)
IV
Paronychia Taxanes,etoposide,capecitabine -Topicalcorticosteroids
-Ifsecondaryinfectionissuspected,cultureguided
antibiotics
IV IB
Nailpigmentation 5-FU,taxanes,hydroxyurea,
cyclophosphamide,doxorubicin,
capecitabine
Mightbediffuseorbanding/streaking.Notreatment
needed.
Hand-foot syndrome(HFS)
Capecitabine,doxorubicin,
citarabine,5-FU,taxanes
Prevention:
-regionalcoolingduringchemotherapyinfusion IB
-nonsteroidalanti-inflammatoryagent IA
-usethickcottonglovesand/orsocks;ureabased
emollients;avoidirritantsandtightclothingand
shoes;avoidextremesoftemperature,pressureand
friction
III
Treatment:
-potenttopicalsteroid III-IV
-forreliefofsymptoms,coolcompressesor
emergenceofhandsandfeetoncoolwater,topical
anestheticsandNSAIDs
III-IV
-Dosereductionortreatmentinterruptionis
sometimesnecessary
III-IV
PATEOsyndrome Docetaxel SeemeasuresforHFSabove
Chemotherapy-induced alopecia
Cyclophosphamide,doxorubicin,
irinotecanandtaxanes
Prevention:scalpcoolingdevices I
Treatment:
-TopicalMinoxidil2% IB
-Topicalminoxidil5%,biotincontainingoral
supplements
IV
-Topicalbimatoprost(foreyelashes) IIA
Table2 Dermatologicadverseeventsoftargetedtherapies.
Drugclass Agents Dermatologic
toxicities
Management Levelof
evidence
EGFRinhibitors -Monoclonal antibodies:
cetuximaband
panitumumab
-TKIspecificfor
EGFR:erlotinib andgefitinib -Lessspecific multikinase inhibitors: vandetanib Papulopustular eruption(startson thefirst2weeks) Prevention:
-Systemicantibioticsforthefirst6---8weeks
(tetracyclines),sunscreen
IB
Treatment:
-Lowpotencytopicalsteroids III
-Systemicantibiotics(tetracyclines) IB
-Systemicisotretinoin(lowdoses) III
-Culture-drivenantibioticsifsecondaryinfection IB
Xerosis -Limitedshowertime,useofgentlecleansers
(pH-neutralsoapsorsyndets),regularuseof
emollients
III
-Topicalsteroidifeczematouslesions III
Paronychiaand
pyogenic
granulomalike
lesions
Prevention:
-Systemicantibiotics(tetracyclines) IB
-Antisepticsolutions III
Treatment:
-Topicalsteroids III
-Systemicantibiotics(tetracyclines) III
-Culture-drivenantibioticsifsecondaryinfection IB
Fissures Protectivecoverings(hydrocolloid,biologicalor
cyanoacrylateglue),barriercreams(petroleum
jelly,zincoxidecream)andthickemollients
IIB
Hair changes
-Nonscarringalopecia:topicalminoxidil IB
-Inflammatoryandscarringalopecia:topical
steroids
III
-Trichomegaly:eyelashtrimming III
-Hypertrichosis:laserhairreduction IB
KITandBCR-ABL inhibitors
Imatinib,nilotinib,
dasatinib
Exanthema(rash) Topicalsteroidsorshortcoursesoforalsteroids III
Hypopigmentation Reversibleaftertreatmentinterruption III
Antiangiogenic agents -SelectiveVEGFR inhibitors: bevacizumaband ranibizumab Non-selective multikinase inhibitors: sorafenib, pazopanib, sunitinib Hand-footskin reaction Prevention:
-Usethickcottonglovesand/orsocks;ureabased
emollients;avoidirritantsandtightclothingand
shoes;avoidextremesoftemperature,pressure
andfriction
III
-Pretreatmentevaluationwithapodiatristwith
callositychoppingandtheuseoforthopedicshoe
insertswhenneeded
III
-Ureabasedemollients IB
Treatment:
-Keratolyticagents III
-Topicalcorticosteroids III
-Potenttopicalsteroid III
-Forreliefofsymptoms,coolcompressesor
emergenceofhandsandfeetoncoolwater,
topicalanestheticsandNSAIDs
III
-Hydrocolloiddressings? IB
Pigmentary changes
-Hypopigmentationofhairandskin(pazopanib
andsunitinib),yellowdiscolorationofskin
(sunitinib)---reversibleafterdiscontinuation
III
Hairandscalp -Seborrheicdermatitis-likerash:topicalsteroids III
-Non-scarringalopecia:topicalminoxidil IV
RAFinhibitors Vemurafeniband dabrafenib
Exanthema (rash)
-Oralantihistamines,topicalorshortcoursesof
systemicsteroids
III
*Temporarytreatmentinterruptionmightbe
Table2(Continued)
Drugclass Agents Dermatologic
toxicities
Management Levelof
evidence
Photosensitivity Prevention:photoprotectivemeasures IIB
Treatment:topicalorshortcoursesofsystemic steroids
III
*Mostlyvemurafenib,UVA-induced
Keratosispilaris
likeeruption
Keratolyticsandemollients,gentleskincare III
Seborrheic dermatitis-like
Topicalsteroids III
Hand-footskin
reaction
Seeabove(antiangiogenicagents)
Keratoacanthomas
andsquamouscell
carcinomas
-Frequentdermatologicalmonitoring III
-Iffewlesions:surgicalexcision III
-Ifmultiplelesions:5-FU,systemicretinoidsor
photodynamictherapy
IIA/B
*AssociationwithaMEKidecreaseslesions
Wartsandverrucal
keratoses
-Destructiveorsurgicalmeasures III
-Topicaltreatments:keratolytics,5-FU,
imiquimod
III
MEKinhibitors Cobimetinibe, trametinibe, selumetinibe Papulopustular eruption SeeEGFR inhibitorsabove Xerosis Paronychia
Exanthema(rash) -Oralantihistamines,topicalorshortcoursesof
systemicsteroids
III
mTORinhibitors Rapamycin,
everolimus, sirolimus
Stomatitis Antisepticwashes,topicalsteroidsand
anesthetics
IV
* NSAID,nonsteroidalanti-inflammatorydrug.
(CTLA-4). This releasing/activationof the immunesystem also affects normal cells, explaining the most common adverseeventsrelatedtothisclass,alsoknownas Immune-Related Adverse Events (irAE). On this group we find the CTLA-4 inhibitor (ipilimumab), PD-1 and PD-1 ligand inhibitors(nivolumab,pembrolizumab,atezolizumab).7,10---13
Relatedcutaneousadverseeventstotheagentsonthisclass, theirmanagementandlevelsofevidencearesummarizedon
table3.
Grading
the
dermatological
adverse
events
TheNationalCancerInstitute’sCommonTerminology Crite-riaforAdverseEvents(CTCAE)isastandardizedtoolusedin oncologytrialstodocumentandgradetoxiceffectsof onco-logic therapies. It is available online with open accessat
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.
It divides AE into systems and has a specific chapter for skinandsubcutaneous tissuedisorders.Ithelps estab-lishacommonterminologyandlanguagebetweendifferent experts (oncologists, dermatologists, nurses, etc.) and to standardizetreatmentsordosemodificationsbasedonthe severityofspecificmanifestations.
Impact
of
dermatological
adverse
events
on
quality
of
life
Qualityoflifeisanimportantissuewhendealingwith onco-logic patients. Differentstudies have already shown that gradingseverityofAEaredifferentfromthephysicianand thepatient’sperspectives.14Therefore,usingpatient’s
self-reportinginstrumentsforDAEarealsoimportant.Different instruments are available such as Skindex-16©, Skindex-29©, Dermatology Life Quality Index (DLQI), DIELH-24 or evenquestionnaires for specific agents suchas the Func-tional Assessment of Cancer Therapy-Epidermal Growth FactorReceptorInhibitors-18(FACT-EGFRI-18).15
Whencomparingdifferentclassesofdrugs,thenumberof DAEsanditsimpactonQoLseemedtobegreateronpatients ontargetedversusnon-targetedtherapies(difference=8.9,
p=0.02).15
Cutaneous
toxicity
as
a
predictive
marker
for
clinical
outcome
Arecent review tried to address the association of cuta-neoustoxicities and clinical outcome. Forpapulopustular eruptioninducedbyEGFRi,thisassociationhasalreadybeen established (four trials, all with p<0.05). For hand-foot skin reactionassociated withsorafenib, it wasassociated
Table3 Dermatologicadverseeventsofimmunotherapy(immune-relatedadverseevents---irAE).
Drugclass Agents* Dermatologictoxicities Management Levelof
evidence ‘‘Checkpoint’’ inhibitors -CTLA-4inhibitors: ipilimumab -PD-1inhibitors: nivolumab, pembrolizumab -PD1linhibitors: atezolizumab
Exanthema(rash) -Mild(<30%BSA):oral
antihistamines,topical
steroids
IV
-Moderate(>30%BSA):oral
steroids(1---2mg/kg);hold immunotherapy IV -Severe(SSJ/TENor necrotic,bullousor hemorrhagic complications):systemic steroid(1---2mg/kg); permanentlydiscontinue immunotherapy IV Pruritus Prevention:
Limitedshowertime,useof
gentlecleansers(pH-neutral
soapsorsyndets),regular
useofemollients
IV
Treatment:
-Oralantihistamines IV
-Topicalororalsteroids IV
-GABAagonists(pregabalin,
gabapentin)
IV
Oraltoxicity
-Lichenoidlesions
-Drymouth
Topicalsteroidsand
anesthetics,goodoral
hygiene
IV
Vitiligo Nodefinitivetreatment IV
Others: Onlycasereports
ontheliterature -Lichenoideruptions -Sarcoidosis -Auto-immuneblistering diseases(bullous pemphigoid) -Psoriasis
BSA,BodySurfaceArea;CTLA-4,CytotoxicTLymphocyteAssociatedAntigen4;PD-1,ProgrammedDeath1;PD-1l,ProgrammedDeath1 Ligand;SSJ,Steven-JohnsonSyndrome;TEN,ToxicEpidermalNecrolysis.
* Dualcheckpointblockade(anti-CTLA-4+anti-PD1)isrelatedtoahighergradeofadverseevents,includingdermatologictoxicities. CasereportsforsevereirAEareavailablewiththeuseofotherimmunomodulatoryagents.
withreduced risk of deathon a systematic review of 12 cohortstudies (p<0.00001; hazard ratio=0.45). However, authorsconcludedthat forother toxicitiessuchasvitiligo andimmunotherapy for melanoma (data based mostly on retrospectiveanalyses),theanalysesarestillobservational andexploratoryandneedfurtherinvestigationfromlarger prospectivestudies.16
Daily
baseline
skin
care
Xerosis is a common dermatological condition in patients on cancer treatment, with incidences ranging from 1 to 84%and can collaboratetoa decrease in QoLand tothe occurrenceof other DAE, such asinfections, sensitization toallergensandpruritus.Itisevenmorefrequentwiththe use of targeted therapies (for xerosis --- RR=2.99, 95% IC 2.0---4.3,p<0.001;forpruritusRR=2.56,95%IC1.51---4.35,
p<0.001).17,18Theskinalsobecomesmoresensitivetothe
ultravioletradiationandmorepronetoskinpigmentation. Therefore,itisfundamentaltoeducatepatientson preven-tivemeasures,evenpriortothestartofanytherapy,that helpmaintainingskinbarrier function,possiblydecreasing theoccurrenceandseverityofDAE.
Some important measures to all cancer patients are: avoidance of alcohol- based lotions and irritating prod-ucts, limited shower time, use of gentle cleansers (pH-neutral soaps or syndets), regular use of emollients and sun protective measures (e.g.: broad spectrum sun-screen --- SPF30 or higher with a UVA-PF, protective clothes).1
The use of deodorants is controversial, but some data show noevidenceof harm,and therefore, patientsmight use thoseproductsin ordertomaintaintheir regular rou-tineandhelpontheirwell-being.19 Theuseofmake-upor
A
B
C
Figure1 Differenthyperpigmentationpatterns:(A)serpentinesupravenoushyperpigmentationafterperipheralchemotherapy
infusion(fluorouracil);(B)nailplatepigmentation(daunorubicin);(C)acrallentiginoses(doxorubicin).
camouflagemay alsohelp onthe self-esteem.Preference fornoncomedogenicproductsisrecommended.
Dermatological
adverse
events
As dermatologists usually start their evaluation on skin exam, the different DAE will be grouped in types of skin reactionsandareasofinvolvement.Intables1---3,readers canfindtheDAEgroupedbyclassofagentsandthelevelof evidenceoftherecommendationsforeachtreatmentused onthisguideline.
Pigmentarychanges
Hyperpigmentationcanoccurat differentsitesandin dif-ferentpatterns(Fig.1).Theycanstartdaystomonthsafter initiationandmostofthetimesfademonthsafter discon-tinuationoftherapy.Itcanoccur:(a)Onphotodistributed areas, preceded or not by photosensitivitysigns;(b) As a serpentinesupravenoushyperpigmentationafterperipheral chemotherapy infusion (e.g.fluorouracil, docetaxel), that might bepreceded ornot byerythema andinflammation;
(c)Inadiffusepattern,sometimesreticulated(doxorubicin, hydroxyurea,methotrexate);(d)Localizedinareasof pres-sure,flexuralareasorunderocclusivedressings(ifosfamide, thiotepa);(e)Asacralpigmentation(alongthecreaselines ormacular,overthepalmsandsoles).4,20
Flagellate dermatitis and pigmentation is related to bleomycin treatment (20%---30% of patients) and occur as a pruritic erythematous linear streaks, followed by pigmentation (Fig. 2). Busulfan treatment can cause an ‘‘Addison-like’’pigmentation,withatanappearance.4
Patientsshouldbeorientedtoadheretosun-protective measuresandbleachingagentsmightalsobeusedto accel-erateclearing.
Targeted therapies can also cause pigmentary changes suchasayellowpigmentationonsunitinibtreatedpatients (VEGFRi).Hypopigmentation (diffuse or localized)is asso-ciatedwithc-kitinhibitors suchasimatinib, especiallyin patientswithdarkerskin,asc-kitalsoregulatesmelanocyte function.Theyareusuallyreversiblewithdosereductionor discontinuation.5
Morerecently,immunotherapyhasbeenlinkedto vitiligo-like lesions, mainly but not only in melanoma treated patients. Associated hair depigmentation can also be
A
B
Figure2 Flagellatedermatitisassociatedtobleomycintreatment:(A)pruriticerythematouslinearstreaks,(B)followedbylinear pigmentation.
observed.Nodefinitivetreatmentexistsanditusually per-sists after the completion of immunotherapy. Reports of whitehairrepigmentationarealsoavailable.10---12,21
Nailchanges
Nail alterations during cancer treatment are frequent, usually well tolerated and disappear under cessation of treatment.However,insomecircumstancestheymightbe symptomaticandinterferewithpatient’sdailyactivities.22
Conventional chemotherapeutic agents are usually relatedtoalterationssuchasmelanonychia(diffuse, trans-verse or longitudinal), leukonychia, onycholysis, Beau’s lines,onychomadesisandonychorrhexis.
Taxanes are associated with painful subungual hemor-rhage, followed by onycholysis and sometimes subungual abscessformation that arequite symptomatic, and might lead to dose reductions or treatment discontinuation (Fig.3). The use of frozen gloves and socksduring infu-sionmightreducetheseverityofnailalterations,butthey are usually not well tolerated (nail toxicity, one study, 45 patients, side-to-side, 11% vs. 51%, p=0.0001).2,4,20
Drainageofhemorrhageandabscessesmightbeneededfor symptomsrelief,aswellascultureguidedantibiotic treat-ments.
Both conventional and targeted treatments can cause nailplatealterationssuchasbrittlenails,nailcrackingand onychoschizia.Thoseeffects canbehandledwith preven-tivemeasuressuchasreductionofcontacttowater,useof cottonglovesbeneathplasticorrubberglovesforanywet work,avoidanceofanydamaging procedure(e.g.: aggres-sivemanicuring),andhydrationwiththickemollients.Oral biotinandlacquerssuchashydroxypropylchitosanand poly-ureaurethanemightbeused,although nocontrolledstudy isyetavailable.22
For onycholysis, avoiding traumas (e.g.: keeping nails short)andhumidityis important. Ifsignsof pseudomonas colonization(greendiscoloration),atopicalantibioticmight be used (we suggest ophthalmologic solutions such as tobramycinorciprofloxacineyedropstwicedaily).
VEGFRiareassociatedwithasymptomatic splinter sub-ungual hemorrhages (black, red or brown longitudinal lines)in 25---70% ofpatients, withfingernails beingmostly affected.5,7
EGFRiarerelatedtofrequentnailtoxicities,occurringin around17.2%ofpatientsonapreviousmeta-analysis.23
Peri-ungueal fissures, paronychia and pyogenic granuloma-like lesions start to develop two or more months after initia-tionoftherapy,onbothfingerandtoenails(Fig.4).They areinitiallysterile,butsecondaryinfectionmayoccur. Pre-ventive measures include the ones listed above and also the use of comfortable shoes, sometimes with cushion-ing inserts for the affected nails, adequate nail cutting and theuse of antiseptic solutionssuch asBurrow’s solu-tion soaks, white vinegar soaks (1:1), bleach soaks (1/4 cupbleach:approx.10lwater),chlorhexidineorpovidone iodine6,24---26orasolutionofsodiumhypoclorite2.5%,sodium
chloride 1.0%, deionized water qsp 100mL (5 drops/1l). The useoforal tetracyclinesiscontroversial astheywere related to a decrease on the incidence of paronychia in sometrialsandshowednobenefitsonothers.27 For
fissur-ing, protective coverings such as hydrocolloid, biological glue or even cyanoacrylate glue to relieve pain and pro-mote healing,barrier creams (petroleum jelly, zinc oxide cream)andthickemollientsmightbeused.Forgranulomas, ifsecondaryinfectionissuspected,cultureisindicatedand proper antibiotics should be prescribed. For non infected lesions, destructivemeasures suchas trichloroacetic acid (70---90%) or cryotherapy might be used. Potent topical steroids,occlusiveornot,arealsoindicated.28 Sometimes
surgical treatment might be necessary. Recently, the use of topicalbetaxolol wasdescribedfor treatinga pyogenic granuloma-likelesioninducedbyEGFRi.29
Acralreactions
Hand-foot syndrome (HFS), also known as palmoplan-tar erythrodysestesia, is a DAE related to conventional chemotherapeutic drugs, common with agents such as capecitabine,doxorubicin,cytarabine,5-FU.Itispreceded
A
B
Figure3 PATEOsyndrome(PeriArticularThenarErythemaandOnycholysis):docetaxeltreatedpatientpresentingwith(A)
erythe-matouslesionswithadistinctdistributiontothedorsalaspectsofthehandsand(B)associatednailchanges---subungualhemorrhage
andonycholysis.
A
B
C
D
E
Figure4 EGFR inhibitorsrelatedadverseevents: (AandB)inflammatorypapulopustularrashwith associatedxerosis(*);(C)
trychomegalyandhypertrichosis; (D)periungual fissuresand(E)pyogenic granuloma-likelesions. (A,B,DandE oncetuximab
treatedpatients;Conpanitumumabtreatedpatient).
by prodrome symptoms such as tingling or pain at the extremities,followedbyasymmetric,sharplydemarcated erythemaandedemaofthepalmsandsoles(Fig.5). Vesi-cles and bullae might also bepresent. Painusually limits dailyactivities andmightbe acauseofdose reductionor discontinuation.Incidenceishigherwithprolongedinfusions ororalagents.2,4
PATEO syndrome (PeriArticular Thenar Erythema and Onycholysis) is a variant of HFS, specific to the taxanes (docetaxel) (Fig. 3). It is characterized by scaly erythe-matous lesions with a distinct distribution to the dorsal aspectsofthehands(overlyingthejoints)andthenar emi-nences. More rarely, it can alsoaffect the dorsum of the feet.Althoughcommon,nailsarenotuniversallyaffected.
It is usually bilateral, not necessarily symmetric. It may start onthefirst chemotherapy cycleor develop progres-sively. Burning sensation and pain are the most reported symptoms.20
Hand-foot skin reaction (HFSR) is another variant of acral toxicity related to targeted therapies, with both monoclonalantibodiesandsmallmoleculestyrosinekinase inhibitors especially with those targeting VEGFR (beva-cizumab, sorafenib, sunitinib) and BRAF (vemurafenib) (Fig.6).Despitethesimilarpalmoplantardistribution,dose dependencyandassociatedpain,HFSRdeveloponfrictionor trauma-proneareas(pressureareas),suchastheheeland lateralaspectsof thesoles and webspaces. Lesions start 2---4weeksafterbeginningoftherapyandarecharacterized
Figure 5 Toxic erythema of chemotherapy (TEC):
com-bination of different lesions caused by direct toxicity of
chemotherapyagentswith(A)lesionsonflexuralareas
(inter-triginous eruption associated withchemotherapy) and(B) on
palmsandsoles(Hand-footsyndrome---HFS).
by hyperkeratosis, resembling skin calluses, occasionally withsuperficial blisteringand erythematoushalos.2,5,6,30,31
Dependingonthedrug,lesionsmightimproveor notover time.32
Prevention
HFS and PATEO: on a prior systematic review, the only twoevidencedbasedmeasuresforprevention(todecrease incidenceand/or severity)werethe useof anonsteroidal anti-inflammatorydrug(NSAIDs---celocoxib)(foranygrade: Odds Ratio --- OR=0.47, 95% IC 0.29---0.78, p=0.003; for Grade 2---3: OR=0.39, 95% IC 0.20---0.73, p=0.003) and dose reduction.Onestudy showedbenefitwiththeuse of regional cooling during chemotherapy infusion (incidence 36%×7.1%, p=0.0097). However, aspreviously discussed, frozen gloves andsocks areusually notwell tolerated by patients; regarding to NSAIDs, the risks and benefits of their use must be weighted; regarding dose reductions, it has direct impact on disease outcome.33,34 The use of
emollients seemed promisor, but with no statistical sig-nificant difference. Pyridoxine was not effective for the prevention.33---35 A small RCT showed benefits with the
useofanantioxidant-containing ointmentwhencompared to placebo on pegylated liposomal doxorubicin treated patients.36ForHFSRoneRCTshowedadecreasedincidence
in any grade and >Grade 2 reaction withthe use of urea 10% cream compared to‘‘best supportive care’’ (for any grade:OR=0.457,95%CI0.34---0.60,p<0.001,for≥Grade 2:OR=0.635,95%CI0.46---0.86,p=0.004).Resultsmightbe questioned, though, because ‘‘best supportive care’’ was indeed nopreventive care.37,38 Anothersmall prospective
trialshowedadecreaseinoccurrenceofHFSRonsorafenib treated patients with the ingestion of a Japanese food (Bonitobroth)whencomparedtonoingestion(HazardRatio, HR=0.097, 95%CI0.011---0.846, p=0.035 onmultivariable analysis).This foodis shown toincrease peripheral blood flow in humans.39 Anotherisolated reportshowedsuccess
withtheuseoftopicalcalcipotriolinonecase.40
Despitetheabsenceofastrongevidence,wedo recom-mendthefollowingpreventivemeasures2,5---7,30,31,41:
Educatepatientsofearlysignsandsymptoms; Usethickcottonglovesand/orsocks;
Applyemollientcreams(ureabasedemollientsin hyper-keratotictype)tohandsandfeetregularly;
Figure6 Hand-footskinreaction(HFSR)associatedwithantiangiogenicagents(VEGFRi):(A)hyperkeratoticlesions(sorafenib)
Avoidirritantssuchasalcohol,harshcleansingagentsand tightclothingandshoes;
Avoid extremes of temperature, pressure and friction (e.g.:repetitiveactivities,stressfulmanualwork,etc.).
ForHFSRalsoincludeapretreatment evaluationwitha podiatristwithcallositychoppingandtheuseoforthopedic shoeinsertswhenneeded.
Treatment
Also low evidence exists on treatment measures. Dose reductionsareeffectivebutinterfereswithdiseaserelated outcomes. One small prospective non-comparative trial showed improvement in QoL and decrease on HFS symp-toms with the use of a topicalnon-occlusive polymer for 8 weeks.42 ForHFSR, one small randomizedphase II trial
showedbenefitwiththetreatmentofGrade1toxicitywith a hydrocolloid dressing containing ceramide with a low-frictionexternalsurfacewhencomparedtourea10%cream (Grade 2---3, 29% vs. 69%, p=0.03).43 Recently, a
system-aticreview showedbenefitsof differentChineseherbson the treatment of acral toxicities. However, most of the studieswerenotblindedandwithalowerquality.44,45 One
case report and a small case series suggest benefits on theuseoftopicalHennaforcapecitabineHFS.46,47Besides
thealreadymentionedpreventivemeasures, recommenda-tions of this board for the treatment of those toxicities include2,5---7,30,31,41:
Continuingtheuseofpreventivemeasures;
Maintaining the use of emollients, and on the case of HFSR, include the use of keratolytic agents (e.g.: urea 10---40%,salicylicacid,etc.);
Addapotenttopicalsteroid;
Forreliefofsymptoms,coolcompressesoremergenceof handsandfeetoncoolwater,topicalanestheticsandNSAIDs mightbeused;
Dose reduction or treatment interruptionis sometimes necessaryuntilsymptomsdecrease.
Skinrashes
One of the problems of better defining the DAE in many oncologytrialsisthatfrequentlyinvestigatorsreportthe dif-ferenttypesofcutaneouseruptionsasaskin‘‘rash’’.Yet, aswewillsee,therearedifferenttypesofcutaneous erup-tions, associated withdifferent classes of drugs and with differenttreatmentoptions.
Acute hypersensitivity reactions: those Type I immunoglobulin E-mediated reactions may occur within minutes to hours of infusion. They manifest as regu-lar hypersensitivity reactions to conventional drugs, as pruritus, flushing, urticaria and even anaphylaxis. The differencereliesthoughonthewaywe dealwithit.With conventional drugs,patients areusuallyorientedtoavoid re-exposure.When dealingwithoncologictreatments,the chemotherapeuticagentisfundamentalfordiseaserelated survival. Therefore,we usuallymaintain the drugfor the nextcyclesandmanagethereactionwithaslowerinfusion, a premedication with corticosteroids and antihistamines beforeeveryinfusionandaclosermonitoring.4,6,7
Exanthema:manytreatmentsmayberelatedtoa non-specific maculopapular rash or morbiliform eruption that
startsgradually,sometimesweeks afterthestart ofdrug, withmildsymptomssuchaspruritus.ThoseDAEcanbe han-dledwithanti-histaminesandtopicalcorticosteroidswhen limited,or withshortcoursesoforal corticosteroidswhen moredisseminated. All classof agents might causethose kind ofreactions, such askinaseinhibitors (e.g.:BRAFi ---vemurafenib/kitand BCR-ABL inhibitors--- imatinib, dasa-tinib), ‘‘checkpoint’’ inhibitors (ipilimumab, nivolumab), andconventionalchemotherapeuticagents(bleomycin, car-boplatin,etoposide,etc.).4,6,7Onlyinrareoccasionssevere
reactionssuchastoxicepidermalnecrolysis(TEN), Steven-Johnsonsyndrome(SSJ)or drugrashwitheosinophiliaand systemic symptoms (DRESS) might occur, but it must be rememberedthatamaculopapularrashmayrepresentthe firstmanifestationofthoselife-threateningconditions. Spe-cialattentionshouldbegivenwhenusingatargetedtherapy aftertheuseofanimmunotherapy(e.g.:melanomapatients treatedwithimmunotherapyandthenswitchedtoaBRAFi) asitmaybeassociatedwithahigherriskofsevereskin toxic-ity(>Grade3andSSJ/TEN).Someauthorssuggestatleasta 4weekintervalbetweentreatmentswiththoseagents.7,48---50
Whenapatientisonimmunotherapy,skinadverseevents to conventional drugs (e.g.: antibiotics) might be more intense,soitisalwaysimportanttoexcludeothercausative agents, before relating the rash to the ‘‘checkpoint’’ inhibitor.
Toxicerythemaofchemotherapy(TEC):thistermis sug-gestedby some authors to unify different manifestations such as HFS, intertriginous eruption of chemotherapy or other used histopathologic terms such as ‘‘eccrine squa-mous syringometaplasia’’, all related to a direct toxicity ofthechemotherapeuticagentandnot duetoanallergic reaction.This typeofDAEis characterizedbyoverlapping features of bilateral painful erythema, edema, and even bullouslesionslocatedonhandsandfeet(seehand-foot syn-drome),and sometimesalsoaffecting intertriginous areas suchas axillaand groins(less frequently ears, knees and elbows) (Fig. 5). It is important to distinguish, because thosemanifestationsareusuallyself-limited,often resolv-ingwithdesquamationandpost-inflammatorypigmentation andnotdemandingaggressivemeasures.Inaddition,lesions develop2---3 weeksafter thechemotherapy cycle,usually whenpatient’sdefensesarelower(e.g.:neutropenia),being manytimesmisdiagnosedasinfectionsorgraft-versus-host disease(GVHD).Treatmentreliesontopicalcorticosteroids andemollients,andeducatingthepatientaboutthenature ofthemanifestation.Itoftenrecrudescesonthesubsequent cycles.Itmightbemilderwithdosereductions.20,51
Papulopustularrash:alsoknownas‘‘acne-likerash’’or ‘‘folliculitis’’,thisisthemostcommondermatological tox-icity of EGFRi treatment (Fig. 4). It usually appears 1---2 weeksafterinitiationoftherapy,startswitherythema, fol-lowedby theeruptionofpapulesandpustules(sterile) on theface,scalp,upperchestandback,withalackof come-dones.Sometimeslesionsextendtothelimbs.Skinisusually dry,itchyandsensible(patientsrefersensationofburning, stinging,tenderness).ThisAEhasahighimpactonpatient’s QoLandonsocial aspectsof dailyliving,beingacauseof dosereductionoreventreatmentdiscontinuation.Therash tendstoimprovearoundthe8thweek,butusuallypersists, asamildereruption,withperiodsofimprovementand wors-ening.Otherfeaturesthatarepresent,especiallylateron
treatment, are the already discussed paronychia, periun-gualfissuresandgranulomas,xerosis,pruritusandtheyet tobediscussedhairalterationssuchastrichomegaly, hyper-trichosisandnon-scarringalopecia.6,23---25,52
Prevention
General daily baseline measures have already been dis-cussedandareofgreatimportanceonthisgroupofagents. Theyinclude theregularuse of emollients,photo protec-tive measures (sun exposure might worsenthe eruption), avoidanceofirritatingagents,limitedshowertimeanduse ofgentlecleansers.Theuseofsystemicantibiotics(mostly tetracyclineagents)onthefirst6---8weeksoftreatmenthas beenevaluatedin sometrialswithdiscordantresults.The availabledatasuggestsomebenefitofthepreventive treat-mentindecreasingtheincidenceandmainlytheintensity ofthepapulopustularrashwhencomparedtonotreatment oreventothereactivetreatment(startedoncetherashis alreadypresent).26,53,54Thisisalsotheopinionofthisexpert
panel.Wesuggesttheuseoforaltetracyclines(e.g. doxycy-cline100mgbid.)duringthefirst6to8weeksoftreatment withEGFRi.On onerandomizedphaseIItrial, topical ery-thromycinwasinferiortooraldoxycyclinefortheprevention ofEGFRskin toxicity.54 Anothertrialshowedsome benefit
withthepreventiveuseoflowpotencytopicalsteroids,but werecommendtheiruseonlyasareactivetreatment.
Treatment
Despite the acne-like appearance, topical agents used to treatacneandacneiformeruptionssuchasbenzoyl perox-ide,retinoicacidsandsalicylicacidcontainingproductsare contra-indicated. Ifthe rash occurs, preventive measures shouldbemaintainedandtothat,topicalsteroids canbe added.Ifmorepronouncedandtetracyclinewasnotstarted forprevention,itcannowbeinitiated.6,23,24Sometimesdose
reductionsmightbenecessary.Ifexcessivecrustingor secre-tion,culturesareindicatedtoexcludesecondarybacterial infection.Inthosecases,cultureguidedantimicrobial treat-ment is indicated. Recently, a single RCT showed benefit withtheuse ofa Chineseherbal topicalcompound (com-pared to placebo) for the treatment of the DAE related totargetedtherapy,includingthepapulopustularrash.45In
addition,therearesomereportsandsomepersonal expe-rience on the use of low dose systemic isotretinoin for refractorycases.55
Acneiform eruption: conventional chemotherapeutic regimens frequently containhigh doses of systemic corti-costeroids,suchasdexamethasoneorprednisone.Forthat reason,steroidrelatedacneiformeruptionmightoccurand shouldbetreatedsimilartothenon-oncologicpatients.
Photosensitivity reactions: oncologic treatments have been reported to cause both phototoxic or photoallergic reactions.Manyconventionalagentssuchas5-FUand tax-anes (mainly to UVB) have reported inflammatory rashes on photo-exposed areas.4,20 With EGFRi, not only
photo-sensitive eruptionscan occur, but alsothe other DAE can beexacerbatedbyphotoexposure.6Oneofthemost
pho-tosensitizing agent is vemurafenib (BRAFi) with a proved sensitivityfor UVA radiation, which is present on fluores-cencelampsandpassesthroughwindows.5,7,56,57Vandetanib
(TKI)isalsoassociatedtoaUVAsensitivity.Preventivesun
protectivemeasuresarefundamental.Ifreactionoccurs,it might behandledwithtopicalsteroids orshortcoursesof oralsteroids.
Keratosis pilaris-like eruption: this adverse event has been linked to the use of BRAFi and is characterized by diffusefollicularkeratoticpapulesinageneralized distribu-tion,resemblingkeratosispilaris.Topicalkeratolyticagents mightbeused.7Vemurafenibcouldalsocause
folliculocen-tricmorbilliformrash(Fig.7).
Scalpandhairabnormalities
Some general recommended measures for hair and scalp daily care include the use of a gentle shampoo, avoiding hotwater,hairdyesandhairfoaming.
Conventional chemotherapy-induced alopecia (CIA): is oneofthemostdistressingeventsincancerpatientstreated withconventionalagents.Itiscausedmainlybyananagen effluviumand is usually(although not always) completely reversible2---6 monthsafter treatmentis discontinued.2,20
It affectsmoreoften scalphair,but eyebrows,eyelashes, andotherbodyareasmightalsobeaffected.Hairlosswill beinfluenced notonlyby thedrug, butalsoby theroute of administration, dosing and schedule (e.g.: high dose, intravenous,intermittentregimensaremorepronetocause complete alopecia). Examples of agents with a high risk includecyclophosphamide,doxorubicin,irinotecanand tax-anes(docetaxelandpaclitaxel).
Prevention
Asystematicreviewofpreventivemeasuresfoundno ben-efitwiththeuseoftopicalminoxidil,orscalpcompression. Benefit wasfound withthe use of a scalp cooling device (RR=0.38, CI 95% 0.32---0.45, p<0.001).58---61 Scalp cooling
systemsincludestaticdevices(coolcaps)anddynamicscalp coolingsystems.Patientsshouldbewarnedthattreatment efficacy is variable(around 50---80% depending onagent). Availabledatasuggestthatthistechnologyismosteffective for taxane-based chemotherapy regimens compared with anthracycline-basedchemotherapyregimens.62Besides,the
useofthecoolingdevicesarenotalwayswelltoleratedas they may cause symptoms like headache and scalp pain. Devices arealsonotreimbursableby insurancecompanies and might have a high cost. Recent studies have shown that the incidenceof scalpmetastasis is notincreased in breastcancerpatients withlocalizeddiseasetreatedwith scalpcooling.63,64However,therearetworeportedcasesof
diseaserecurrenceinpatientswithhematological malignan-cies (mycosis fungoidesand acute myeloidleukemia).65,66
Becauseofthat,scalpcoolingshouldbeavoidedin hemato-logicalmalignancies.67
Treatment
Minoxidilwasnot effectivein preventingCIA,but asmall trialshowedthatminoxidil2%wasassociatedwithafaster regrowthofhair(timetoregrowthof86vs.136daysonthe placebogroup).68Otheragentssuchastopicalcalcitriolare
underinvestigation, butstillwithnodefinitive results.2,69
Basedonthestudiesandonauthorsdailypractice,we rec-ommend the use of topicalminoxidil 5% once daily after theendofthechemotherapycycles.Foreyebrowsand
eye-Figure7 BRAFinhibitorrelatedadverseevents:multiplekeratoachantomas(A)andlowgradesquamouscellcarcinomas(B)after
withdrawalofMEKinhibitorandmaintenanceofBRAFinhibitor;(C)associatedkeratosispilaris-likeeruptiononthelowerlimbs.
lashes,topicalbimatoprostmight beused(onecontrolled study for eyelash showed benefit at 12 months).70 Biotin
andotheroralsupplementsmightbeadded.Camouflageand supportforpatientsarealsoimportantstrategies.
Reversibility:CIAiscompletelyreversibleinmostofthe cases. When incomplete/suboptimal hair regrowth occurs after 6 months of discontinuing therapy, it is considered a persistent CIA (pCIA). It has a usually diffuse, non-scaringpatternandoccurmoreoftenwithprebonemarrow transplantation high dose regimens (usually busulfan and cyclophosphamide)orwithtaxanes.20,71
Anotherfrequentpatternofpersistentalopeciaon can-cer patients is described as endocrine therapy-induced alopecia.Formany hormonereceptor-positivebreast can-cersurvivor’sselectiveestrogenreceptormodulators(e.g., tamoxifen, toremifene), aromatase inhibitors (e.g., anas-trozole,letrozole,exemestane)andgonadotropin-releasing hormoneagonist(e.g.,leuprolide)areusuallyadministered for 5---10 years toreduce the risk of recurrence.5---10 This
estrogen deprivation might lead to androgenetic pattern alopecia.Topical minoxidilcan beused.As for theuseof systemictherapies for androgenic alopecia(e.g., spirono-lactone,finasteride), thereis a putative risk of hormonal
stimulationof endocrine receptor-positive tumors, sothe useoftheseagentsmust bediscussedwiththeoncologist andusedwithcaution.67,71
Targetedtherapiesinducedhair abnormalities:changes inhair quality,textureand growthpattern mightbe seen aroundthe2ndor3rdmonthoftreatment.
Scalp:scalphairgrowsslowerandwithafragilequality.A seborrheicdermatitis-likerashmaydevelop(especiallywith VEGFRiandBRAFi).Alsothepapulopustularrashaffecting thefaceandtrunkmightinvolvethescalp(especiallywith EGFRi).Alopecia isusuallymild and withan androgenetic pattern, but cases of inflammatory non-scarring alopecia havebeendescribed,ascasesoferlotinib-induced cicatri-cialalopecia.5,6
Forthoseinflammatory changes,wesuggest theuseof anti-dandruffshampoos andtopicalcorticosteroids (lotion or shampoo). If bacterialinfection is suspected,cultured guidedantibioticsareindicated.
Face, eyelashes and eyebrows: trichomegaly (longer, thickerandoftencurledeyelashes)andhypertrichosis are frequent (Fig. 4). Inward eyelashes may result in kerati-tis,thereforeeyelashclippingisadvisedandpatientswith ocularsymptomsshouldbereferredtoanophthalmologist.
Forhypertrichosis, topical, cosmeticinterventions canbe used(e.g.waxingor bleaching).When availablelaserand photoepilationtreatments aremost effective andarenot contra-indicated.69Creamsforepilationshouldbeavoided
due to their sensitizing potential in those subjects that alreadyhaveaskinbarrierdysfunction.
Immunotherapy induced hair abnormalities: cases of alopecia with a clinical and histologic pattern consistent with alopecia areata (AA) have been reported. Patients shouldbetreatedsimilarlytonon-oncologicAAcases.Also reports of hair depigmentation and repigmentation have been described. Even though we advise patients toavoid hair dyeing, it is not contra-indicated, and if there is an importantcosmeticconcern,dyesmightbeused.69
Changesinmelanocyticnevi
BRAF inhibitors: might be associated to the appearance oferuptive melanocyticnevi(EMN), changeof preexisting nevi (both the increase and acquisition of dermatoscopic structuresaswell astheregression of nevi thathave the BRAFmutation)andtheappearanceofnewmelanomas.72,73
Therefore,closedermatoscopicfollow-upisrecommended. TheinvolutionofBRAFinhibitor-inducedEMNfollowingthe concomitantadditionofMEKinhibitorhasbeendescribed.74
Immunotherapy: recently, regression of multiple melanocytic nevi after immunotherapy for melanoma has beendescribed.75,76
Otherparticulartoxicities
Epidermalneoplasms related toBRAF inhibitors: keratoa-canthomas,squamouscellcarcinomasandverrucalkeratosis area common DAE of BRAFi, they might alsooccur with some antiangiogenicagents (Fig.7). This is probablydue to the paradoxical stimulation of the MAPK pathway in BRAF wild-type cells. When MEK inhibitors are used in association,this AE ismuchless frequent. Lesions canbe treatedwithsurgicalexcision(whenonlyafewlesionsare present), destructive treatments (cryotherapy, curettage, etc.),topicaltreatments(keratolytics,5-FU,imiquimod)or photodynamictherapy.7
Stomatitis related to mTOR inhibitors (rapamycin, everolimus, sirolimus): stomatitis is the most commonAE andmightbesevereleadingtodoseadjustments.Different from conventional chemotherapy mucositis (broad ulcer-ation with pseudo membrane formations), mTOR related stomatitismanifestsasdiscreteaphthaeonnon-keratinized epithelium.They can behandled withantiseptic washes, topicalsteroidsandanesthetics.7
Other eruptions related to immunotherapy: a non-specificmaculopapularrash,asreportedabove,represents themostprevalenttypeofImmune-RelatedAdverseEvents (irAE) to this class of agents. However,peculiar types of reactionshavebeendescribedandinclude:
Lichenoidreactions:thoseeruptionscandeveloponboth skin and/or mucosae (oral and genital). Oral involvement mightalsoincludexerostomiaandtastechange;
Psoriasisandrosacea:thisagentsmight induce exacer-bationornewonsetofpsoriasis;
Auto-immunebullousdiseases:thedevelopmentof auto-immuneblisteringdisorders,especiallybullouspemphigoid, havebeenreported.
Sarcoidosis: also reports of sarcoidosis (new onset or reactivation)arebeingrecentlypublished.
Vitiligo:immunotherapy hasbeen linkedtovitiligo-like lesions,mainlybutnotonlyinmelanomatreatedpatients.64
Apointofdiscussionisaboutwhetherornottheuseof corticosteroidsmayantagonizetheefficacyof immunother-apy. Current clinical data is limited and controversial. In some retrospective analyses, it was not associated with inferior responses to the oncologic treatment. A recent systematic reviewconcludedthat it‘‘maynot necessarily lead to poorer clinical outcomes’’.77 On the other hand,
retrospective analysis on lung cancer patients using cor-ticosteroids at baseline or for irAE suggested a possible deleterious effect.78,79 Mostof thecurrent guidelinesand
expertpanelsdonotcontra-indicateitsuse.7,10---13 Asthere
are no definitive conclusions, we suggest that corticos-teroidsshouldbe usedwithcaution andalwaysdiscussing its use with the rest of the team, especially the oncolo-gists.Forsteroid-refractorycases,otherimmunomodulatory agents such as mycophenolate, infliximab, methotrexate andothers,andalsorituximabforblisteringdiseasesmight be necessary and afew reports with theiruse have been published.
Final
considerations
Dermatological adverse events are one of the most frequently observed toxicities from cancer treatments. Even though they rarely appear as life-threatening man-ifestations, they can lead to dose reductions or even discontinuation ofoncologic therapy, interferingwith dis-ease outcome. In addition, they have a great impact in patient’squalityoflife.Beingabletorecognizeandmanage thoseskin-relatedtoxicitiesgivesdermatologistsan impor-tantroleonthemultidisciplinaryteam,fundamentalforthe bestsupportivecareofcancerpatients.
Larger prospective randomized trials focusing on the managementofthedermatologicaladverseeventsarestill needed,butwiththeincreasingdevelopmentand recogni-tionofthefieldofoncodermatology,thisrealityiseachday closer.
Financial
support
Galderma.
Authors’
contributions
Jade Cury Martins Approval of the final version of the manuscript; conception andplanning of the study; elabo-ration and writing of the manuscript; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases;criticalreviewofthemanuscript.
AdrianaPessoaMendesEris:Approvalofthefinalversion of the manuscript;conception andplanning of the study;
obtaining,analysis,andinterpretationofthedata;effective participationinresearchorientation;intellectual participa-tioninthepropaedeuticand/ortherapeuticconductofthe studiedcases;criticalreviewofthemanuscript.
Cristina Martinez Zugaib Abdalla: Approval of thefinal versionofthemanuscript;conceptionandplanningof the study;obtaining, analysis,andinterpretation ofthe data; effectiveparticipationinresearchorientation;intellectual participationin thepropaedeuticand/or therapeutic con-ductofthestudiedcases;criticalreviewofthemanuscript. Giselle de Barros Silva: Approval of the final version of the manuscript;conception and planning of thestudy; obtaining,analysis,andinterpretationofthedata;effective participationinresearchorientation;intellectual participa-tioninthepropaedeuticand/ortherapeuticconductofthe studiedcases;criticalreviewofthemanuscript.
Veronica Paula Torel de Moura: Approval of the final versionofthemanuscript;conceptionandplanningof the study;obtaining, analysis,andinterpretation ofthe data; effectiveparticipationinresearchorientation;intellectual participationin thepropaedeuticand/or therapeutic con-ductofthestudiedcases;criticalreviewofthemanuscript. Jose Antonio Sanches: Approval of the final version of the manuscript; conception and planning of the study; obtaining,analysis,andinterpretationofthedata;effective participationinresearchorientation;intellectual participa-tioninthepropaedeuticand/ortherapeuticconductofthe studiedcases;criticalreviewofthemanuscript.
Conflicts
of
interest
Nonedeclared.
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