CONTINUING MEDICAL EDUCATION

Cutaneous adverse effects of targeted therapies

Part I: Inhibitors of the cellular membrane

James B. Macdonald, MD,a,b Brooke Macdonald, BA,c Loren E. Golitz, MD,d,e

Patricia LoRusso, DO,f and Aleksandar Sekulic, MD, PhDg

Provo, Utah; Aurora, Colorado; Detroit, Michigan; and Scottsdale, Arizona

Learning objectives

After completing this learning activity, participants should be able to identify the most common cutaneous adverse events associated with targeted therapies; describe the

etiopathogenesis of cutaneous adverse effects associated targeted therapies; and recognize clinical features of common cutaneous adverse effects associated with targeted therapies.

Disclosures

None declared.

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There has been a rapid emergence of numerous targeted agents in the oncology community in the last decade.This excitingparadigmshift indrugdevelopment lendspromise for the future of individualizedmedicine.Giventhe pace of development and clinical deployment of targeted agents with novel mechanisms of action,dermatologyprovidersmaynotbe familiarwith the full spectrumofassociated skin-related toxicities.Cutaneousadverse effects are among themost frequently observed toxicitieswithmany targeted agents, and their intensitycan be dose-limiting or lead to therapy discontinuation. In light of the often life-saving nature of emergingoncotherapeutics, it is critical that dermatologists both understand the mechanisms and recognize clinical signsand symptoms of such toxicities in order to provide effective clinical management. Part I of this continuingmedical education article will review in detail the potential skin-related adverse sequelae, the frequency ofoccurrence, and the implications associatedwithon- andoff-target cutaneous toxicities of inhibitors actingat thecell membrane level, chiefly inhibitors of epidermal growth factor receptor, KIT, and BCR-ABL, angiogenesis,and multikinase inhibitors. ( J Am Acad Dermatol 2015;72:203-18.)

Key words: adverse sequelae; alopecia; antiangiogenic agents; anticancer; BCR-ABL; bevacizumab; cancertreatment; canertinib; cetuximab; chemotherapy; cutaneous adverse effects; dasatinib; dermatologictoxicities; disturbed wound healing; drug eruption; drug rash; drug reaction; dry skin; dual kinase inhibitors;epidermal growth factor receptor inhibitors; erbB receptor; erlotinib; gefitinib; genital rash; HER2;hyperkeratotic handefoot skin reaction; imatinib; KIT; lapatinib; macular eruption; monoclonal antibodies;morbilliform; mucocutaneous hemorrhage; mucositis; multikinase inhibitors; nilotinib; panitumumab;papulopustular eruption; paronychia; pazopanib; platelet-derived growth factor receptor; photosensitivity;pigment changes; ranibizumab; side effects; small molecule; sorafenib; stomatitis; sunitinib; supportiveoncodermatology; targeted therapy; toxic erythema; tyrosine kinase inhibitors; vandetanib; vascularendothelial growth factor; xerosis.

INTRODUCTIONKey pointsd Targeted therapies offer more precise onco-logic treatment options; however, they arenot free of adverse effects

the Departments of Dermatologya and Pathology,b Central

tah Clinic, Provo; Macdonald Graphic Design, Inc,c Provo;

epartments of Dermatologyd and Pathology,e University of

olorado-Denver, Aurora; Department of Oncology, Wayne

ate University,f Detroit; and the Department of Dermatology,g

ayo Clinic, Scottsdale.

ing sources: None.

licts of interest: None declared.

pted for publication July 22, 2014.

d Cutaneous adverse effects are among themost frequently encountered, and signifi-cantly impact both quality of life and healthcare economics

Correspondence to: James B. Macdonald, MD, Departments of

Dermatology and Pathology, Central Utah Clinic, 1055 N 500 W,

Ste 111, Provo, UT 84604. E-mail: macdonjb@gmail.com.

0190-9622/$36.00

� 2014 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2014.07.032

Date of release: February 2015Expiration date: February 2018

203

Abbreviations used:

EGFR: epidermal growth factor receptorHhSP: hedgehog signaling pathwayVEGFR: vascular endothelial growth factor

receptor

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d Dermatologists can provide key input intreatment of patients with targeted cancertherapies

Virtually all cancers are driven by molecularaberrations that ultimately lead to uncontrolled pro-liferation. This notion has spurred the developmentof a spectrum of therapies specifically aimed at themolecular mechanisms contributing to cancer devel-opment and progression. The emergence of thisclass of agents, often referred to as ‘‘targeted thera-pies,’’ offers a promise of more effective treatmentstailored to a specific disease and possibly even to anindividual patient’s cancer.

Although designed to be significantly more ‘‘pre-cise’’ than traditional chemotherapies, targeted ther-apies frequently induce adverse effects (AEs).Cutaneous toxicities are among the most frequentlyobserved AEs1 and, when severe or protracted, canresult in significant morbidity, requiring dose modi-fication or drug discontinuation.2 The morbidity canaffect patient’s quality of life, including patient’sphysical,3 emotional,4 and psychological well-be-ing.5 In addition, AEs can affect medication adher-ence, risk of infection, and cancer therapy dosing6,7

and result in a substantial economic burden5 andpotentially time-exhaustive clinic visits for cancerpatients. In one analysis, management of dermato-logic toxicities of targeted therapies was estimated ata median of $1920 per patient.8

Given the increasing use of targeted therapies,dermatology providers are encountering growingnumbers of oncology patients who are experiencingcutaneous side effects of varied pathogeneses andcomplexity. The resulting need for a dual clinicalexpertise has led to collaborative efforts betweendermatologists and oncologists, including the intro-duction of supportive oncodermatology fellowshipprograms.5 To allow for uniform reporting andproper cataloging of side effects between specialistscaring for cancer patients, a standardized gradingsystem has been established,9 and dermatologic AEshave been stratified accordingly.10

In this 2-part review, we address the key skinand skin appendageerelated toxicities of themost prominent targeted anticancer therapiesand discuss the incidence, pathogenesis, clinicalpresentations, and management strategies by drug

category (Table I). Part I will focus on inhibitors ofmembrane-associated therapeutic targets (Fig 1),while part II details inhibitors of intracellularsignaling pathways and immunotherapies.

EPIDERMAL GROWTH FACTORRECEPTOR INHIBITORSKey pointsd Epidermal growth factor receptor inhibitorsgenerate a unique constellation of skin tox-icities, including papulopustular eruption,hair and nail changes, mucositis, andphotosensitivity

d The severity of papulopustular eruptiondirectly correlates with epidermal growthfactor receptor inhibitor efficacy and patientoutcomes

d Prophylaxis and the early management ofcutaneous toxicities may prevent dose reduc-tion or dose discontinuation

Epidermal growth factor receptor (EGFR)inhibitors are among the first families of targetedtherapies and are used in the treatment of severalmalignancies, including colorectal, head and neck,nonesmall cell lung, and breast cancers.11 This classof EGFR inhibitors includes monoclonal antibodiesto EGFR (eg, cetuximab and panitumumab), small-molecule tyrosine kinase inhibitors specific for EGFR(eg, erlotinib and gefitinib), dual kinase inhibitors ofEGFR and HER2 (ie, lapatinib, neratanib, and afati-nib), inhibitors of erbB receptors (ie, canertinib), andother less specific multikinase inhibitors (eg, vande-tanib). Most agents targeting EGFRs produce asimilar spectrum of dermatologic toxicities,12 asdetailed below.

The unique constellation of class-specific cuta-neous AEs associated with EGFR inhibition clearlypoint to the important role of EGFR in epidermal andpilosebaceous homeostasis.13-15 Indeed, EGFRs areabundantly expressed in the epidermis and itsappendages,16 consistent with the high incidenceof AEs induced by EGFR inhibition. Interestingly,EGFR has also been shown to play a putative role inrestraining interleukin-1 (IL-1)-dependent inflamma-tory reactions at the hair follicle level, possiblyshedding light on the acneiform papulopustulareruptions17 seen in conjunction with EGFRblockade. In addition to altering IL-1 and tumornecrosis factorealfa,18 EGFR effects on IL-8 havemore recently been implicated as a mechanismmediating EGFR-induced AEs.19 The observed skintoxicities are clearly related to EGFR itself, ratherthan off-target effects of EGFR inhibitors, because thereversal of EGFR inhibitoreinduced receptor

Table I. Management of cutaneous adverse effects of targeted therapies

Targeted therapy

class Agents within class Dermatologic toxicities Management

Level of

evidence

EGFR inhibitors Monoclonal antibodies toEGFR:

cetuximab and panitumumabTKI specific for EGFR: erlotiniband gefitinib

Dual kinase inhibitors of EGFRand HER2: lapatinib

Inhibitors of erbB receptors:canertinib

Less specific multikinaseinhibitors: vandetanib

Papulopustular eruption Preventative: low-potency topicalsteroids (class VII) andsunscreen; consider prophylacticsystemic antibiotics (tetracyclines)

IB

Treatment: low-potency topicalsteroids (class VI/VII); clindamycin1% topical

III

Systemic antibiotics: tetracyclines IIIIsotretinoin (20-30 mg/day) III

Xerosis/fissures Bland emollient creams andkeratolytics: urea, salicylic acid,lactic acid, and zinc oxide

IIB

Medium- to high-potency topicalsteroids (class II-IV); liquid gluesor cyanoacrylate

IIB

Hair changes: kinking,trichomegaly, hirsutism,alopecia (pattern orcicatricial), or poliosis

Nonscarring hair loss: topicalminoxidil

IB

Scarring hair loss: topical steroidsor antibiotic spray

III

HypertrichosisRegular eyelash trimming IIIEflornithine IVLaser hair reduction IB

Mucositis Topical steroids IIBAntiseptic washes IIIAnesthetic rinses III

Nail changes: paronychia,onycholysis, pyogenicgranulomaelike lesions,or brittle nails

Antiseptic soaks IBTopical steroids or calcineurininhibitors

IB

Systemic antimicrobials:tetracyclines or culture-driven

III/IB

Biotin for brittle nails IIBPhotosensitivity Strict sun precautions, including

photoprotective clothing andthe use of broad-spectrumsunscreens

III

KIT and BCR-ABLinhibitors

Imatinib, nilotinib, anddasatinib

Edema Limited sodium diet (2 g/day);diuretics if severe

III

Morbilliform eruption Topical steroids (class III/IV) or shortcourse of oral steroids; treatmentinterruption if grade III/IV

III

Pigmentary changes Typically reversible with dosereduction/termination

III

Antiangiogenicagents

Selective VEGFR inhibitors:bevacizumab andranibizumab

Mucocutaneoushemorrhage

Initiation or continuation oftreatment is not recommended

IV

Disturbed wound healing Consider delaying start/restart oftreatment until 28 days aftersurgery

III

Discontinue treatment for allwound complications

III

Continued

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Table I. Cont’d

Targeted therapy

class Agents within class Dermatologic toxicities Management

Level of

evidence

Nonselective antiangiogenesismultikinase agents:sorafenib, sunitinib, andpazopanib

Hyperkeratotic handefootskin reaction

Prevention: pretreatmentevaluation with podiatrist,orthopedic shoe inserts

III

Management IIIGrade I: emollients and keratolyticsGrade II: add topical steroids(class I/II) and topical anesthetics,nonsteroidal antiinflammatorydrugs

Grade III: add antiseptic soaks;treatment interruption

Inflammatory eruptions Topical steroids (class III/IV) or shortcourse of systemic steroids

IV

Hair changes: alopecia,kinking, anddepigmentation

Generally reversible after treatmentis stopped

IIB

Concealment measures, minoxidil5% foam, and frequent clipping

IV

Level of evidence: IA evidence includes evidence from metaanalysis of randomized controlled trials; IB evidence includes evidence from at

least 1 randomized controlled trial; IIA evidence includes evidence from at least 1 controlled study without randomization; IIB evidence

includes evidence from at least 1 other type of experimental study; III evidence includes evidence from nonexperimental descriptive studies,

such as comparative studies, correlation studies, and case control studies; IV evidence includes evidence from expert committee reports or

opinions or clinical experience of respected authorities, or both.

EGFR, Epithelial growth factor receptor; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.

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dephosphorylation with menadione (vitamin K3)results in decreased keratinocyte toxicities.20

Cutaneous AEs in patients who are taking EGFRinhibitors range in incidence from 50% to 90%21 andinclude a spectrum of toxicities. The most prevalentreactions are papulopustular eruption, xerosis, hairchanges, mucositis, and paronychia.

Papulopustular eruptionThe eruption of papules and pustules in a

seborrheic distribution is the most common andearliest cutaneous side effect of anti-EGFR agents(Fig 2), occurring in a dose-dependent fashion in[75% of patients after 1 to 2 weeks of therapy.22,23

Although commonly described as acneiform,24 theeruption lacks comedones and nodulocysts and,unlike acne, is commonly associated with pruritus.25

Perhaps the best nomenclature is papulopustulareruption in a seborrheic distribution, to avoidconnotation of an acne-like process—largelybecause the treatments differ.12,25

The eruption consists of folliculocentric pruriticpapules evolving into pustules that may coalesceinto lakes of pus involving the head, neck, trunk, andproximal upper extremities. Rupture of thesepustules may lead to crusting and hyperkeratosis(Fig 3). Grade severity is based on the body surfacearea (BSA) involved and degree of limitation inperforming activities of daily living (ADL).10 Severe

eruption occurs in\10% of patients.23,26 The histo-pathologic results reveal aseptic suppurative follicu-litis15; however, the epidermal disruption associatedwith evolving papules and pustules often leads tobacterial superinfection. While generally occurringwithin the first weeks of therapy, in a subset ofpatients the eruption can appear after $ 3 weeks oftreatment.27 Dose-escalation and reinitiation of ther-apy24 have been reported to accentuate flares.Although photoexposure has been reported toaggravate the flares28 (Fig 2), sunscreen use in aplacebo controlled trial did not prevent or attenuateEGFR inhibitoreinduced eruption.29 Sites treatedwith previous radiation are typically spared,30 likelybecause of radiation-induced adnexal unit drop-out.Although a history of seborrhea has not been linkedto a greater risk of severe eruption,24 there may be acommon genetic predisposition to developing follic-ulitis and responding to EGFR-directed treatment.31

Durable postinflammatory hyperpigmentation canoccur, especially in patients with darker skin.12 Anelevated plasma creatine kinase level has beenlinked to rash severity, and may have potential inpredicting which patients develop severeeruptions.32

Treatment of papulopustular eruption. Be-cause the development of this eruption and itsseverity directly correlate with tumor response toEGFR blockade and overall survival,18,33 patients

Fig 1. Molecular signaling pathways. Targeted agents listed are meant to be representative andare not intended to be all-inclusive for targeted agent families. GF, Growth factor; RTK, receptortyrosine kinase; SHh, sonic hedgehog; SMO, smoothened.

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should be counseled to expect some degree ofinflammatory eruption. Management with topicaland/or systemic modalities is based on the extentof the eruption and degree of patient discomfort. Sunprotection may help, especially in patients withFitzpatrick skin types I to III.28 Hot water bathswere reported to exacerbate the eruption and shouldbe avoided.34 Pruritus is a commonly associatedcomponent of the rash,35 and can be alleviatedwith antihistamines (eg, cetirizine, loratadine, andhydroxyzine). When severe, the authors find titratingdoses of doxepin most useful.

Grade 1 eruptions (\10% BSA with or withoutpruritus10) may bemanaged successfully with topicalmedications alone, including antibiotics, antiseptic

creams, and/or low potency topical corticoste-roids,25,36 although the latter are typically reservedfor use on the scalp because facial use may haveuntoward effects on the eruption.25 Topicalcalcineurin inhibitors are helpful antiinflammatoryagents,37 yet their regular use is hampered by irritantpotential, off-label use, and cost. Because theeruption lacks comedones, comedolytics, such asretinoids, are not indicated and can be irritating.38

Menadione (vitamin K3) may be a useful topical toolin the future20 but is not yet commercially available.Nonacneigenic makeup may be recommended as acamouflage measure.

Grade 2 and 3 eruptions ($ 10-30% BSA, tender-ness, pruritus, and/or superinfection10) often require

Fig 2. Papulopustular eruption associated with epithelialgrowth factor receptor inhibitors. A, Papules and pustulesare present in a seborrheic and photoexposed distribution.B, High-power view of follicle-centered papules of thechest and abdomen.

Fig 3. Papulopustular eruption and alopecia associatedwith epithelial growth factor receptor inhibitors. Pustulerupture and subsequent crusting and hyperkeratosisoccurring on the scalp associated with ivory white plaquesof scarring alopecia.

Fig 4. Hair changes associated with epithelial growthfactor receptor inhibitors. Note the acquired course textureand kinkiness of the scalp hair.

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systemic treatment. Tetracyclines are consideredfirst-line agents and are likely active through theirantiinflammatory properties.12 Given the higherprevalence of bacterial superinfection withStaphylococcus species than in acne vulgaris,24

cyclines likely also play an antimicrobial role.However, the prophylactic use of tetracyclines maynot result in attenuation of eruption severity,39

contrary to previous reports.38,40 Regional suscepti-bility patterns of Staphylococcus species may requireuse of penicillinase-resistant beta-lactam antibiotics.Isotretinoin, in low doses, has been shown tobe effective.41-43 The use of systemic steroids isgenerally avoided because they may induce a similareruption.25

XerosisApproximately one-third of patients receiving

EGFR inhibitors exhibit progressive xerosis in adose-dependent fashion over weeks while ontherapy24; typically, the dryness is most pronouncedalong the extremities during months 1 to 3 oftreatment. Increased skin fragility can occur leadingto fissuring and easy bruisability.44 There may besignificant pain because of fissuring and severepruritus,35 and secondary skin infection withStaphylococcus aureus or, rarely, herpes simplexvirus can occur.25

Fig 5. Trichomegaly associated with epithelial growth factor receptor inhibitors.

Fig 6. Paronychia associated with epithelial growth factorreceptor inhibitors.

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Treatment of xerosis. Patients are instructed toavoid dehydrating skin practices and skin careproducts (ie, bath foams, shower gels, harshsoaps, and very hot water). The early initiation offrequent moisturization with a thick, bland emollientcan be preventative. Topical gels, if used in the initialtreatment of a crusted papulopustular eruption, mayultimately potentiate xerosis45,46—at which pointvehicles should be changed to creams or ointments.Attention to the appropriate balance betweenocclusive ointments, which ameliorate dryness butmay facilitate folliculitis and drying topical agents,which are soothing to acute inflammation yetexacerbate xerosis, must be kept in mind.46 In lightof recently elucidated mechanisms, the associatedpruritus may be treated with antihistamines and,when severe, the neurokinin-1 receptor inhibitoraprepitant has been successful.47,48

Hair changesChanges in hair quality, texture, and growth

pattern can be seen starting in the second or thirdmonth of treatment. The scalp hair grows moreslowly, adopts a more fine and brittle quality, andbecomes kinky49 (Fig 4). Eyelash hair changes arecharacteristic and include hairs becoming long, rigid,and thicker (trichomegaly50-56; Fig 5). Inward lashcurling may result in keratitis.57 The eyebrows may

also thicken and develop hypertrichotic spread ontothe periocular skin or glabella.58 Women may expe-rience hirsutism of the upper lip, whereas dimin-ished need for shaving of the male beard may benoticed. Alopecia is mild and usually manifested inan androgenetic hair loss pattern25; however,erlotinib-induced cicatricial alopecia and inflamma-tory nonscarring alopecia have been described59,60

(Fig 3). Poliosis has also been documented.51

Management of hair changes. Cutting of theeyelashes may be necessary to prevent keratitis.Frequent brushing helps loosen scalp hair kinkiness,making it easier to style and less brittle. Facialhypertrichosis tends to be readily reversible uponinterruption of treatment; however, depilatorycreams or laser epilation may speed clearance forthose on long-term treatment.

MucositisThe oral mucosa may develop aphthae, xero-

stoma, or geographic tongue.44 Genital involvementis less common, manifesting as vulvovaginitis,balanitis, or genital apthae. As noted, conjunctivitisand keratitis may occur.57

Treatment of mucosal toxicities. Aphthae aremanaged in a similar fashion to idiopathic aphthosiswith local therapies (ie, topical steroids, antisepticwashes, or anesthetics). Lubricants decreasediscomfort of nasal or vaginal dryness. Lubricatingeyedrops ameliorate most ocular symptomsassociated with dryness. However, ophthalmologicconsultation should be considered in cases ofchronic corneal irritation to prevent ulceration orother serious ocular complications.57

Nail changesNail toxicity is frequently encountered during

treatment with EGFR inhibitors; all-grade nail toxicityoccurred in 17.2% of patients in a recent metaanal-ysis.61 Nail changes can affect the entire nail unit,including the nail bed (onycholysis), nail fold(paronychia [Fig 6] and pyogenic granulomaelike

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lesions), and nail matrix (dyspigmentation and brittlenails).27,62-65 Nail fold inflammation may progress toappear similar to pyogenic granuloma, particularlyof the great toes; while initially sterile, superinfectionwith bacteria or fungi may occur. These changes cancause significant debilitation, necessitating doseadjustment or even temporary discontinuance ofthe targeted therapy.62

Nail treatments. Treatment measures includewet dressings, cushioning inserts within shoes topad the affected nails, topical or systemic antibiotics/antifungals, and pain control. Caution againstill-fitting shoes should be provided. Nail foldinflammation puts the nail unit at high risk ofinfection, and daily antiseptic soaks are a judiciousmeasure, as is the early application of mild tomedium potency topical corticosteroids wheninflammation is noted.66 Systemic antibiotics/antifungals may be considered when superinfectionis detected; however, because infectious organismsare not the primary etiologic factor of EGFRinhibitoreinduced paronychia, improvement maybe modest.62 A recent report showed promise withthe daily application of autologous platelet-richplasma for paronychia.67

PhotosensitivityTelangiectasia,21 hyperpigmentation,21 and

photosensitive eruption28 have been reported, sup-porting in vitro studies showing that ultravioletradiation results in altered keratinocyte survival andproliferation in the setting of EGFR blockade.68,69

Photosensitivity management. Hyperpigmen-tation gradually fades over months after treatmentis discontinued. Bleaching agents and cosmeticcamouflage may provide acceptable patient satis-faction. Dutiful sun precautions are prudent whiletaking EGFR inhibitors because photoexposuremay exacerbate dermatologic toxicities.28 Althoughtelangiectasias gradually clear after treatmentdiscontinuation, vascular light devices (ie, pulsed-dye laser or intense pulsed light therapy) orelectrocoagulation may accelerate telangiectasiadisappearance.

Long-term skin sequelaeThe AEs that most commonly persist beyond 6

months of therapy are hair changes, pruritus,xerosis, and nail inflammation. Although mostpatients experience resolution of the papulopustu-lar eruption, in some patients it may persist beyond6 months.

Management. Long-term cutaneous toxicitiesmay significantly alter a patient’s quality of life70

and may be dose-limiting. Close collaboration in a

multidisciplinary fashion, particularly between thetreating oncologists and dermatologists, canpromote successful long-term management andprevent dose decreases or drug discontinuation inmost instances. Debilitating pruritus may bemanaged with aprepitant.27,35,47

KIT AND BCR-ABL INHIBITORSKey pointsd Among the oldest targeted inhibitors, block-ing agents of KIT and BCR-ABL have beendescribed to cause a series of cutaneoustoxicities, including a broad spectrum ofinflammatory eruptions

d Most adverse effects in this class aredose-related and reversible after drugdiscontinuation

Imatinib, nilotinib, and dasatinib are inhibitors oftyrosine kinases generated from the bcr-abl fusionprotein, c-Kit, and platelet-derived growth factorreceptors (PDGFRs). The bcr-abl protein is the resultof chromosome 9:22 translocation found in chronicmyelogenous leukemia (CML), while the majority ofgastrointestinal stromal tumors (GISTs) have aconstitutively active c-Kit receptor. PDGFR kinasesare involved in some types of hypereosinophilicsyndrome and chronicmyelomonocytic leukemia. Inaddition to the common use of KIT and bcr-ablinhibitors in these settings, efficacy of this class ofagents was documented in dermatofibrosarcoma,systemicmastocytosis, AIDS-related Kaposi sarcoma,and KIT-mutated melanoma.6,71,72 Cutaneous AEsare the most frequent nonhematologic sequelae ofthis family and are generally not severe.

EdemaFacial edema, sometimes accompanied by

severe weight gain,73 may appear in the majorityof patients74-76 in a dose-dependent fashion.75

Modulation of interstitial fluid homeostasis fromPDGFR inhibition is likely contributory to the fluidcollection,77 and diuretics may be required ifsevere.78 Edema mimicking dermatomyositis hasbeen described.79

Morbilliform eruptionA majority of patients will develop a pruritic

generalized morbilliform eruption that begins onaverage 9 weeks after treatment initiation.80,81

Rarely, the eruption may be severe (grade 3 or 4).80

Female sex and imatinib were independent riskfactors of a morbilliform eruption after multivariateanalysis in 1 study.75

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Pigmentary changesDyspigmentation associated with imatinib use

has been described in a localized, patchy, ordiffuse distribution. This is consistent with thedocumented role of c-kit in the physiology ofmelanocytes, regulating melanogenesis, prolifera-tion, migration, and survival.82,83 Patients with darkerskin are generally more heavily affected.6,80

Hypopigmentation of the skin, which also mayinclude the hair,84,85 is more common than increasedpigment change.86 Worsening of preexisting vitiligohas been described.87 Onset is 4 weeks on average,74

and the changes are generally reversible afterdiscontinuation of the drug.78

Other inflammatory eruptionsReports have linked the new-onset or exacerbation

of preexisting eruption of many inflammatory skinconditions to the use of imatinib, nilotinib, anddasatinib. These include lichenoid reactions,88-95 pso-riasis,75,96,97 pityriasis roseaelike eruption,98-100 acutegeneralized exanthematous pustulosis,101-103 DRESSsyndrome,104 StevenseJohnson syndrome,73,105 urti-caria,86 acute neutrophilic dermatosis,106-108 photo-sensitivity,75,109 pseudolymphoma,110 porphyriacutanea tarda,111,112 small vessel vasculitis,113

panniculitis,75,113,114 perforating folliculitis,115 anderythroderma.116-121

AlopeciaAlopecia is listed in the package insert of nilotinib;

however, the clinical and histologic features areincompletely described. One report noted general-ized alopecia with histologic findings of a scarringprocess.122

Treatment considerations. Cutaneous effectsof this drug family are generally reversible, and localtreatment measures can abate symptoms, preventingtargeted treatment interruption. Severe or persistentdose-dependent manifestations may require a dosereduction or temporary stoppage.

ANTIANGIOGENESIS AGENTSKey pointd The inhibition of angiogenesis also affectsnormal skin homeostasis, leading to muco-cutaneous hemorrhage and poor woundhealing

While endothelial cells in normal tissue aretypically not mitotically active,123 neoplastic tissuefeatures high cellular turnover and rapid growthcapacity. Neovascularization is an important elementto maintaining oxygen supply to the rapidlyproliferating neoplastic cells. More than 30 growth

factors involved in the promotion and inhibition ofangiogenesis have been identified.124 Vascularendothelial growth factor (VEGF) and the VEGFtyrosine kinase receptor system play an integral rolein this process. Activin receptor-like kinase-1 (ALK1)has also emerged as a potential target in anti-angiogenesis treatment of cancer.125 The selectiveblockade of VEGF using monoclonal antibodieshas been available to oncologists since bevacizumabwas approved by the US Food and DrugAdministration in 2005. Along with ranibizumab,which was released in 2007, VEGF inhibitors arealso used intravitreally for the treatment of maculardegeneration.

VEGF inhibitors result in a decreased number ofendothelial cells and the decreased formation ofmicrocapillaries within tumor tissue. In addition,vascular permeability is impaired, thereby indirectlyinhibiting tumor growth.126 Because these mecha-nisms are also critical to maintaining normal tissuehomeostasis, it is not unexpected that therapeuticVEGF inhibition would also be associated withuntoward mucocutaneous side effects.

Mucocutaneous hemorrhageBecause of the effect of VEGF inhibitors on

vascular permeability and proliferation, their usemay result in mucosal bleeding and/or cutaneoushemorrhage.127 Mild mucosal bleeding, mostcommonly manifesting as epistaxis, is seen in 20%to 40% of patients who are taking bevacizumab.128

Initiation of VEGF inhibitor treatment is notrecommended in the presence of skin and/ormucosal hemorrhage.

Disturbed wound healingInhibition of the VEGF pathway can disrupt

wound repair and result in delayed wound healingin a dose-dependent fashion128 and fistula forma-tion.129 This becomes a consideration for surgicalplanning in both the adjuvant and neoadjuvantsettings.130,131

MULTIKINASE INHIBITORSKey pointsd Multikinase inhibitors affect many tyrosinekinase systems and result in a vast array ofskin-related adverse effects

d Handefoot skin reaction is a poorly under-stood painful complication that oftennegatively affects drug dosing; treatmentsfor handefoot skin reaction are limited

d Inflammatory, appendageal, and neoplasticskin toxicities overlap with other drugcategories

Fig 7. Hyperkeratotic handefoot skin reaction of sorafenib. Hyperkeratotic plaques overlyingpoints of pressure on the (A) hands and (B and C) feet.

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Sorafenib, sunitinib, pazopanib, and vandetanibare small molecule inhibitors of the tyrosine kinaseactivity of the intracellular portion of the VEGFreceptor. They also inhibit other tyrosine kinasereceptors, such as PDGFR, EGFR, KIT, RET, Flt3,and RAF. As such, many of the cutaneous sideeffects observed with their use overlap withthose described elsewhere of more target-specifictherapies. Focus on the findings unique to thesemultikinase inhibitors will be made in this section,with only a brief mention of the overlappingfeatures.

Hyperkeratotic handefoot skin reactionHyperkeratotic handefoot skin reaction (HFSR) is

a painful complication seen most frequently duringthe early weeks of use with sorafenib (all grade,10-63%; grade $ 3, 2-36%),132-138 sunitinib (allgrade, 10-28%; grade $ 3, 4-12%),139-142 andpazopanib (all grade, 11%; grade $ 3, 2%).143

Hyperkeratotic plaques develop predominantlyover sites of pressure or friction (Fig 7, A and B).Plaques may have significant inflammation144 andxerotic hyperkeratosis, often in a bilateral symmetricdistribution,145,146 causing pain and debilitation thatinterfere with activities of daily living.147 Sequentialbiopsy specimens reveal progressive accumulationof hyperkeratosis with focal parakeratosis.148 HFSRdoes not appear to be related to increased excretionof the agent through sweat149; rather, the pathogen-esis is likely related to VEGF inhibition/vesselregression and negative effects on trauma-inducedvascular repair capacities.150

Management strategies. Patients should beinformed of this dose-dependent reaction, andpreventative measures should be instituted fromthe onset of treatment. Pretreatment evaluationwith a podiatrist is useful to treat preexistinghyperkeratotic plaques and prescribe orthopedicsoles along with wide, flexible shoes. Keratolytic

agents,151 pyridoxine,152 or systemic agents, such asretinoids,153 have not been successful in preventingHFSR.

Should HFSR occur, treatment considerations12

include the following: grade 1 (minimal skin changeswithout pain): emollients, keratolytic creams, and gelor foam-based shoe inserts—no dosage adjustment istypically needed; grade 2 (skin changes with painlimiting instrumental ADL): potent topical corticoste-roids applied consecutively for 7 to 10days in additionto treatment measures for grade 1 toxicity—targetedtreatment dose reduction by 50% should be consid-ered; and grade 3 (severe skin changes with debili-tating pain limiting self-care ADL): in addition totreatment measures for grade 2 HFSR, patients shouldperform local antiseptic baths of blisters and ero-sions—targeted treatments should be interrupted forat least 1 week, and only resumed at a reduced doseafter recovery of toxicity to grade 0 or 1.

Inflammatory eruptionsSkin eruptions of varying morphology have been

described in the early weeks after initiation ofsorafenib (all grade, 10-60%), sunitinib (all grade,13-24%), and pazopanib (all grade, 6-8%).Morbilliform eruptions beginning on the facewith centripetal spread are most common, butchloracne-like eruption,154 erythema multiformeelike eruption,155 toxic epidermal necrolysis, anddrug hypersensitivity syndromes have beenreported.12

Hair changesHair changes in texture, density, and color can be

seen with multikinase inhibitors. Alopecia occurs inup to 44% of sorafenib patients,144,156 but lessfrequently with sunitinib (5-21%)12 and pazopanib(8-10%).143,157,158 Reversible hair depigmentation isseen during therapy with sunitinib (7-14%)159-161 andpazopanib (27-44%).143,158 Cutaneous depigmentation

Fig 8. Genital eruption associated with sorafenib. Notethe psoriasiform plaques on the scrotum and groin.

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VOLUME 72, NUMBER 2Macdonald et al 213

may also be seen with pazopanib.12 Changes inpigmentation of the hair and skin are felt to be relatedto c-KIT inhibition159; however, it may not be a directeffect on the KIT receptor.12,162

Genital involvementLocalized eruptions involving the scrotum or

vulva extending onto inguinal skin may occur,including erythematous, psoriasiform, lichenoid,and desquamative forms163,164 (Fig 8). Penileinvolvement may result in phimosis.12

OtherReversible yellow discoloration of the skin can be

seen in patients who are undergoing sunitinibtreatment,165 possibly because of cutaneousdeposition. Sunitinib may induce facial edema166

and pyoderma gangrenosumelike ulcerations.167

Eruptive nevi may occur with sunitinib or sorafe-nib.168-170 Sorafenib may induce hyperkeratoticsquamoproliferative lesions similar to those seenwith BRAF inhibitors.171-178 Asymptomatic subun-gual splinter hemorrhages are commonly seen inboth sorafenib and sunitinib patients.164 Acutefolliculitis, xerosis, photosensitivity, and thedevelopment of blue-gray macules of dyspigmenta-tion may occur with vandetanib.146 As a general rule,these are reversible effects after treatment isdiscontinued.

CONCLUSIONCutaneous adverse effects are among the most

frequently observed, with many targeted therapies.Dermatologists can provide a useful role in earlyrecognition and mitigation of skin-related toxicities,thereby influencing the need for dose-reduction ordrug discontinuation. With continued expansion ofthe family of targeted therapies, providers caringfor those with cutaneous conditions will becomeintegral components to the multidisciplinary teamapproach of oncologic care.

We thank Lisa Litzenberger for her generousassistance in the preparation of the images in thisarticle.

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