EGFR-Targeted Therapy and Related Skin Toxicity

OT

w

r

w

i

u

a

t

DP

v

c

CT

i

R

m

m

a

s

p

IPW

i

s

t

a

p

t

s

o

t

f

CwEsslm

sswsTawc

SlidEkt

B

NDPnD

RBe

©0d

152 Seminars in Oncology Nursing, Vol 22, No 3 (August), 2006: pp 152–162

BJECTIVES:o discuss the mechanism by

hich epidermal growth factor

eceptor (EGFR)-targeted agents

ork, the resulting cutaneous tox-

cities, the pathophysiology of the

nique rash associated with these

gents, and the management of

hese skin problems.

ATA SOURCES:ublished scientific papers, re-

iew articles, book chapters, and

linical experiences.

ONCLUSION:hese new targeted agents result

n unique cutaneous toxicities.

esearchers and clinicians have

ade numerous suggestions for

anaging the various side effects,

lthough there is currently no re-

earch to guide evidence-based

ractice.

MPLICATIONS FOR NURSING

RACTICE:ith any new treatment option, it

s imperative that nurses under-

tand how agents work to enrich

heir own knowledge base, as well

s have a strong foundation for

atient education. It is important

hat nurses understand potential

ide effects of these agents, know

f possible interventions, and par-

icipate in research to identify ef-

ective interventions.

From Dana-Farber Cancer Institute,oston, MA.Linda Morse, RN, MSN: Clinical Research

urse, The Lowe Center for Thoracic Oncology,ana-Farber Cancer Institute, Boston, MAamela Calarese, RN, MS, CS: Nurse Practitio-er, The Lowe Center for Thoracic Oncology,ana-Farber Cancer Institute, Boston, MAAddress correspondence to Linda Morse,

N, MSN, Dana-Farber Cancer Institute, 44inney St, LG1B12, Boston, MA 02115;-mail: [email protected]

2006 Elsevier Inc. All rights reserved.

bd

749-2081/06/2203-$30.00/0oi:10.1016/j.soncn.2006.04.005

EGFR-TARGETED

THERAPY AND

RELATED SKIN

TOXICITY

LINDA MORSE AND PAMELA CALARESE

ANCER therapy has received tremendous benefitfrom recent discoveries in the field of molecularbiology. This has led to new agents that allow usto exploit characteristics unique to malignantcells. Among these are molecular therapies,

hich target the human epidermal growth factor receptor (HER1/GFR). EGFR is one of the most widely studied and best under-tood of the HER family of targets. It is also over-expressed ineveral cancers, particularly colorectal cancer and non–small cellung cancer, suggesting that it has some role in tumor develop-

ent.1

The new agents are generally well tolerated, with a unique set ofide effects and toxicities. They do not produce the myelosuppres-ion, severe nausea and vomiting, or total alopecia often associatedith traditional chemotherapy. Their side effect profile is more

pecifically directed against the skin and gastrointestinal tract.hese side effects can have a devastating effect, and preventionnd treatment are critical in promoting quality of life.2 This articleill address cutaneous toxicity, the most common toxicity asso-iated with EGFR inhibition therapy.

HER1/EGFR INHIBITION

ignal transduction is the chemical system responsible for cel-lular communication. Cells receive extracellular and intracel-

ular signals that direct them to carry out certain functions,ncluding differentiation, division, and apoptosis or cellulareath.3,4 Signals are transferred across the cell membrane. HER1/GFR is one member of a family of membrane receptor tyrosineinases (TK) known as the HER family.1 HER1/EGFR is a proteinhat crosses the cell membrane. It has three domains: a ligand-inding receptor domain that is extracellular, a transmembrane
omain that attaches the receptor protein to the cell and carries

sdc

ggtttcomc(atmtHtucbgm

cbfn

tapoot

itmamtSmactl(pk

lNttoatsi

tiiomscaotkartmt

FtHilgtpaacn

EGFR-TARGETED THERAPY-RELATED SKIN TOXICITY 153

ignals from outside to inside the cell, and a TKomain that is located in the cytoplasm of theell.1,3,5

In any cell, normal or malignant, binding of therowth factor receptor by a ligand (epidermalrowth factor or transforming growth factor-� inhe case of HER1/EGFR) leads to the binding ofwo receptors (dimerization), and activation ofhe TK receptor, starting a cascade of complexhemical events (the intracellular signal pathwayr signal transduction). These signals are trans-itted to the cell nucleus where processes such as

ell proliferation and differentiation, apoptosisprogrammed cell death), angiogenesis, adhesion,nd motility are regulated.4–6 Normally, these ac-ivities are very carefully controlled. However,utations of the receptors or overexpression of

he targets can lead to inappropriate activation ofER1/EGFR or dysregulation.7 The result is sus-

ained phosphorylation (stimulation) and contin-ally activated signal transduction pathways. Thisontinued stimulation results in the characteristicehaviors of malignant cells: uncontrolled cellrowth and proliferation, inhibition of apoptosis,etastasis, and angiogenesis.1,3,5,6,8,9

Regulation of tumor growth is a complex pro-ess. The advent of targeted therapies and tumoriology has highlighted the importance of growthactors and their receptors in the mechanism ofeoplastic growth and metastasis.10

In general, signaling can be blocked in one ofhree ways: regulating downstream signaling fromreceptor by changing the activity of messenger

roteins, inhibiting the expression of the receptor,r decreasing the amount of ligand available. Mostf the progress in this area has been in the firstwo categories.1

Agents designed to inhibit HER1/EGFR signal-ng can be divided into two broad classes. Agentshat target the extracellular ligand-binding do-ain of the molecule are known as large-molecule

nti-EGFR monoclonal antibodies (MOA). MOAsay interfere with receptor binding or dimeriza-

ion. Trastuzumab (Herceptin; Genentech Inc,outh San Francisco, CA) acts against anotherember of the HER family, HER2, by this mech-

nism. MOAs such as cetuximab bind to the re-eptor, thereby preventing binding of the ligand tohe same receptor. MOAs may also bind to theigand and prevent ligand binding to the receptorsee Fig 1). Substances that target the intercellularortion are called small-molecule EGFR-tyrosine
inase inhibitors (TKIs).1,3,11,12 These agents, er- T
otinib (Tarceva; OSI Pharmaceuticals, Melville,Y) and gefitinib (Iressa; AstraZeneca, Wilming-

on, DE), act by competing with adenosineriphosphate (ATP) binding at the TK site. An-ther approach is to form conjugates of a ligand orntibody and a cytotoxic agent.13 There is inves-igation into the combination of inhibitors, andtudies suggest that combinations may lead tomproved antitumor activity.12

By exploiting what we know about signalransduction, a variety of processes character-stic of malignant growth can theoretically benterrupted if the external HER1/EGFR domainr the TK domain are blocked.1,6,11 TKs act asessengers that ultimately influence gene tran-

cription in the nucleus, regulating fundamentalellular processes such as the cell proliferationnd differentiation, motility, and apoptosisr survival.9,14 Although they were originallyhought to be a separate process, it is nownown that there is a link between HER1/EGFRnd angiogenesis.11 Activation of HER1/EGFResults in stimulation of VEGF (vascular endo-helial growth factor) and production of matrixetalloproteinases, enzymes that break down

he surface of the cells lining the capillaries.

IGURE 1. Examples of ways to target EGFR. From lefto right: Antibodies such as trastuzumab may inhibitER2 receptor dimerization. Antibodies such as cetux-

mab may act as receptor antagonists, preventing EGFRigand binding. Antibodies against ligand may block li-and-receptor binding. Small molecules, such as erlo-inib or gefitinib, target and inhibit TK activity by com-eting with ATP. Conjugates of a ligand or antibody andcytotoxic agent may kill the cell and/or inhibit TK

ctivity. (Reprinted with permission.13 Color illustrationsan be viewed at the journal’s website at www.ursingoncology.com.)

his promotes the development of new blood

http://www.nursingoncology.com


vgHdt

ctvUtbchtwt

bAtFaGnsbpfsTb

Raddotcwt9i

fias

dt2ddnsmcnto

trtf

FptwCw

154 L. MORSE AND P. CALARESE

essels for the nourishment of the tumor (an-iogenesis) necessary for cancer survival.1,6,11,15

ER1/EGFR is also known to stimulate the pro-uction of an “anti-apoptotic” protein that in-erferes with cell death.1,6,11

One MOA that targets HER1/EGFR is commer-ially available: cetuximab (Erbitux; ImClone Sys-ems Inc, Somerville, NJ), which is injected intra-enously. Cetuximab is presently approved by theS Food and Drug Administration (FDA) for the

reatment of metastatic colorectal cancer and iseing tested in clinical trials against other can-ers, especially non–small cell lung cancer andead and neck cancer. Again, this MOA binds tohe extracellular HER1/EGFR receptor, competingith the EGF ligand and interfering with signal

ransduction.5,16

Small-molecule TKIs cross the cell membrane andind to the intracellular TK, prevent binding withTP, and interrupting the signaling pathway. All are

aken orally. Two agents have been approved by theDA for the treatment of non–small cell lung cancer,lthough they are being tested in other cancers.6

efitinib is currently available to only a limitedumber of patients who have previously shown re-ponse after a clinical trial failed to show a survivalenefit over placebo. However, it is clear that certainatients do respond to this agent. Clinical trials tourther define this group continue.17 Erlotinib is theecond EGFR-TK inhibitor approved by the FDA.his agent also interferes with ATP/TK binding,locking signaling within the cell.6,9

RASH ASSOCIATED WITH HER1/EGFRTARGETED THERAPY

ash is the most common adverse event asso-ciated with these therapies. It is an important

nd often distressful side effect. The exact inci-ence is complicated by lack of consistency in theescriptive terminology. Incidence is in the rangef 45% to 100%.14,18–20 In clinical trials with erlo-inib, rash occurred in 76% of patients who re-eived erlotinib compared with 17% of patientsho received placebo. Rash led to a dose reduc-

ion in 12% of patients.20 Rash was apparent in0% of patients who received the MOA cetux-mab.14,16

With the oral EGFR inhibitors, the time fromrst dose of drug to the development of rash is anverage of 8 to 10 days, reaching maximum inten-
ity in 2 weeks. With cetuximab, the time to i
eveloping grade 1, asymptomatic rash was lesshan 1 week.21,22 Rash is generally mild, grade 1 or. Rash can also be severe, requiring reduction ofrug dose or withdrawal of treatment. The inci-ence of grade 3 rash is not more than 13%, witho grade 4 (life-threatening) rashes reported. Theeverity of rash seems to be dose-dependent, withilder rash perhaps indicating lower plasma con-

entrations of drug.19 Several researchers and cli-icians have observed a positive correlation be-ween the presence of rash and clinical responsef the tumor.14,23–28

The rash has an acneiform appearance, charac-eristically papular/pustular. Figure 2 presentsashes characteristic of patients receiving gefitinibherapy.29 The distribution is similar to acne (eg,ace, scalp, chest, upper back). Typically appear-

IGURE 2. Moderate and severe rashes that occur inatients receiving gefitinib. The rash occurs especially onhe face, back, and chest and will regress if the drug isithheld or dose decreased. (Reprinted with permission.29

olor illustrations can be viewed at the journal’s website atww.nursingoncology.com.)

ng about 1 week after beginning therapy, the rash


tthdgiaq

ToEaid

amgudwosm

HtclrpEcoclpimen

vcfstl

ntffrii

liiabctuHitfwat

Rataltameiptvar

Aoofintos


ends to improve, and waxes and wanes as long asherapy continues. Many patients report the rashas an intermittent “flare” quality, whereby oneay it will be more prominent than on anotheriven day. It is not clear why there are differencesn the duration of rash.19,22,30 The limbs, scalp,nd buttocks can also be involved, but less fre-uently.31

Little is known about the etiology of the rash.here are also no clear evidence-based guidelinesn how to treat the rash, although as use of HER1/GFR-targeted agents becomes more commonnd they are used earlier in disease, it becomesncreasingly important to develop successful evi-ence-based interventions.19

Recently the HER1/EGFR Inhibitor Rash Man-gement Forum, a group of oncologists and der-atologists with experience in HER1/EGFR-tar-

eted agents, was convened to try to betternderstand the problem and to make recommen-ations for management of the rash.18 This reviewill include several of their observations and rec-mmendations, those of other clinicians and re-earchers, as well as our clinical experiences inanaging these side effects.

RASH PATHOPHYSIOLOGY

ER1/EGFR is expressed in the skin. Particularareas include the basal layer of the epidermis,

he outer root sheath of the hair follicle, the seba-eous epithelium (sweat glands), eccrine epithe-ium, dendritic antigen-presenting cells, and a va-iety of connective tissue cells. These areas areotential targets.18,32–34 The exact role of HER1/GFR in skin is not understood.19 However, it islear that the use of EGFR inhibitors had an effectn skin tissue. In a study of 56 skin specimensollected from 28 patients receiving OSI-774 (er-otinib), there was a significant decrease in phos-ho-EGFR expression in 30% to 50% of patients,ndicating biological effects in the normal epider-

is. There was no change in the thickness of thepidermis, although thinning of the stratum cor-eum was observed.35,36

Microscopically, the rash is characterized byarious inflammatory changes. Early changes in-lude infiltration of T lymphocytes around theollicular infundibulum. This can be followed byuperficial lymphocytic perifolliculitis or suppura-ive superficial folliculitis, perhaps because of fol-
icular rupture. Pustules contain collections of i
eutrophils within the follicles, such as in infec-ious folliculitis. While cultures do not reveal in-ection, the area may become secondarily in-ected. There is no association between severity ofash and type of skin or a history of acne. Changesn the skin are thought to be a direct result ofnterference with the signal pathway.14,21,22

The rash may be a new dermatologic entity. Un-ike acne vulgaris, the sebaceous glands are notnvolved.37 The rash is not associated with the non-nflammatory comedones that are characteristic ofcne vulgaris. The HER1/EGFR rash is characterizedy pustules, which if severe, develop a “honey-ombed” crust. Many of the terms used to describehe rash suggest that it is similar to acne. Frequentlysed terms include acne, acne-like, and acneiform.owever, this inflammatory rash is different. Given

ts unique characteristics, it is not surprising thatreatments developed for acne do not generally workor the HER1/EGFR rash. The use of these terms,hich suggest a particular etiology, have confusednd may continue to be confused in the litera-ure.18,19,38

Recommendations of the HER1/EGFR Inhibitorash Management Forum include the use of moreccurate terms to describe this new rash. Sugges-ions include phenotypic, descriptive terms suchs pustular/papular rash, pustular eruption, or fol-icular and intrafollicular pustular eruption. Usinghese more accurate terms, the rash has a char-cteristic pustular/papular appearance. It is com-only accompanied by dry skin, pruritis, and

rythema. Although the pustules are usually ster-le, secondary infections are more common thanreviously thought.14,18 Research is needed to fur-her define how this rash is different from acneulgaris, why it occurs in this particular location,nd what factors determine the severity of theash.18

OTHER CUTANEOUS TOXICITIES

lthough rash is the most common skin toxic-ity related to HER1/EGFR-targeted therapy,

ther manifestations of cutaneous reactions canccur. These include pruritus, dry skin, hand/nger/heel fissures, palmar/plantar desquamation,ail and cuticle cracking (paronychial inflamma-ion), nasal ulcers, and vaginal dryness. Pruritus isften associated with rash.38 We have also ob-erved changes in the hair, including thinning,
ncreased curliness, and aberrant hair and lash

gw

Ttcoqwattctgrrsd2fmdtRti

ratou

SrpiDlm(gtcAUocl

gmc


rowth.14,39 These changes are more commonith the EGFR-TKIs than the MOA agents.14

COMMON TOXICITY CRITERIA GRADING

he common toxicity criteria (CTC) grading forcutaneous toxicity related to EGFR-targeted

herapies is inadequate.14,18 Table 1 lists the CTCategories relevant to HER1/EGFR-related cutane-us toxicities. Several categories do not ade-uately describe cutaneous toxicities associatedith these therapies. For example, the fissuresnd pain associated with paronychial inflamma-ion often seen with treatment are not captured byhe category of “nail changes.” Perhaps a new CTCategory is required. Patients may develop rashhat, although only grade 2 in severity on the CTCrading criteria, is intolerable to the patients andequires dose reduction.22 Changes to the CTC forash have been suggested, with grade 2 rash beingubdivided into two categories: grade 2A would beefined as a symptomatic rash (tolerable); gradeB would be defined as a symptomatic rash, inter-ering with daily life with intervention/manage-

ent perhaps indicated; grade 3 would clearlyefine when the rash has reached dose-limitingoxicity and whether treatment should be held.ash intensity would be the primary element of

he grading system rather than the body area

TABCommon Toxicity Criteria Relevant to

Grade 1

Rash: acne/acneform

Intervention not indicate

Rash/desquamation Macular or papulareruption or erythemawithout associatedsymptoms

Dry skin AsymptomaticNail changes Discoloration, ridging,

pittingPruritus/itching Mild or localizedRash: hand-foot

reactionMinimal skin changes o

dermatitis (eg,erythema) without pa

Hair loss/alopecia Thinning or patchy

nvolved. Only after clearly defining and catego- A

izing this unique rash will researchers be able toccurately describe the problem and compare in-erventions.18,19 Refinement of the categorizationf this rash is especially necessary if it is to besed as a surrogate marker for drug activity.19

NATURAL HISTORY AND INTERVENTION

kin toxicity commonly begins as dry skinwithin a week of beginning therapy. Grade 1

ash soon appears. It is asymptomatic, macular orapular with slight erythema, and usually local-zed to the face, anterior chest, and upper back.iscomfort is minimal. Patients report mild or

ocalized pruritus, which is alleviated by the use ofild soaps, such as Basis (Deiersdorf, UK), Dove

Johnson Diversey, Sturtevant, WI), or Neutro-ena (Johnson & Johnson, Princeton, NJ). Addi-ional use of bland emollients such as Eucerinream (Deiersdorf, UK) or Vaseline Intensive Caredvanced Healing lotion (Chesebrough PondsSA Co, Greenwich, CT) are a few examples ofver-the-counter products that may be benefi-ial.2,18,31 Systemic antihistamines may also re-ieve symptoms.14

The skin effects can rapidly deteriorate torades 2 and 3 in a matter of days. Patients reportoderate to severe itching, with break outs lo-

ated primarily on the face, scalp, chest, and back.

1.1/EGFR-Related Cutaneous Toxicity

Grade 2

Intervention indicated

Macular or papular eruption or erythema withpruritus or other associated symptoms;localized desquamation or other lesionscovering �50% BSA

Symptomatic, not interfering with ADLPartial or complete loss of nails, pain in nail

bedsIntense or widespreadSkin changes (eg, peeling, blisters, bleeding,

edema) or pain, not interfering withfunction

Complete

LEHER

d

r

in

s these symptoms progress, patients can become

opaistq

oaipitEanactbsscrosf

S

cneSgsq

Ddhsassuobt

ouaIecwgt

te, J


verwhelmed by their appearance. If the rashroduces severe generalized erythroderma withssociated macular or vesicular eruption, as seenn grade 3 toxicity, patients also report pain andometimes fevers. Measures need to be institutedo treat these symptoms efficiently and maintainuality of life.40

There are no published controlled clinical trialsn the optimum treatment for skin effects associ-ted with the HER1/EGFR inhibitors. Many of thenterventions are based on individual clinical ex-erience and patient response. Interventions maynclude alcohol-free skin lotions and emollients toreat dryness. Immunomodulatory creams such aslidel (Novartis, Cidia, PR) have been used andre especially interesting given the inflammatoryature of the rash. Topical or oral antibiotics suchs minocycline,18,38,41,42 clindamycin, and tetra-ycline38 have been reported to be beneficial inhe treatment of pustular lesions. Systemic anti-iotics are prescribed for individuals who developevere erythroderma with associated fever fromecondary infections. Secondary infections typi-ally produce changes in the appearance of theash. There may be yellowish crusting with oozingf secretions from eruptions. These lesions can beeen in the nares, outer ear canals, and any skinold.2,18

The benefit of topical steroid use is unclear.18,41

TABCon

Grade 3

Associated with pain, disfigurement,ulceration, or desquamation

Severe generalized erythroderma ormacular, papular, or vesiculareruption; desquamation covering�50% BSA

Interfering with ADLInterfering with ADLIntense or widespread, interfering

with ADLUlcerative dermatitis or skin

changes with pain interfering withfunction

___

Abbreviations: BSA, body surface area; ADL, activities of daData from Common Terminology Criteria for Adverse EvenServices, National Institute of Health, National Cancer Institu

teroids as treatment for rashes associated with e

etuximab or HER1/EGFR inhibitors is generallyot recommended because they have not shownfficacy and may even promote super infections.ystemic steroid use may be warranted in severerade 3 and 4 skin toxicity. However, the course ofteroids should be brief to prevent long-term se-uelae associated with their use.2

Rash can be covered with makeup such asermablend (HSN, St Petersburg, FL) or any foun-ation the patient finds helpful. Although makeupas not been found to exacerbate rash, patientshould be instructed to effectively cleanse the skinnd to remove makeup with gentle cleansers. Ifun exposure aggravates the rash, a good sun-creen should be used daily. Medications normallysed to treat acne vulgaris, such as benzoyl per-xide and topical retinoids, should not be usedecause they will dry the skin and may aggravatehe situation.18,31,38

As a component of the skin, the nails are quiteften affected as the course of treatment contin-es. Patients report nail and cuticle changes afterpproximately 8 weeks of continuous therapy.nitially, cuticles become slightly swollen, withrythema at the margin of the nail. This nailhange is consistent with paronychial infections,hich are acute or chronic infections of periun-ual tissues located in the tips of the digits.21 If notreated in a timely manner, the infection may

1.ed

Grade 4 Grade 5

___ Death

eneralized exfoliative,ulcerative, or bullousdermatitis

Death

___ ______ ______ ___

___ ___

___ ___

ingTCAE) Version 3.0. US Department of Health and Humanune 10, 2003.

LEtinu

G

ily livts (C

xtend under the nail and suppurate, resulting in

wqsomu

dtSlamsfpm

ttmamsatspeu(tas

mtsomossie

tlnsSa

itcfitcopTaw

Dsptwtahw6cTmapsatpnwbat

aeteiadElito

c


eeping from cracks in the cuticles. The area isuite painful and, if advanced, can have associatedtreaking into the adjacent joint. Unlike rash, par-nychia does not improve with continued treat-ent and may take weeks to heal after discontin-

ation of cancer therapy.26

Intervention is aimed at treating infection andecreasing discomfort. Hot soaks are performedhree times daily along with systemic antibiotics.oaking the affected areas in a bacteriostatic so-

ution and using topical antibiotic ointments willlso help. Epsom salt soaks are beneficial in pro-oting drainage of purulent discharge. Burow’s

olution (aluminum acetate) soaks may be help-ul. These latter measures are often instituted asart of the daily hygiene in individuals who re-ain on EGFR inhibitors.14,21,42,43

This class of agents may also cause changes inhe palmar and plantar skin surfaces. On exam,he palms of the hands and bottoms of the feetay reveal dry desquamation, although if shoes

re ill-fitting or the hands experience trauma, thisay become more inflamed and bothersome. Fis-

ures may be present in the finger creases as wells the fingertips. Interventions may include mois-urization of the skin and well-fitting shoes andoft socks. Patients should avoid carrying heavyackages. Fissures should be kept clean and cov-red. Liquid cyanoacrylate (BAND AID Brand Liq-id Bandage; Johnson & Johnson) and Crazy GlueCartell Chemical Co. Ltd, China) have been usedo protect the fissures and may promote healingnd comfort.14,38 This fissuring may be so bother-ome that dose reduction is necessary.

Interruption in the integrity of the mucousembranes is also observed in patients receiving

reatment with these agents.21 A standardized de-criptive rating system is useful for quantifyingral mucositis and following the condition of theucous membranes over time. If lesions are noted

n the buccal mucosa, tongue, and lips, with as-ociated erythema and difficulty eating or takingufficient oral fluids, a steroid elixir may be usefuln reversing these symptoms and facilitating nec-ssary nutritional intake.Patients may experience irritation and sores on

he mucous membranes inside the nostrils. Theseesions may be uncomfortable and can lead to theeed to hold or dose-reduce therapy. To preventecondary infection, Bactroban Nasal (Glaxo-mithKline, Research Triangle Park, NC) can bepplied daily inside the nostrils.18

Irritation of the eyelid is another symptom that o

s reported less often. It typically occurs withinhe first 4 weeks of treatment and starts withomplaints of dry eyes, progressing to red lids, andnally, crusting with weeping ulcerative lesions inhe eyelash follicles. The appearance is similar toonjunctivitis and can even look like a blepharitisr hordeolum. These lesions can become quiteainful, and photosensitivity is not uncommon.reatment is usually effective within a day or 2nd consists of ophthalmic antibiotic ointment,arm soaks, and natural tears.Varying grades of alopecia is also observed.uring the initial studies, alopecia was not ob-erved, but as the drugs are now being taken forrolonged periods of time, hair loss is an issuehat must be addressed. The alopecia associatedith HER1/EGFR inhibition is characterized by

hinning and is sporadic and patchy in appear-nce. Conversely, hypertrichosis (increasedair growth) is sometimes seen, especially inomen who have taken erlotinib for more thanmonths. Excessive hair growth is seen on the

heeks, chin, and in particular, the eyelashes.his development is especially disconcerting;any women will resort to shaving. Hair bleach

nd chemical depilatories further aggravate theotential for skin rash.19,39 Treatment of exces-ive hair growth is tenuous, in that one must beware of the adverse effects of the agents used toreat this issue. The best approach is laser orhotodynamic therapy, although these tech-iques are expensive. There are depilatoriesith lower concentrations of alcohol andleach, which may be better tolerated. Smallreas of skin need to be tested first to check forolerance.

Food increases the bioavailability of the oralgents, perhaps leading to increased exposure andnhanced adverse events. Patients should beaught to take pills 1 hour before or 2 hours afterating. The oral drugs are metabolized primarilyn the liver, particularly by CYP3A4. Some drugsre known to inhibit or induce CYP3A4, therebyecreasing or increasing plasma levels of theGFR inhibitor. This potential interaction can

ead to either decreased efficacy of the EGFRnhibitor, or an increase in adverse events. Pa-ients should be taught to discuss prescription andver-the-counter medications.31,42

As the use of these agents becomes moreommon, nurses need to be aware of the timing
f side effects to intervene early, thereby pro-

vi

GewSslcantc

pbuclprrtT

g(cncha

tccGh“ufiwmatSb

iwe

sihhGewdm

elollecblsl

iehaGmc

urpptethmdd

wslocc


iding patients with the optimum in good qual-ty care.

CASE STUDY

ail is a 54-year-old business executive whopresented to her primary care physician after

xperiencing intermittent upper back discomfort,hich had persisted for an indeterminate time.he attributed this discomfort to her busy travelchedule, which meant lifting heavy luggage. Re-ief of this discomfort had been moderately suc-essful, initially with the use of anti-inflammatorygents that over the course of a few months wereo longer effective. The discomfort had progressedo constant pain. Massage, physical therapy, mus-le relaxants, and narcotics were ineffective.Magnetic resonance imaging revealed a com-

ression fracture at the second thoracic vertebralody (T2). As an incidental finding, enlarged nod-les were seen. Computed tomography of thehest revealed left lung nodules with a dominanteft lower lobe mass, hilar adenopathy, as well asleural-based disease. She was referred to tho-acic surgery for evaluation and biopsy. Biopsyevealed tumor positive for adenocarcinoma cellype. The tumor cells were positive for CK7 andTF1 and negative for CK20.Gail’s medical history included seasonal aller-

ies, asthma, gastroesophageal reflux diseaseGERD), and osteoporosis. Her family history in-luded two maternal aunts with breast cancer ando family history of thoracic malignancies. So-ially, she had a history of cigarette smoking inigh school, smoking a pack per week for 1 year,nd no known asbestos exposure.After a course of palliative radiation therapy to

he thoracic spine and a recovery period, Gailonsented to begin erlotinib at 150 mg/day on alinical trial. After taking erlotinib for 10 days,ail called to report that she was “all red,” andad very itchy areas on her head and chest. Thisrash” was worse than she expected. She was seenrgently in the clinic. On exam, she had diffuseaint erythema present in the T-zone of her face,ncluding the forehead, cheeks, and chin. Thereere no lesions or pustules. Her scalp was alsoildly erythematous without lesions. Gail was re-

ssured that her symptoms were consistent withhe grade 1 skin toxicity associated with erlotinib.he was reminded to use a mild soap and to use
land moisturizers. She was also instructed to S
ncrease her oral fluids to hydrate her skin andas reassured that she could continue taking therlotinib.On day 14 of erlotinib, Gail called to report

evere burning, itching, swelling, and tendernessn multiple areas on her face. She reported thater eyes were tearing and she had lesions insideer nostrils. Because of the severity of the rash,ail was unable to go to work as she was toombarrassed by her appearance. The discomfortas interfering with sleep. She reported that it wasifficult to chew because it was painful to open herouth.Gail was again seen urgently in the clinic and on

xam was found to have marked erythematousesions that were present in a confluent mannern her cheeks, forehead, and chin. Many of theesions had exudate and some were weeping yel-owish discharge. Her scalp had multiple scatteredrythematous macules, all with yellow exudativeenters. Her nostrils were dry and crusted, withoggy, erythematous inferior turbinates noted bi-aterally. Her conjunctiva was edematous with as-ociated erythema, and her upper lids were swol-en.

After a complete blood count to evaluate fornfection, it was determined that Gail was experi-ncing a grade 3 skin toxicity. Erlotinib was with-eld, and she was started on systemic antibioticslong with an immunomodulator cream (Elidel).ail was also advised to continue washing withild soap and to use oral antihistamines to de-

rease the itching and burning.She remained off erlotinib for 1 week while

ndergoing treatment for the skin effects. Uponeturn to the clinic, her skin was markedly im-roved. The coalesced erythema that had beenresent on her face was completely resolved. All ofhe lesions were dry and crusted over without anyxudates. The nares were healed and the inferiorurbinates were also pink and non-injected. Shead returned to work and felt more like her nor-al self. She was also able to eat and drink with no

ifficulty. She was restarted on erlotinib at a re-uced dose of 100 mg/day.This dose reduction was well-tolerated for 2eeks. Gail called to report that her eyes were red,

wollen, and runny. Crusting had formed in theashes over night, resulting in her having difficultypening her eyes in the morning. She was seen inlinic and on physical exam had erythema of theonjunctiva with edematous upper and lower lids.
he was afebrile and her sclera was non-injected.

Hdactem

1h

GnrstPmvti

rPirwTbf

oaadmTNts

pgii

epretm

sosiisn

EtcidcdvapoEmfpscn

Tt

t2

E

i


er dose of erlotinib was continued at 100 mgaily. She was given a prescription for ophthalmicntibiotic ointment and instructed to use warmompresses four times each day. She was alsoaught to use daily baby shampoo washes to heryelids. Her symptoms resolved after approxi-ately 4 days.Gail continues to tolerate the dose of erlotinib

00 mg daily, and on her most recent chest scanad documented partial response to therapy.

NURSING INTERVENTION

iven the location and distribution of the ex-pected rashes, there is much that oncology

urses can do to prepare and help prevent theashes from overwhelming patients. Sunscreenhould be worn at all times, as these drugs makehe skin more sensitive to the effects of the sun.atients should be taught to use a mild soap andoisturizer as soon as they begin treatment. Pre-

ention of rash and skin dryness has been showno decrease the severity of symptoms in somendividuals.2,19,42

Once side effects begin it is imperative to accu-ately describe the rash or associated skin issues.atients may call to report a “horrible rash,” whilen the clinic their symptoms are minimal and theash is barely a grade 1. Or patients may arriveith ulcerative, oozing, erythematous pustules.hey fear that if they “tell anyone,” treatment wille withheld. This group poses a special challengeor teaching and management.

The rashes have been described as “acneiformr acne-like.” However, the manifestations associ-ted with the HER1/EGFR inhibitors do not havessociated comedones and therefore are not, byefinition, acne.19 More accurately, the lesions areacular, erythematous, or papular with pustules.he lesions can be scattered or coalesced. Theational Cancer Institute Common Toxicity Cri-

eria (NCI-CTC) rating system is the most univer-
al way of describing these symptoms to date. As A
REFEREN

n DeVita VT, Hellman S, Rosenberg SA (eds): Principles and

PW

i3

e

reviously discussed, it is important to devise arading system that more precisely captures thismportant and increasingly common group of tox-cities.

Minimizing the unsightly appearance is key innabling patients to live their lives as normally asossible. Use of foundations to minimize facialedness is important to women. For men, using anlectric razor infrequently and using mild mois-urizers with mild astringents for dry skin willinimize redness.Finally, emotional support is essential. Social

ervice, support groups, or simply talking withther patients who have managed to modify theirymptoms and maximize their quality of life ismportant. Patients with skin effects often feelsolated. The highly visible presentation of thekin effects coupled with feelings of isolation canegatively affect quality of life.Managing the symptoms associated with HER1/

GFR inhibitors will promote the ability of pa-ients to adhere to their treatment regimen. Theategory of HER1/EGFR inhibitors is a truly excit-ng approach to treating a variety of cancers. Asata continues to accrue about these agents, on-ology nurses will ultimately devise written evi-ence-based guidelines for the assessment, inter-ention, and treatment of the unique issuesssociated with these cutting-edge targeted thera-ies. We are learning more about cancer cell biol-gy at a very rapid pace. The next generation ofGFR inhibitors is currently in clinical develop-ent. How to manage the side effects that result

rom this therapy is an enormous problem foratients, and they are looking to us for the an-wers. Investigating treatments for the cutaneousomplications of EGFR therapy is an area ripe forursing research.

ACKNOWLEDGMENT

he authors thank Eileen M. Creaton, MS, RN, OCN of Genen-ech BioOncology for her help in obtaining the graphic, and Dr
rthur Skarin for use of the photographs.
CES

1. Mass RD. The HER receptor family: A rich target forherapeutic development. Int J Radiat Oncol Biol Phys004;58:932-940.

2. Viale PH. Current Topics in Colorectal Cancer TargetingGFR for Oncology Nurses. 2005, Project ID: 2752 ES 16, No. 2.

3. Carpenter C, Cantley LC. Molecular targets in oncology,

ractice of Oncology. Ed 7. Philadelphia, PA, Lippincott,illiams & Wilkins, 2004, pp 73-83.

4. Aberle MF, McLeskey SW. Biology of lung cancer withmplications for new therapies. Oncol Nurs Forum 2003;0:273-280.

5. Perez-Soler R. HER1/EGFR targeting: Refining the strat-
gy. The Oncologist 2004;9:58-67.

Ngt

t

VOW

c

r2

b

m(i

ga

amA2

e2

o

lt

Eai1

HO

p2

sg1

prv

owL

pP

mv2

ce2

pCrr2

adc

cd

ne[

Tm

a6

t2

nrh

eOR

ebg2

psiO

pJ

a3


6. Houlihan N, Tyson L, Wood L. Targeted Therapies inon-Small Cell Lung Cancer. A Continuing Education Mono-raph for Oncology Nurses. Pittsburgh, PA, Oncology Educa-ion Services, 2005.

7. Wood LS. Rationale for EGFR as a target for cancerherapy. Semin Oncol Nurs 2002;18(suppl 4):3-10.

8. Stetler-Stevenson WC. Invasion and metastasis, in DeVitaT, Hellman S, Rosenberg SA (eds): Principles and Practice ofncology. Ed 7. Philadelphia, PA, Lippincott, Williams &ilkins, 2004, pp 73-83.9. Vlahovic G, Crawford J. Activation of tyrosine kinases in

ancer. The Oncologist 2003;8:531-538.10. Lockhart C, Berlin JD. The epidermal growth factor

eceptor as a target for colorectal cancer therapy. Semin Oncol005;32:52-60.11. Herbst RS. Review of epidermal growth factor receptor

iology. Int J Radiat Oncol Biol Phys 2004;59:21-26.12. Huang S, Armstong E, Benavente S, et al. Dual-agentolecular targeting of the epidermal growth factor receptor

EGFR): Combining anti-EGFR antibody with tyrosine kinasenhibitor. Cancer Res 2004;64:5355-5362.

13. Noonberg SB, Benz CC. Tyrosine kinase inhibitors tar-eted to the epidermal growth factor receptor subfamily: Roles anticancer agents. Drugs 2000;59:753-767.14. Halpern AC, Thomas M. Anti-EGFR therapy-related rash

nd other adverse events: Etiologies, prevention, and manage-ent. Teleconference, American Academy of CME, Inc, 2005.vailable at: http://www.academycme.org/ (accessed May 11,006)15. Herbst RS, Shin DM. Monoclonal antibodies to target

pidermal growth factor receptor positive tumors. Cancer002;94:1593-1611.16. Thomas M. Cetuximab: Adverse event profile and rec-

mmendations for toxicity. Clin J Oncol Nurs 2005;9:332-338.17. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in

ung cancer: Correlation with clinical response to gefitinibherapy. Science 2004;304:1497-1500.

18. Perez-Soler R, Delord JP, Halpern A, et al. HER1/GFR inhibitor-associated rash: Future directions for man-gement and investigation outcomes from the HER1/EGFRnhibitor rash management forum. The Oncologist 2005;0:345-356.19. Perez-Soler R, Saltz L. Cutaneous adverse effects withER1/EGFR-targeted agents: Is there a silver lining? J Clinncol 2005;22:5235-5246.20. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in

reviously treated non-small cell lung cancer. N Engl J Med005;353:123-132.21. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous

ide-effects in cancer patients treated with the antiepidermalrowth factor receptor antibody C225. Br J Dermatol 2001;441:1169-1176.22. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and

harmacologic study of OSI-774, an epidermal growth factoreceptor tyrosine kinase inhibitor, in patients with ad-anced solid malignancies. J Clin Oncol 2001;19:3267-3279.23. Janne PA, Gurubhagavatula S, Yeap BY, et al. Outcomes

f patients with advanced non–small cell lung cancer treatedith gefitinib (ZD 1839; Iressa) on an expanded access study.ung Cancer 2004;44:221-230.24. Clark C, Perez-Soler R, Siu L, et al. Rash severity is

redictive of increased survival with erlotinib HCL [abstract].
roc Am Soc Clin Oncol 2003;22:196.
25. Park J, Park BB, Kim JY, et al. Gefitinib (ZD 1839)onotherapy as a salvage regimen for previously treated ad-

anced non–small cell lung cancer. Clin Cancer Res004;10:4383-4388.

26. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial ofetuximab in patients with refractory colorectal cancer thatxpresses the epidermal growth factor receptor. J Clin Oncol004;22:1201-1208.

27. Saltz L, Rubin MS, Hochster H, et al. Acne-like rashredicts response in patients treated with cetuximab (IMC-225) plus irinotecan (CPT-11) in CPT-11-refractory colo-

ectal cancer (CRC) that expresses epidermal growth factoreceptor (EGRF) [abstract 559]. Clin Cancer Res001;7:3766.

28. Saltz L, Kies M, Abbruzzese JL, et al. The presencend intensity of the cetuximab-induced acne-like rash pre-icts increased survival in studies across multiple malignan-ies [abstract 204]. Proc Am Soc Clin Oncol 2003;22.

29. Skarin A. Systemic and mucocutaneous reactions tohemotherapy. In: Atlas of Diagnostic Oncology. Ed 3. Phila-elphia, PA, Mosby, 2003, pp 597-610.

30. Bejak A, Shepherd F, Tu D, et al. Symptom response inon–small cell lung cancer (NSCLC) patients treated withrlotinib: Quality of life analysis of NSCLC. CTG BR-21 Trialabstract 7018]. J Clin Oncol 2005;23:625s.

31. Kim E. Cutaneous adverse events associated witharceva. South San Francisco, CA, Genentech Medical Com-unications, 2005.

32. King LE, Gates RE, Stoscheck CM, et al. The EGF/TGFlpha receptor in skin. J Invest Dermatol 1990;94(suppl):164S-170S.

33. Jost M, Kari C, Rodeck U. The EGF receptor—An essen-ial regulator of multiple epidermal functions. Eur J Dermatol000;10:505-510.

34. Hansen LA, Alexander N, Hogan ME, et al. Geneticallyull mice reveal a central role for epidermal growth factoreceptor in the differentiation of the hair follicle and normalair development. Am J Pathol 1997;150:1959-1975.

35. Malik SN, Siu LL, Rowinsky EK, et al. Pharmacodynamicvaluation of the epidermal growth factor receptor inhibitorSI-774 in human epidermis of cancer patients. Clin Canceres 2003;9:2478-2486.

36. Tan AR, Yang X, Hewitt SM, et al. Evaluation of biologicnd points and pharmacokinetics in patients with metastaticreast cancer after treatment with erlotinib, an epidermalrowth factor receptor tyrosine kinase inhibitor. J Clin Oncol004;22:3080-3090.

37. Baselga J, Rischin D, Ranson M, et al. Phase I safety,harmacokinetic, and pharmacodynamic trial of ZD1839, aelective oral epidermal growth factor receptor tyrosine kinasenhibitor in patients with five selected solid tumor types. J Clinncol 2002;20:4292-4302.

38. Shah NT, Kris MG, Pao W, et al. Practical management ofatients with non–small-cell lung cancer treated with gefitinib.Clin Oncol 2005;23:165-174.

39. McLaughlin P. The significance of hair changes associ-ted with cetuximab [Abstract 163]. Oncol Nurs Forum 2005;2:467-468.

40. Busana KJ, Capodieci P, Motzer T, et al. Cutaneous side

http://www.academycme.org/

eg2

g

o2


ffects in cancer patients treated with the anti-epidermalrowth factor receptor antibody, C225. Br J Dermatol001;144:1169-1176.41. Purdom M. Management of acneiform rashes related to

efitinib therapy. Clin J Oncol Nurs 2004;8:309-310. a

42. Pizzo B. New directions in oncology nursing care: Focusn gefitinib in patients with lung cancer. Clin J Oncol Nurs004;8:385-392.43. Yamamoto DS, Viale PH, Zhao G. Picture this: Severe

cneiform rash. Clin J Oncol Nurs 2004;8:631-641.

Documents

EGFR-Targeted Therapy and Related Skin Toxicity