Annals of Oncology Advance Access published August 13, 2010

review Annals of Oncology

doi:10.1093/annonc/mdq387

Interdisciplinary management of EGFR-inhibitor-

induced skin reactions: a German expert opinion
K. Potthoff1*, R. Hofheinz2, J. C. Hassel3, M. Volkenandt4, F. Lordick5, J. T. Hartmann6,
M. Karthaus7, H. Riess8, H. P. Lipp9, A. Hauschild10, T. Trarbach11 & A. Wollenberg4
1
Department of Radiation Oncology, University of Heidelberg, Heidelberg; 2Department of Hematology and Oncology, University of Mannheim, Mannheim; 3Department
of Dermatology, University of Heidelberg, Heidelberg; 4Department of Dermatology and Allergology, Ludwig-Maximilians-University of Munich, Munich; 5Department of
Hematology and Oncology, Klinikum Braunschweig, Braunschweig; 6Department of Hematology and Oncology, University of Tuebingen, Tuebingen; 7Department of
Hematology and Oncology, Stadtisches Klinikum Neuperlach, Munich; 8Department of Medical Oncology and Hematology, Charite University, Berlin; 9Department of
Pharmacology, University of Tuebingen, Tuebingen; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Hematology and Oncology, University of
Essen, Essen, Germany

Received 27 October 2009; revised 27 May 2010; accepted 27 May 2010

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Background: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as

review
cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors,
such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects
are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patients quality of life.
Purpose: The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with
skin reactions undergoing anti-EGFR treatment.
Material and methods: An expert panel from Germany with expertise in medical oncology, dermatology or clinical
pharmacology was convened to develop expert recommendations based on published peer-reviewed literature.
Results: The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor
therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment
approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should
always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction.
For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by
EGFR-inhibitor therapy were proposed.
Conclusion: This paper presents a German national expert opinion for the treatment of skin reactions in patients
receiving EGFR inhibitor therapy.
Key words: acneiform rash, cetuximab, EGFR inhibitors, panitumumab, skin reaction, treatment recommendations

introduction dermatologic side-effects include acneiform skin rash;

Inhibitors of the epidermal growth factor receptor (EGFR) are
used in a growing range of tumor types to improve clinical
outcome. EGFR may be inhibited with anti-EGFR-specific
monoclonal antibodies or small molecule tyrosine kinase
inhibitors. Cetuximab (Erbitux
), a chimeric immunoglobulin
G1 monoclonal antibody, and panitumumab (Vectibix
),
a fully human immunoglobulin G2 monoclonal antibody, have
regulatory approval in many countries, as have the EGFR small
molecule tyrosine kinase inhibitors erlotinib (Tarceva
) and
gefitinib (Iressa
).
Dermatologic toxic effects are the most common side-effects
associated with anti-EGFR therapy. EGFR inhibitor-mediated
*Correspondence to: Dr K. Potthoff, Department of Radiation Oncology, University of
Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. Tel: +49-6221-
56-37099; Fax: +49-6221-56-5353; E-mail: Karin.potthoff@med.uni-heidelberg.de
hyperpigmentation; xerotic skin; pruritus; skin fissures; nail
changes; disorders of mucous membranes, eyes and hairwith
an incidence ranging from 49% to 100% of patients [1].
Though mild (grade 01) to moderate (grade 2) toxic effects
are common in cetuximab- or panitumumab-treated patients,
15% of patients experience severe reactions (grade 3) [2,
3]. A systematic review of published data from 8998 cancer
patients treated in prospective clinical trials concluded that
there are no reported deaths from skin rash [4].
Almost all available studies addressing EGFR-inhibitor-
induced skin rash suggest that its severity is a suitable surrogate
marker for efficacy of anti-EGFR therapy [58]. Racca et al. [9]
observed significant correlation between cutaneous toxicity and
objective response rate. Recently, a retrospective exploration of
several panitumumab trials by Peeters et al. [10] confirmed an
association between clinically graded skin toxicity and patient-
reported outcome, quality of life, longer progression-free survival

The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
review
and overall survival. The authors suggest that skin reactions
should be treated while continuing EGFR-targeted therapy. Data
from the EVEREST trial [11] and from a phase II trial with
FOLFIRI and panitumumab [12] did not show any correlation
between skin rash and efficacy of anti-EGFR therapy.
Despite the benefits of anti-EGFR agents, toxic effects of the
skin may eventually result in poor patients compliance, lower
adherence to cancer therapy, more dose delays and
interruptions or discontinuation of antineoplastic therapy [1,
1315]. Finally, toxic effects of the skin may significantly reduce
the quality of life [14, 16, 17]. Though potential treatment
suggestions for EGFR inhibitor-associated toxic effects of the
skin have been evaluated in clinical trials, standard guidelines
have not been published so far.
materials and methods and consensus
formation
panel composition
The panel comprised clinicians and a pharmacist from Germany with
expertise in medical oncology, dermatology or clinical pharmacology and
special knowledge of the treatment of EGFR-inhibitor-induced skin reactions.
data source
Data source was based on recent published literature and data presented
during the Annual meeting of the American Society of Clinical Oncology
(ASCO) 2008, the World Congress of Gastrointestinal Cancer, Barcelona 2008,
the European Cancer Organisation-15 Congress 2008, the ASCO GI 2009 and
the ASCO 2009. Published clinical trials in Medline, Cochrane Library,
Cochrane Controlled Trials Register, and EMBASE Drugs and Pharmacology
databases were included. Information was accessed until 8 April 8 2010.
methods of consensus development
A task force of clinical experts in the fields of medical oncology and
dermatology prepared the first manuscript based on the data source
described. All members of the panel were asked to agree on a consensus
statement following a period of consensus meetings and discussion based
on the draft manuscript. The expert opinion represents the German
perspective of the management of EGFR-inhibitor-induced skin toxicity
and includes personal experiences of the expert panel. All members of the
panel participated in the preparation of the final manuscript, which was
circulated for review.
results
EGFR-inhibitor-induced toxic effects of the skin are well
described and claimed to be a class effect of this substance
group [18]. Although rarely life threatening, they can cause
significant discomfort and may impact the quality of life and
well-being of the patient [4, 14, 16, 922]. Skin toxicity often
has a cosmetic and stigmatizing effect leading to low self-esteem
and social isolation. Consequently, emotional factors are most
significantly affected [16].
pathophysiological characteristics of skin
reactions
The EGFR plays an important role in differentiation and
development of skin follicles. EGFR is constitutively expressed by
normal epidermal and follicular keratinocytes in the basal layer
2 | Potthoff et al.
Annals of Oncology
of the epidermis, in the outer root sheath of hair follicles, in
sebaceous and eccrine epithelium; by dendritic cells and various
connective tissue cells [2326]. EGFR signaling stimulates
epidermal growth and differentiation, accelerates wound healing
and stimulates vasoconstriction and keratinocyte migration
[27,28]. EGFR stimulation activates phosphatidylinositol
turnover, subsequently leading to diacylglycerol formation.
During EGFR inhibitor therapy, phosphorylated EGFR is
abolished and inflammatory cell chemoattractants like CXCLs
and CCLs are released. Inhibitory proteins for growth-like
cyclin-dependent kinase inhibitor p27 are upregulated, whereas
phosphatidylinositol turnover, diacylglycerol formation, the
proliferation marker Ki67 and MAPK expression are reduced
[25]. This results in an abnormal maturation and skin
differentiation, growth and migration arrest, an increased rate of
apoptosis and an inflammatory response leading to tissue
damage and skin atrophy. Severe acute skin reactions show
massive neutrophilic infiltration of the epidermis and, profound
apoptosis [27, 29, 30]. Immunohistochemistry and in situ
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hybridization reveal an increased expression of p27Kip1 in
keratinocytes [31], whereas chronic skin changes are
characterized by epidermal atrophy, disappearance of follicular
structures and epidermal fissures [27]. In summary, EGFR
inhibitor treatment induces a complex pattern of tissue injury
and inflammatory cell recruitment, damaging the basal
epidermis, the sweat and sebaceous glands and hair follicles.
clinical presentation of dermatologic toxic effects
acneiform rash. Acneiform rash, the most frequent EGFR-
inhibitor-induced skin toxicity, occurs in 45%100% of
patients [1] and usually develops within the first 24 weeks of
treatment (Figure 1). Patients present with macular, papular or
pustular lesions mainly localized in cosmetically sensitive areas,
e.g. regions rich in sebaceous glands like face (Figure 2) and
upper trunk but can extend to the extremities, too [22, 32, 33].
In most cases, the rash is mild and well tolerated but
tenderness, pain, disfigurement and even acneiform dermatitis
worsening to exfoliative dermatitis may occur. The reported
incidence of severe skin reactions grade 3/4 is 0%17%,
slightly more seen in patients treated with monoclonal
antibodies than in patients treated with EGFR small molecule
tyrosine kinase inhibitors [1, 34, 35].
Figure 1. Typical time course of skin reactions induced by epidermal
growth factor receptor inhibitor therapy.
Annals of Oncology review
The skin rash associated with EGFR inhibitors is different
from acne vulgaris, as there are no comedones. Histopathology
confirms a sterile eruption consisting of follicular papules and
pustules in an acneiform distribution. Therefore, the term
acneiform rash should consequently be used instead of acne
or acne-like rash to describe this EGFR-inhibitor-induced skin
rash. The rash usually improves with time, but rarely resolves
completely as long as EGFR inhibitors are administered.
Infectious complications or localized abscesses requiring
surgery may occur in patients with an acneiform rash, but
a fatal outcome following sepsis, as previously described in one
patient, is not a direct consequence of the rash [36].
photosensitivity. Some patients show widespread erythema,
infiltration and pustules in sun-exposed areas, which is
attributed to a photosensitizing capacity of the substance class
[13, 37, 38]. Higher grades of solar dermatitis with blistering,
Figure 2. Acneiform rash in a 68-year-old patient treated with cetuximab
however, are rare.
and irinotecan for metastatic colorectal cancer. (A) Acneiform rash grade 2,
pruritus. Pruritus, mostly due to mild exsiccation, develops in 18 days after beginning cetuximab treatment. (B) Same patient 3 weeks after

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15 % of patients (grade 3/4: 1%), usually 23 weeks after the beginning topical treatment with clindamycin; cetuximab was continued as
initiation of anti-EGFR therapy [12]. Some patients complain recommended for grade 2 acneiform rash by the manufacturers SmPC.
of irritation or pain [39].
xerotic skin. Xerotic skin occurs in 4%100% of patients.
First symptoms occur after 12 months of EGFR inhibitor
therapy and tend to increase with time (Figure 1). Dry skin may
occur in the face, trunk, extremities and mucous membranes,
leading to perineal and vaginal dryness. Osio et al. [17]
reported on an incidence of xerotic skin manifestations of
100% in patients treated with EGFR inhibitors for >6 months.
fissures. Painful fissures on the tips of fingers and toes are
frequently reported during EGFR inhibitor therapy; the overall
incidence is 18% (grade 3/4: 3%) [10, 12, 39]. Fissures are
typically located on the fingertips or over the interphalangeal
joint of the fingers or toes and are highly associated with xerotic
skin [32].
nail changes. Paronychia, an inflammation of the nail folds, is
an infrequent, but painful side-effect of EGFR inhibitor therapy Figure 3. Paronychia in a 78-year-old patient treated with panitumumab
[40]. An example of a patient suffering from paronychia is for metastatic colorectal cancer. (A) Four months after beginning
shown in Figure 3. Paronychia usually does not develop before panitumumab treatment. (B) Four weeks later after daily local desinfection
48 weeks from start of therapy and occurs in 12%58% of and systemic antibiotics with oral doxycycline 100 mg b.i.d. while
patients. Osio et al. [17] pointed out a frequence of paronychia continuing panitumumab treatment.
of >50% for patients on EGFR inhibitors for longer than 6
months. Bacterial and fungal superinfections may stimulate the telangiectasia, hyperpigmentation and disorders of mucous
development of granulation tissue [41]. Therefore, for membranes like stomatitis, mucosal dryness and inflammation
diagnostics, bacterial and fungal cultures are recommended [22].
[39]. In rare cases, onycholysis, partial or complete loss of the
nail plate, have been described. eye disorders. Eye disorders that have been reported in patients
undergoing EGFR inhibitor therapy include conjunctivitis,
hair growth abnormalities. There are single reports of patients blepharitis, dry eyes or increased lacrimation, as well as growth
developing finer, curlier and brittle scalp hair, as well as of eyelashes (trichomegaly) [43].
localized facial hypertrichosis and trichomegaly especially of the
eyelashes, which may occur within a few weeks or months after kinetics and typical time course of skin reactions
the start of EGFR inhibitor treatment [42]. Few cases of severe
Skin reactions tend to start in the second week after initiation
hair disorders, even leading to alopecia of the scalp and beard
of EGFR inhibitor therapy. The onset varies between
are reported [32], but the causal relationship remains unclear.
individuals depending on preexisting skin conditions and the
other EGFR inhibitor-associated dermatologic toxic effects. Other susceptibility of the individuals. Different patterns of skin
EGFR inhibitor-mediated dermatologic reactions include reactions seem to have their individual characteristic time

doi:10.1093/annonc/mdq387 | 3
review
frame of peak and onset (Figure 1). The acneiform rash is
usually first, starting with an acneiform maculopapular rash
followed by papulopustular rash and crusting [1, 44]. The
severity of the acneiform skin rash usually peaks at 23 weeks
after initiation of therapy. Pruritus, often associated with
xerotic skin and exsiccation dermatitis, typically starts after 23
weeks. Fissures do usually not occur before 68 weeks of
therapy. Paronychia and hair changes may start after 8 weeks of
treatment [32, 45]. The median time to resolution after the
final dose of EGFR inhibitor is reported to be 28 days [46].
grading of skin reactions
The National Cancer Institute (NCI) has developed the common
terminology criteria for adverse events (NCI-CTCAE), including
a grading scale for severity that is widely used for adverse events
reported in clinical trials [47, 48]. The NCI-CTCAE version 3.0
grading scale published in 2006 has been used most often for
evaluation of EGFR-inhibitor-induced skin toxicity. In addition,
acneiform reactions can be accurately followed over time with
a skin-lesion-based grading system focusing on treatment results
on a long-term objective basis [49].
The NCI-CTCAE criteria, however, are not optimal for
grading EGFR-inhibitor-related toxic effects [50]. An updated
4.0 version has been published recently, but this version again,
due to the expert panels opinion, does not reflect the clinical
situation. The relevant criteria of CTCAE versions 3.0 and 4.0
are compared in Table 1. In the expert panels opinion, grading
for EGFR-inhibitor-induced toxic effects of the skin should be
preferably based on the grade of severity and not on the pattern
of distribution, i.e. localized versus generalized. Very recently,
a skin toxicity study group of the Multinational Association of
Supportive Care in Cancer proposed a class-specific grading
scale to standardize assessment and to improve reporting of
EGFR-inhibitor-associated dermatologic adverse events by
detection of dermatologic toxic effects with greater sensitivity,
specificity and range [51].
management guidelines and treatment
recommendations
To date, few management guidelines for EGFR-inhibitor-
mediated dermatologic toxic effects are published. Most of
them, however, are not evidence based. The management of
EGFR-inhibitor-induced skin toxicity is largely empiric and
supportive [40]. There are at least three full papers on
randomized controlled trials on prophylactic use of oral
tetracycline (which indicated that tetracycline may be effective)
[52], topical tazarotene (which stated tazarotene to be
ineffective) [53] and topical pimecrolimus (which showed
pimecrolimus to be ineffective) [54].
In the Medline, listed English literature recommendations
based on expert consensus meetings were reported from an
European view [55], from an American view [43] and from
a Canadian view [56]. In addition, a Swiss oncologic
dermatologic consensus statement was recently published [57].
Various groups published recommendations based on
personal experiences [1, 13, 32, 5860].
Most important to know is that EGFR-inhibitor-induced
skin reactions can be effectively treated at all stages and at all
4 | Potthoff et al.
Annals of Oncology
grades that might occur [27]. All dermatologic effects usually
are reversible and generally heal without sequelae within
4 weeks after treatment discontinuation [9]. In most cases,
therapeutic benefit has been already observed after 35 days
and after 1week clinically relevant amelioration has been seen.
Due to personal experiences, in most of the patients, dry skin
can be observed even weeks or months after end of EGFR
inhibitor therapy. Prophylactic treatment has not been entered
into routine clinical practice, although first results have pointed
out a significant benefit of preemptive treatment [14, 6164].
Treatment recommendations reported here are based on
severity, i.e. grade, and stage of dermatologic reaction. They are
divided into general recommendations and side-effect-specific
recommendations. Importantly, these recommendations do not
offer personalized medical diagnosis or patient-specific
treatment advice. All decisions regarding patient care must
integrate the unique characteristics of the patient and the
individuals response to different treatment modalities.
Frequent clinical follow-up by an experienced dermatologist or
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oncologist is obligatory, i.e. at least every 2 weeks, including
immediate consultation if flare-up occurs [22, 32].
general treatment recommendations
General treatment suggestions include the use of gentle soaps
and shampoos, moisturizer treatment, avoidance of sun
exposure and use of sunscreen with high sun protection
factor (e.g. SPF30) [21, 26, 27, 65, 66]. They are summarized in
Table 2. Treatment that is not recommended and should be
avoided is summarized in Table 3.
treatment recommendations for specific clinical
symptoms
There is no specific treatment available; therapeutic options
include topical and systemic approaches. In the literature,
treatment suggestions include moisturizer, drying agents, mild
skin cleansers, topical antiseptics, topical antibiotics, systemic
antibiotics and topical or systemic steroids. In general,
treatment should be started as early as possible after onset of
dermatologic reactions. Our stage- and grade-adapted
recommendations are based on time-course-dependent stages
of anti-EGFR-induced skin reactions (Table 4). They are as
given below.
treatment of acneiform rash. In contrast to acne vulgaris, the
skin of patients with an acneiform rash is not seborrhoic and
will even become xerotic within a few weeks. Therefore,
moisturizing of the skin may be useful. Beginning topical
antibiotic treatment with erythromycin, metronidazole or
nadifloxacin twice daily is recommended for early-stage and
low-grade papulopustular skin reactions [55]. Cream or lotion
preparations should be preferred to take advantage of an
additional moisturization effect. Systemic treatment should at
least be started if skin reactions grade 2 occur. Topical
solutions or alcohol-containing gel formulations should be
avoided because they may enhance dryness. Topical
corticosteroids are not generally recommended [22, 32], but
may be beneficial especially in a combination regimen with
topical antibiotics, e.g. nadifloxacin [68, 69]. Topical
Annals of Oncology review
Table 1. Grading of skin reactions

NCI CTCAE v3.0 NCI CTCAE v4.0

a
Rash/desquamation (acne/acneiform)
Grade 1 Macular or papular eruption or erythema without associated
symptoms (intervention not indicated)
Grade 2 Macular or papular eruption or erythema with pruritus or other
associated symptoms; localized desquamation or other lesions
covering <50% of BSA (intervention indicated)
Grade 3 Severe, generalized erythroderma or macular, papular or
vesicular eruption; desquamation covering 50% of body
surface area (associated with pain, disfigurement, ulceration,
or desquamation)
Grade 4 Generalized exfoliative, ulcerative, or bullous dermatitis ()
Grade 5 Death
Acneiform rasha
Papules and/or pustules covering <10% BSA, which may or may
not be associated with symptoms of pruritus or tenderness
Papules and/or pustules covering 10%30% BSA, which may
or may not be associated with symptoms of pruritus or
tenderness; associated with psychosocial impact; limiting
instrumental ADL
Papules and/or pustules covering >30% BSA, which may or may
not be associated with symptoms of pruritus or tenderness;
limiting self-care ADL; associated with local superinfection
with oral antibiotics indicated
Papules and/or pustules covering any % BSA, which may or may
not be associated with symptoms of pruritus or tenderness
and are associated with extensive superinfection with i.v.
antibiotics indicated; life-threatening consequences
Death

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Photosensitivity
Grade 1 Painless erythema Painless erythema and erythema covering <10% BSA by an
increase in sensitivity
Grade 2 Painful erythema Tender erythema covering 10%30% BSA
Grade 3 Erythema with desquamation Erythema covering >30% BSA and erythema with blistering;
photosensitivity; oral corticosteroid therapy indicated; pain
control indicated (e.g. narcotics or nonsteroidal
anti-inflammatory drugs)
Grade 4 Life threatening; disabling Life-threatening consequences; urgent intervention indicated
Grade 5 Death Death
Pruritus
Grade 1 Mild or localized Mild or localized; topical intervention indicated
Grade 2 Intense or widespread Intense or widespread; intermittent; skin changes from
scratching (e.g. edema, population, excoriations,
lichenification, oozing/crusts); oral intervention indicated;
limiting instrumental ADL
Grade 3 Intense or widespread and interfering with ADL Intense or widespread; constant; limiting self-care ADL or
sleep; oral corticosteroid or immunosuppressive therapy
indicated
Nail changes
Grade 1 Discoloration; ridging (koilonychias); pitting In v4.0 nail changes are divided into
Nail discoloration: grade 1: asymptomatic; clinical or
diagnostic observations only; intervention not indicated
Grade 2 Partial or complete loss of nail(s); pain in nail bed(s) Nail loss: grade 1: asymptomatic separation of the nail bed from
the nail plate or nail loss; grade 2: symptomatic separation
of the nail bed from the nail plate or nail loss; limiting
instrumental, ADL
Grade 3 Interfering with activities of daily living. Nail ridging: grade 1: asymptomatic; clinical or diagnostic
observations only; intervention not indicated

Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and v4.0 [47, 48].
a
Acneiform rash and rash/desquamation as well as rash/acne/acneiform for better comparability of v3.0 and v4.0.
ADL, activities of daily living; BSA, body surface area; NCI, National Cancer Institute.

hydrocortisone 1% cream or topical calcineurin inhibitors,
such as pimecrolimus, were reported to be effective, too [70].
Recently, however, a randomized controlled trial showed
pimecrolimus to be ineffective for cetuximab-induced
rash [54].
Oral tetracyclines, such as doxycycline or minocycline,
reduce the severity and extent of the acneiform eruption [14,
52, 53]. They are recommended for skin rash grade 2.
Although microbial pathogens are typically absent in early-
stage EGFR-inhibitor-induced skin reactions, oral tetracyclines
are recommended for their immunomodulating and anti-
inflammatory effects [71, 72]. The adverse events of
minocycline include vestibular dizziness and loss of balance, as
well as postinflammatory hyperpigmentation, drug-induced

doi:10.1093/annonc/mdq387 | 5
review Annals of Oncology

Table 2. General recommendations for prophylaxis while receiving anti-EGFR inhibitor treatment

Personal hygiene
Sun protection
Moisturizer treatment
Prevention of paronychia
Use of gentle soaps and shampoos for the body, i.e. pH5 neutral bath and shower formulations and tepid water
Use of very mild shampoos for hair wash
Only clean and smooth towels are recommended because of potential risk of infection. The skin should be patted dry
after a shower, whereas rubbing the skin dry should be avoided
Fine cotton clothes should be worn instead of synthetic material
Shaving has to be done very carefully
Manicure, i.e. cutting of nails, should be done straight across until the nails no longer extend over the fingers or toes.
Cuticles are not allowed to be trimmed because this procedure increases the risk of nail bed infection
Sunscreen should be applied daily to exposed skin areas regardless of the season. Hypoallergenic sunscreens with a high
SPF (at least SPF30, PAPA free, UVA/UVB protection), preferably broad spectrum containing zinc oxide or titanium
dioxide are recommended
Patients should be encouraged to consequently stay out of the sun
Protective clothing for sun protection and wearing of a hat should be recommended
It is important to moisturize the skin as soon as anti-EGFR therapy is started
Hypoallergenic moisturizing creams, ointments and emollients should be used once daily to smooth the skin and to
prevent and alleviate skin dryness [67]
Patients should keep their hands dry and out of water if ever possible

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They should avoid friction and pressure on the nail fold as well as picking or manipulating the nail
Topical application of petrolatum is recommended around the nails due to its lubricant and smoothing effects on the
skin. Petrolatum prevents evaporation of moisture by forming a film on the surface

EGFR, epidermal growth factor receptor.

Table 3. Treatments that should be avoided secondarily infected rash. Secondary infection of skin rash may
occur at later stages, which includes impetiginisationan
important complication caused by staphylococci or
Treatment to be avoided Rational
streptococci. Staphylococcus aureus is the most frequently
Greasy creams for basic care Such creams might facilitate the detected infectious agent, less frequent infections include
(e.g. pure petrolatum) development of folliculitis due to their
herpes simplex, herpes zoster and dermatophytes [74].
occlusive properties
Abscesses may require incision and drainage to prevent sepsis.
Manipulation of skin Risk of infection
Bacterial swabs should be taken and calculated anti-infective
Hot blow-drying of the hair
treatment should be started.
Wearing of tight shoes
Topical acne medications,a They may irritate and worsen anti- treatment of xerotic and eczematous skin. The keystone of
e.g. retinoids, alpha- EGFR-induced skin rash due to their treatment of dry skin is to avoid dehydrating body care such as
hydroxy-acid and benzoyl drying effects [44]. Topical retinoids hot showers and excessive use of soaps, and to return moisture
peroxide gel or cream may be irritating, and systemic by applying emollients. These should be applied at least once
retinoids may aggravate xerosis and daily to the whole body. Inflammatory skin conditions such as
increase itch sensation and are not eczema and fissures might develop on xerotic skin [66, 75].
generally recommended
Alcohol-containing lotions or gels should be avoided in favor of
Topical steroidsa They may cause perioral dermatitis and
oil-in-water creams or ointments [1, 55]. Erythema and
skin atrophy if used inadequately [26]
desquamation are indicative of ongoing eczema and can be
a
Both substance classes should, in the panels view, only be used under the treated with topical steroid preparations such as prednicarbate
supervision of a dermatologist, as unwanted side-effects may occur if used cream. For erythema and/or desquamation, grade 3 short-term
inadequately. Individual patients with anti-EGFR-induced acneiform rash oral systemic steroids are recommended.
may benefit from topical adapalene, a synthetic retinoid with a significantly
treatment of pruritus/itching. Skin moisturizer and urea- or
lower incidence of irritative side-effects compared with tretinoin and a very
polidocanol-containing lotions are suitable to soothe pruritus.
low rate of systemic absorption after topical administration. Due to the
Systemic treatment with oral H1-antihistamines such as
panels view, adapalene, however, should be kept on a list of optional drugs
without proven efficacy and with only use under strict supervision of
cetirizine, loratadine, or fexofenadine as well as clemastine may
a dermatologist. provide relief of itching for patients with grade 2/3 pruritus.
treatment of fissures. Fissures can be treated topically with
propylene glycol 50% in water for 30 min under plastic
hepatitis and a lupus-like syndrome [73]. Doxycycline occlusion every night, followed by application of hydrocolloid
exhibits more light sensitizing effects. There is no evidence- dressing. Alternatively, antiseptic baths such as potassium
based preference for any of the above-mentioned permanganate in a concentration of 1 : 10 000 or topical
tetracyclines for treatment of anti-EGFR-induced skin rash application of silver nitrate solutions may be used to accelerate
grade 2 so far. wound closure [22, 55]. In addition, the surrounding skin

6 | Potthoff et al.
Annals of Oncology review
Table 4. Stage- and grade-specific treatment of skin reactions

Severity Intervention concerning Specific intervention

EGFR inhibitor therapy
STAGE 1: ACNEIFORM RASH
Acneiform rash
Mild (grade 1)
Usually localized Continue EGFR inhibitor therapy Consider topical antibiotics, e.g. clindamycin 2% or
Minimally symptomatic Monitor for change in severity topical erythromycin 1% cream or metronidazole
No impact on ADL 0.75% or topical nadifloxacin 1%
No sign of superinfection
Isolated scattered lesions: cream preferred
Multiple scattered areas: lotion preferred

REASSESS AT LEAST AFTER 2 WEEKS OR AT ANY WORSENING OF SYMPTOMS!

If worsening or no improvement: see recommendations for grade 2 toxicity.
consider referral to a dermatologist (depending on own clinical experience)
Moderate (grade 2)
Generally mild symptoms Continue EGFR inhibitor therapy Skin-type-adjusted moisturizer
Minimal impact on ADL Monitor for change in severity Topical treatment like grade 1 plus short-term

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No sign of superinfection
If worsening or no improvement: see recommendations for grade 3 toxicity.
Severe (grade 3)
Severe symptoms (e.g. pruritus,
tenderness)
Significant impact on ADL
Potential for superinfection
If worsening or no improvement: see recommendations for grade 4 toxicity.
Life threatening (grade 4)
REASSESS AFTER 2 WEEKS!
Refer to a dermatologist!
Reduce EGFR inhibitor dose as per label!
Monitor for change in severity
REASSESS AFTER 2 WEEKS!
Refer to a dermatologist!
Dose interruption or permanent
discontinuation of EGFR inhibitor
as per label!
topical steroidb, e.g. prednicarbate cream 0.02 %
and an oral antibiotic (for at least 2 weeks)
Doxycyclinea 100 mg b.i.d. or
Minocycline hydrochloride 100 mg b.i.d.
Skin-type-adjusted moisturizer
Topical and systemic treatment, see grade 2
Refer to dermatologist
Consider oral isotretinoin (cave: No combination
with oral tetracyclines because of possible increase
in intracranial pressure) or systemic steroids
See grade 3; refer to dermatologist!
Individual treatment concept!
Systemic steroids are additionally recommended

STAGE 2: EARLY AND LATE XEROTIC SKIN REACTIONS

Pruritus
Mild (grade 1)
Continue EGFR inhibitor therapy Topical polidocanol cream
Consider oral antihistamines, e.g.
diphenhydramine, dimethindene,
cetirizine, levocetirizine,
desloratadine, fexofenadine or
clemastine)
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for moderate toxicity
Moderate (grade 2)
Continue EGFR inhibitor therapy See grade 1 plus
Monitor for change in severity Oral antihistamines, e.g. cetirizine, dimetinden,
loratadine, fexofenadine, clemastine
Consider topical steroidsb, e.g. topical hydrocortisone

doi:10.1093/annonc/mdq387 | 7
review Annals of Oncology

Table 4. (Continued)

Severity Intervention concerning Specific intervention

EGFR inhibitor therapy
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for severe toxicity
Severe (grade 3)
Reduce EGFR inhibitor dose as per label See grade 2
Monitor for change in severity
Xerosis (dry skin)
Mild (grade 1)
Continue EGFR inhibitor therapy Soap-free shower gel and/or bath oil
Avoid alcoholic solutions and soaps
Urea- or glycerin-based moisturizer
In inflammatory lesions consider topical steroidsb
(e.g. hydrocortisone cream)
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for grade 2 toxicity
Moderate (grade 2)

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Continue EGFR inhibitor therapy See grade 1
Monitor for change in severity In inflammatory lesions consider topical steroidsb
(e.g. hydrocortisone cream)
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: See recommendations for grade 3 toxicity
Severe (grade 3)
Reduce EGFR inhibitor dose as per label See grade 2
Monitor for change in severity Xerotic dermatitis: topical steroidsb of higher potential
(e.g. prednicarbate, mometasone furoate
Consider oral antibiotics
Fissures
Mild (grade 1)
Continue EGFR inhibitor therapy Propylene glycole 50 % in water for 30 minutes under
plastic occlusion every night, followed by
application of hydrocolloid dressing, or antiseptic
baths (e.g. potassium permanganate therapeutic
baths, final concentration of 1 : 10,000) or
povidoneiodine baths)
Topical application of silver nitrate solutions
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for grade 2 toxicity
Moderate (grade 2)
Continue EGFR inhibitor therapy See grade 1. Consider oral antibiotics
Monitor for change in severity
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for grade 3 toxicity
Severe (grade 3)
Reduce EGFR inhibitor dose as See grade 2
recommended in SmPc
Monitor for change in severity
Nail and periungual toxic effects
Prophylaxis
Continue EGFR inhibitor therapy Minimize trauma and pressure to nails
Education on proper nail trimming
Nongreasy basic care
Mild (grade 1)
Continue EGFR inhibitor therapy See prophylaxis plus
Antiseptic hand bath, e.g. povidone iodine 1 : 10,
potassium permanganate 1 : 10,000 bath

8 | Potthoff et al.
Annals of Oncology review
Table 4. (Continued)

Severity Intervention concerning Specific intervention

EGFR inhibitor therapy
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: See recommendations for grade 2 toxicity
Moderate (grade 2)
Continue EGFR inhibitor therapy See grade 1
Monitor for change in severity Consider silver nitrate solution for granulation tissue
Povidoneiodine ointment
Consider oral antibiotics (tetracyclines if not
superinfected, otherwise consider oral quinolones)
REASSESS AFTER 2 WEEKS!
If worsening or no improvement: see recommendations for grade 3 toxicity
Severe (grade 3), refractory
Reduce EGFR inhibitor dose as per label See grade 2
Monitor for change in severity Oral antibiotics as indicated by resistance results
Consider surgical intervention
REASSESS AFTER 2 WEEKS!

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If worsening or no improvement: see recommendations for grade 4 toxicity
Life threatening (grade 4)
Stop EGFR inhibitor therapy as per label See grade 3
Systemic antibiotics intravenously following resistance
results
Individual treatment concept!

Adapted from [27, 44, 46, 66] and own clinical experiences.
a
Patient should be taking the drug on an empty stomach at the same time each day.
b
Use of a topical steroid should be employed only short-term based on your institutions guidelines.
ADL, activities of daily living; EGFR, epidermal growth factor receptor.

should be kept smooth with urea-containing ointments.
Prophylaxis of fissures by use of urea and glycerol containing
agents may be better than any treatment.
treatment of nail changes. Paronychia should be treated with
daily antiseptic baths to avoid bacterial superinfection.
Topically povidone-iodine-based ointments could be applied.
Hypergranulative tissue formations can be treated with silver
nitrate application on a weekly basis. In severe cases, systemic
oral antibiotics such as doxycycline or minocycline should be
given, but interruption of EGFR inhibitor therapy should be
considered only if treatment fails. When bacterial or fungal
superinfection is suspected, systemic treatment should be based
on the results of bacterial culture [40]. Surgical procedures may
be helpful in selected cases [1].
when to refer to a dermatologist?
The referral to a dermatologist depends on ones own clinical
experiences. In general, lesions classified as grade 3 or higher
should always be managed collaboratively by an oncologist and
a dermatologist. Grade 2 skin reactions may be managed by an
oncologist provided he or she has in-depth knowledge and
extensive clinical experience in the field of toxic effects of the
skin. Otherwise a dermatologist should be consulted. Lesions of
any grade with an unusual appearance or distribution should
always be examined by a dermatologist. Necrosis, blistering,
petechial or purpuric lesions and signs of infection including
cellulitis or atypical dermatologic manifestations that might be
unrelated to EGFR-inhibitor-induced rash should be
immediately examined by a dermatologist.
when to adjust treatment with anti-EGFR
monoclonal antibodies?
If a patient experiences a severe skin reaction grade 3, anti-
EGFR monoclonal antibody therapy must be interrupted
according to SmPC. Treatment, e.g. with panitumumab or
cetuximab, may only be resumed if the reaction has resolved to
grade 2 or below.
is prophylactic treatment recommended?
Prophylactic treatment needs to be safe, well tolerated and not
interfering with the antitumor effect of EGFR inhibition. There
are three randomized controlled studies reported where
prophylactic tetracyclines were applied [52, 53, 63, 64]. Jatoi
et al. [52] compared tetracycline 500 mg b.i.d. versus placebo
and showed that the incidence of skin reactions was similar, but
itching and burning were less severe. Scope et al. [53]
concluded that oral minocycline may be useful in decreasing
severity of acneiform eruption during the first month of
cetuximab treatment, while there was an apparent lack of
benefit of minocycline beyond 2 months. The STEPP trial,
a phase 2, open-label study of prophylactic versus reactive skin
toxicity treatment in panitumumab-treated patients with
metastatic colorectal cancer revealed a statistically significant
reduction of the incidence rates of specific grade 2 or higher

doi:10.1093/annonc/mdq387 | 9
review
toxic effects of the skin of >50% for patients in the prophylactic
treatment arm [6164]. Prophylactic treatment comprised skin
moisturizer, sunscreen (PABA free, SPF 15, UVA/UVB
protection), a topical steroid (1% hydrocortisone cream) and
doxycycline 100 mg b.i.d. [14, 64, 76]. An improved quality of
life and fewer dose delays were reported in the prophylactic
skin treatment arm, while there have been no differences in
antineoplastic efficacy [63, 64, 76]. In summary, however, there
remain a number of unresolved issues due to prophylactic
treatment, e.g. whether or not to give prophylactic agents and,
if given, whether to use topical and/or systemic approaches.
conclusion
Dermatologic toxic effects are the most common side-effects of
EGFR inhibitor therapy. Patients are frequently unable to cope
with these side-effects, leading to poor adherence to cancer
therapy, dose reduction, dose interruption or even cessation
and potentially a reduced quality of life. To date, there are no
evidence-based treatment algorithms for the management or
prophylaxis of skin reactions associated with anti-EGFR
treatment. Thus, besides a precise grading system, a better
treatment plan for managing all grades and forms of these
complications is warranted. The German interdisciplinary
expert recommendations provided here are suggestions for the
grading of EGFR-inhibitor-induced skin reactions as well as
general, grade-specific and stage-adapted treatment approaches
for the treatment of skin reactions induced by EGFR inhibitors.
The most important conclusion is that EGFR-inhibitor-
induced skin reactions can be effectively treated at all stages and
at all grades [26]. All dermatologic effects induced by EGFR
inhibitors are supposed to be reversible.
Concerning the grading of skin toxicity, we recommend
using the NCI-CTCAE version 4.0 grading scale, but one has to
be aware of the worldwide dissemination of version 3.0 and its
usage in clinical trials until recently. Importantly, in our
opinion, in addition to the NCI-CTCAE grading scale, grading
should be strictly based on the grade of severity and not on the
pattern of distribution. Since Bauer et al. [77] had observed an
underreporting of dermatologic adverse drug reactions in
colorectal cancer clinical trials due to incorrect assessment of
skin reactions, a continuous training of physicians in correct
grading should be obligatory and adverse effects reporting
standards for oncology clinical trials should be developed [78].
Concerning treatment strategies, one should always keep in
mind that dermatologic care is supportive and aims at
maintaining quality of life while continuing EGFR inhibitor
treatment [15, 55]. Our recommendation on the start of
treatment of skin reaction is to intervene as early as possible at
the first sign of dermatologic reactions. Basic skin care
combined with a specific therapy adapted to the stage and grade
of skin reaction is recommended. Topical antibiotics like
metronidazole, erythromycine or nadifloxacin are
recommended at the early onset of skin reactions; systemic oral
antibiotics, i.e. the synthetic tetracyclines doxycycline or
minocycline, are recommended for grade 2 dermatologic
toxic effects due to their anti-inflammatory properties [71, 72].
In most cases, this approach allows patients to continue anti-
EGFR treatment without interruption, dose delay or drug
10 | Potthoff et al.
Annals of Oncology
Table 5. Summary of recommendations
The recommendations of the panel are as follows
Skin care recommendations should be given to every EGFR patient upon
initiation of EGFR inhibitor treatment
Treatment intervention should be started immediately after onset of skin
reactions
Treatment intervention should at least be started if grade 2 skin reaction
occurs
In general, a combination of skin-type-adjusted basic skin carea and
a specific therapy adapted to stage and grade of skin reaction is
recommended
Specific therapy
Topical antibiotics like clindamycin, erythromycin, metronidazole or
nadifloxacin are recommended at the early onset of skin reactions
Systemic treatment should be considered if grade 2 skin reaction
occurs. Oral tetracyclines, such as doxycycline or minocycline, are
recommended for treatment of anti-EGFR-induced skin
rash grade 2
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All severely affected patients and all atypical reaction patterns should
be examined by a dermatologist
a
Skin moisturizer, sun protection.
discontinuation [27] and should aim to maintain quality of life
of the patient. Our recommendations are summarized in
Table 5. Importantly, individual clinical judgement must always
be provided when reviewing the treatment algorithms.
Recently, topical use of menadione, a vitamin K2 precursor
[79, 80] or vitamin K1 cream containing urea and 0.1% K1
vitamin applied twice daily [81] showed effectiveness in down-
staging of EGFR-inhibitor-induced rash. Due to results from
the STEPP trial, prophylactic treatment seems to be
a promising management strategy [64]. Nevertheless, the expert
panel concluded that confirmatory trials, e.g. randomized phase
3 trials, are required in order to recommend prophylactic
treatment for routine clinical practice. In the future, however, if
data on prophylactic treatment are more robust, this might
become first choice.
Importantly, the optimal treatment of skin toxicity may only
be achieved by a cooperation of medical oncologists,
dermatologists and pharmacists. Considering evidence-based
treatment approaches, prospective controlled clinical trials are
warranted to further optimize the treatment of anti-EGFR-
induced skin reactions.
funding
KP has received lecture honoraria from Amgen. FL has
received lecture honoraria from Amgen, Merck and Roche. AH
has received honoraria from Amgen, Astra Zeneca, Merck
and Roche. TT has received research grants and travel
support from Amgen. AW has received research grants and
honoraria, and is a paid consultant for Amgen, Merck and
Roche.
acknowledgements
The German expert opinion reflects the consensus opinion of
the authors. The consensus process has been initiated with two
Annals of Oncology
consensus meetings. The authors would like to acknowledge
support from AMGEN GmbH for the organization of both
meetings. AMGEN GmbH had no influence on the content of
the manuscript or the circulation of the manuscript for review
by the expert panel.
disclosures
All authors declare that they have no competing interests. All
authors confirm that, concerning the publication, there is no
funding source that might generate a conflict of interest.
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