review
Background: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as
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
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
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
Annals of Oncology
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.
review
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
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.
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].
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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
oncologist is obligatory, i.e. at least every 2 weeks, including
immediate consultation if flare-up occurs [22, 32].
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Annals of Oncology
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Grade 1
Rash/desquamation (acne/acneiform)
Macular or papular eruption or erythema without associated
symptoms (intervention not indicated)
Macular or papular eruption or erythema with pruritus or other
associated symptoms; localized desquamation or other lesions
covering <50% of BSA (intervention indicated)
Severe, generalized erythroderma or macular, papular or
vesicular eruption; desquamation covering 50% of body
surface area (associated with pain, disfigurement, ulceration,
or desquamation)
Generalized exfoliative, ulcerative, or bullous dermatitis ()
Death
Photosensitivity
Painless erythema
Grade 2
Grade 3
Painful erythema
Erythema with desquamation
Grade 4
Grade 5
Grade 1
Grade 2
Grade 3
Grade 1
Pruritus
Mild or localized
Intense or widespread
Nail changes
Discoloration; ridging (koilonychias); pitting
Grade 2
Grade 3
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
Painless erythema and erythema covering <10% BSA by an
increase in sensitivity
Tender erythema covering 10%30% BSA
Erythema covering >30% BSA and erythema with blistering;
photosensitivity; oral corticosteroid therapy indicated; pain
control indicated (e.g. narcotics or nonsteroidal
anti-inflammatory drugs)
Life-threatening consequences; urgent intervention indicated
Death
Mild or localized; topical intervention indicated
Intense or widespread; intermittent; skin changes from
scratching (e.g. edema, population, excoriations,
lichenification, oozing/crusts); oral intervention indicated;
limiting instrumental ADL
Intense or widespread; constant; limiting self-care ADL or
sleep; oral corticosteroid or immunosuppressive therapy
indicated
In v4.0 nail changes are divided into
Nail discoloration: grade 1: asymptomatic; clinical or
diagnostic observations only; intervention not indicated
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
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.
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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
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
Rational
Manipulation of skin
Hot blow-drying of the hair
Wearing of tight shoes
Topical acne medications,a
e.g. retinoids, alphahydroxy-acid and benzoyl
peroxide gel or cream
Topical steroidsa
They may irritate and worsen antiEGFR-induced skin rash due to their
drying effects [44]. Topical retinoids
may be irritating, and systemic
retinoids may aggravate xerosis and
increase itch sensation and are not
generally recommended
They may cause perioral dermatitis and
skin atrophy if used inadequately [26]
Both substance classes should, in the panels view, only be used under the
supervision of a dermatologist, as unwanted side-effects may occur if used
inadequately. Individual patients with anti-EGFR-induced acneiform rash
may benefit from topical adapalene, a synthetic retinoid with a significantly
lower incidence of irritative side-effects compared with tretinoin and a very
low rate of systemic absorption after topical administration. Due to the
panels view, adapalene, however, should be kept on a list of optional drugs
without proven efficacy and with only use under strict supervision of
a dermatologist.
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Intervention concerning
EGFR inhibitor therapy
Specific intervention
Skin-type-adjusted moisturizer
Topical treatment like grade 1 plus short-term
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
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Annals of Oncology
Table 4. (Continued)
Severity
Intervention concerning
EGFR inhibitor therapy
Specific intervention
See grade 2
Mild (grade 1)
See grade 1
In inflammatory lesions consider topical steroidsb
(e.g. hydrocortisone cream)
See grade 2
Xerotic dermatitis: topical steroidsb of higher potential
(e.g. prednicarbate, mometasone furoate
Consider oral antibiotics
Fissures
Mild (grade 1)
Continue EGFR inhibitor therapy
See grade 2
Prophylaxis
Mild (grade 1)
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Table 4. (Continued)
Severity
Intervention concerning
EGFR inhibitor therapy
Specific intervention
See grade 1
Consider silver nitrate solution for granulation tissue
Povidoneiodine ointment
Consider oral antibiotics (tetracyclines if not
superinfected, otherwise consider oral quinolones)
See grade 2
Oral antibiotics as indicated by resistance results
Consider surgical intervention
See grade 3
Systemic antibiotics intravenously following resistance
results
Individual treatment concept!
Adapted from [27, 44, 46, 66] and own clinical experiences.
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.
a
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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-inhibitorinduced 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 antiEGFR treatment without interruption, dose delay or drug
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
doi:10.1093/annonc/mdq387 | 533
review
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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