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Ann Oncol 2010 Potthoff Annonc Mdq387
Ann Oncol 2010 Potthoff Annonc Mdq387
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
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 Annals of Oncology
and overall survival. The authors suggest that skin reactions of the epidermis, in the outer root sheath of hair follicles, in
should be treated while continuing EGFR-targeted therapy. Data sebaceous and eccrine epithelium; by dendritic cells and various
from the EVEREST trial [11] and from a phase II trial with connective tissue cells [2326]. EGFR signaling stimulates
FOLFIRI and panitumumab [12] did not show any correlation epidermal growth and differentiation, accelerates wound healing
between skin rash and efficacy of anti-EGFR therapy. and stimulates vasoconstriction and keratinocyte migration
Despite the benefits of anti-EGFR agents, toxic effects of the [27,28]. EGFR stimulation activates phosphatidylinositol
skin may eventually result in poor patients compliance, lower turnover, subsequently leading to diacylglycerol formation.
adherence to cancer therapy, more dose delays and During EGFR inhibitor therapy, phosphorylated EGFR is
interruptions or discontinuation of antineoplastic therapy [1, abolished and inflammatory cell chemoattractants like CXCLs
1315]. Finally, toxic effects of the skin may significantly reduce and CCLs are released. Inhibitory proteins for growth-like
the quality of life [14, 16, 17]. Though potential treatment cyclin-dependent kinase inhibitor p27 are upregulated, whereas
suggestions for EGFR inhibitor-associated toxic effects of the phosphatidylinositol turnover, diacylglycerol formation, the
skin have been evaluated in clinical trials, standard guidelines proliferation marker Ki67 and MAPK expression are reduced
have not been published so far. [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
materials and methods and consensus damage and skin atrophy. Severe acute skin reactions show
formation massive neutrophilic infiltration of the epidermis and, profound
apoptosis [27, 29, 30]. Immunohistochemistry and in situ
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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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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frame of peak and onset (Figure 1). The acneiform rash is grades that might occur [27]. All dermatologic effects usually
usually first, starting with an acneiform maculopapular rash are reversible and generally heal without sequelae within
followed by papulopustular rash and crusting [1, 44]. The 4 weeks after treatment discontinuation [9]. In most cases,
severity of the acneiform skin rash usually peaks at 23 weeks therapeutic benefit has been already observed after 35 days
after initiation of therapy. Pruritus, often associated with and after 1week clinically relevant amelioration has been seen.
xerotic skin and exsiccation dermatitis, typically starts after 23 Due to personal experiences, in most of the patients, dry skin
weeks. Fissures do usually not occur before 68 weeks of can be observed even weeks or months after end of EGFR
therapy. Paronychia and hair changes may start after 8 weeks of inhibitor therapy. Prophylactic treatment has not been entered
treatment [32, 45]. The median time to resolution after the into routine clinical practice, although first results have pointed
final dose of EGFR inhibitor is reported to be 28 days [46]. out a significant benefit of preemptive treatment [14, 6164].
Treatment recommendations reported here are based on
grading of skin reactions severity, i.e. grade, and stage of dermatologic reaction. They are
divided into general recommendations and side-effect-specific
The National Cancer Institute (NCI) has developed the common
recommendations. Importantly, these recommendations do not
terminology criteria for adverse events (NCI-CTCAE), including
offer personalized medical diagnosis or patient-specific
a grading scale for severity that is widely used for adverse events
treatment advice. All decisions regarding patient care must
reported in clinical trials [47, 48]. The NCI-CTCAE version 3.0
integrate the unique characteristics of the patient and the
grading scale published in 2006 has been used most often for
individuals response to different treatment modalities.
evaluation of EGFR-inhibitor-induced skin toxicity. In addition,
Frequent clinical follow-up by an experienced dermatologist or
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Table 1. Grading of skin reactions
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, 52, 53]. They are recommended for skin rash grade 2.
such as pimecrolimus, were reported to be effective, too [70]. Although microbial pathogens are typically absent in early-
Recently, however, a randomized controlled trial showed stage EGFR-inhibitor-induced skin reactions, oral tetracyclines
pimecrolimus to be ineffective for cetuximab-induced are recommended for their immunomodulating and anti-
rash [54]. inflammatory effects [71, 72]. The adverse events of
Oral tetracyclines, such as doxycycline or minocycline, minocycline include vestibular dizziness and loss of balance, as
reduce the severity and extent of the acneiform eruption [14, well as postinflammatory hyperpigmentation, drug-induced
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Table 2. General recommendations for prophylaxis while receiving anti-EGFR inhibitor treatment
Personal hygiene 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
Sun protection 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
Moisturizer treatment 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]
Prevention of paronychia Patients should keep their hands dry and out of water if ever possible
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
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Table 4. Stage- and grade-specific treatment of skin reactions
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Table 4. (Continued)
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Annals of Oncology review
Table 4. (Continued)
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. unrelated to EGFR-inhibitor-induced rash should be
Prophylaxis of fissures by use of urea and glycerol containing immediately examined by a dermatologist.
agents may be better than any treatment.
treatment of nail changes. Paronychia should be treated with when to adjust treatment with anti-EGFR
daily antiseptic baths to avoid bacterial superinfection. monoclonal antibodies?
Topically povidone-iodine-based ointments could be applied. If a patient experiences a severe skin reaction grade 3, anti-
Hypergranulative tissue formations can be treated with silver EGFR monoclonal antibody therapy must be interrupted
nitrate application on a weekly basis. In severe cases, systemic according to SmPC. Treatment, e.g. with panitumumab or
oral antibiotics such as doxycycline or minocycline should be cetuximab, may only be resumed if the reaction has resolved to
given, but interruption of EGFR inhibitor therapy should be grade 2 or below.
considered only if treatment fails. When bacterial or fungal
superinfection is suspected, systemic treatment should be based is prophylactic treatment recommended?
on the results of bacterial culture [40]. Surgical procedures may
Prophylactic treatment needs to be safe, well tolerated and not
be helpful in selected cases [1].
interfering with the antitumor effect of EGFR inhibition. There
are three randomized controlled studies reported where
when to refer to a dermatologist? prophylactic tetracyclines were applied [52, 53, 63, 64]. Jatoi
The referral to a dermatologist depends on ones own clinical et al. [52] compared tetracycline 500 mg b.i.d. versus placebo
experiences. In general, lesions classified as grade 3 or higher and showed that the incidence of skin reactions was similar, but
should always be managed collaboratively by an oncologist and itching and burning were less severe. Scope et al. [53]
a dermatologist. Grade 2 skin reactions may be managed by an concluded that oral minocycline may be useful in decreasing
oncologist provided he or she has in-depth knowledge and severity of acneiform eruption during the first month of
extensive clinical experience in the field of toxic effects of the cetuximab treatment, while there was an apparent lack of
skin. Otherwise a dermatologist should be consulted. Lesions of benefit of minocycline beyond 2 months. The STEPP trial,
any grade with an unusual appearance or distribution should a phase 2, open-label study of prophylactic versus reactive skin
always be examined by a dermatologist. Necrosis, blistering, toxicity treatment in panitumumab-treated patients with
petechial or purpuric lesions and signs of infection including metastatic colorectal cancer revealed a statistically significant
cellulitis or atypical dermatologic manifestations that might be reduction of the incidence rates of specific grade 2 or higher
doi:10.1093/annonc/mdq387 | 9
review Annals of Oncology
toxic effects of the skin of >50% for patients in the prophylactic Table 5. Summary of recommendations
treatment arm [6164]. Prophylactic treatment comprised skin
moisturizer, sunscreen (PABA free, SPF 15, UVA/UVB The recommendations of the panel are as follows
protection), a topical steroid (1% hydrocortisone cream) and Skin care recommendations should be given to every EGFR patient upon
doxycycline 100 mg b.i.d. [14, 64, 76]. An improved quality of initiation of EGFR inhibitor treatment
life and fewer dose delays were reported in the prophylactic Treatment intervention should be started immediately after onset of skin
skin treatment arm, while there have been no differences in reactions
antineoplastic efficacy [63, 64, 76]. In summary, however, there Treatment intervention should at least be started if grade 2 skin reaction
remain a number of unresolved issues due to prophylactic occurs
treatment, e.g. whether or not to give prophylactic agents and, In general, a combination of skin-type-adjusted basic skin carea and
if given, whether to use topical and/or systemic approaches. a specific therapy adapted to stage and grade of skin reaction is
recommended
Specific therapy
conclusion Topical antibiotics like clindamycin, erythromycin, metronidazole or
Dermatologic toxic effects are the most common side-effects of nadifloxacin are recommended at the early onset of skin reactions
EGFR inhibitor therapy. Patients are frequently unable to cope Systemic treatment should be considered if grade 2 skin reaction
with these side-effects, leading to poor adherence to cancer occurs. Oral tetracyclines, such as doxycycline or minocycline, are
therapy, dose reduction, dose interruption or even cessation recommended for treatment of anti-EGFR-induced skin
and potentially a reduced quality of life. To date, there are no rash grade 2
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All authors declare that they have no competing interests. All
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