Epidermal growth factor receptor (EGFR) inhibitors are an increasingly important treatment option for metastasized cancer in patients. In addition to the pivotal role of EGFR in the development and progression of malignant tumors, EGFR is also important for proliferation and differentiation of the human epidermis and hair follicles. As a consequence, cutaneous side-effects are frequently observed during cancer therapy with EGFR inhibitors. During the first few weeks of treatment, acneiform eruptions are the earliest common side-effect. Xerosis and fissures are complications appearing in later treatment phases. Paronychia and alterations in hair growth are less common and generally seen after a longer period of treatment. We present an overview of the various cutaneous side-effects associated with EGFR inhibition and discuss their respective therapeutic options.
anti-EGFR, epidermal growth factor receptor inhibitors, cutaneous side-effects, acneiform eruption, paronychia, xerosis, management
The epidermal growth factor receptor (EGFR), a 170-kd transmembrane glycoprotein, is a member of the type 1 receptor tyrosine kinase (TK) family. The EGFR is physiologically expressed in epithelial tissues and hair follicles, where it contributes to epidermal proliferation, differentiation, and hair growth. In addition, EGFR is overexpressed in many solid tumors, where it is involved in tumor growth, cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis.1 Preclinical and clinical studies have shown that inhibiting EGFR is a valid strategy in anticancer therapy.1,2
Different strategies for EGFR inhibition have been described,3 two of which entered routine clinical use: EGFR-targeting monoclonal antibodies (MoAbs) bind specifically to the extracellular domain of the receptor and competitively inhibit ligand binding,1 and tyrosine kinase inhibitors suppress EGFR signaling at the intracellular domain of the receptor.1 Experimental data exist for EGFR ligand toxin and EGFR immunotoxin conjugates. These novel drugs are composed of an EGFR ligand or EGFR-binding antibody and a cytotoxic agent. Finally, antisense oligonucleotides specific for the EGFR or EGFR ligand messenger ribonucleic acids (RNAs) may decrease EGFR expression, thus resulting in inhibition of proliferation and induction of apoptosis.
As of July 2010, there are two monoclonal antibodies (cetuximab, Erbitux® and panitumumab, Vectibix®) and one receptor tyrosine kinase inhibitor (Gefitinib, Iressa®) that are currently licensed for clinical use in many countries.1 Gefitinib is a historic tyrosine kinase inhibitor that did not show significant survival benefit.4 Lapatinib (Tykerb®/Tyverb®) and canertinib (CI-1033) are currently developed tyrosine kinase inhibitors.4-5 Lapatinib is under investigation for the second-line treatment of metastatic colorectal cancer, whereas canertinib is being studied for progressive, recurrent, locally advanced or metastatic non-small cell lung carcinoma, and metastatic breast cancers.6,7
The safety profile of EGFR-inhibitors is characterized by a class effect comprised of unique skin reactions, including acneiform rash, xerosis, eczema, paronychia, and changes in the hair and nails.8 Hyperpigmentation, trichomegaly, and telangiectasia are less commonly seen. EGFR inhibitor-induced urticarial and anaphylactoid reactions are frequently seen in the US, but these are rarely encountered in Europe.9-10 Here, we review the diagnostic procedures and current treatment options for the more common side-effects of EGFR inhibitors.4,8,11-16
Acneiform eruptions are the earliest and most characteristic side-effect of EGFR inhibition. The incidence may be as high as 75% to 100% of cases.2,4,8,14,16-19 Evidence suggests that severity of the skin rash might be a surrogate marker determining clinical outcome of patients receiving EGFR inhibitor treatment.1,19-21 The eruption usually occurs after 1 week of treatment. The characteristic distribution pattern is similar to that of acne vulgaris, but there are no comedones present. Although these eruptions are considered a class effect from EGFR inhibition, antibody-induced eruptions tend to be more severe than TK1 induced skin changes.4
The pathogenesis of acneiform eruptions caused by EGFR is not yet fully understood. Histopathological analysis showed a neutrophilic suppurative infiltrate in the dermis, particularly involving the follicular infundibula. The follicles are frequently enlarged and sometimes obstructed by excess keratinocytes. The sebaceous glands are usually not affected. No consistent changes in the cutaneous microflora have been found.4
Grading of acneiform eruptions is performed with two different scoring systems, depending if quick severity classification or sensitive follow-up of treatment success is the goal of grading. The oncological classification, National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0, allows for a quick severity estimation of skin toxicity reactions. It provides a clinical score with five grades of severity.4 The dermatological skin score (WoMoScore) is a sensitive dermatologic scoring system for the long-term assessment of acneiform skin rashes that has been used in our department since 2006.22 The final WoMoScore is calculated from body involvement, facial involvement, and clinical grading of erythema, papulation, postulation, scaling, and crusts, providing a clinical score ranging from 0 to 100.22 Mild skin changes score up to 20, moderate cases range between 20 and 40, whereas severe acneiform eruptions exceed a WoMoScore of 40.20
Treatment of Acneiform Eruptions
Treatment of mild acneiform eruptions mostly involves
conventional topical medications used for acne vulgaris, such as metronidazole, erythromycin, and clindamycin.4,8
Topical combination therapy with nadifloxacin 1% cream and prednicarbate 0.25% cream is our standard regimen for moderate acneiform eruptions.22 An uncontrolled, open label, follow-up study involving 29 cancer patients with cetuximab- induced acneiform eruptions initially demonstrated clinical efficacy with significant reduction of the WoMoScore after 1,
2 and 6 weeks of therapy.22 Both drugs were selected because nadifloxacin has antimicrobial as well as immunomodulatory effects on the antigen-presenting function of Langerhans cells and keratinocytes,23 and prednicarbate is a well established anti-inflammatory topical corticosteroid with an improved risk- benefit ratio.24
Preclinical data suggest that topical application of the potent phosphatase inhibitor menadione (vitamin K3) might rescue the inhibition of EGFR and downstream signaling molecules in the skin of mice receiving systemic EGFR inhibitors erlotinib (Tarceva®) or cetuximab.25 In a non-randomized study with
30 patients, acneiform eruptions were reduced significantly by the topical use of a cream containing urea and 0.1% K1 vitamin (Reconval K1®).26
Oral tetracyclines have been used for the treatment of acne vulgaris for more than 50 years27 because of their anti- inflammatory and immunomodulatory properties.28-30 These broad-spectrum polyketide antibiotics reduce neutrophilic chemotaxis and inhibit the production of proinflammatory cytokines and matrix metalloproteinase 9.29 Some recent studies investigated the benefit of prophylactic tetracycline for EGFR- induced acneiform eruptions.31-32 Tetracycline-treated patients reported less itching, burning, stinging, and other subjective symptoms compared with placebo. However, prophylactic tetracyclines did not lower the total incidence of the rash.31-32
Tetracyclines are clearly effective, but they may lead to unwanted systemic effects that are not encountered with topical treatment.
Our first choice for severe acneiform eruptions is early treatment with a combination of low dose oral retinoid, topical nadifloxacin, and topical prednicarbate.21-22 We limit the use of this highly effective “triple therapy” to the first 2-3 months of EGFR- inhibitor treatment.21 Some authors have raised the issue of increased xerosis or reduced anticancer properties of the EGFR- inhibitors, 5,10,11 whereas others see a potential synergistic effect of this combinatorial approach.11
Management of acneiform skin eruptions is influenced by the level of dermatological background of the treating physician.33
Dermato-oncologists are using oral isotretinoin more frequently, compared with oncologists, and are delaying EGFR inhibitor treatment less frequently because of skin toxicities.33 An interdisciplinary approach in cooperation with dermatologists is highly recommended to improve patient treatment.8,33
EGFR inhibitor-induced paronychia is seen in about 10% to 15% of all treated patients and may be quite painful, adversely affecting their quality of life.12 It generally does not develop during the first 6 weeks of treatment. Patients frequently present with involvement of the great toenails. Fingernail involvement may lead to significant functional impairment. Periungual abscesses and pyogenic granuloma may develop in some cases.4,8,15 A recent study showed that a wide variety of Gram-positive and Gram- negative bacteria, as well as Candida albicans, may be cultured from the nail lesions.15
Initial stages of paronychia should be treated with topical antiseptic measures and application of antiseptic or antibiotic ointments. Antiseptic treatment should be continued after systemic therapy has been initiated. Systemic treatment of paronychia is recommended for all painful or infected lesions, as there is a risk for the development of erysipelas, deep panaritium, and tendon sheath phlegmon. Calculated antibiotic treatment of paronychia is recommended with oral cephalosporines, but oral fluoroquinolones may also be used, especially if Gram-negative infection is suspected. Surgical intervention may be necessary in selected cases, such as ingrown toe nails.4,8,15
Xerosis is also considered a class effect of EGFR inhibitors, as it affects most treated patients to a variable degree. Xerosis typically presents as dry, scaly, itchy skin that can be found on any part of the human body. Some patients may also experience dryness of vaginal and perineal regions. Xerosis may progress to chronic asteatotic eczema and become infected with Staphylococcus aureus or herpes simplex virus. Severe cases of pulpitis sicca (dry skin on the tips of the fingers and toes) with painful rhagades have also been described.4,8
First-line treatment of xerosis is the liberal use of emollients, which should be started within the first days of initiating EGFR inhibitor treatment. This prophylactic approach is safe and effective, and may prevent the onset of eczema. 4,8
Painful fissures on the tips of fingers and toes, on the nailfolds, and especially over the interphalangeal joints may develop as a consequence of excessively dry skin. Fissures are less common late phase reactions from therapy with EGFR inhibitors. They occur in about 25% of patients and are characterized by pain, severe tenderness, and poor healing tendency.4,8 Fissures are challenging to treat. Silver nitrate solution, creams containing urea under plastic occlusion, and topical antibiotics can be used. Liquid cyanoacrylate glue may be tried for recurrent cases.4,8
Further Cutaneous Side-effects
Trichomegaly, with or without additional hypertrichosis, may develop after 2 to 5 months of continuous anti-EGFR treatment. Trichomegaly may cause visual discomfort, but can be effectively treated by trimming the eye lashes. The higher expression of EGFR in the outer root sheath of the hair follicles may be causative for this infrequent but characteristic side-effect.4,8,12
Hyperpigmentation may appear after several months of EGFR inhibitor therapy. As bleaching creams have not been shown to be effective, patients must wait for the hyperpigmentation to fade over several months.4,12
Telangiectasias may occur together with acneiform eruptions and follow the same pattern on the face and trunk. These telangiectasias vanish with time, but often leave some degree of hyperpigmentation.4,12
Painful aphthae and larger erosions may appear on the oral mucosa, lips, and nose, as well as on the anal and genital mucosa. Localized measures that are pain-relieving and soothing will provide considerable symptomatic relief.
Patients must be warned to stay out of the sun, because photosensitivit y is increased during therapy with EGFR inhibitors and quite severe acneiform reactions can be triggered by UV exposure. Consequently, the prophylactic use of sunscreens is highly recommended to prevent these solar-induced reactions.
EGFR inhibitors are associated with a unique group of class- specific cutaneous toxicities, which include acneiform eruptions, paronychia, xerosis, hyperpigmentation, trichomegaly, and telangiectasia. As the use of EGFR inhibitors increases, a growing number of cutaneous side-effects will be treated by dermatologists. The discomfort caused by the cutaneous toxicities can reduce compliance with anti-EGFR therapy. For this reason, consequent treatment and psycho-dermatological support are very important. Almost all side-effects are temporary and will resolve several weeks after discontinuation of EGFR inhibitor therapy. It is import to educate patients about these side-effects, in order to increase compliance.
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