1 Department of Dermatology, University Hospital, Katholieke Universiteit Leuven 2 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
* Correspondence to: Prof. Dr E. Van Cutsem, Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: +32-16-344-218; Fax: +32-16-344-419; Email: eric.vancutsem{at}uz.kuleuven.ac.be
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Abstract |
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Key words: acneiform eruption, cetuximab, epidermal growth factor receptor, erlotinib, gefitinib
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Introduction |
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The chimeric antibody cetuximab has been investigated alone and in combination with irinotecan in patients with refractory metastatic colorectal cancer and has shown a consistent activity in EGFR-expressing chemotherapy-refractory CRC [2]. In the pivotal BOND study, the combination of cetuximab plus irinotecan led to a response rate of 23% in patients with irinotecan refractory EGFR-positive metastatic CRC and to a tumour stabilisation in 33% of patients. The response rate after cetuximab alone in this trial was 11% [2
]. In this and other studies, no correlation was found between the strength of the EGFR expression as determined by immune-histochemistry and response rate [2
, 8
]. Therefore more tools are needed to define tumours in which EGFR inhibitors are really active.
Panitumumab (ABX-EGF) is a fully human monoclonal antibody that inhibits the EGFR. As monotherapy, a response rate of 11% has been found in chemorefractory CRC [4]. The humanised monoclonal antibody matuzumab (EMD72000 is in early phase 2 development in different tumour types [5
]. The EGFR tyrosine kinase inhibitors gefitinib, erlotinib and EKB-569 have been studied less extensively in CRC, but seem to be less active in CRC [6
, 7
].
EGFR inhibitors are generally well tolerated and do not have the severe systemic side-effects usually seen with cytotoxic drugs. However, they often cause signs of skin toxicity, most often an acneiform eruption [210
]. A correlation has been suggested between the acneiform eruption and EGFR inhibitor antitumour activity [2
, 3
, 10
]. Prospective studies including skin and tumour biopsies are, however, needed to clarify and explain this possible relationship.
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Clinical findings |
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The acneiform eruption arises a few days after treatment with the EGFR inhibitor, to reach a maximum after 2 [9] to 3 weeks [2
] following commencement of the therapy. More rarely (11%) the rash occurs in a delayed fashion after the first 3 weeks of treatment (with cetuximab) [2
]. Some spontaneous improvement can be seen even when treatment is continued [9
]. However, a flare-up of the rash can occur following each infusion of further treatment [23
]. The eruption disappears in a few weeks time when treatment is discontinued leaving sometimes residual hyperpigmentation and xerosis [21
]. No relationship has yet been observed between the appearance or severity of the rash and a history of oily skin, acne [20
] or rosacea.
Microscopic evaluation of the skin lesions shows a picture of a neutrophilic folliculitis and perifolliculitis [20, 21
, 23
, 26
]. An early infiltration with T-lymphocytes is followed by a hyperkeratotic, ectatic appearance of the follicular infundibula and a florid, neutrophilic suppurative infiltrate [20
]. Intra-epidermal acantholysis is sometimes present but the significance of this finding is unknown [20
]. In contrast to true acne, no clear formation of comedones is seen [28
], although the absence of early biopsy specimens cannot exclude the formation of a microcomedo as the trigger of inflammation. The pustules are notably sterile with negative cultures or stainings for bacteria, fungi, yeasts (including Malassezia furfur) or Demodex mites [23
, 24
] but no quantitative or longitudinal microbiological investigations have been carried out yet. The (pre-existing?) presence of Propionibacterium acnes or Malassezia furfur could only be demonstrated in a few exceptional cases [20
, 21
, 24
].
Xerosis and related changes
Patients receiving EGFR inhibitors can gradually develop a dry skin over weeks resembling the xerosis in atopic eczema [21, 25
, 27
]. Patient's old age, previous therapy with cytotoxics and history of atopic eczema will accentuate the cutaneous dryness, which manifests with dry, scaly, itchy skin especially of the limbs and of skin areas that were affected by acneiform eruption [21
]. The xerosis may develop into chronic asteatotic eczema. When secondary infection of the xerotic skin with Staphylococcus aureus occurs, a flare-up of acute oozing dermatitis and sometimes yellow crusting may be seen. Rarely the compromised epidermal barrier in these patients is the portal of entry for secondary infection with herpes simplex virus, manifesting with a monomorphous picture with numerous tiny vesicles. The fingertops and toes may develop a dry pulpitis with dry scaly eczema. Painful fissures may arise on the fingers and toes, mainly at the tops, in the nail folds and over the interphalangeal joints [20
, 27
] (Figure 2). Along with the xerosis, increased skin fragility and easy bruising are observed in patients receiving EGFR inhibitors [21
]. Sometimes involvement of the mucosae can be seen with vaginal dryness [27
] or aphtous ulcers of the oral or nasal mucosa [20
, 25
].
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Pathophysiology |
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In the spectrum of drug-induced skin changes, the combination of the itchy acneiform eruption, xerosis, paronychia, hair changes and telangiectasia is entirely unique. Classical inducers of acneiform eruption are corticosteroids, vitamin B and antiepileptics, but this rash usually does not itch and is not accompanied by the other skin findings elicited by EGFR inhibitors [28]. Oral retinoids may induce xerosis and paronychia but not acneiform changes [43
]. The only common finding in the kaleidoscope of dermatologic effects induced by EGFR inhibitors is that they occur in sites where EGFR is known to be expressed, namely the basal epidermal cells, sebaceous glands, hair follicle outer root sheath and hair shaft and the capillary system [44
].
The mechanism by which inhibition of EGFR leads to acneiform eruption and the other dermatologic symptoms is largely unknown. EGFR activation serves essential functions in the skin such as the promotion of keratinocyte proliferation, survival and motility and the regulation of differentiation and keratinisation [45]. Hence EGFR occupies a central role in carcinogenesis, psoriasis and wound healing [45
]. Wound healing problems are, however, not seen with EGFR inhibitors. Numerous pharmacodynamic studies have confirmed molecular effects in the skin of patients treated with different EGFR inhibitors. Not unexpectedly, a dramatic decrease of the phosphorylation status of the EGFR in the epidermis and in the percentage of activated MAPK-positive epidermal cells was noticed in gefitinib-treated patients [12
] together with thinning of the corneal layers, decreased labelling of cells with the proliferation marker Ki67 and increased numbers of cells that are immunohistochemically positive for the cyclin-dependent kinase inhibitor p27, a marker for growth arrest [46
]. Epidermal p27 upregulation was also seen in cetuximab-treated patients [20
] as well as decreased thickness of stratum corneum and decreased Ki67 labelling following erlotinib therapy [16
]. The keratinocyte growth arrest and thinning of the corneal layers is in line with EGFR's role in maintaining keratinocyte proliferation [45
] and in promoting late terminal differentiation [47
] but is hard to explain the acneiform aspect of the eruption (a follicular papulopustular eruption mostly confined to the seborrheic areas) observed in the majority of patients receiving EGFR inhibitors. The expression of EGFR in the pilosebaceous unit, both in follicular keratinocytes and in sebocytes [44
], is likely to play an, as yet, unidentified but major role in the follicular localisation of the eruption in regions rich in sebaceous glands. Similar folliculitis changes in the skin of EGFR knockout mice confirm the importance of EGFR in the hair follicle (or pilosebaceous unit) [42
].
The study of the pathophysiology of acne or acneiform eruptions is considerably hampered by the lack of reliable animal models [28]. In an in vitro acne model system, EGF was recently demonstrated to facilitate the development of acne by causing disorganisation of infundibular keratinocytes enhancing the entry of inflammatory sebum into the dermis [48
]. These results sharply contrast with the acneiform eruption in patients on EGFR inhibitors. This discrepancy may be explained by the limitations of the in vitro model or by the fact that both EGFR overstimulation and inhibition lead to disorganisation of the pilosebaceous unit leading to follicular inflammation. In addition, it should be stressed that no blackheads or whiteheads precede the follicular papules or pustules of an acneiform eruption, unlike acne, which typically starts with the formation of comedones by follicular hypercornification due to seborrhoea [28
].
Until now, most of the considerations about the mechanisms behind EGFR inhibitor-induced acneiform eruption imply effects on (follicular) keratinocyte proliferation and differentiation that cause secondary inflammation. However, EGFR targeted therapies may affect the immune system more directly as well, by unblocking cutaneous chemokine production resulting in leukocyte chemotaxis and infiltration in the skin based on a recent study attributing a role to cutaneous EGFR in the suppression of chemokine production [49].
The EGFR inhibitor-induced xerosis can be explained more easily by the established role of EGFR in the maintenance of the integrity of the epidermal permeability barrier [50], whereas the skin fragility and epidermal thinning refer to the involvement of EGFR in keratinocyte proliferation, differentiation and survival [45
]. Moreover dryness and fragility of the skin can be reproduced in EGFR knockout mice [41
].
The hair changes reflect the role of EGFR and its ligands in hair follicle biology and hair cycling. Similar hair changes can be seen in transgenic mice or spontaneous mutants affecting EGFR, its ligands or its partner receptors [42, 51
53
], including long and curly whiskers corresponding to the trichomegaly in patients on EGFR inhibitors [33
, 34
].
Paronychia and pyogenic granuloma of the nail fold resemble the side-effects of systemic retinoids [43]. Retinoids are also well known to cause xerosis but no acneiform eruption, telangiectasia or hyperpigmentation [43
]. This partly overlapping side-effect profile may be due to the downregulating effects of retinoids on the EGFR system [54
] or alternatively to the similar effects of retinoids and EGFR inhibitors on epidermal proliferation and differentiation [43
, 45
]. Xerosis and desquamation of nail fold and nail bed epidermis may cause epidermal squames to be stuck between the nail plate and the surrounding epidermis inducing chronic irritation and inflammation [55
]. The development of pyogenic granuloma may reflect effects on angiogenic factors such as vascular endothelial growth factor (VEGF) that are overexpressed in these lesions [56
]. The effects of retinoids on VEGF expression in vitro are known to depend on culture conditions displaying inhibition as well as stimulation [57
]. EGFR inhibitors have been demonstrated to inhibit VEGF expression and angiogenesis [58
] but it is unknown whether these drugs could also induce VEGF in some tissues (skin) under certain circumstances. Moreover, the very peculiar development of telangiectasia could also be linked to disturbances in the production of angiogenic factors.
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Management |
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General measures
To ensure a maximal hydration of the skin, the use of bath oil or shower oil (instead of shower gel or soap) and of tepid water to wash should be encouraged. To prevent xerosis, an emollient cream (especially on the limbs) can be used. Sun exposure should be avoided and/or effective sun barrier preparations should be used to minimise the risk of hyperpigmentation.
Acneiform eruption
For mild grade 1 reactions, no treatment or treatment with topical anti-acne or anti-rosacea agents with anti-inflammatory properties can be started (e.g. metronidazole gel or cream, erythromycin or clindamycin gel or lotion, benzoylperoxide gel or cream on the face or salicylic acid in alcoholic lotion on chest/back). One should bear in mind that this topical treatment has drying properties and may aggravate xerosis. When the acneiform eruption is fading or becoming scaly, one should switch topical treatment to cream bases instead of alcoholic lotions or gels.
In patients treated with erlotinib, no effect was seen with topical retinoids, vitamin D analogues or steroids [9]. Except in the presence of eczema (see below), the use of topical or systemic steroids should be avoided since they are well known to induce or aggravate acne, acneiform eruption, rosacea or telangiectasia [28
]. Moreover systemic steroids may interfere with the antibody-dependent cytotoxic action of EGFR antibodies. Although anticomedonal topicals such as retinoids (tretinoin) or
-hydroxyacids have been advocated in some reports [21
, 61
], we would not recommend them because of the lack of comedones [27
] and the possible aggravation of xerosis and eczema [21
].
For grade 2 reactions, topical treatment as for grade 1 can be used together with topical menthol cream or an oral antihistamine (cetirizine, loratadine, hydroxyzine) when itch is present and an oral tetracycline (minocycline 100 mg/day, lymecycline 300 mg/day or doxycycline 100 mg/day) [21, 23
]. Thanks to their anti-inflammatory properties, tetracyclines exert marked anti-acne effects, when given in a course of at least 3 months [28
]. Oral isotretinoin is not recommended because of its overlapping side-effect profile (xerosis, paronychia) [43
] and its unknown interaction with the antitumoural properties of EGFR inhibitors.
In the case of grade 3 reactions, delay of therapy with EGFR inhibitors should be taken into consideration. In addition to the aforementioned topicals, compresses with physiologic solution can be applied in the case of acute inflammation. Oral anti-histamines and oral tetracyclines at high (maximal anti-inflammatory) doses (minocycline 2x100 mg/day, lymecycline 2x300 mg/day or doxycycline 2x100 mg/day) complete the treatment. The dose can be tapered as soon as the acute inflammation has faded.
Grade 4 reactions, although extremely seldom, should be treated in specialised burn care units and EGFR inhibitors should be immediately stopped for good.
Xerosis
Apart from the general hydrating measures, the right vehicle choice to treat skin conditions is indispensable to alleviate skin dryness. In this respect alcoholic lotions or gels should be discontinued when the first signs of dryness appear and switched to oil in water creams instead (on face/chest/back). On the limbs greasy (water in oil) creams or even ointments can be used for moderate to severe xerosis. The right balance should, however, always be kept since occlusive ointments may facilitate the development of folliculitis lesions. When eczema is present, topical weak corticosteroids are recommended for a short term (12 weeks). When eczema becomes wet, a swab for bacterial (or viral culture) can be taken and treatment with topical (fusidic acid) or in severe cases systemic antibiotics (penicillinase-resistant pennicillins) can be added. In the rare case of herpes simplex virus superinfection, treatment with systemic antiviral drugs is necessary. Fissures can be treated with propyleneglycol 50% solution under plastic occlusion, salicylic acid 10% ointment, a hydrocolloid dressing, flurandrenolone tape or liquid cyanoacrylate glue [27].
Paronychia
As a preventive measure, it is important to avoid friction and pressure on the nail fold by wearing shoes that are not too tight. The paronychia caused by EGFR blockers are not infective in nature but render the nail folds very sensitive to infection [30, 32
]. Topical antiseptics or antibiotics (soaks and/or creams) should, therefore, be used on a regular basis. In our hands, a drying paste containing an antiseptic (chlorhexidine), an anti-yeast (nystatin) and in severe cases a topical corticosteroid [29
, 31
] has proved helpful in the treatment of paronychia. In case of secondary bacterial infection, oral antibiotics can be administered according to the antibiogram. Although the nail fold inflammation caused by EGFR inhibitors mimics the clinical picture of an ingrown nail, partial nail bed excision has no effect. Total nail extraction with destruction of nail matrix may help but then the nail is permanently lost (own experience). Silver nitrate application on a weekly basis will improve pyogenic granuloma.
Telangiectasia
Telangiectasia caused by treatment with EGFR inhibitors, unlike spontaneous telangiectasia, will gradually disappear over months. In selected cases electrocoagulation or pulsed dye laser therapy can be applied to accelerate disappearance.
Hyperpigmentation
Since the excessive pigmentation appears to be mostly postinflammatory in nature, adequate prevention and treatment of acneiform eruption and eczema is important. Another preventive measure is to avoid the unfavourable effect of the sun, by minimising sun exposure and encouraging the use of sun blocking creams. Bleaching creams are not very helpful; the hyperpigmentation will fade spontaneously with time (months).
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Conclusion |
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Received for publication February 3, 2005. Revision received May 3, 2005. Accepted for publication May 3, 2005.
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References |
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