Clinical Management of EGFRI Dermatologic Toxicities: The European Perspective

Dermatologic treatment of epidermal growth factor receptor inhibitor (EGFRI) skin toxicity is supportive and aims at maintaining quality of life while continuing EGFRI therapy. Despite the lack of randomized controlled trials or evidence-based guidelines, most cases of acneiform eruption are well controlled by topical metronidazole and oral minocycline 100 mg qd. For severe reactions, the minocycline dose is doubled and saline compresses are used. For superinfection with Staphylococcus aureus, oral cefuroxime axetil can be added for a short term. Emollients and topical steroids can be administered for skin dryness or eczema. Paronychia is the hardest to treat but antiseptic soaks and a corticosteroid paste can alleviate symptoms to some degree.

A clear medical need exists for supportive dermatologic treatment of epidermal growth factor receptor inhibitor (EGFRI) skin toxicity. Because the eruption usually affects the visible skin of the face and may cause itch or pain, it often has such a dramatic impact on self-esteem and quality of life that the patient may wish to stop the EGFR-targeted treatment.[1,2] However, because the drug can be life extending or possibly also life saving, its cessation is definitely not the first option to consider. This situation contrasts with the classic drug eruption in which dermatologic advice focuses on identifying and stopping the responsible drug. In patients treated with EGFRIs, dermatologic care is not causal but supportive and aims at maintaining quality of life while the EGFRI is continued.[1]

Who Provides Dermatologic Care and When Should a Patient Be Referred to a Dermatologist?

The oncology nurse plays a central role in patient education and communication about the skin problems that can be encountered during therapy with EGFRIs.[2] The nurse explains the skin problems, the general measures, the do's and don'ts, and the need to immediately contact a physician in case of complications. Patient brochures and packages with useful samples (eg, sun-blocking cream, shower oil, emollient, and hand cream) can help with this task (personal experience).

Mild-to-moderate cases of papulopustular reaction (PPR) can well be managed by the oncologist/internist with standard treatment regimens (eg, topical metronidazole ± oral tetracycline). Grade 3 acneiform eruption and other skin manifestations, however, require more specialized care by a dermatologist.[1] Indeed, all principles of topical therapy (eg, appropriate vehicle choice according to acuity of inflammation and skin site) converge in the care of EGFRI skin reactions (see below). Hence, a good collaboration between the oncologist and dermatologist is indispensable. The dermatologist should be available for immediate consultation in case of flare up, and frequent dermatologic follow-up is usually needed (eg, before the next infusion to evaluate whether or not it will be possible). The dermatologist must be familiar with EGFRI skin toxicity. For that purpose, interactive training sessions on EGFRI skin effects are performed with local oncologists, gastroenterologists, pneumologists, dermatologists, and oncologic nurses in Belgium (personal experience). Caregivers (in contrast to patients) should also be prepared for the worse-case scenarios of EGFRI skin toxicity to facilitate the management of rare severe cases.

General Measures and Treatment Principles

Adequate sun-protective measures (eg, hat, clothes, and sun-blocking creams) are advised because sun exposure aggravates acneiform eruption[3] and induces hyperpigmentation.[1] The patient is also instructed to avoid skin-care products that dry out the skin (eg, bath foam, shower gel, soap, and very hot water) and to switch to bath/shower oil and lukewarm water. An emollient/hand cream can be used on the limbs and hands to prevent xerosis and fissures, especially after a bath/shower, swimming, or sauna. The use of greasy ointments on the face and trunk is avoided because these ointments may aggravate PPR.[1] Anecdotal experience in the United States suggests that the application of cold compresses during EGFRI infusion ("cryotherapy") can prevent acneiform eruption.[2]

The right vehicle choice is essential to successful topical treatment of EGFRI skin reactions. For an acute pustular or edematous reaction, drying vehicles such as compresses, gels, or oil-in-water creams can be used, but emollient ointments are inappropriate because they occlude the skin pores and thus worsen follicular inflammation. In the chronic stage of the eruption with dry, flaky skin, drying vehicles must be switched to rich water-in-oil cream or an ointment so as to not aggravate the xerosis. Therefore, topical treatment is tailored to the situation of the individual patient and may change over time, meaning that no topical treatment scheme is universally applicable for all patients at all times.[1]

When an EGFRI (eg, cetuximab [Erbitux]) is combined with radiotherapy (eg, for head and neck cancer), the management is not different than in the absence of radiotherapy, because the above-mentioned therapies are not known to interfere with radiotherapy.[4]

Skin Toxicity Treatment Algorithms

The treatment of EGFRI skin toxicity in Europe is mainly based on reported personal experience and anecdotal or small-series case reports, but evidence-based controlled trials are still lacking. European dermatology has a rich historical tradition with the emergence of different schools (French, German, and Anglo-Saxon), each with its own emphasis in management of skin diseases.[1,5-8] Therefore, the preference for one particular tetracycline or topical agent, or for all or no preparation by the pharmacist, may differ from country to country. A European consensus conference on EGFRI skin toxicity with dermatologists, gastroenterologists, and oncologists was held in Brussels in September 2004, and a consensus manuscript with treatment recommendations and a treatment algorithm was published in 2005.[9] In addition, a number of European groups have published their own experiences with treatment of EGFRI skin toxicity.[1, 5-8]

Treatment of Acneiform Eruption

For the authors, use of topical metronidazole and oral minocycline is the standard of treatment. As topical therapy, we prefer metronidazole (as a 2% preparation in cetomacrogol cream or as 0,75% Rozex cream) for its mildness because it is normally used for the very sensitive skin of rosacea patients.[10] Others use topical anti-acne agents, such as erythromycin, clindamycin, and benzoyl peroxide,[6,9] but the use of these preparations may be problematic as they are meant for young, resilient acne skin. Moreover, EGFRI-induced PPR of the face probably shares more characteristics with inflammatory rosacea than with acne. Topical metronidazole can be used twice a day or in between as needed. It does not need to be used in a preventive manner because it acts quite rapidly and effectively when papulopustular lesions appear. Topical retinoids are used by some[9] but lack rationale (no comedones) and are too irritating for the skin.[1] Some European doctors use topical corticosteroids, but the consensus is that the possible risks on the face and on the trunk (induction of steroid rosacea or acne, atrophy, telangiectasia, chronic abuse with tachyphylaxis, and steroid dependence) outweigh the advantages.[1,9] For papulopustular lesions on the scalp, we make an exception because this skin site-in contrast to the face, chest, and upper back-is quite resistant to local steroid side effects. Calcineurin antagonists are being used as first-line therapy in some centers in the United States,[11] but are only rarely used for this indication in Europe; a rationale for their use certainly exists, but it is hampered by irritation of the skin and the price (not a labeled indication with risk of not being reimbursed). Topical menadione[12] is not yet available in Europe. We also instruct the patient to adhere to the prescribed topical treatment and discourage the use of over-the-counter products that are marketed for skin irritation (eg, tea tree oil)[2] but very often cause contact allergy. Camouflage techniques have been used with success to hide the skin changes provoked by EGFRIs.[5] However, they are not advised in the acute phase of the rash (occlusive effect).

PPR-associated itch can easily be controlled with an oral antihistamine of choice.[1] The initiation of oral tetracyclines is mostly based on clinical judgment (insufficient response to topical metronidazole or extensive disease) they are not used in a preventive way. The preferred type of tetracycline is different from country to country. Minocycline, 100 mg qd, is most often used in Northern Europe, but it is sometimes avoided because of the rare occurrence of drug-induced lupus, hepatitis, or hyperpigmentation.[9] Doxycycline, 100 mg qd (may cause photosensitivity), and lymecycline, 300 mg qd, are alternatives. Like metronidazole, tetracyclines are not administered for their antibiotic properties but for their anti-inflammatory properties;[10] and are usually given for months.[1] In case of severe grade 3 reactions, the tetracycline dose is doubled until grade 2 toxicity is reached again. For grade 3 reactions with numerous or confluent pustules, extensive exudation, or marked edema, saline compresses (15 minutes, 2 to 3 times a day) are very helpful for rapid clearance of the inflammation.[1] (See also Figure 1.) Compresses can dry out the skin, therefore, they should only be applied for a limited duration (a few days), and each application should be followed by repeated application of metronidazole cream.

PPR by EGFRIs is essentially sterile, but the skin is highly prone to superinfection with Staphylococcus aureus (Figure 2). Because tetracyclines are rarely active against S aureus, a penicillinase-resistant penicillin (eg, flucloxacillin, 500 mg tid) or cephalosporin (eg, cefuroxime axetil, 500 mg bid) could be added for 5 days. Usually a swab is taken so that the antibiotic can be directed accordingly in case of resistance. Superinfection with herpes simplex virus is rare but requires oral (eg, valacyclovir) or intravenous (eg, acyclovir) antiviral drugs.[1]

In case of a grade 3 reaction, the patient should be reevaluated before the next infusion of the EGFRI to assess whether or not EGFRI therapy should be interrupted. Very often, a grade 3 reaction improves so rapidly on dermatologic therapy that EGFRI therapy can be continued in an unchanged manner. In the rare cases in which a grade 3 reaction is more persistent, despite appropriate dermatologic support, the EGFRI administration will be canceled, and a reassessment takes place before the next infusion (personal experience).

Despite its efficacy for EGFRI-dependent rash,[7] we advise against the use of oral isotretinoin because of the uncertainty of whether or not it interferes with EGFRI antitumor activity by downregulating EGFR expression. Moreover, isotretinoin shares a large number of side effects with EGFRIs (eg, xerosis, sensitivity for S aureus superinfection, paronychia, and pyogenic granuloma), which may lower tolerability.[1] Systemic steroids are also to be avoided in the treatment of acneiform eruption because they may induce a similar eruption themselves.[1]

Treatment of Xerosis, Eczema, and Fissures

Skin xerosis obviously benefits from the general hydrating measures described above. In addition, an appropriate vehicle choice is indispensable. In this respect, alcohol-containing lotions or gels for treating acneiform eruption should be discouraged in favor of oil-in-water creams (eg, metronidazole cream), and the use of saline compresses for severe rash should be limited in duration. 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 because occlusive ointments may facilitate the development of folliculitis lesions.[1]

When eczema is present, a topical weak-to-medium strength corticosteroid cream is recommended for a short term (1 to 2 weeks). Salicylic acid can be added to the steroid when fingertip eczema is present. When the eczema becomes wet, superinfection should be suspected, and a swab for bacterial (or viral) culture can be taken. A treatment with topical (eg, fusidic acid) or, in severe cases, systemic anti-S aureus antibiotics can be added for 5 to 10 days (eg, flucloxacillin, 500 mg tid, or cefuroxime axetil, 500 mg bid). In the rare case of herpes simplex superinfection, treatment with systemic antiviral drugs is necessary.[1]

Fissures can be treated with propylene glycol 50% aqueous solution under plastic occlusion (daily for 30 minutes), salicylic acid 10% ointment (Figure 3), a hydrocolloid dressing, or liquid cyanoacrylate glue.[1]

Treatment of Paronychia

Paronychia is often very distressing and painful for the patients because it impedes walking or the normal use of fingers. Unfortunately, paronychia is also very challenging to manage because no treatment yields complete relief. Wearing shoes that are not too tight is an important preventive measure to minimize friction and pressure on the nail fold. Paronychia caused by EGFR blockers is not infective in nature but renders the nail folds very sensitive to infection. Therefore, antiseptic (eg, chloramines or povidon iodine) soaks or creams are advised for use on a daily basis. When superinfection is suspected, swabs can be taken and oral anti-S aureus antibiotics (eg, flucloxacillin) given. A drying paste containing an antiseptic (eg, chlorhexidine), an anti-yeast (eg, nystatin), and a potent topical corticosteroid can be helpful in alleviating symptoms. Oral tetracyclines can be helpful as well in treating paronychia.[13] Oral nonsteroidal anti-inflammatory drugs can be administered to control the pain. Silver nitrate application on a weekly basis improves pyogenic granuloma. Despite the clinical appearance mimicking an ingrown nail, partial nail-bed excision has no effect on EGFRI-caused paronychia. Total nail extraction with destruction of nail matrix cures the paronychia, but the permanent loss of the nail limits the usefulness of this technique. In severe, recalcitrant cases, interruption of the EGFR blocker may be considered, but just as the length of time it takes for the paronychia to appear after the start of therapy, it may also take weeks for it to improve after cessation of EGFRI.[1]

Treatment of Hair Changes, Hyperpigmentation, and Telangiectasia

Eyelashes that cause conjunctival irritation by their excessive length can be trimmed. Hypertrichosis is treated with eflornithine cream (Vaniqua) or by laser epilation.

Sun protection and adequate treatment of acneiform eruption and eczema are most important to avoid subsequent hyperpigmentation. Bleaching creams are not very helpful, but camouflage by a beautician helps to correct the skin color. Left untreated, the hyperpigmentation may fade spontaneously over months.[1]

Telangiectasia caused by EGFRIs will also gradually disappear over months. Therefore electrocoagulation or pulsed dye-laser therapy are only rarely applied to accelerate disappearance. Excellent results can also be achieved with camouflage.[5]

Treatment of Mucosal Changes

Xerophthalmia, conjunctivitis, and blepharitis can be managed with artificial tears, trimming of the eyelashes, topical antibiotics, and topical corticosteroids (eye drops or ointment). When superinfection with S aureus occurs, a swab is taken and an oral antistaphylococcal antibiotic can be added. Refractory cases should be sent to an ophthalmologist because complications such as corneal ulcers may occur.[14] Tetracycline or antiseptic mouthwash alleviates stomatitis symptoms. For aphthous ulcers of the mouth, topical steroids or anesthetics can be used. Dryness of the nose or the vagina responds fairly well to lubricants or ointments that contain an antibiotic or antiseptic.

Conclusion

Despite the absence of evidence-based guidelines, the vast majority of patients experiencing EGFRI-induced skin toxicity are easily managed without dose adjustment or interruption of the EGFRI. Topical metronidazole and oral minocycline are the mainstay of treatment of acneiform eruption. Frequent use of emollients is the basis to control xerosis and to prevent development of eczema or fissures. Sun protection is advised to all patients.

References

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Funding for this supplement was provided by Amgen.

References:

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3. Luu M, Lai SE, Patel J, et al: Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23:42-45, 2007.

4. Bernier J, Bonner J, Vermorken JB, et al: Consensus guidelines for the management of radiation dermatitis and co-existing acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Ann Oncol doi:10.1093/annonc/mdm400, 2007.

5. Robert C, Soria J-C, Spatz A, et al: Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491-500, 2005.

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11. Lacouture ME, Basti S, Patel J, et al: The SERIES clinic: An interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol 4:236-238, 2006.

12. Perez-Soler R: Topical vitamin K3 (menadione) prevents erlotinib and cetuximab-induced EGFR inhibition in the skin (abstract 3036). J Clin Oncol 24:3036, 2006. Slide presentation available at www.asco.org.

13. Suh K-Y, Kindler HL, Medenica M, et al: Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. Br J Dermatol 154:191-192, 2006.

14. Melichar B, Nemcova I: Eye complications of cetuximab therapy. Eur J Cancer Care 16:439-443, 2007.