Clinical Management of EGFRI-Associated Dermatologic Toxicities: Pharmacy Perspective

This article describes agents used to treat the dermatologic toxicities commonly seen during therapy with epidermal growth factor receptor inhibitors. Therapeutic options include topical emollients, antibiotics, corticosteroids, and other agents for supportive care. While medical approaches to these adverse reactions are still in a "learning phase," continued experience will provide further insight into effective management strategies.

Epidermal growth factor receptor (EGFR) is overexpressed in many tumor types,[1] which makes it an ideal target for biologic and small molecule–targeted agents. Dermatologic toxicity with EGFR inhibitor (EGFRI)-associated agents can manifest in many forms. The most common form is a papulopustular reaction (PPR),[2-5] which can range from mild discomfort to a fulminant pustular eruption, and can lead to serious complications.

Pharmacists are not only charged with the dispensing, admixture, administration, and monitoring of these therapies, but are also becoming more involved in the recognition, diagnosis, and treatment of these dermatologic toxicities from this new class of agents. More challenging is the evidence that the degree of PPR may reflect the degree of efficacy of therapy. This development means that PPR (and other dermatologic toxicities) will become a routine problem in patients treated with these agents, making supportive therapy for these effects part of the treatment plan. A precise grading system will become necessary, as well as a better treatment plan for managing all grades and forms of these complications.

The "newness" of these agents makes potential complications difficult to recognize. All patients experience some degree of PPR-usually grade 1 or 2. However, some cases of PPR can be severe and challenging to manage. Although designated an "acneiform" or "acnelike" rash, it is treated much differently than the typical eruptions we see with acne vulgaris. Typically, dermatologic manifestations of acne vulgaris are best managed with drying agents such as benzoyl peroxide. This therapy, however, is not used with EGFRI-associated PPRs. We are discovering that the process of eruption and fading is more of a drying process, and we must moisturize EGFRI-associated PPR to make the patient more comfortable during the time it develops, waxes, and wanes. In this article, we describe some of the agents used to treat the dermatologic toxicities commonly seen with EGFRI-associated therapy.

Topical Emollients

Caution should be exercised in selecting topical gels and lotions that contain alcohol or alcohol-type drying agents. Again, this PPR is a "drying" rash, requiring more of an emollient-type agent to keep the drying, brittle eruptions well moisturized. Ointments, creams, bath oils, and soap substitutes are the most common types of emollients recommended by dermatologists to make the PPR more bearable. Cetaphil cleanser and Eucerin lotion are two popular over-the-counter emollients. Baths that incorporate Aveeno oatmeal products also have a soothing benefit.

Another important consideration for patients is the fact that sunlight may exacerbate the PPR. Patients should be counseled on the use of sunscreens and protective clothing. Numerous sunscreen products are on the market with moisturizers in their formulas, thereby providing protection from the sun as well as much needed moisture to the skin. Products that protect from both ultraviolet A and ultraviolet B radiation-that is, agents containing zinc oxide or titanium dioxide-should be preferred. Patients should be encouraged to stay out of the sun, if possible. However, when they must venture outdoors, they should be cautioned about following the appropriate measures to protect themselves from the sun.

Antibiotics

Antibiotics, both systemic and topical, are often utilized to treat EGFRI-related PPR. Oral tetracyclines-specifically, minocycline and doxycycline-are most often employed in treatment. Both of these drugs seem to have efficacy in treating PPR. Most often, the selection of agents seems to be based on the clinician's experience.

Minocycline has been associated with a rare, drug-induced, lupus-type syndrome, hepatitis, and hyperpigmentation, as well as vestibular changes that can lead to dizziness and loss of balance (minocycline package insert, 2006). Dosage is frequently 100 to 200 mg/d, and the drug can be taken with food or milk to minimize gastrointestinal (GI) toxicity. Doxycycline has been associated with a rare exfoliative dermatitis and, more importantly, photosensitivity. Dosage is usually 100 to 200 mg/d, and although patients should be instructed to take the drug on an empty stomach, it does present problems with GI irritation. Administration with food can decrease absorption of the drug up to 20% (doxycycline package insert, 2006). Of all the tetracyclines, doxycycline has the least affinity for calcium, and when the drug is taken with milk or antacids, gastrointestinal toxicity can be minimized.

Topically, metronidazole and clindamycin are the two agents most commonly used. Success with metronidazole in this setting is thought to be the result of the similarity of EGFRI-associated PPR to inflammatory rosacea, for which metronidazole is also very effective. The cream or lotion preparations of these agents should be prescribed, to take advantage of the cream/lotion base (often a water-in-oil emulsion), which can aid in moisturization. The use of the topical solution or gel formulations should be avoided due to the alcohol content, which can enhance dryness.

Corticosteroids

Corticosteroids, both oral and topical, are incorporated into many treatment protocols for EGFRI-induced PPR (Table 1).[6] Their use is mainly indicated for the more severe grades of PPR. When corticosteroids are used topically, the clinician should be cautioned about using higher-potency creams on the face.

Patients are often given prescriptions for topical agents in quantities that are well below what is needed. This practice often results in the patient applying too little of the medication or limiting its use because of monetary concerns. When long-term treatment is anticipated, a prescription for an amount that will encourage and not discourage use is more economical and will result in a better treatment outcome.

As a rule, 1 g of cream covers an area of skin approximately 10 × 10 cm (4 × 4 in). The same amount of ointment will cover an area approximately 5% to 10% larger.[7] The fingertip unit (FTU) is described in dermatology textbooks.[7] One FTU is the amount of cream or ointment dispensed from the tube applied from the distal skin crease to the tip of the index finger, approximately equivalent to 0.5 g. The amount needed to cover the entire body is approximately 30 to 60 g for a single application. The amount needed for 1 week of therapy for the entire body, applied twice daily, is 420 to 840 g (14 to 28 oz). When a patient needs to apply cream for a month, the amount needed is approximately 1.8 to 3.6 kg (60 to 120 oz).

Although some commercially available topical agents are available in 120-g tubes or jars, many do not come in sizes larger than 60 g. When creams are prescribed, awareness of this issue is important so that patients receive an amount that will provide the benefit they need for the required length of time. Most retail pharmacies can place the contents of multiple tubes of product into one conveniently sized ointment jar, rather than dispense three or four separate tubes, depending on the patient's preference.

Oral corticosteroids are not without associated toxicities. Short courses of methylprednisolone (eg, Medrol Dosepak) are often prescribed for more severe grade 3 or 4 dermatologic complications. Edema, insomnia, nervousness, and elevated serum glucose levels, along with the entire collection of corticosteroid toxicities, should be considered before therapy is initiated.

Supportive Care and Symptom Management

For symptoms of pruritus, oral as well as topical antihistamines can provide relief for patients. Hydroxyzine, 25 to 50 mg orally, and diphenhydramine, 25 to 50 mg orally, are suitable choices to treat symptoms of pruritus. Topical diphenhydramine cream is also an option for patients experiencing pruritus, without associated central nervous system toxicities, although its use is limited due to the possibility of developing contact dermatitis. For ulcerative lesions that may occur in the grade 3 to 4 levels of dermatologic toxicity, silver sulfadiazine ointment is often used to lower the risk of infectious complications and to promote healing.

Conclusions

No consensus exists among physicians regarding the best way to treat the dermatologic complications of EGFR inhibitors, as medical approaches to the problem are currently in a "learning phase." These newer agents provide us with new challenges in supportive care management of patients with diverse dermatologic adverse reactions. Continued experience with the management of these adverse reactions will provide further insight into effective management strategies for EGFRI-associated dermatologic toxicities.

Disclosures:

Lew Iacovelli has served on an advisory board and been a speaker for Amgen; he has served on speaker's bureaus for Pfizer and Novartis.

Funding for this supplement was provided by Amgen.

References:

1. Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20(18 suppl):1s-13s, 2002.

2. Needle MN: Safety experience with IMC-225: An anti-epidermal growth factor receptor antibody. Semin Oncol 29(5 suppl 14):55-60, 2002.

3. Basam KJ, Capodieci P, Motzer R, et al: Cutaneous side effects in cancer patients treated with the anti-epidermal growth factor receptor antibody C225. Br J Dermatol 144:1169-1176, 2001.

4. Albaneil J, Rojo F, Averbach S, et al: Pharmacodynamic studies of epidermal growth factor receptor inhibitor ZD 1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110:110-124, 2002.

5. Hidalgo D, Siu LI, Nemunartis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001.

6. Murphy JL (ed): Monthly Prescribing Reference, p 106. New York, Haymarket Media, 2004.

7. Arndt KA, Hsu JTS: Manual of Dermatologic Therapeutics, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2007.