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EGFR Inhibitors: Toxicities and Strategies for Effective Management


Rash Associated With EGFR Inhibitors

Cutaneous reactions associated with EGFR inhibitors include rash, dryness of the skin and mucus membranes, ocular abnormalities, hair changes and alopecia, nail changes, and hand and foot reactions.


The most distressing toxicity associated with EGFR inhibitor therapy may well be the rash. Many patients are unable to tolerate this potentially disfiguring toxicity, leading to premature discontinuation or dose reduction of the offending agent. EGFRs are expressed in the epidermis, the sweat glands, and hair follicles of the skin.[3] EGFR inhibitor-induced skin toxicity is believed to be caused by an increase in keratinocyte production that occludes skin follicles and impairs their differentiation. Altered function of epidermal keratinocytes may cause the outer layers of the skin to shed, decreasing skin thickness.[4] Skin cells exposed to EGFR inhibitors may also release cytokines that attract neutrophils, monocytes, and lymphocytes to the area, resulting in an inflammatory reaction manifested as a papulopustular rash.[4] Although these pathologic changes appear to have an inflammatory rather than an infectious etiology, if the rash is severe enough, bacteria may overgrow and make the skin susceptible to superinfection.[5]

It is estimated that rash occurs in 60% to 80% of patients, with the majority experiencing a mild to moderate rash.[6] Severe symptoms necessitating dose alterations occur in up to 20% of the patients with rash. There is no apparent association between the severity of EGFR inhibitor-induced rash and skin type or prior history of acne or other rashes.[7] There is, however, some evidence that rash induced by erlotinib, but not gefitinib, may correlate with treatment efficacy and survival.[8,9] Until these observations are confirmed with large prospective trials, we cannot assume that the absence of rash in a patient indicates that treatment with EGFR inhibitors is ineffective.[5] However, since a number of studies have linked rash and survival, every attempt should be made to manage the rash with supportive medications so that dose reductions and discontinuations of EGFR-inhibitor treatment are prevented.[10]

Assessment of Rash

The terms acne, acne-like, and acneiform are often used erroneously to describe EGFR inhibitor-associated rash. EGFR inhibitor-induced rashes are generally pruritic, contain pustules, and respond to anti-inflammatory agents. In contrast, acne is infectious in nature, often contains comedones (blackheads), and is best treated with antiacne agents.[4] Although the rash of EGFR-inhibitor treatment may resemble acne, clinicians are advised to use descriptive terms such as "pustular/papular rash, pustular eruption, or follicular and intrafollicular pustular eruption."[11]

The National Cancer Institute's Common Toxicity Criteria (CTC) for adverse events are generally used to grade symptoms for clinical trials but have some limitations in describing EGFR inhibitor-induced rashes. The CTC grading criteria (Table 2) use percentage body surface area affected as an indication of whether a rash is Grade 2 or 3, but these rashes are almost always restricted to the face, scalp, and upper torso.[12] Modified EGFR inhibitor-specific grading systems, based on interference with daily life and potential for superinfection, have been proposed but none are universally accepted.[5,11] Therefore, nurses should follow the CTC grading criteria when assessing patients with rash, as this is the current standard.

Table 2. Grading of EGFR Inhibitor-Associated Skin, Hair, Nail, and Eye Changes

Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Dry skin Asymptomatic Symptomatic, not interfering with ADL Interfering with ADL ---
Hair loss or alopecia (scalp or body) Thinning or patchy Complete --- ---
Hyperpigmentation Slight or localized Marked or generalized --- ---
Nail changes Discoloration, ridging (koilonychias), pitting Partial or complete loss of nail(s), pain in nail bed Interfering with ADL ---
Pruritus or itching Mild or localized Intense or widespread Intense or widespread and interfering with ADL ---
Rash or desquamation Macular or popular eruption or erythema without associated symptoms Macular or popular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering < 50% of BSA Severe, generalized erythroderma or macular, popular, or vesicular eruption; desquamation covering &8805; 50% of BSA Generalized exfoliative, ulcerative, or bullous dermatitis
Rash: hand-foot skin reaction Minimal skin changes or dermatitis (eg, erythema) without pain Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function Ulcerative dermatitis or skin changes with pain interfering with function ---
Dry eye syndrome Mild, intervention not indicated Symptomatic, interfering with function but not interfering with ADL; medical intervention indicated Symptomatic or decrease in visual acuity interfering with ADL; operative intervention indicated ---
Eyelid dysfunction (includes erythema and trichiasis) Asymptomatic Symptomatic, interfering with function but not ADL; requiring topical agents or epilation Symptomatic; interfering with ADL; surgical intervention indicated ---
Ocular surface disease (includes conjunctivitis) Asymptomatic or minimally symptomatic but not interfering with function Symptomatic, interfering with function but not interfering with ADL; topical antibiotics or other topical intervention indicated Symptomatic, interfering with ADL; operative intervention indicated ---
ADL = activities of daily living; BSA = body surface area
From: National Cancer Institute. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events. (2006): Cutaneous Reactions. Available at: Accessed August 25, 2008.

EGFR inhibitor-associated rash usually appears about 1 week after initiating treatment and is generally located on the face and upper torso.[7] The rash follows a fairly distinctive course, with erythema and changes in sensation occurring around week 1, development of papulopustular rash during weeks 1 to 3, crusting of the pustular lesions during weeks 3 through 5, and hyperpigmentation for up to 2 months afterward.[5] It is somewhat common for the rash to wax and wane over time with intermittent flare-ups, but the mechanism of this phenomenon is not known.

Management of Rash

To date, no clinical trials have established the optimal treatment for EGFR inhibitor-associated rash. The recommendations for treatment are based instead on the presumed pathophysiologic mechanisms of the rash and on anecdotal evidence. (Figure 2)

Algorithm for management of EGFR-inhibitor-induced rash, based on rash severity.
Figure 2. Algorithm for management of EGFR-inhibitor-induced rash, based on rash severity.[5] From: Lynch TJ, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621.

Nonpharmacologic Management of Rash. To prevent dryness and rash, cleansing with mild soaps and twice daily moisturizing with thick, emollient-based creams are recommended.[13] Other ways to prevent skin dryness include avoiding prolonged hot showers, remaining well hydrated, and using only products that are alcohol-, fragrance-, and dye-free.[10]

EGFR inhibitor-induced rashes can be very distressing to patients. Cosmetics and foundations can be used to hide the rash, but these products should be removed with gentle cleansers.[14] Inform patients that prolonged sun exposure can exacerbate the rash. Counsel patients on the proper use of broad spectrum sunscreen (SPF 15 or greater) and advise that physical sun blocks such as zinc oxide are preferable to chemical blocks.[5] Benzoyl peroxide acne treatments and retinoids are discouraged, as they may dry the skin further, causing more inflammation/irritation, possibly worsening papular lesions.[11]

Pharmacologic Management of Rash. Treatment of EGFR inhibitor-induced rash is based on severity (Figure 2). Topical and oral antibiotics (minocycline, doxycycline) have anti-inflammatory effects on the rash in addition to reducing the risk of secondary infection.[11] Topical 1% clindamycin is an early treatment option for mild, localized papular lesions. Oral doxycycline or minocycline 100 mg twice daily can be used to treat Grade 2 and higher rashes, but there is currently no agreement on the length of the antibiotic course. It is generally recommended that the patient be re-evaluated after 2 weeks of treatment with oral antibiotics.

Oral steroids and topical nonsteroidal immunomodulatory agents are often used for their potential anti-inflammatory effects. Oral steroids such as a methylprednisolone are recommended for severe, refractory Grade 3 and 4 rash. Although steroids may be beneficial in treating severe skin rash, their use may result in steroid-induced acne, which can complicate matters.[11]

Topical steroid creams (hydrocortisone 2.5% cream) can be quite effective but should not be used for more than 14 days at a time because they may cause skin thinning and increase the risk of secondary infection.[5]

Topical immunomodulatory agents (such as pimecrolimus 1% cream) may decrease erythema and pustules associated with the rash but have not been studied for long-term use so should be used with caution.[14] These agents may also produce a burning sensation when first applied.[14]

Although there are no published data on prophylactic treatment of EGFR inhibitor-induced rash, the STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) trial recently revealed that patients who used skin creams, topical steroids, and oral doxycycline from the start of treatment with panitumumab had fewer Grade 2 rashes.[15] However, these data are very new and the prophylactic medical treatment of rash is not widely accepted or practiced.

Because the rash may be a marker of the efficacy of EGFR-inhibitor therapy, every effort should be made to manage the rash with optimal doses of medication. Modifying the EGFR-inhibitor dosage or discontinuing the EGFR inhibitor altogether should only be considered if the rash is resistant to treatment or is an intolerable Grade 3 or 4 rash.[13]