ABSTRACT: Agents that inhibit epidermal growth factor receptor (EGFR) signaling are associated with dermatologic effects, primarily a papulopustular rash. These effects are generally mild-to-moderate in severity, but may negatively affect quality of life and lead to treatment delays, dose modifications, and discontinuation of therapy. These findings underscore the need for effective ways to prevent and manage the dermatologic effects of EGFR inhibitors. Evidence-based guidelines are lacking, but algorithms have been developed based on the available evidence, clinical experience, and our understanding of the effects of EGFR inhibition in skin. More recently, the first results from prospective, controlled trials specifically evaluating strategies for preventing or reducing the severity of cutaneous reactions have been reported. These reports represent the first step toward an evidence-based approach to the prevention and management of these important effects.
The epidermal growth factor receptor (EGFR) is a validated target for cancer therapy, and treatment with EGFR inhibitors (EGFRIs) is an effective antitumor strategy associated with fewer adverse events than conventional chemotherapy, with a distinct toxicity profile.[1,2] The most common toxicity associated with EGFRI therapy is dermatologic reactions, particularly a papulopustular rash, which occurs in nearly all patients. Given the important role of EGFR in maintaining skin integrity, these effects are not unexpected. Cutaneous toxicity has been observed with all agents that target EGFR, and is therefore considered a class effect.
EGFRI-related dermatologic effects are generally mild or moderate in severity. Even when they are not severe, these events may pose clinical concerns, such as risk of secondary infections, and patients must find ways to cope with chronic discomfort, itching, and the appearance of the rash. The rash predominantly affects visible areas of the body, which can cause distress and anxiety in some patients and negatively affect self-image and self-esteem. This may increase the likelihood of poor compliance or discontinuing therapy, especially if being considered in the future for use in the adjuvant setting.
Recent studies have formally assessed the impact of EGFRI-related rash on quality of life and have noted a direct correlation between National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade of the rash and the dermatology-specific quality of life. Investigators have noted that of the three domains evaluated in a patient population that developed a papulopustular rash while being treated with EGFR inhibitors—symptomatic, functional, and emotional—the domain that was impacted the most was emotional.[6,7] Rash can lead to treatment discontinuation in up to one-third of patients treated with EGFRIs.
The potential for negative clinical consequences and the risk of impaired quality of life and poor treatment compliance underscores the need for effective management strategies for EGFRI-related dermatologic reactions. Current approaches to rash management are empirical and vary widely among care providers. Evidence-based guidelines have been impossible to establish due to the lack of data from adequately controlled clinical trials.[6,8] Consensus reports regarding the optimal approach to rash management have been developed, but these are based largely on anecdotal evidence and clinical experience.[4,9-11] Prospective, controlled trials evaluating strategies for managing or preventing EGFRI-related rash are underway, and the first results from some of these trials were recently reported.[12,13] These trials represent the first steps beyond current strategies toward an evidence-based approach to the management of EGFRI-related rash.
The dermatologic effects of EGFRIs are unique in the spectrum of drug-induced skin changes. Papulopustular rash is the most common manifestation, but other cutaneous effects, such as xerosis, pruritus, paronychia, and changes in hair growth, have been observed (Figure 1).
Prospective studies specifically evaluating the cutaneous effects of EGFRIs describe the rash as pruritic, follicular, papulopustular, erythematous lesions.[14,15] The most commonly affected area is the face, including the nose, chin, nasolabial folds, perioral area, cheeks, and forehead. The shoulders and trunk may also be affected, particularly the V-shaped areas of the chest and back.[11,16] In some cases, the lower back, abdomen, and limbs may also be affected.
Severe cases of rash are relatively uncommon; in patients treated with cetuximab (Erbitux), for example, the reported incidence of grade 3/4 rash is 5% to 17%.[17,18] The reported incidence of rash with gefitinib (Iressa) (25%–33%) is somewhat lower than that reported with erlotinib (Tarceva), panitumumab (Vectibix), and cetuximab (75%–90%).
Importantly, EGFRI-related rash does not share the clinical or histologic features of acne vulgaris. Unlike acne, EGFRI-induced rash often produces pruritic lesions, responds to anti-inflammatory medication, fails to respond to acne medications, affects more areas of the body (such as the arms and lower legs), and does not produce comedones.[4,6] Microbiologic cultures are often negative,[14,15] although secondary infections may occur. The papulopustular stage is typically followed by a crusting stage, in which purulent material dries and forms visible crusts on the skin surface. The crusts consist of neutrophilic and keratinocytic debris, parakeratotic cells, fibrin, and serum and should not be confused with an opportunistic infection.[4,6] EGFRI-induced rash should also be differentiated from allergic reactions and steroid-induced acne.
Xerosis and Pruritus
Approximately 7% to 35% of patients treated with EGFRIs develop dry, scaly, or itchy skin (xerosis). Xerosis often affects the limbs and areas previously affected by papulopustular rash.[11,19] It may develop into chronic eczema and increase the risk of secondary infections.
Paronychia with associated swelling of nail folds has been reported. It occurs in approximately 12% to 16% of patients and is considered a late event, often arising 4 to 8 weeks after treatment initiation.[3,11] Paronychia is characterized by inflammation of the nail fold, painful fissuring, and brittle nails. Severe complications, such as pyogenic granuloma, have been reported.
Changes in Hair Growth/Ocular Toxicity
Treatment with EGFRIs can cause variable effects on hair growth, depending on the location on the body. Hair loss occurs in 14% to 21% of patients, whereas increased growth of eyelashes and eyebrows (trichomegaly) occurs in 12% to 14% of patients.[3,21] Other reported hair changes include development of curlier, finer, or more brittle hair on the scalp, reduced beard growth, and excessive eyelash curling.[7,21]
In particular, trichomegaly of the eyelashes, which can scratch the eye, may be accompanied by conjunctivitis and other ocular disorders that can lead to significant discomfort and blurred vision.
Telangiectasias and Hyperpigmentation
Telangiectasias have been observed and may be related to the indirect antiangiogenic effects associated with EGFR inhibition. If left untreated, telangiectasias will gradually disappear over months, but pulsed dye laser therapy may accelerate this process. Hyperpigmentation appears to be a residual effect of inflammation and usually fades spontaneously over time. Patients should be advised to avoid sun exposure and to use adequate sunscreen to limit exposure to ultraviolet (UV) radiation; this may help avoid hyperpigmentation.
Duration and Onset of Rash
The dermatologic effects of EGFR therapy can be generally classified as early effects (sensory disturbances, erythema, edema, papulopustular rash, crusting) and late effects (hyperpigmentation, hair changes, paronychia/fissuring, xerosis) (Figure 2). In most cases, papulopustular rash develops within the first 3 weeks of treatment, and typically peaks in severity 3 to 5 weeks after treatment initiation.[10,18] Delayed onset, ie, after the first 3 weeks of treatment, has been observed in a minority (11%) of patients treated with cetuximab. The severity of the rash may wax or wane during treatment, and spontaneous resolution has been reported, which may complicate assessment of the efficacy of interventions. After treatment is stopped, the rash usually resolves within 4 weeks but may leave residual hyperpigmentation and xerosis.[10,19]
Paronychia and fissuring are late effects that usually develop 2 to 4 months after treatment initiation. These effects can be persistent and endure for several months after treatment cessation. Hair changes have a variable onset; they can sometimes occur as early as 7 to 10 weeks after treatment initiation, or up to several months later. Xerosis develops after the papulopustular rash has resolved, which usually occurs during the second month of treatment.
EGFR is expressed in undifferentiated and proliferating keratinocytes in the basal and suprabasal layers of the epidermis. Keratinocytes rely on EGFR to regulate proliferation, differentiation, migration, and survival.[6,23] EGFR expression is particularly abundant in and around follicles. Normally, activated EGFR and several EGFR-dependent downstream factors, such as MAPK and Ki67, can be found in keratinocytes in the basal layer of the epidermis.
The effects of EGFRIs on skin are directly linked to their ability to interfere with EGFR signaling.[11,15] Treatment with an EGFRI abolishes EGFR expression in basal layer keratinocytes, and increases expression of factors related to premature differentiation and growth arrest, such as p27KIP1, KRT1, and STAT3. In fact, inhibition of EGFR signaling has been shown to reduce DNA synthesis, arrest growth, and induce premature differentiation in keratinocytes. It also inhibits migration and promotes adhesion, which prevents the normal excursion of keratinocytes from the basal layer to the corneal layer, which is necessary for their maturation. In addition, inhibition of EGFR attracts inflammatory cells to the skin, causing apoptosis and tissue damage. As a result of these changes, the epidermis and corneal layer become thinner, which impairs barrier function and sensitizes the skin to UV radiation.
The cascade of molecular and cellular events initiated by EGFR inhibition in skin corresponds with many of the specific clinical manifestations seen during EGFRI therapy (Figure 3). Immediate symptoms of burning, redness, and swelling, for example, are linked to the inhibition of EGFR in basal keratinocytes, which attracts inflammatory cells and causes vascular dilation and increased permeability, all of which activate nociceptive fibers in the skin. Delayed effects of abnormal keratinocyte maturation and differentiation are expressed as late clinical effects, such as xerosis and hair and nail changes.
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