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.[3] 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.[4] 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.[5]
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.[1]
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.[1] 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.
Clinical Manifestations
The dermatologic effects of EGFRIs are unique in the spectrum of drug-induced skin changes.[11] 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).[6]
Papulopustular Rash
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.[11]
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%).[1]
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.[4] 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.[4]
