Epidermal growth factor receptor inhibitors (EGFRIs) are highly specific agents that target molecular pathways involved in the pathogenesis of multiple cancers. They are associated with lower rates of systemic and hematopoietic toxicity when compared with conventional cytotoxic chemotherapy but lead to a constellation of dermatological toxicities in up to 90% of patients.1,2 (Table 1). Therefore, it is critical that dermatologists become familiar with these agents and their respective toxicities, in order to adequately evaluate, manage, and counsel their patients.

Table 1. Dermatological Side Effects of Epidermal Growth Factor Inhibitors

The epidermal growth factor receptor (EGFR/ErbB1/HER1) is a tyrosine kinase receptor that regulates cell proliferation, differentiation, migration, survival, and DNA repair.3 The EGFR is primarily expressed in basal and suprabasal keratinocytes, outer layers of the hair follicle, and pilosebaceous and eccrine glands.4,5 EGFR inhibitors used clinically include monoclonal antibodies (mAbs), such as cetuximab (Erbitux®) and panitumumab (Vectibix®), and low-molecular-weight agents, such as gefitinib (Iressa®) and erlotinib (Tarceva®). Lapatinib (Tykerb®) is another small molecule that has dual activity against tyrosine kinases of ErbB2 (Her2/neu) and EGFR.

Folliculitis

The majority (~90%) of treated patients will develop pruritic erythematous follicular papules and pustules on the seborrheic areas within the first 2 weeks of treatment; however, the eruption usually improves within 8 weeks of therapy. Most of the eruptions are mild (Grade 1), but moderate to severe eruptions affect approximately 60% of patients.6 With lapatinib, the eruption is less frequent and severe when compared with cetuximab, erlotinib, and panitumumab.6

As measured by Skindex-16 (a patient-reported quality-of-life [QoL] questionnaire that investigates the effect of a skin condition on emotional, functional, and symptomatic aspects), higher grades of rash result in an overall decreased QoL.7 In addition, a mean cost of $2715 per patient results from managing these reactions.8 A survey showed that 32% of oncology providers discontinued therapy, and 76% temporarily interrupted treatment, because of the rash. Only 8% referred patients to a dermatologist,9 with some reporting a lack of confidence that dermatologists would offer an effective therapeutic intervention. Risk factors for rash development include being a non-smoker, being elderly (≥70 years),10 and having lower Fitzpatrick skin phototype.11 The appearance of the rash in sun-exposed areas, such as the face (82%) and the V-shaped regions of the chest and back (64%), may also support this relationship.12  Mainly, this folliculitis predominates in sebaceous gland-rich areas, rather than being sun induced.

Histology of the affected skin shows a superficial mixed dermal infiltrate surrounding hyperkeratotic or ectatic follicular infundibula or a florid neutrophilic suppurative folliculitis and ruptured follicles. Apoptotic keratinocytes are present in affected areas, as well as a thin stratum corneum with loss of its normal basket-weave configuration, with foci of parakeratosis.13 Comedones are not seen, in contrast to acne vulgaris.

Grading Systems Used to Assess Rash Severity

The most common grading system used to assess the severity of dermatologic reactions to cancer drugs is the Common Terminology Criteria for Adverse Events (CTCAE), the latest version of which (4.0) was published 2009 (Table 2).14 Accurate grading of dermatologic toxicities is critical for communication with the oncologist. Treatment for the rash can be either pre-emptive/prophylactic or reactive (once it has developed).

Table 2. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The NCI CTCAE is a descriptive terminology that can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each adverse event term. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. See also: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf. ADL, activities of daily living; IV, intravenous; NSAID, non-steroidal anti-inflammatory drug; BSA, body surface area.

Folliculitis Therapy

Topical and oral antibiotics and corticosteroids remain the mainstay of therapy for eruptions from EGFRIs. Topical retinoids are not effective and may cause irritation.9,15,16 Recommended treatment options include a combination of topical corticosteroids and/or topical antibiotics applied alone or together with oral antibiotics, depending on the severity of the rash.16 The use of systemic semi-synthetic antibiotics (doxycycline) for moderate and severe eruptions, in the absence of a superinfection, is recommended based partially on their anti-inflammatory properties.16,17 Clinicians should remain alert for signs of superinfections, which develop in 38% of patients (most commonly with Staphylococcus aureus).18 The use of intranasal mupirocin has been recommended to diminish the risk of secondary infection.16 Dose modifications to the causal EGFRI are recommended to minimize severity; however, this limits exposure to life-prolonging anticancer therapy, which is particularly important because patients who develop rash appear to derive more antitumor benefit. Thus, treatment of the rash with concomitant maintenance of EGFRI therapy is ideal whenever possible.

Xerosis

Xerosis occurs in up to 35% of patients.6 Xerotic dermatitis with superinfection may develop. Painful fissuring of the distal fingertips or heels can appear in up to 33% of patients. In particular, ammonium lactate or salicylic acid for body areas, and zinc oxide (20-40%) for fissures on the fingertips and heels, are effective. Cyanoacrylate glue has also been reported to aid in healing fissures better.19 Areas of xerotic dermatitis necessitate a 1-2-week course of topical mid-potency corticosteroids.16 Areas of secondary infection should be cultured to determine the appropriate therapy. In cases of significant pruritus where oral anti-histamines and topical corticosteroids do not provide sufficient relief, oral gabapentin or pregabalin has been reported to be effective.17 

Hair Changes

Alopecia on the frontal scalp and body hair and enhanced hair growth on the face are often observed. Non-scarring and scarring inflammatory alopecia, with an interstitial infiltrate of lymphocytes, plasma cells, and multinucleate giant cells, has been reported.20 Trichiasis can result in corneal ulceration, and such patients should be referred to an ophthalmologist.2 Hair abnormalities, such as trichomegaly and hypertrichosis, are seen in 62.5% and 56.0% of patients, respectively, on long-term EGFRI therapy.6

Periungual and Nail Changes

After 4-8 weeks of EGFRI therapy, paronychia with erythema, edema and tenderness of the nailfolds has been reported in up to 24% of patients, and painful granuloma-like lesions may form.21 Superinfections can also occur in the periungual tissue. Histology shows a dermal infiltrate comprising plasma cells, lymphocytes, and neutrophils. Treatment consists of topical antibiotics or topical silver nitrate.12 EGFRI therapy may also lead to onychoschizia and brittle hair.

Conclusions

EGFRIs are a group of anticancer drugs used widely against the most frequently fatal cancers, such as lung, colorectal, pancreatic and breast cancers. The majority of patients will experience dermatological side effects, which may affect QoL and threaten consistent anticancer drug administration. Effective management of these untoward events is critical for the maintenance of QoL and to achieve the best possible clinical outcome. Dermatologists are uniquely positioned to manage these conditions and improve the lives of patients. Early evaluation and intervention of such patients is important in order to ensure that they receive life-prolonging therapy.

References

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