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Epidermal Growth Factor Receptor Inhibitors: Cutaneous Side Effects and Their Management

Seena Monjazeb, MD; Janice Wilson, MD; Brent Kelly, MD School of Medicine, Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

Conflicts of interest: The authors have no conflicts to disclose.

ABSTRACT

Epidermal growth factor receptor (EGFR) inhibitors are part of an emerging class of anticancer medicines known as "targeted therapy," which target pathways more specific to neoplastic proliferation than traditional chemotherapeutic agents. Adverse effects of such treatments are thought to be less severe, but can still be significant. Because EGFR is preferentially expressed in epithelial tissues, including the skin and hair follicle, cutaneous side effects of these agents are quite common. Not only can these toxicities severely affect patients' quality of life, but in some specific instances, they can be associated with increased response to therapy. It is of paramount importance that clinicians familiarize themselves with and understand the basic management of the range of cutaneous adverse effects caused by these drugs.

Key Words: epidermal growth factor receptor, EGFR, epidermal growth factor receptor inhibitor, EGFR inhibitor, erlotinib, cetuximab, targeted therapy, antineoplastic therapy, medication toxicity, cutaneous side effects, cutaneous adverse events, acneiform eruption, paronychia

Introduction

The epidermal growth factor receptor (EGFR) is expressed in epithelial tissues as well as hair follicles. It contributes to epidermal proliferation, differentiation, and hair growth. Upregulating mutations of EGFR have been found in many solid tumors.1 The discovery of EGFR's role as an oncogene has led to the development of many new inhibitors for the treatment of various neoplasms of the head, neck, colon, and lung. These drugs have been shown to increase the rate of response to treatment, delaying disease progression and improving quality of life. Standard chemotherapeutic agents nonspecifically affect cells that proliferate rapidly; in contrast, EGFR inhibitors (EGFRIs) target pathways more specific to survival of neoplastic cells, thus belonging to a new class of chemotherapeutic agents - so-called "targeted therapy." These targeted therapies are usually associated with fewer systemic side effects than standard chemotherapy.2

There are several different types of EGFRIs, including small molecule tyrosine kinase inhibitors, monoclonal antibodies, and multikinase inhibitors. Small molecule tyrosine kinase inhibitors, such as gefitinib and erlotinib, selectively bind the adenosine triphosphate (ATP)-binding site of the EGFR tyrosine kinase receptor, inhibiting the receptor's intracellular domain via preventing phosphorylation.3,4 Both gefitinib and erlotinib are approved for the treatment of non-small cell lung cancer, and erlotinib in combination with gemcitabine is approved for the treatment of advanced pancreatic cancer.

In contrast, monoclonal antibodies that target EGFR, such as cetuximab and panitumumab, bind to its extracellular domain and competitively inhibit endogenous ligand binding to the receptor.3,4 These antibodies are approved for the treatment of advanced EGFR-expressing colorectal cancer, and cetuximab is also approved for treatment of squamous cell carcinoma of the head and neck. There are also combination therapies that affect multiple receptors such as lapatinib (approved for human epidermal growth factor receptor 2-positive [HER2+] breast cancer) and afatinib (approved for non-small cell lung cancer), which inhibit both the EGFR and HER2 receptors, and vandetanib (approved for advanced medullary thyroid cancer), which inhibits EGFR, vascular endothelial growth factor (VEGFR), and rearranged during transfection (RET) activities.

Although these drugs have been proven to be very effective for normally untreatable advanced neoplasms, EGFRIs cause cutaneous side effects in 50% or more of patients undergoing treatment.1 The most common of these adverse reactions include acneiform eruptions, paronychia, xerosis, mucositis, and alopecia, and less common side effects include trichomegaly, hirsutism, and hyperpigmentation. The occurrence of some EGFRIassociated cutaneous toxicities is actually associated with clinical response to the medication. However, cutaneous side effects can result in decreased quality of life and may cause interruption or discontinuation of therapy despite effectiveness.3 Therefore, it is important to understand the cutaneous side effects of EGFRIs and their management in order to improve quality of life, increase compliance and avoid unnecessary interruption or cessation of treatment.

Cutaneous Toxicities

Mechanism

EGFR is expressed in undifferentiated keratinocytes in the basal layer of the epidermis and the outer layers of the hair follicle, and plays a key role in normal differentiation and proliferation in these tissues. EGFR is activated by ligands such as EGF and transforming growth factor-alpha (TGF-α), and its effects are mediated via downstream pathways including the MAPK (mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt pathways. Downstream effects include growth stimulation, protection from apoptosis, inhibition of differentiation, loss of intercellular attachments, and increased migration. EGFR expression is lost as keratinocytes leave the basal layer and terminally differentiate towards corneocytes.3-6

Inhibition of EGFR signaling leads to apoptosis of normal keratinocytes, but not of melanocytes or fibroblasts. EGFR inhibition also induces terminal differentiation, and has been shown to inhibit formation of the cornified cell envelope and cause premature hair keratinization and maturation of the inner root sheath. Migration of cells is also decreased and attachment is promoted, interfering with normal movement of cells towards the layers of the epidermis and follicle as they mature. These effects are reflected in findings of decreased epidermal thickness and decreased stratum corneum found in skin specimens of patients treated with EGFRIs. Downregluation of EGFR-signaling also seems to result in increased recruitment of inflammatory cells, contributing to the inflammatory nature of several EGFRI-related cutaneous toxicities.3-6

The culmination of all of these effects of EGFR blockade results in overall disruption of the integrity of the skin and follicle with associated inflammation. The high incidence of mucocutaneous side effects reflects the importance of EGFR and its function in the epidermis, hair follicle and periungual tissue.

Acneiform Eruptions

Acneiform eruptions are the most common skin reaction found in those undergoing EGFRI therapy, with 43-85% of patients affected. It is the most common side effect of cetuximab and panitumumab, reported in up to 90% of patients. It is also the earliest side effect, presenting only 7-10 days after initiation of drug therapy. The pathological mechanism underlying EGFRIassociated acneiform eruptions differs than that of traditional acne, lying mainly in the follicular instability caused by disruption of EGFR-related normal growth, induction of apoptosis and early differentiation, as opposed to follicular occlusion.2

The acneiform eruption manifests as a papulopustular eruption that affects mainly the head, neck, and upper trunk, normally sparing sites undergoing radiation therapy. It can, however, affect areas spared by traditional acne, such as the lower legs and dorsal arms.2 Acneiform eruptions due to EGFRI therapy are characterized by a lack of comedones and often display crusting and confluence. Pruritus is more frequent than in traditional acne.2 This eruption is associated with treatment efficacy, showing an increased survival rate when present.3,4 The effects are dose dependent and improvement in the eruption can be seen within 1-2 weeks of discontinuation of therapy.

Treatment focuses more on reducing inflammation than relieving follicular occlusion, and current treatment guidelines are based on the severity of the eruption. A grading scale from 1-4 is used to determine severity (Table 1). For grade 1 eruptions, sun protection, emollients, topical clindamycin, and topical hydrocortisone 1-2.5% are recommended. For grade 2 eruptions, oral tetracyclines such as doxycycline or minocycline 100 mg twice daily should be added. Progression to grade 3 calls for EGFRI dose reduction, oral corticosteroids, and delay in the interval of treatment.5,7,8 Patients will rarely present with grade 4 lesions, but should immediately discontinue EGFRI therapy and be seen by a burn care specialist. It is important to note that, in contrast to traditional acne, retinoids are not effective. Retinoids do not improve the follicular instability caused by EGFRIs and can even exacerbate it. They can also aggravate the concomitant xerosis that is seen with EGFRI therapy. Prophylactic treatment is controversial, as the eruption aids in determining treatment efficacy; however, oncologists will often recommend emollients and may prescribe hydrocortisone or topical clindamycin in anticipation of at least a mild eruption.

Severity of cutaneous toxicity Description of symptoms
Grade 1 Asymptomatic macular or papular eruption or erythema
Grade 2 Symptomatic macular or papular eruption or erythema affecting <50% of body surface area (BSA); localized desquamation or other lesions affecting <50% of BSA
Grade 3 Symptomatic macular, papular, or vesicular eruption affecting ≥50% of BSA; desquamation affecting ≥50% of BSA; severe, generalized erythroderma
Grade 4 Generalized exfoliative, ulcerative, or bullous dermatitis
Table 1. Classification system of acneiform eruptions caused by EGFRIs

Adapted from Hu JC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007 Feb;56(2):317-26.7

Paronychia

Nail changes are a common cutaneous side effect in those undergoing EGFRI therapy and are seen in up to 17% of patients.9,10 Patients present with painful inflammation and suppuration of the periungual skin 4-6 weeks after initiation of therapy. EGFRI-induced paronychia is characterized by abnormal periungal desquamation that results in friable pyogenic granuloma-like changes of the lateral nail folds, as well as pain of the distal finger tufts.11,12 Disruption and fragility of the epidermis caused by EGFRIs may lead to increased susceptibility of skin to penetration by nail fragments, which may be more brittle with EGFR inhibition, a mechanism similar to that seen in retinoidinduced periungual inflammation.2

Paronychia rarely leads to the cessation of therapy; however it does have a significant impact on the patient's quality of life.1 Although the lesions are sterile, secondary infection with Staphylococcus aureus or Candida albicans has been documented.1,3,13 Treatment is dependent on the severity of the reaction. Local care consists of using petrolatum emollients, as well as antiseptic soaks and cushioning of the soles. For reactions that are mild-tomoderate, disinfectants, topical antibiotic ointments, and mid to high potency topical corticosteroids under occlusion are recommended. Although rare, certain cases may be severe enough to require surgical debridement, electrodessication, or cessation of therapy.3,14

Alopecia

Both non-scarring and scarring alopecia has been documented as a side effect of long-term EGFRI therapy. EGFR seems to play a role in maintaining the immune privilege of the hair follicle, and the resultant inflammation leads to hair loss, with eventual follicular destruction.2 Patients usually present with fine, brittle hair with frontal balding about 2-3 months after drug initiation. At this non-scarring stage, alopecia typically resolves after discontinuation of therapy, although hair quality may be affected.13 With time, scarring alopecia can occur and lead to permanent hair loss. Management usually consists of topical steroids to reduce inflammation and prevent scarring.13,15

Xerosis

Xerosis is a common side effect of EGFRI therapy due to the deteriorated stratum corneum, which results in increased transepidermal water loss. This can lead to inflammation and xerotic dermatitis. Patients present 1-2 months after initiation of therapy. Pruritus is also a frequently occurring symptom. Xerosis can accompany or follow the acneiform eruption associated with therapy. Treatment for EGFRI-induced xerosis follows a strategy similar to atopic dermatitis, which includes avoidance of hot baths and extreme temperatures, and using moisturizing soaps that are free of fragrances and thick moisturizing creams or emollients. Preventative measures, consisting of education on dry skin care and bathing techniques, are recommended.13 If the xerosis is severe, topical steroids may be required.13

Other Cutaneous Toxicities

There have been other rare side effects reported with the use of EGFRIs, including trichomegaly and facial hirsutism. Patients may present 1-2 months after initiation of therapy, and the abnormal hair growth lasts for the duration of therapy with the EGFRI. Patients with trichomegaly may experience discomfort and corneal abrasions due to abnormal eyelash growth. Management consists of eye lash clipping every 2-4 weeks and referral to an ophthalmologist for complications. Patients with hirsutism can be managed with laser hair removal as well as topical eflornithine.16,17 Oral complications are uncommonly reported in patients receiving EGFRI therapy. The most common oral side effect observed is mucositis. Patients present with broad areas of erythema and aphthous-like stomatitis.13 Localized measures for symptom relief such as ice chips and thorough oral care are normally sufficient; pain management with analgesics may be necessary.

Although eventually fading over several months, hyperpigmentation has also been reported in a few cases, which is believed to be due to post inflammatory changes secondary to EGFR-induced acneiform eruptions and dermatitis. Management guidelines for this hyperpigmentation focuses on treating the acneiform eruption and eczema. It is also recommended for these patients to limit sun exposure in order to prevent exacerbation of existing hyperpigmentation. There has been no efficacy shown in the use of bleaching creams.7

Conclusion

The use of EGFRIs for chemotherapy is on the rise due to their observed efficacy and decreased rate of nonspecific and hematopoietic side effects. However, due to EGFR's important role in the skin and hair follicle, EGFRIs are associated with frequent mucocutaneous toxicities. It is important to understand these adverse effects and their management in order to avoid unnecessary interruption of therapy and decreased quality of life. The most common dermatologic toxicities include acneiform eruptions, paronychia, alopecia, and xerosis. Many of these side effects can be managed, which can increase compliance and help reduce the physical and emotional burden that patients face.

References

  1. Ehmann LM, Ruzicka T, Wollenberg A. Cutaneous side-effects of EGFR inhibitors and their management. Skin Therapy Lett. 2011 Jan;16(1):1-3.
  2. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006 Oct;6(10):803-12.
  3. Cowen E. Skin Reactions from new anti-cancer therapies. Lecture presented: The Annual Dermatology Foundation Clinical Symposia: Advances in Dermatology, January 21, 2016; Naples, Florida.
  4. Patel A. Cutaneous reactions of targeted drug therapy. Lecture presented: Houston Dermatological Society, February 8, 2016; Houston, Texas.
  5. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005 Sep;16(9):1425-33.
  6. Stulhofer Buzina D, Martinac I, Ledic Drvar D, et al. The most common cutaneous side effects of epidermal growth factor receptor inhibitors and their management. Acta Dermatovenerol Croat. 2015 23(4):282-8.
  7. Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007 Feb;56(2):317-26.
  8. Lynch TJ, Jr., Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitorassociated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007 May;12(5):610-21.
  9. Garden BC, Wu S, Lacouture ME. The risk of nail changes with epidermal growth factor receptor inhibitors: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2012 Sep;67(3):400-8.
  10. Capriotti K, Capriotti JA. Chemotherapy-associated paronychia treated with a dilute povidone-iodine/dimethylsulfoxide preparation. Clin Cosmet Investig Dermatol. 2015 8:489-91.
  11. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol. 2001 Jun;144(6):1169-76.
  12. Pomerantz RG, Mirvish ED, Geskin LJ. Cutaneous reactions to epidermal growth factor receptor inhibitors. J Drugs Dermatol. 2010 Oct;9(10):1229-34.
  13. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011 Aug;19(8):1079-95.
  14. Fox LP. Nail toxicity associated with epidermal growth factor receptor inhibitor therapy. J Am Acad Dermatol. 2007 Mar;56(3):460-5.
  15. Burtness B, Anadkat M, Basti S, et al. NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw. 2009 May;7 Suppl 1:S5-21.
  16. Hamzavi I, Tan E, Shapiro J, et al. A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol. 2007 Jul;57(1):54-9.
  17. Smith SR, Piacquadio DJ, Beger B, et al. Eflornithine cream combined with laser therapy in the management of unwanted facial hair growth in women: a randomized trial. Dermatol Surg. 2006 Oct;32(10):1237-43.

In this issue:

  1. Vitamin B Derivative (Nicotinamide) Appears to Reduce Skin Cancer Risk
  2. Epidermal Growth Factor Receptor Inhibitors: Cutaneous Side Effects and Their Management
  3. Update on Drugs and Drug News - September-October 2017