• The rash is characterized by interfollicular- and follicular-based erythematous papules and pustules and is usually seen during the first 2 weeks of therapy 1,2
• The follicular skin lesions are without microcomedones and comedones characteristic of acne, thus indicating that this rash in not acne vulgaris 1,2,4
• The rash tends to wax and wane during therapy, with “flare ups” occasionally noted following infusions 3,5
• Rash symptoms typically resolve without scarring within 1 to 2 months of stopping treatment3
• Several studies have demonstrated a positive correlation between rash and tumor response and/or survival with cetuximab and erlotinib; findings are less consistent with gefitinib1-3

Photos courtesy of Pamela Hallquist Viale.

Pathophysiology 

The pathophysiology of EGFRI-associated skin rash is not completely understood, but interference with the proliferation, differentiation, migration, and attachment of keratinocytes is believed to occur with EGFRI therapy, resulting in recruitment of inflammatory cells and injury to the cutaneous tissues.8 Since EGFR is highly expressed in the epidermal keratinocytes, sebaceous glands, and the epithelium of the hair follicle, inhibition of these receptors can produce characteristic dermatologic effects.9

Guidelines

There are no established evidence-based guidelines on the treatment of rash symptoms associated with EGFRIs, and many of the interventions are based on anecdotal reports or colleagues’ experience. Many were based primarily on effectiveness noted with anti-acne strategies.

A National Comprehensive Cancer Network (NCCN) consensus panel report10 published treatment recommendations for the rash based on expert opinion. These recommendations are that

• Patients should use emollients for the dry skin, or xerosis, that accompanies EGFRI therapies
• Sunscreen should be employed early on, as inhibition of the receptors for EGF lessens the protective nature of the receptors, allowing sun exposure to worsen rash symptoms. Sunscreen products should have a high sun protection factor (SPF)

Mild rash symptoms may not require intervention; if needed, clindamycin gel and/or topical hydrocortisone may be adequate. Moderate rash symptoms may require the previous treatments, or consideration of pimecrolimus 1%, plus a tetracycline analog agent, such as oral doxycycline 100 mg twice daily or minocycline 100 mg twice daily.  Severe rash requires dose interruption of the EGFRI agent, tetracycline analog treatment, and application of hydrocortisone cream, clindamycin gel, or pimecrolimus, plus a steroid dose pack given orally.11 Figure 2 shows rash before and after treatment. Each tier of care requires careful assessment of patient response to therapeutic strategies for treatment of rash.10  Dermatologic consultation is advisable for refractory or severe cases.

Limited evidence exists in the form of randomized, controlled trials for management of EGFRI-associated rash; however, several studies were reported in the last 2 years regarding rash treatment. The results of selected studies are listed in Table 1.

Based on the information from the trials in Table 1, clinicians should consider preemptive therapy with a tetracycline analog agent. The action of the tetracycline analog agents is primarily anti-inflammatory.16,17,19,21 Topical anti-acne therapies were not considered helpful and should be avoided. Regenecare gel may be helpful in reducing symptoms, although larger trials are necessary to confirm usefulness of this treatment.12 Colloidal oatmeal lotion may be useful in reducing inflammation associated with the rash, although additional studies are needed to confirm the role of this therapy.13

Photos courtesy of Mario E. Lacouture.

Grading and Management of EGFRI-Associated Rash

Although grading of the EGFRI rash has typically been done with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) scales,22 recent proposals from consensus panels of experts have identified the limitations of the CTCAE, as it is subject to variable interpretation and calls for involvement of body surface area in calculating different grades of rash.11,23  Recommendations for simplifying the approach to grading, for ease of clinicians taking care of these patients and for more accuracy, now exist. This simplified approach (as illustrated below) calls for 3 categories: mild, moderate, and severe (Table 2).11

Based on information from Lynch et al.11

Other Cutaneous Toxicities

There are other cutaneous toxicities associated with HER1/EGFR targeted therapy. These include nail bed toxicity (paronychia), hair alterations, xerosis, telangiectasia, nasal mucositis, and ocular irritation.1,2,4

Paronychia 2,4,7

• Described as painful inflammation of tissue around fingernails and toenails; more commonly seen in the big toe and thumbs observed in 12% to 16% of patients (Figure 3, left)
• Often delayed, developing after 4 to 8 weeks of treatment
• Symptoms may be improved by wearing shoes that are not too tight; avoiding friction; using hot soaks and cushioning to provide comfort; using Epsom salt soaks to help promote drainage; using topical antiseptic or antibiotic ointments may help

Hair Alterations 2,4

• Hair changes may occur 2 to 3 months after initiation of therapy, with hair thinning and developing dry, brittle, or curly texture
• Trichomegaly (increased hair growth of the eyelashes and eyebrows may occur, although it is rare (Figure 3, right)
• Waxing or electrolysis may be recommended

Xerosis and Related Changes, Skin Fissures 2,4

• Xerosis (abnormally dry skin) is a common side effect of HER1/EGFR-targeted therapy
• Painful fissures may develop on the fingers and toes, in the nail folds, and over the interphalangeal joints
• Hydration of the skin with the use of bath oil or shower oil may help alleviate symptoms. Gels and soap should be avoided, because they may exacerbate dryness; dryness may be alleviated by using emollient creams
• Liquid BandAid may be helpful in protecting fissures

Telangiectasia 4

• Defined as chronic dilation of groups of capillaries leading to elevated dark red blotches on the skin
• May be seen in early onset of rash symptoms, appearing on the face, nose, chest, back and limbs around a follicular pustule
• Tend to fade in time, leaving some hyperpigmentation
• Consider dermatology consult for possible laser therapy

Nasal Mucositis 1

• Sores and irritation may develop inside the nostrils, which may become uncomfortable
• Bactroban Nasal can be applied to help prevent secondary infection

Ocular Irritation 7

• Manifests as dry eyes, progressing to erythematous lids and crusting in the eyelash follicles; looks like blepharitis or conjunctivitis
• Rare, but if it occurs, it is usually within the first 4 weeks of therapy
• Treatment may consist of ophthalmic antibiotic ointment, warm soaks, natural tears

Left, M. Lawrenson, Wikipedia. Right, Criado and Rocha Lima.24

Assessment Tools

The different scales and description of the rash make it difficult to compare the severity of rashes.8 Table 3 is commonly used to grade adverse events associated with papulopustular rash, the most common type of EGFRI-associated skin rash.

Based on information from Oishi,4 Lacouture et al,7 NCI.22
ADL = activities of daily living; BSA = body surface area; IV = intravenous.

An alternate grading scale for EGFRI-associated skin toxicity is the MASCC EGFR Inhibitor Skin Toxicity Tool (MESTT) available through the Multinational Association of Supportive Care in Cancer (MASCC) Web site at http://www.mascc.org/mc/page.do?sitePageId=98483.

Implications for Health Care Professionals

Health care professionals caring for patients on EGFRI therapy need to become competent in treatment of these common dermatologic toxicities. Because rash indicates a probable response to therapy, it is incumbent on the health care professional to implement care strategies for these toxicities, helping patients to maintain therapy for longer periods of time.  Education of the patient regarding the characteristics and time course of the rash and associated toxicities is crucial.4 Care strategies should be instituted early and based on the expert recommendations and clinical trial results of EGFRI rash treatment.25,26

When necessary, dose modifications are important; however, this option is not considered optimal, as the goal of therapy is to keep patients on therapy when responding.4 Prescribing information for the EGFRI drug should be consulted for dose modification recommendations. EGFRI therapy is an integral part of cancer treatment today, and management of the dermatologic toxicities associated with this therapy is crucial to achieving good patient outcomes.

References

1. Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the management forum. Oncologist. 2005;10:345-356.
2. Dick S, Crawford G. Managing cutaneous side effects of epidermal growth factor receptor (HER1/EGFR) inhibitors. Community Oncol. 2005;2:492-496.
3. Sipples R. Common side effects of anti-EGFR therapy: acneiform rash. Semin Oncol Nurs. 2006;22:28-34.
4. Oishi K. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncol Nurs Forum. 2008;35:103-111.
5. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol. 2005;16:1425-1433.
6. Fish-Steagall A, Searcy P, Sipples R. Clinical experience with anti-EGFR therapy. Semin Oncol Nurs. 2006;22(1 suppl 1):10-19.
7. Lacouture M, Basti S, Patel J, Benson A. The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4:236-238.
8. Eaby B, Culkin A, Lacouture M. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2007;12:283-290.
9. Galimont-Collen AFS, Vos LE, Lavrijsen APM, et al. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007;43:845-851.
10. 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 Cancer Netw. 2009:7(suppl 1):S5-S21.
11. Lynch TJ Jr, 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.
12. Kozloff MF, Gowlande PA, Vlamakis J, et al. Evaluation of Regenecare™ Topical Gel in the treatment of skin rash associated with cetuximab (Erbitux®), Tarceva® and other EGFR inhibitor-treated cancer patients. http://www.mpmmedicalinc.com/pdf/Regenecare_Study_Ingalls_April07.pdf.
13. Alexandrescu DT, Vaillant JG, Dasanu CA. Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine-kinase inhibitors. Clin Exp Dermatol. 2007;32:71-74.
14. Ocvirk J, Rebersek M. Managing cutaneous side effects with K1 vitamin crème reduces cutaneous toxicities induced by cetuximab. J Clin Oncol. 2008;26(suppl). Abstract 20750.
15. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25:5390-5396.
16. Jatoi A, Rowland K, Sloan JA, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer. 2008;113:847-853.
17. Lacouture MC, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:1351-1357.
18. Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol. 2009;61:614-620.
19. Jatoi, A, Dakhil, SR, Sloan, JA et al. Prophylactic tetracycline does not diminish the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash: results from the North Central Cancer Treatment Group (Supplementary N03CB). Support Care Cancer. 2010;[Epub ahead of print September 6, 2011].
20. Jatoi A, Thrower A, Sloan JA, et al. Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N05C4). Oncologist 2010;15:1016-1022.
21. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
22. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v4.03.  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
23. Agero ALC, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657-670.
24. Criado PR, Rocha Lima AA. Blepharitis and trichomegaly induced by detuximab. An Bras Dermatol. 2010;85:919-920.
25. Morse L, Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol Nurs. 2006;22:152-162.
26. Viale PH. Management of EGFRI associated toxicities: rash, pruritus, xerosis. Oncol Nurse. 2008;1:10-11.

Key Definitions

blepharitis—inflammation of the eyelid

comedones—bumpy skin, commonly known as blackheads

HER1/EGFR—human epidermal growth factor receptor or HER family; agents that target HER1/EGFR are 2 types: tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies (MAb). When activated, EGFR leads to cell proliferation, inhibits cells death, enhances angiogenesis, and triggers metastasis. Rash is the common side effect of HER1/EGFR inhibitors

interfollicular—between follicles

microcomedones—follicular casts