Cutaneous Toxicity of Epidermal Growth Factor Receptor Inhibitors

Presented by: Julie Rogan, BSN, OCN
The University of Pennsylvania
Last Modified: October 1, 2013

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Penn MedicineContinuing Education Information

This continuing education activity is designed to enable nurses and nurse practitioners in clinical practice to understand the clinical significance of cutaneous toxicities caused by epidermal growth factor receptor inhibitors (EGFRIs), identify their presentation, associated causative agents and describe the prevention and management of these side effects.

This activity has been approved for 0.9 contact hour by the Hospital of the University of Pennsylvania, Department of Nursing Development and Education, an approved provider of continuing nursing education by the PA State Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

To receive continuing education credits for this activity:

  • Read the article below.
  • Click on the link at the end to go to the posttest, fill in your contact information and complete the test.
  • If you do not achieve a passing score, you will return to the test and be able to retake the posttest.
  • If you achieve a score of 80% or higher, you can proceed to the evaluation form.
  • Once you submit the evaluation, the CE certificate will pop up. Please print this for your records. You will also receive a copy by email.

The presenters and planning committee report no conflicts of interest.
This activity expires September 15, 2015.

The educational objectives of this activity are:

  • Identify the clinical significance of cutaneous toxicities of EGFRIs.
  • Describe the pathophysiology and clinical presentation of these toxicities.
  • List current evidence-based recommendations for prevention and treatment.

Introduction & Clinical Significance

Over the past few decades, much has changed in how cancer is treated. Novel treatments and targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have been developed through a better understanding of the biology of cancer (Krause, 2013). One beneficial category of targeted therapies is epidermal growth factor receptor inhibitors (EGFRIs).

EGFRIs are strikingly different from traditional chemotherapy. These agents are efficacious in the treatment of lung, colorectal, and head and neck cancers (Reguiai et al., 2012). EGFRIs induce fewer systemic side effects than chemotherapy, although they cause a papulopustular rash in 60-80% of patients taking the medications (Lacouture et al., 2010). The visibility and discomfort of the rash may cause patients to experience a decreased quality of life, through anxiety, depression, sleep disturbances, and social isolation, which could lead them to want to discontinue the EGFRI (Boone et al., 2007; Pomerantz, Mirvish, & Geskin, 2010; Reguiai et al., 2012; and Scope et al., 2007). However, clinicians have reported a correlation between the benefit of EGFRIs and the development and intensity of the rash (Boone et al., 2007; Eaby, Culkin, & Lacouture, 2008; Guttman-Yassky et al., 2010; Monti & Motta, 2007; and Pomerantz et al., 2010). Nurses' awareness of the cutaneous toxicities associated with EGFRIs enables them to educate patients about the prevention and management of these unique side effects to ensure compliance with the treatment plan (Boone et al., 2007; and Eaby et al., 2008).

Clinical practice guidelines have recently been published that advise oncology professionals about best practices in alleviating patient discomfort related to cutaneous toxicities caused by EGFRIs. Very few randomized controlled trials have investigated the management of EGFRI-induced cutaneous toxicities, so case reports, small studies, and nonrandomized studies were used to compile the guidelines published by Lacouture et al. (2011) and Reguiai et al. (2012). Studies are currently being performed to investigate any long-term changes caused by EGFRIs (Lacouture et al., 2010).

Pathophysiology

Epidermal growth factor (EGF) is a signaling pathway that is activated by the binding of certain ligands to epidermal growth factor receptors (EGFRs), which allow keratinocytes to proliferate and migrate (Monti & Motta, 2007). When the EGF pathway is altered, cutaneous injury occurs (Eaby et al., 2008). The skin dries, becomes inflamed, and forms a papulopustular rash (Eaby et al., 2008). Guttman-Yassky et al. (2010) report hyperplasia where the rash occurs, an increase in production of inflammatory mediators, and an increase in the formation of keratinocytes. Inflammatory dendritic cells and T-cells produce direct inflammatory mediators to cause cutaneous inflammation and induce apoptosis of cancer cells (Guttman-Yassky et al., 2010). EGFR is a target for anticancer therapy because it is often overexpressed by tumors (Pomerantz et al., 2010). EGFRIs are useful for tumors that have dysregulated EGFR expression, and those that are resistant to chemotherapy and radiation (Kardaun and van Duinen, 2007).

Monoclonal antibodies (MAbs) target the extracellular surface of the receptor and prevent the binding of ligands, while EGFR tyrosine kinase inhibitors (TKIs) are smaller molecules that can penetrate into the cytoplasm of the malignant cell (Eaby et al., 2008; Pomerantz et al., 2010). Cetuximab and panitumumab are examples of monoclonal antibody EGFRIs, and erlotinib, gefitinib, and lapatinib are examples of EGFR TKIs (Lacouture et al., 2011; and Pomerantz et al., 2010).

  • Cetuximab is a chimeric human-murine IgG1monoclonal antibody used for metastatic colorectal carcinoma and for advanced squamous cell carcinoma of the head and neck (Pomerantz et al., 2010).
  • Panitumumab is a human IgG2 monoclonal antibody used for the treatment of refractory metastatic colorectal carcinoma (Pomerantz et al., 2010).
  • Erlotinib is used for treatment of non-small cell lung caner (NSCLC) and for pancreatic cancer (Guttman-Yassky et al., 2010; Pomerantz et al., 2010).
  • Gefitinib was studied as treatment for refractory metastatic NSCLC (Pomerantz et al., 2010).
  • Lapatinib is used to treat breast cancer (Lacouture et al., 2011).

Clinical Presentation

Papulopustular Rash

The most common side effect of EGFRIs is a rash (Eaby et al., 2008; Guttman-Yassky et al., 2010; and Lacouture et al., 2011). The rash is papulopustular, and appears in a follicular pattern across the face, nose, head, neck, upper extremities, and upper portion of the trunk (Guttman-Yassky et al., 2010). Exudate from the papules may form a crust (Monti & Motta, 2007). The rash appears within one to five weeks of initiating the EGFRI, and resolves within a month after stopping the medication and can wax and wane over the course of treatment (Eaby et al., 2008). Patients who have this rash for an extended period of time are at increased risk for infection (Kardaun and van Duinen, 2007).

The rash induced by MAbs is more purulent and pustular than the one induced by TKIs (Eaby et al., 2008; and Scope et al., 2007). The difference in the pharmacokinetics of the medications is thought to explain this, as MAbs are administered intravenously on a weekly or biweekly basis, and TKIs are oral agents that are taken daily, resulting in differences in peak and trough concentrations (Eaby et al, 2008). Patients receiving cetuximab are more likely to develop a rash if they are male and younger than 70 years old, and patients receiving erlotinib are more likely to develop a rash if they are a nonsmoker, older than age 70, and fair skinned (Lacouture et al., 2011).

Lacouture et al. (2011) and Reguiai et al. (2012) recommend the prophylactic use of oral antibiotics, specifically minocycline or doxycycline, when starting EGFRIs. Lacouture et al. (2011) recommend the prophylactic use of hydrocortisone cream, and to treat the rash topically with steroid and antibiotic creams. Reguiai et al. (2012) do not recommend the use of antibiotic creams. The use of retinoids is controversial because they may excessively dry the skin, but Pomerantz et al. (2010) report having successfully reduced the appearance of EGFRI-induced rashes in several patients who failed to respond to antibiotics and steroids.

Preventive measures are emphasized to diminish the severity of cutaneous toxicities induced by EGFRIs. Lacouture et al. (2011), Pomerantz et al. (2010), and Reguiai et al. (2012) recommend the daily use of an alcohol-free emollient and a broad-spectrum sunscreen for general prevention of cutaneous toxicities.

The rash is graded to provide guidance to prescribers about when to adjust therapy. The NCI Common Toxicity Criteria (2006) grading is used most commonly:

  • A mild grade 1 rash covers less than 10% of a patient's body, may or may not cause pain or pruritis, and does not interfere with the patient's daily routine (Eaby et al., 2008; Reguiai et al., 2012).
  • A moderate grade 2 rash covers 10-30% of the patient's body, limits a patient's daily routine, and causes pain and pruritis (Eaby et al., 2008; Reguiai et al., 2012).
  • A severe grade 3 rash is one that covers greater than 30% of the patient's body, limits the patient's personal activities, causes pain and pruritis, and puts the patient at a high risk for infection (Eaby et al., 2008; Reguiai et al., 2012).

The dose of the EGFRI should be reduced in cases of a severe rash that is interfering with the patient's activities of daily living or one that puts the patient at risk for a superinfection (Eaby et al., 2008). A majority of prescribers choose to decrease the dose of EGFRI when a patient has a severe rash, and about a third will discontinue therapy (Lacouture et al., 2011). Each drug has specific recommendations from the manufacturer for dose reductions (Reguiai et al., 2012).

Differential Diagnoses

The papulopustular rash may at first appear to be acneiform, but it differs in that there are no comedones present in the rash associated with EGFRIs (Guttman-Yassky et al., 2010; and Pomerantz et al., 2010). The rash also differs from acne vulgaris as it does not involve the sebaceous glands, and can cover the upper extremities, neck, and the entire head (Guttman-Yassky et al., 2010; and Pomerantz et al., 2010).

Radiodermatitis and Mucositis

Radiodermatitis almost always occurs in patients receiving both an EGFRI and radiation therapy, and is more likely to be high-grade (Lacouture et al., 2011). To prevent radiodermatitis, Lacouture et al. (2011) recommend washing and drying the area that will be irradiated right before treatment, and later applying topical corticosteroid creams to the site. Reguiai et al. (2012) only recommend the use of corticosteroid creams for radiodermatitis if the rash covers more than 10% of the patient's body.

Radiodermatitis grading also contributes to the decision to halt or discontinue treatment. Higher grades of radiodermatitis have more potential for infection (Lacouture et al., 2011).

  • Grade I radiodermatitis involves dry desquamation and moderate erythema.
  • Grade II has exudative lesions, bright red erythema, and desquamation in skin folds.
  • Grade III has weeping desquamation outside of skin folds and pitting edema (Reguliai et al., 2012).

If the patient has a moderate grade 2 rash, along with grade II radiodermatitis, the EGFRI should be temporarily discontinued (Reguiai, et al. 2012). Radiotherapy and the EGFRI should be temporarily discontinued if the patient has grade II radiodermatitis and grade 3 severe rash (Reguiai et al., 2012). If the patient develops a grade 2 or 3 rash and grade III radiodermatitis, the radiotherapy and EGFRI should be temporarily discontinued (Reguiai et al., 2012).

Radiation causes more severe mucositis in patients who are treated with EGFRIs, but the mucositis is site specific to where the patient is being irradiated (Lacouture et al., 2010). Patients should be educated about maintaining good oral hygiene and reporting pain to providers (Lacouture et al., 2011). Patients may require supportive nutrition (Lacouture et al., 2011). Recommendations for the treatment of mucositis include cryotherapy, steroids, and systemic antibiotics (Lacouture et al., 2011). Lacouture et al. (2011) stress the importance of treating the patient's pain associated with mucositis.

Xerosis

Xerosis (dry skin) is a common side effect of EGFRIs that typically occurs after the development of the rash. It is caused by the inability of the keratinocytes to properly synthesize lipids and proteins (Monti & Motta, 2007). Eaby et al. (2008), Gridelli et al. (2008) and Ocvirk & Cencelj (2009) recommend the following preventative measures to manage excessively dry skin:

  • Maintain adequate hydration.
  • Avoid long, hot showers, opting for lukewarm water and mild soap. Apply moisturizer within 15 minutes of showering.
  • Avoid laundry detergents and skin care products with perfumes and/or containing alcohol.
  • Using saline nasal spray followed by petroleum jelly may reduce nosebleeds.
  • Use a lubricant during sexual intercourse.

Xerosis can be treated with emollient creams and bath oils when involving less than 30% of the body, but when it is severe, Reguiai et al. (2012) recommend emollient ointments and hydrocolloid dressings.

Pruritis

Pruritus usually accompanies the rash or xerosis, and may be treated topically with mentholated lotions (Lacouture et al., 2011). Patients may also benefit from a second-generation non-sedating antihistamine, such as loratadine (Lacouture et al., 2011). First -generation antihistamines, such as hydroxyzine or diphenhydramine, can be taken at night, as they may cause drowsiness (Lacouture et al., 2011). Antihistamines should be used cautiously, if at all, in elderly patients, because of the risk of adverse reactions (Lacouture et al., 2011).

Fissures

Fissures are cracks in the skin that may occur with extreme xerosis (Eaby et al., 2008; Lacouture et al., 2011; and Monti & Motta, 2007). Fissures are painful and bleed easily, and occur on fingertips, knuckles, palms, and soles (Lacouture et al., 2011; and Monti & Motta, 2007). Fissures appear two to four months after beginning treatment with an EGFRI (Eaby et al., 2008). Eaby et al. (2008) recommend preventing fissures with a heavy application of emollient ointment to the hands and feet and encasing them in socks or gloves before going to bed at night. Diluted bleach soaks (1/4 cup bleach in 3 gallons water) are recommended to prevent infection in fissures (Lacouture et al., 2011). Lacouture et al. (2011) also recommend sealing fissures with liquid glue, such as Liquid Bandaid, to prevent infection.

Paronychia

Patients may develop paronychia, which is a painful inflammation of the proximal and lateral nail folds of the fingers and toes, most often the thumbs and great toes (Boone et al., 2007; Eaby et al., 2008; Gridelli et al., 2008; Monti & Motta, 2007; and Pomerantz et al., 2010). Crusted lesions appear, that lead to ingrown nails (Gridelli et al., 2008). Paronychia develops within two to four months of initiating treatment (Eaby et al., 2008). Paronychia is treated with topical corticosteroids, and the continued use of oral antibiotics (Lacouture et al., 2011; and Reguiai et al., 2012). If a secondary infection is confirmed, Reguiai et el. (2012) advise discontinuing the prophylactic oral antibiotic and initiating an antibiotic to treat the infection. These painful lesions heal slowly over several months once the EGFRI has been discontinued (Gridelli et al., 2008).

Eaby et al. (2008) and Gridelli et al. (2008) recommend preventing paronychia by advising the patient to wear comfortable shoes, avoid biting nails, avoid artificial nails, and to trim nails safely. Lacouture et al. (2011) recommend the prevention of infection in paronychia through diluted bleach soaks or diluted vinegar soaks.

Changes in Hair

Trichomegaly, the increased growth and curling of eyelashes, may occur one to two months after initiating an EGFRI (Boone et al., 2007; Eaby et al., 2008; Monti & Motta, 2007; and Pomerantz et al., 2010). Trichomegaly can cause corneal abrasions (Lacouture et al., 2011). Eaby et al. (2008) and Lacouture et al. (2011) advise trimming the eyelashes for patient comfort.

Hypertichosis, the increased growth of facial hair, may occur one to two months after initiating an EGFRI (Boone et al., 2007; Eaby et al., 2008; Monti & Motta, 2007; and Pomerantz et al., 2010). Eflornithine cream or laser hair removal are topical treatments for hirsutism that can be recommended to female patients receiving EGFRIs (Lacouture et al., 2011). Waxing is not recommended (Lacouture et al., 2011).

Alopecia may occur two or three months after therapy with an EGFRI begins (Lacouture et al., 2011). Alopecia is not preventable, and regrowth of hair will occur when therapy is stopped (Lacouture et al., 2011). The effects of scarring alopecia can be diminished by following the previously mentioned recommendations for the treatment and prevention of the papulopustular rash (Lacouture et al., 2011).

Nursing Implications

EGFRIs are given in both the clinic (IV) and home (oral) settings. Nurses may encounter patients with these side effects in an infusion center, in the physician's office or via a phone call from the patient. Nurses will need to become comfortable assessing these unique side effects over the telephone. Compliance with oral medications is critical to improved outcomes. Therefore patients should be assessed for their ability to be compliant and the nurse should educate them about the importance of taking the medication as scheduled and providing tips and tools to stay on track (pill boxes, reminder on a smartphone, taking same time of day, etc.).

Food increases bioavailability of the drug and, in turn, can increase side effects. Therefore, nurses should advise patients to take orally administered agents on an empty stomach to potentially limit rash severity. Patients should be reminded to moisturize their skin and use a sunscreen when being exposed to sunlight. Nurses should remind patients that the rash is not an allergic reaction, but instead, an expected side effect of the drug and to notify the nurse or doctor if the rash is uncomfortable or affects activities of daily living. If a patient calls to report diarrhea, they should be asked about frequency and consistency, as well as oral fluid intake. Age is an important factor, as elderly patients may become dehydrated much quicker, requiring IV fluid hydration. Patients should be taught to use over-the-counter anti-diarrheal medication, but understand that if that is not working, to call the office. Also, avoiding foods high in fiber and following a bland diet with breads and rices can prevent or lessen diarrhea.

The number of FDA approved targeted therapies continues to grow and nurses must be knowledgeable about the unique side effects associated with these agents. Knowing how to prevent and manage EGFRI-induced cutaneous toxicities empowers nurses to better educate patients and families about how to maintain quality of life while undergoing this efficacious treatment (Peuvrel et al., 2012). Successful management of cutaneous toxicities can maximize the benefit to the patient (Eaby et al., 2008).

References

Boone, S. L., Rademaker, A., Liu, D., Pfeiffer, C., Mauro, D. J., & Lacouture, M. E. (2007). Impact and Management of Skin Toxicity Associated with Anti-Epidermal Growth Factor Receptor Therapy: Survey Results. Oncology, 72, 152-159. DOI: 10.1159/000112795

Eaby, B., Culkin, A., & Lacouture, M. E. (2008). An Interdisciplinary Consensus on Managing Skin Reactions Associated With Human Epidermal Growth Factor Receptor Inhibitors. Clinical Journal of Oncology Nursing, 12(2), 283-290. DOI:10.1188/08.CJON.283-290

Gridelli, C., Maione, P., Amoroso, D., Baldari, M., Bearz, A., Bettoli, V., Cammilluzzi, E., Crino, L., De Marinis, F., Di Pietro, F. A., Grossi, F., Innocenzi, D., Micali, G., Piantedosi, F. V., & Scartozzi, M. (2008). Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: Results of an Experts Panel Meeting. Critical Reviews in Oncology/Hematology, 66, 155-162. doi:10.1016/j.critrevonc.2007.10.004

Guttman-Yassky, E., Mita, A., De Jonge, M., Matthews, L., McCarthy, S., Iwata, K. I., Verweij, J., Rowinsky, E. K., & Krueger, J. G. (2010). Characterization of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib. European Journal of Cancer, 46, 2010-2019. doi:10.1016/j.ejca.2010.04.028

Kardaun, S. H., & van Duinen, K. F. (2007). Erlotinib-induced florid acneiform rash complicated by extensive impetiginization. Clinical and Experimental Dermatology, 33, 46-49. doi: 10.1111/j.1365-2230.2007.02556.x

Krause, T. (2013, February). Targeted Therapies in Oncology. Presentation at Effects of Cancer and Cancer Therapy Class, Philadelphia, PA.

Lacouture, M. E. et al. (2010). A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Supportive Care in Cancer, 18, 509-522. DOI: 10.1007/s00520-009-0744-x

Lacouture, M. E., Anadkat, M. J., Bensadoun, R. J., Bryce, J., Chan, A., Epstein, J. B., Eaby-Sandy, B., & Murphy, B. A. (2011). Clinical Practice Guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Supportive Care in Cancer, 19(8), 1079-1095. DOI: 10.1007/s00520-011-1197-6

Monti, M., & Motta, S. (2007). Clinical management of cutaneous toxicity of anti-EGFR agents. The International Journal of Biological Markers, 22, (1), S53-S61.

National Cancer Institute. (2006). Common terminology criteria for adverse events (CTCAE) [v.3.0].

Ocvirik, J. & Cencelj, S. (2010). Management of cutaneous side-effects of cetuximab therapy in patients with metastatic colorectal cancer. Journal of the European Academy of Dermatology and Venereology, 24, 453-459. DOI:10.1111/j.1468-3083.2009.03446.x

Peuvrel, L., Bachmeyer, C., Reguiai, Z., Bachet, J. B., Andre, T., Bensadoun, R. J., Bouche, O., Ychou, M., & Dreno, B. (2012). Survey on the management of skin toxicity associated with EGFR inhibitors amongst French Physicians. Journal of the European Academy of Dermatology and Venereology, 1-11. DOI: 10.1111/j.1468-3083.2011.04421.x

Pomerantz, R. G., Mirvish, E. D., & Geskin, L. J. (2010). Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors. Journal of Drugs in Dermatology, 9, (10), 1229-1234.

Reguiai, Z., Bachet, J. B., Bachmeyer, C., Peuvrel, L., Beylot-Barry, M., Bezier, M., Boucher, E., Chevelle, C., Colin, P., Guimbaud, R., Mineur, L., Richard, M. A., Artru, P., Dufour, P., Gornet, J. M., Samalin, E., Bensadoun, R. J., Ychou, M., Dreno, B., & Bouche, O. (2012). Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm. Supportive Care in Cancer, 20, 1395-1404. DOI 10.1007/s00520-012-1451-6

Scope, A., Agero, A. C., Dusza, S. W., Myskowski, P. L., Lieb, J. A., Saltz, L., Kemeny, N. E., & Halpern, A. C. (2007). Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption. Journal of Clinical Oncology, 25(34), 5390-5396. DOI: 10.1200/JCO.2007.12.6987

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