# Background
The epidermal growth factor receptor (EGFR) plays a central role in tumour growth and proliferation, and over-expression of EGFR is correlated with a poor prognosis, disease progression, and reduced sensitivity to chemotherapy. 1 EGFR-targeted agents are used in several types of cancer, including lung, colorectal, breast, pancreatic, and head and neck. Classes of EGFR inhibitors include monoclonal antibodies (e.g. cetuximab, panitumumab, pertuzumab) and small molecular weight tyrosine kinase inhibitors (e.g. erlotinib, gefitinib, lapatinib, afatinib, osimertinib). These agents have been evaluated in phase II and III trials and are increasingly being incorporated into therapeutic plans for patients, both as front-line therapy, and after progression on standard chemotherapy.
EGFR inhibitors are generally well tolerated and are not associated with the moderate or severe systemic side effects of standard cancer therapies such as chemotherapy or radiation. However, because of the role of EGFR in skin biology they are associated with a variety of dermatologic reactions. 2 The most commonly reported side effect is acneiform (papulopustular) rash; Table 1 lists the incidence rate for each EFGR inhibitor. Acneiform rash is typically localized to the face, scalp, upper chest and back. Although it is usually mild or moderate in severity, it can cause significant physical and psychosocial distress in patients, which may lead to decreased quality of life, and disruption or discontinuation of therapy. 3,4 Thus, timely and appropriate interventions are essential. 5 

# Table 1. Incidence of acneiform eruption and skin rash EFGR Inhibitor
Incidence of Acneiform Eruption and Skin Rash Afatinib
- Acneiform eruption: ~90% 6 - Skin rash: 90% 6
- In LUX-Lung 3 and 8, incidence of Grade 3 cutaneous reactions ranged from 6.6% to 16.2% 7 

# Cetuximab
- Acneiform eruption: 15-88% 8
- Skin rash: 28-44% 8
- Acneiform rash occurred in 76-88% of patients; severe acneiform rash occurred in 1-18% of patients 9 Erlotinib
- Acneiform eruption: 4-5% 10
- Skin rash: 49-85% 10 o Grade 3: 5-13% o Grade 4: <1% Gefitinib
- Acneiform eruption: 6% 11 - Skin rash: 52%, 11 mainly mild or moderate 12 

# Lapatinib
- Acneiform eruption: not reported 13 - Skin rash: 28-44% (combination therapy with capecitabine or letrozole) 13  - Skin rash: 11-34% (combination therapy with trastuzumab and docetaxel), 18 mainly mild or moderate 19 The onset of acneiform rash is most commonly observed during the first one to two weeks of treatment with an EGFR inhibitor, although the range of onset reported in the literature is between two days and six weeks. 5 The rash typically progresses through four phases: 1
- Phase one (weeks 0-1): sensory disturbance with erythema and edema;
- Phase two (weeks 1-3): papulopustular eruptions;
- Phase three (weeks 3-5): crusting; and,
- Phase four (weeks 5-8): erythematotelangiectasias (red areas).
The lesions are usually sterile, but a secondary bacterial or fungal infection at the site of the eruption has been described in some cases.  The severity of the rash waxes and wanes throughout these four phases, and typically resolves without permanent scarring within two months of therapy discontinuation, although scarring secondary to bacterial or fungal overgrowth can also occur. 1,21 The purpose of this document is to provide recommendations for the prevention and treatment of EGFR inhibitor therapy causing rash.
Guideline Questions 

# Target Population
The recommendations outlined in this guideline apply to adult cancer patients treated with EGFR inhibitors (i.e. afatinib, cetuximab, erlotinib, gefitinib, lapatinib, osimertinib, panitumumab, pertuzumab) either alone or in combination with other treatments.

# Recommendations
- Grading a) Accurate grading of acneiform rash associated with EGFR inhibitors is essential to ensure timely and appropriate interventions. We recommend using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), which is the most widely used classification system in clinical trials. 25 (Level of Evidence: V, Strength of Recommendation: C).
CTCAE defines acneiform rash as a disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, and upper chest and back. 

# Rash and Response to Treatment Relationship
a) Rash occurrence has been statistically associated with efficacy of EGFR targeted therapies.  See Table 3 for a summary of key evidence. However, we cannot conclude from these studies that EGFR inhibitor therapy is ineffective if no or only mild rash occurs. 41 (Level of Evidence: I, Strength of Recommendation: A)
b) The goal of all cancer treatment is to minimize toxicity, maximize treatment adherence, and maintain a good health-related quality of life. Therefore, before starting treatment with an EGFR inhibitor clinicians should explore patient tolerance for cutaneous side effects through a discussion that includes occurrence, timing, severity, prevention and management of acneiform rash.  (Level of Evidence: V, Strength of Recommendation: B) c) EGFR inhibitors should be administered at their maximum tolerable doses to obtain the most effective outcomes and should be accompanied with appropriate supportive care or preventive measures to counteract the rash. 44,45 (Level of Evidence: II, Strength of Recommendation: B) 

# Prevention of Rash
a) Before starting treatment with EGFR inhibitors, clinicians should perform an assessment of patients for pre-existing cutaneous conditions (e.g. psoriasis, acne vulgaris, rosacea) that could worsen with exposure to EGFR inhibitors. 46 (Level of Evidence: V, Strength of Recommendation: B) b) Patients should be informed about general skin care practices to prevent or reduce the severity of acneiform rash, including:  c) For most patients starting EGFR-inhibitor therapy, antibiotic prophylaxis can be used concomitantly with a topical steroid (1% hydrocortisone cream) for the first six weeks to reduce the incidence and severity of acneiform rash and improve quality of life.  In this role, the antibiotics are used for their anti-inflammatory properties and not their antimicrobial effects. We recommend second-generation tetracyclines, either minocycline or doxycycline 100-200 mg daily (single or divided doses). While minocycline is less photosensitizing, doxycycline has a more favorable safety profile. 53 See Table 4 for a summary of key evidence. (Level of Evidence: I, Strength of Recommendation: A) Although rare, for patients with allergies or intolerance to tetracyclines, erythromycin 500 mg twice a day or trimethoprim 160 mg/sulfamethoxazole 800 mg twice a day may be used as an alternative to minocycline or doxycycline. (Level of Evidence: V, Strength of Recommendation: C) d) Studies have been unable to demonstrate a clinically significant benefit of adding tazarotene cream, 52 dapsone gel, 54 and vitamin K1 cream 55 to minocycline or doxycycline. Similarly, topical erythromycin has not been shown to be an effective replacement for oral doxycycline, and therefore these drugs are not recommended. 56  - Combined odd ratio associated with incidence of folliculitis in each study was 0.19 (95% CI, 0.12-0.31; fixed effect model p<0.0001), indicating that the administration of a tetracycline in preventive therapy was associated with a significantly lower incidence of grade 2-3 folliculitis - Prophylactic tetracycline treatment also associated with an improvement in quality of life of patients in 3 of 4 studies in which this parameter analyzed

# Management of Rash
The management of acneiform rash induced by EGFR inhibitors is largely based on small-scale prospective trials, case reports and case series. As a result, management approach varies as shown in Appendix C which summarizes relevant guidelines and consensus statements published within the last 10 years. The recommendations presented below are a consensus of members of the Alberta Provincial Tumour Teams who have experience prescribing EGFR inhibitors and/or treating skin conditions (shown as pathway in Appendix A).
a) General recommendations. Overall management strategy for acneiform rash should be individualized and will depend on the type, severity, location and need to continue treatment. Consultation with a dermatologist is recommended, particularly for rash that does not improve within one to two weeks of treatment or if the patient is severely symptomatic. (Level of Evidence: II, Strength of Recommendation: B) b) Grade 1 rash. Patients should continue EGFR-inhibitor therapy at the prescribed dose. We recommend treatment with topical clindamycin 2% plus hydrocortisone 1% lotion twice daily for four weeks. If after four weeks of treatment the rash has not improved or has worsened, patients should be treated for a Grade 2 rash. (Level of Evidence: V, Strength of Recommendation: C) c) Grade 2 rash. Patients should continue EGFR-inhibitor therapy at the prescribed dose. We recommend treatment with topical clindamycin 2%, hydrocortisone 1% lotion plus either oral minocycline 100 mg twice daily or doxycycline 100 mg twice daily for four weeks, if not used prophylactically. If after four weeks of treatment the rash has not improved or has worsened, patients should be treated for a Grade 3-4 rash. (Level of Evidence: V, Strength of Recommendation: C) d) Grade 3 rash. A dose reduction of EGFR-inhibitor therapy, as per label, may be required (see Appendix D). Obtain bacterial/viral culture if infection is suspected. We recommend treatment with topical clindamycin 2%, hydrocortisone 1% lotion plus either oral minocycline 100 mg twice daily or doxycycline 100 mg twice daily for four weeks, plus oral prednisone up to 0.5 mg/kg daily for seven to 14 days. Referral to a dermatologist is recommended if rash does not improve after four to eight weeks. (Level of Evidence: IV, Strength of Recommendation: C)
- If after four weeks of treatment the rash does not improve or worsens, low-dose isotretinoin (20 to 30 mg/d) 57 or acitretin (25 mg/d) 58  53- *Articles were excluded from the final review if skin toxicity was not a rash or was not related to EGFR-inhibitor treatment (N=7); publication included a description of symptoms only (N=7); publication did not include enough details on treatment types or doses, timelines for observed responses, or specific outcomes (N=6); publication was not accessible through the library system (N=2). - If toxicity recurs, restart at a lower dose (1000 mg/day when administered with capecitabine and 1250 mg/day when administered with letrozole).

# Osimertinib: 16
- Dose adjustments are not necessary for generally manageable adverse reactions.
- If dose reduction or modification is necessary based on individual safety and tolerability, then the dose should be reduced to 40 mg taken once daily. - Dose reduction guidelines for adverse reactions toxicities are provided in the table below.

# Adverse Reaction Dose Modification
Grade 3 or higher Withhold for up to 3 weeks If Grade 3 improves to Grade 0-2 after withholding for up to 3 weeks Restart at same dose (80 mg) or lower dose (40 mg) Grade 3 that does not improve to Grade 0-2 after withholding for up to 3 weeks Permanently discontinue Panitumumab: 67 - If patient develops dermatologic toxicities that are Grade 3 or are considered intolerable, dose modifications according to the table below are recommended. - Dose reductions not recommended for pertuzumab.

# Acneiform Eruption Secondary to EGFR and MEK Inhibitors
Appendix D: Interruptions/Dose Reductions of EFGR Inhibitors for Patients with Persistent Rash Afatinib: 7 - Interrupt for up to 14 days until Grade 0/1 for prolonged or intolerable Grade 2 (7 days of rash).
Resume with dose reduction by 10 mg decrements.
- Interrupt for up to 14 days until Grade 0/1 for any Grade 3. Resume with dose reduction by 10 mg decrements.

# Cetuximab: 9
- If patient experiences severe acneiform rash (Grade 3/4), adjust treatment according to table below. - If rash improves and is no longer severe, resume treatment without any change in dose level.
- If severe acneiform rash recurs further interruption of therapy with dose reductions at pretreatment after improvement (initially to 200 mg/m 2 and subsequently to 150 mg/m 2 ) or discontinuation of therapy may be required. Erlotinib: 66 - Patients with severe skin reactions may require a dose reduction or temporary interruption of therapy. When dose reduction is necessary, it is recommended to reduce in 50 mg steps.

# Gefitinib: 12
- Patients with skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose once toxicity has resolved.

# Lapatinib: 14
- Consider discontinuation or interruption of dosing when patient develops toxicity Grade 2.
- Restart dosing at either 1250 mg/day when administered with capecitabine or 1500 mg/day when administered with letrozole, when the toxicity improves to Grade 1.

# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Thoracic Malignancies, Gastrointestinal, Head and Neck, and Breast Tumour Teams. Members of these Tumour Teams include medical oncologists, radiation oncologists, surgical oncologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from these three provincial Tumour Teams and a Knowledge Management Specialist from the Guideline Utilization Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Resource Unit Handbook.
This guideline was originally developed in 2012. The guideline was revised and reposted in November 2020. 

# Levels of Evidence