Pinto, C., Barone, C.A., Girolomoni, G., Russi, E.G., Merlano, M.C., Ferrari, D., Maiello, E. (2011). Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist, 16, 228–238.

To identify appropriate prophylactic and therapeutic interventions for the assessment and management of skin toxicities including rash, dryness, pruritus, paronychia, hair abnormality, and mucositis in patients with cancer receiving treatment including epidermal growth factor receptor inhibitors (EGFR-Is) (e.g., cetuximab) alone or in combination with chemotherapy or radiotherapy.

In the absence of definitive evidence from clinical trials, a group of Italian expert clinicians produced recommendations for skin toxicity management in patients receiving EGFR-Is. The RAND Corporation/University of California, Los Angles (UCLA) Appropriateness Method was used for obtaining consensus on the expert opinions.

The consensus panel comprised an advisory board of nine expert clinicians from different clinical settings (six medical oncologists, two radiation oncologists, and one dermatologist). A group of 40 panelists was identified.

The database searched was MEDLINE (2005 to October 2009). Potentially relevant abstracts presented at annual meetings or gastrointestinal symposia of the American Society of Clinical Oncology and the European Society of Medical Oncology were examined.

Search keywords were EGFR inhibitors, cetuximab, skin toxicity, skin rash, and radiation dermatitis.

Studies were included in the review if they were

• In English language
• Observational, prospective studies about assessment and treatment
• Randomized, double-blind, placebo-controlled, or uncontrolled
• Retrospective and uncontrolled
• Systematic reviews and meta-analyses
• Consensus guidelines
• Reporting on available data for drugs tested in phase 3 (including abstracts).

Studies were excluded if they were published before 2005.

Patients were undergoing the active treatment phase of care.

General Prophylactic Measures Before Starting Cetuximab Treatment:

• Perform medical history and full-body skin evaluation with attention to xerosis, atopic dermatitis, and severe acne vulgaris.
• Education and general interventions may include the following.
  • Use sunscreens.
  • Avoid habits or products that can produce dry skin (e.g., hot water, alcohol-based cosmetics).
  • Enhance skin hydration (e.g., use bath oils).
  • Use alcohol-free moisturizing creams frequently.
  • Use tocopherol oil or gel.
  • Avoid tight shoes.
  • Avoid excessive beard growth, shaving with a regular shaving razor (e.g., sharp multiblade), using pre–shaving cream emollients and moisturizing aftershave, using alcohol and aftershave, or using an electric razor.

Rash

Management of Grade 1 Skin Rash (Adapted From the National Cancer Institute [NCI] Common Toxicity Criteria [CTC], Version 3):

• For skin lesions and symptoms including papules, pustules, or symptom-free erythema, do not modify cetuximab dose, interrupt treatment, or use topical or systemic treatment.
• Administer general educational and prophylactic measures.

Management of Grade 2 Skin Rash:

• Skin lesions include eruption with papules (grade 2A) or pustules (grade 2B) covering less than 50% of the body surface, with moderate symptoms and that do not interfere with daily activities.
• Do not modify cetuximab dose or interrupt treatment.
• Topical treatments include the following.
  • Antibiotics: clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel, BID until improvement to grade 1.
  • Avoid benzoyl peroxide products.
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatments include the following.
  • Prevalence of pustules (grade 2A): No systemic treatment is recommended.
  • Prevalence of pustules (grade 2B): Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.

Management of Grade 3 Skin Rash:

• Skin lesions and symptoms include eruption with papules (grade 3A) or pustules (grade 3B) covering more than 50% of the body surface, with severe symptoms that interfere with daily activities.
• Cetuximab dose modification or treatment interruptions include the following.
  • First occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to grade lower than 2. If the rash improves, continue at 250 mg/m². If the rash does not improve, discontinue therapy.
  • Second occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash improves, continue at a reduced dose of 200 mg/m². If the rash does not improve, discontinue therapy.
  • Third occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash does not improve, continue at a reduced dose of 150 mg/m². If the rash still does not improve, discontinue therapy.
  • Fourth  occurrence: Discontinue therapy definitively.    
• Topical treatment:
  • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products. 
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatment:
  • Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.
  • Corticosteroids: Use methylprednisolone 0.4 mg/kg orally or prednisone 0.5 mg/kg orally for up to 10 days.
• Systemic treatment for grade 3, highly symptomatic or nonresponsive patients:
  • Retinoids: isotretinoin 0.3–0.5 mg/kg orally
  • Corticosteroids: methylprednisolone or dexamethasone via IV
  • Antihistamines: clorfenamine intramuscularly (IM) or via IV
  • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV

Management of Grade 4 Skin Rash:

• Skin lesions include generalized rash with severe symptoms that require emergency treatment.
• Discontinue therapy immediately and definitively.
• Topical treatment:
  • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products.
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatment:
  • Retinoids:  isotretinoin 0.3–0.5 mg/kg orally
  • Corticosteroids:  methylprednisolone or dexamethasone via IV
  • Antihistamines: chlorpheniramine IM or via IV
  • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV
  • Hydration via IV
  • Hospitalization

Xerosis, Fissures, and Eczema

Prevention:

• General educational and prophylactic measures are important.
• Regular use of emollient ointments, almond oil, and preparation of polyethylene glycol is recommended.

Management:

• For eczema, use topical treatment with medium-potency corticosteroids for one to two weeks.
  • Betamethasone dipropionate 0.05%–0.1% cream
  • Clobetasone 0.05% cream
  • Ointment fluocinolone acetonide
  • Hydrocortisone butyrate 0.1% cream
  • Consider simple or occlusive dressing for the extremities.
  • Topical antibiotic is recommended for superinfection.
    • Fusidic acid 2% cream
    • Bacitracin cream
    • Mupirocin 2% cream

Paronychia

Prevention:

• Avoid friction and pressure on the nail fold (e.g., avoid tight shoes).

Management:

• Wash with antiseptics including diluted hydrochloric acids solution or boric acid solution 3%.
• Use creams containing corticosteroids and antiseptics.
  • Betamethasone 0.05% plus clioquinol 3% ointment
  • Betamethasone 0.1% plus gentamicin 0.05% cream
  • Betamethasone 0.1% plus gentamicin 0.1% cream
  • Betamethasone valerate 0.1% plus fusidic acid 2% cream
  • Triamcinolone acetonide 3% plus chlortetracycline 0.1% ointment
  • Triamcinolone benetonide 2% plus fusidic acid 0.03% cream
• Use oral antibiotics for superinfection.
  • Amoxicillin or clavulanic tablets
  • Cefalexin tablets
  • Clindamycin capsules
• Use analgesic drugs (nonsteroidal anti-inflammatory drugs) orally.

The use of cetuximab in treating colorectal and head and neck cancer has significantly affected patient outcomes. A strategic approach to managing skin toxicities that includes consensus recommendations from experts will guide clinicians in minimizing the incidence of skin rash, improve compliance, and optimize patient outcomes.

Nurses who will be managing grade 1 and 2 skin toxicities should receive education. In addition, use of a multidisciplinary approach when managing skin rashes is paramount. Facilities may choose to create algorithms as an effective strategy to establish consistent processes for the assessment and management of skin toxicities induced by EGFR-I therapy.