Cetuximab is an immunoglobulin (Ig) G-1 monoclonal antibody indicated for the treatment of squamous cell carcinomas of the head and neck and KRAS (Kirsten rat sarcoma virus oncogene homologue) wild-type metastatic colorectal cancer. It binds to the epidermal growth factor receptor (EGFR) and inhibits the activation of the tyrosine kinase pathway. The inhibition of this pathway blocks important cell mechanisms such as signal transduction, regulation of cellular activity, and cell division. Inhibition of the EGFR hinders re-epithelisation of the skin during the wound healing process, and decreases antibacterial activity of the epidermis. EGFR inhibition also disrupts the innate immune response of the skin to wound healing. As a result of this, cetuximab reduces skin integrity. Cutaneous toxicities are therefore common during treatment with cetuximab.

A study conducted by Pfeiffer et al. of weekly versus biweekly cetuximab demonstrated that patients without skin toxicities had a shorter progression free survival (3.4 months versus 6.2 months; P=0.004) and shorter overall survival (6.3 months versus 9.9 months; P=0.004). These results indicate that the efficacy of cetuximab is correlated to the presence of cutaneous toxicities. There is a distinct correlation between rash severity and patient survival.

While clinicians may use the presence of rash as a surrogate marker for cetuximab efficacy, this skin toxicity needs to be managed to prevent significant morbidity in patients and the possible cessation of an effective treatment, especially since treatment of rash does not interfere with patient survival. Although cutaneous toxicity may not be life threatening, depending on its severity, it may result in dose reduction or even cessation of treatment. There are four distinct cutaneous manifestations; folliculitis (infection in hair follicles), xerosis (dry skin), paronychia (inflammation of skin bordering toenails or fingernails), and hair changes. These types of cutaneous toxicities are common to all EGFR inhibitors (EGFRI). The recommendations of management may be applied to the entire class.

Folliculitis appears as acne-like papules and pustules that occur on the face, scalp, and upper trunk. It occurs in 85% of patients undergoing EGFRI treatment. 10-20% of patients develop grade 3-4 folliculitis. This acneiform rash appears during the first weeks to months of therapy. Survey results gathered from 110 oncology practices showed that 60% of patients required dose reductions, 75% dose interruptions, and 32% drug discontinuation.

Treatments that may be beneficial include; oral antibiotics (e.g. tetracyclines: minocycline, doxycycline, and erythromycin), topical retinoids, oral isotretinoin, and low-potency corticosteroids. It is important to note that topical retinoids need to be used with caution as they may aggravate the condition by drying the skin. Hydrocortisone 1% is the preferred treatment for pruritus (itch) associated with folliculitis.

Xerosis (abnormally dry skin) manifests between the first and second months of treatment. Xerosis can be managed with the frequent application of moisturisers and the use of soap substitutes. Pruritus associated with xerosis can be managed with systemic antihistamines and oily calamine or 1% menthol in aqueous cream. For more severe cases of xerosis, with fissures, 20% urea cream, liquid Duoderm® or flexible collodion may be beneficial.

Paronychia involves the swelling or inflammation of the nail folds on the fingers and toes. Usually this toxicity manifests at a later stage, six months after therapy. In a study with 152 patients who were undergoing treatment with cetuximab, 27 patients developed paronychia. Prevention of paronychia has been observed with daily use of mild corticosteroid cream and antiseptic soaks of saline, or diluted bleach. Pain and discomfort associated with paronychia may warrant dose changes, however interruptions are generally not necessary. Paronychia management aims to minimise trauma and inflammation, and to prevent infection of the skin bordering the nails.

Hair changes generally occur after 2–3 months: they include trichomegaly (long curly eyelashes), hypertrichosis (increased facial hair), frontal alopecia, and dry brittle scalp hair. When treatment has been discontinued, alopecia tends to resolve.

Despite practice variations and few controlled studies, the Multinational Association for Supportive Care in Cancer (MASCC) Skin Toxicity Study Group assembled committees to develop guidelines for the management and prevention of cutaneous toxicities arising from the use of EGFRI, as summarised below.

Prophylactic management of folliculitis is crucial. The high incidence of EGFRI skin rash after two to four weeks of therapy warrants prophylactic management. The MASCC guidelines recommend that patients use hydrocortisone 1% cream with moisturiser and sunscreen twice daily. Antibiotics are to be given prophylactically; doxycycline 100mg twice daily for 1–6 weeks or minocycline 100mg daily for eight weeks from EGFRI commencement. Minocycline is less photosensitising then doxycycline, however doxycycline is preferred in patients with renal impairment. The frequent and daily application of vitamin K1 cream (Pliazon®) is recommended by the manufacturer, Merck Serono, and is included in their Erbitux® (cetuximab) patient pack. This, however, is not recommended in the MASCC guidelines as the published reports supporting the use of the vitamin K1 cream are based on studies without control groups. There is some speculation that the use of minocycline 50mg daily and doxycycline 50mg daily may suffice.

Treatment of acneiform rash includes a potent corticosteroid of the oncologist’s choice (in Australia) and clindamycin 1%, whereas the pruritus associated with folliculitis requires only a mild steroid. Systemic treatments include a prophylactic tetracycline (at the doses recommended above). However, isotretinoin at low doses of 20-30mg/day has been reported as beneficial if all other treatments have not been successful.

Prevention of xerosis, as per the MASCC guidelines, is not based on randomised clinical trials as none are available. Prevention includes regular moisturising of skin, avoiding soaps, and bathing in tepid water. Treatment measures for mild to moderate xerosis include emollient creams containing urea or colloidal oatmeal. For scaly areas; salicylic acid 6% and zinc oxide (13–40%) is recommended. Medium to high potency steroid creams are recommended for severe xerosis.

To prevent paronychia, frequent use of diluted bleach soaks (0.005% sodium hypochlorite) and the avoidance of irritants is recommended. Treatment of paronychia includes corticosteroids, tetracyclines, antibacterials (according to culture and sensitivities) and biotin for brittle nails. MASCC recommendations for paronychia prevention and treatment are based on expert opinions and case reports as there is no evidence to support approved treatments.

Prevention of non-scarring alopecia is not recommended but treatment includes minoxidil 2% or 5% twice daily. Scarring alopecia, however, should be prevented using the same measures used to reduce the inflammation of folliculitis. Use of steroid shampoos are indicated in treatment. To prevent complications from trichomegaly, eyelashes should be trimmed regularly.

Although there are limited documented randomised controlled studies that investigate the cutaneous toxicities of EGFRI use, there are many case reports and data which show that common toxicities occur in a large percentage of patients undergoing EGFRI treatment. The principle of cutaneous toxicity management in cetuximab (and other EGFRI) treatment is to treat early, and fully, for as long as is required to prevent and manage these toxicities without impacting on the patients’ outcomes.

References:

  1. Buckley N, Chairman, Editorial Advisory Committee. Australian Medicines Handbook. Adelaide, South Australia. Australian Medicines Handbook Pty Ltd. 2013. p. 574-575.
  2. Lacouture ME, Anadkat MJ, Bryce J, Chan A, Epstein JB, Murphy BA, et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. [Online] 2011;19: 1079-1095. Available from: doi: 10.1007/s00520-011-1197-6. [Accessed: 3rd May 2014]
  3. Mitchell EP, PÉrez-soler R, Van Cutsem E and Lacouture ME. Clinical Presentation and Pathophysiology of EGFRI Dermatologic Toxicities. Psychiatric Times. [Online] 2007. Available from: http://www.psychiatrictimes.com/review-article/clinical-presentation-and-pathophysiology-egfri-dermatologic-toxicities.   [Accessed: 7th May 2014]
  4. Pfeiffer P, Nielsen D, Bjerregaard J, Qvortrup C, Yilmaz M and Jensen B. Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Annals of Oncology. 2008; 19: 1141-1145.
  5. Sinclair R. Anticipating and managing the cutaneous side effects of epidermal growth factor receptor inhibitors. Asia-Pacific Journal of Clinical Oncology. 2014; 10(Suppl.1): 11-17.
  6. Sorensen OE, Thapa DR, Roupe KM, Valore EV, Roberts AA, Schmidtchen A, et al. Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. The Journal of Clinical Investigation. [Online] 2006;116(7): 1878-1185. Available from: doi:10.1172/JCI28422. [Accessed: 3rd May 2014]

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