Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors 종양혈액내과 노태준 S. Segaert1 & E. Van Cutsem Department of Dermatology, University Hospital, Katholieke Universiteit Leuven; Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium

Introduction Epidermal growth factor receptor (EGFR) Neoplastic cell proliferation Migration Stromal invasion Resistance to apoptosis Angiogenesis. Inhibition of EGFR Impair tumour growth Have made EGFR an attractive target for the development of cancer therapeutics.

epidermal growth factor receptor Iressa

EGFR inhibitors EGFR Monoclonal Ab. against the EGFR Cetuximab (Erbitux TM ) Panitumumab (ABX-EGF) Matuzumab (EMD72000) EGFR tyrosine kinase inhibitors Gefitinib (Iressa TM ) Erlotinib (Tarceva TM ) EKB-569 antibody

Skin toxicity EGFR inhibitors Generally well tolerated. (do not have the severe systemic side- effects usually seen with cytotoxic drugs) Most often an acneiform eruption. A correlation has been suggested between the acneiform eruption and EGFR inhibitor antitumour activity Prospective studies including skin and tumour biopsies are, however, needed to clarify and explain this possible relationship.

Acneiform eruption The most frequently reported side-effect Both monoclonal antibodies and tyrosine kinase inhibitors The rash seems to be dose dependent in more than 50% up to 100% of patients The eruption : seborrheic areas (rich in sebaceous glands) the face, the neck and retroauricular area, the shoulders, the upper trunk (V-shaped), the scalp.

Acneiform eruption (A) papular lesions on the chest (B) V-shaped papulopustular eruption on the back (C) close up of follicular pustules (D) confluent pustules on the nose

Incidence

Simplified classification National Cancer Institute Common Toxicity Criteria version 2.0 (NCI CTC v2.0) National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0)

Acneiform eruption The acneiform eruption arises a few days after treatment with the EGFR inhibitor. to reach a maximum after 2 to 3 weeks following commencement of the therapy. Some spontaneous improvement can be seen even when treatment is continued. The eruption disappears in a few weeks time when treatment is discontinued leaving sometimes residual hyperpigmentation and xerosis.

Xerosis Patients receiving EGFR inhibitors can gradually develop a dry skin over weeks resembling the xerosis in atopic eczema. Patient’s old age, previous therapy with cytotoxics and history of atopic eczema will accentuate the cutaneous dryness Dry, scaly, itchy skin especially of the limbs and of skin areas that were affected by acneiform eruption. When secondary infection of the xerotic skin with Staphylococcus aureus occurs, a flare-up of acute oozing dermatitis and sometimes yellow crusting may be seen. Xerosis, dry eczema and fissure over the interphalangeal joint of the finger

Nail changes Nail changes are seen in 10%– 15% of patients and are a late event (starting usually not earlier than 4–8 weeks) during the treatment course. Paronychia manifesting with inflammation of the nail fold (mainly of the great toe; other toes and fingers may be involved as well) is usually the first sign. This paronychia can be very painful and mimics an ingrown toenail in the severe cases where pyogenic granuloma of the nail fold develops. Paronychia and pyogenic granuloma of the nail fold of the big toe

Hair changes During prolonged treatment with EGFR inhibitors, changes of the hairs can be noticed. Very characteristic are the long, curly, rigid eyelashes, also named trichomegaly. The scalp hairs grow more slowly and adopt a finer, more brittle and curly aspect. Trichomegaly (long curly eyelashes).

Telangiectasia Early during the development of acneiform eruption or with subsequent flares of the rash, scattered telangiectasia may appear On the face, on and behind the ears, on the chest, back and limbs, usually in the vicinity of a follicular pustule. Unlike other telangiectasia, the lesions tend to fade over months usually leaving some hyperpigmentation. Telangiectasia.

Hyperpigmentation Post-inflammatory hyperpigmentation is typically seen following acneiform eruption or other causes of skin inflammation such as eczema or an inflamed sebaceous cyst. Sun exposure aggravates the hyperpigmentation. Hyperpigmentation following acneiform eruption with also some new erythematous lesions.

Pathophysiology Side effect that is directly linked to specific inhibition of the EGFR. First, similar cutaneous effects develop regardless of the mechanism of action of the EGFR inhibitor as a monoclonal antibody or as an EGFR-specific tyrosine kinase inhibitor. Secondly, the cutaneous effects appear to be dose- dependent as shown for gefitinib and panitumumab. Thirdly, there is growing evidence for a possible correlation between tumour response and the presence or extent of skin rash

Pathophysiology In the spectrum of drug-induced skin changes The combination of the itchy acneiform eruption, xerosis, paronychia, hair changes and telangiectasia is entirely unique. Corticosteroids, vitamin B and antiepileptics - this rash usually does not itch and is not accompanied by the other skin findings elicited by EGFR inhibitors. Oral retinoids - xerosis and paronychia but not acneiform changes.

Pathophysiology EGFR is known to be expressed, basal epidermal cells sebaceous glands, hair follicle outer root sheath, hair shaft capillary system. EGFR activation promotion of keratinocyte proliferation regulation of differentiation and keratinisation EGFR central role in Carcinogenesis Psoriasis Wound healing

Management (general) Maximal hydration of the skin the use of bath oil or shower oil (instead of shower gel or soap), tepid water To prevent xerosis an emollient cream (especially on the limbs) Sun exposure should be avoided minimise the risk of hyperpigmentation.

For mild grade 1 reactions no treatment topical anti-acne (metronidazole gel, erythromycin or clindamycin gel) For grade 2 reactions topical treatment an oral antihistamine(cetirizine, loratadine, hydroxyzine) an oral tetracycline (doxycycline 100 mg/day) Management Acneiform eruption Management

For grade 3 reactions Topicals treatment Oral anti-histamines oral tetracyclines at high doses (doxycycline 2100 mg/day) For grade 4 reactions although extremely seldom should be treated in specialised burn care units EGFR inhibitors should be immediately stopped for good.

Management Eczema Management General hydrating measures In this respect alcoholic lotions should be discontinued Switched to oil in water creams instead topical weak corticosteroids are recommended for a short term (1–2 weeks)

Management Paronychia Management Wearing shoes that are not too tight. The nail folds very sensitive to infection. Topical antiseptics or antibiotics should be used on a regular basis. In case of secondary bacterial infection, oral antibiotics can be administered according to the antibiogram.

Management Telangiectasia Management Telangiectasia will gradually disappear over months. In selected cases electrocoagulation or pulsed dye laser therapy can be applied to accelerate disappearance.

Management Hyperpigmentation Management Prevention and treatment of acneiform eruption and eczema is important. Sun blocking creams. Bleaching creams are not very helpful The hyperpigmentation will fade spontaneously with time (months)

Conclusion Treatment efficacy and rash : marker for tumor response. The acneiform eruption responds well to topical anti- acne therapy and tetracycline antibiotics. Future clinical research is required to meet the need for a more accurate classification and for more evidence- based treatment of skin toxicity.