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SKIN REACTIONS SECONDARY TO ANTICANCER AGENTS Gabriella Fabbrocini,1 Rosanna Izzo,2 Luigia Panariello,3 Giuseppe Monfrecola4

1. Associate Professor, Venereal and Cutaneous Diseases, Division of and Venereology, Department of Clinical Medicine and Surgery, University of Naples ‘Federico II’, Italy 2. Doctor, Department of Clinical Medicine and Surgery, University of Naples ‘Federico II’, Italy 3. Specialist, Clinical Dermatology, University of Naples ‘Federico II’, Italy 4. Professor, Venereal and Cutaneous Diseases, Division of Dermatology and Venereology, Department of Clinical Medicine and Surgery, University of Naples ‘Federico II’, Italy

Disclosure: No potential conflict of interest. Received: 17.09.13 Accepted: 11.11.13 Citation: EMJ Dermatol. 2013;1:38-43.

ABSTRACT

In recent decades, new chemotherapeutic agents have been introduced in cancer therapy. The skin is often the target for the toxicity of these drugs. Skin side-effects may decrease the compliance and the quality of life of these patients. To cure and to prevent these side-effects dermatologists can cooperate with oncologists. In this paper we propose a brief review of the main toxic skin events caused by chemotherapeutic agents, in particular linked to the epidermal growth factor receptor (EGF-R) inhibitor.

Keywords: Skin reaction, chemotherapy, EGF-R inhibitors, radiodermatitis.

INTRODUCTION , hand-foot syndrome and are described below. New Antineoplastic Agents and Skin Toxicities EGFR INHIBITORS AND THE In recent decades, new chemotherapeutic agents PAPULOPUSTULAR FOLLICULAR RASH have been introduced for cancer treatments, with various different side-effects: in particular Among the innovative therapeutic strategies the use of molecular target therapy has shown in chemotherapy, the epidermal growth evidence of significant skin side-effects.1 New factor receptor (EGFR) inhibitors (cetuximab, drugs and new therapeutic schedules have panitumumab, erlotinib, gefitinib) approved brought many malignancies to a better prognosis for lung and colon-rectum tumours showed and a longer survival. But sometimes many an increasing skin toxicity, causing widespread side-effects occur, reducing the complianceskin dryness (in >90% of patients) and a of the patients and decreasing their quality of papulopustular follicular rash which can be life.2,3 Sometimes it is necessary to interrupt the complicated by pruritus, pain and infections.3,5 therapy. The aim of the dermatological research The papulopustular follicular rash, very often is to identify the correct prevention and involves the seborrhoeic areas, scalp and chest, therapy of these skin reactions. Common skin and less frequently, the extremities and the back, reactions undergoing chemotherapy include with and pustules. For these reasons it is alopecia, papulopustular rash, hand-foot syndrome, also defined as an acneiform rash but the paronychia and mucositis.4 Alopecia and mucositis pathogenesis and histology is completely are very well-known side-effects of chemotherapy. different from .6 Its peculiar characteristic No data will be presented in this review. is the association of a typical sebaceous gland Additional information on papulopustular follicular disease with a marked xerosis, suggesting

38 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 39 the keratinocyte itself is involved in the wall rupture, stimulating neutrophil chemotaxis pathogenesis.1 EGFR is expressed in epidermal and pustule formation. On the other hand, in keratinocytes, in hair follicle epithelium and in EGFRI rash the primary event is the damage the sweat glands. Its activation plays a of sebaceous glands and follicular epithelium, crucial role in keratinocyte proliferation and which leads to alteration in keratinocytes growth differentiation.7 Its inhibition induces growth and differentiation. This causes the release of arrest and apoptosis, decreasing cell migration, cytokines and the infiltration of mononuclear increasing cell attachment and differentiation, leucocytes (‘sterile ’).9 The severity of and stimulating inflammation.8 the papulopustular rash is dose-dependent and correlates with an improved tumour response Although the rash has been defined as and survival.8 The incidence of papulopustolar rash ‘acneiform,’ distinctions should be done. The varies from 12-35%8,10 and it often represents one EGFRI (EGFR-inhibitor)-induced papulopustular of the cutaneous aspects persistently influencing eruption does not present comedones. In acne, the patient’s quality of life. Gutzmer et al.11 the primary process is sebaceous hyperplasia and described cutaneous adverse reaction by lipid release into the follicular lumen; it leads to targeted therapies (Table 1) and the classification comedo formation and overgrowth of of severity cutaneous adverse events during Propionibacterium acnes that result in follicular therapy with various EGFRI (Table 1 and 2).

Table 1. Cutaneous adverse events by targeted therapies.

Target structure Main indications Substances Cutaneous adverse events Frequency (reference) EGFR inhibitors Carcinomas of lung, Erlotinib, Papulopustular rash, ++ pancreas, gefitinib, perifollicular , +/- gastrointestinal tract, lapatinib, xerosis cutis/prunitus, ++ breast; cetuximab, eczema craquele, + squamous cell carcinomas of panitumumab fissures/rhagades, ++ the head and neck paronychia, ++ hypertrichosis, + hair follicle abnormalities + Multikinase Renal cell carcinoma, Sorafenib, Maculo-papular rash, ++ inhibitors hepatocellular carcinoma sunitinib, hand-foot syndrome, ++/pazopanib + pazopanib hair discoloration, ++/sorafenib - skin discoloration, ++ (only sunitinib) xerosis cutis/prunitus, + facial , + alopecia, + epithelial skin tumours, + (only sorafenib) subungual splinter + haemorrhages BCR/ABL Certain leukaemia entities, Imatinib, Maculo-papular rash, ++ 0-kit gastrointestinal stomal tumour nilotinib, periorbital oedema, ++ (only imatinib) dasatinib xerosis cutis/prunitus, + light sensitivity, + alopecia, + pigmentation disorders, + pustules/folliculitis +/- Mutated BRAF In clinical trials, Vemurafenib Maculo-papular rash, ++ with focus on (PLX4032, light sensitivity, ++(only vernurafenib) RG7204, epithelial skin tumours, ++ RO5185426), alopecia, + GSK2118436 hand-foot syndrome + MEK In clinical trials, Selumetinib Papulopustular rash, ++ with focus on melanoma (AZD6244) xerosis/prunitus, + GSK1120212 paronychia, + CI-1040 fissures/rhagades + (PD184352)

(++ very frequent [≥10%], + frequent [≥1%], +/- occasionally [≥0.1%], - seldom/never [<0.1%]) Adapted from Gutzmer et al.11

38 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 39 Table 2. Classification of severity of cutaneous adverse events (as defined by the National Cancer Institute Common Toxicity Criteria, version 4.03).

Papulopustular (acneiform) rash Maculo-papular rash Hand-foot syndrome

Grade 1 <10% body-surface area, with or <10% body-surface area, with Minimal skin changes without symptoms or without symptoms (e.g. (e.g., erythema, oedema, or of pruritus or tenderness pruritus, tightness, or burning) hyperkeratosis) without pain Grade 2 10-30% body-surface area, with 10-30% body-surface area, Skin changes (e.g., peeling, or without symptoms with or without symptoms (e.g. , bleeding, oedema, of pruritus or tenderness; with pruritus, tightness, or burning), or hyperkeratosis) with pain; psychosocial impact; limiting limiting instrumental activities limiting practical activities instrumental activities of daily of daily living living Grade 3 >30% body-surface area, with or >30% body-surface area, Severe skin changes without symptoms with or without associated (e.g.,peeling, blisters, bleeding, of pruritus or tenderness; limiting symptoms; limiting self-care oedema, or hyperkeratosis) with self-care activities of daily living: activities of daily living pain; limiting self-care activities associated with local super- infection with oral antibiotics indicated Grade 4 Covering any percent of the body-surface area; with or without symptoms of pruritus or tenderness; associated with extensive superinfection with IV antibiotics indicated; life- threatening consequences Grade 5 Death

Adapted from Gutzmer et al.11

Recently, Curry et al.12 divided skin reactions primarily responsible for this side-effect.13-17 into two groups: cutaneous inflammations Sunitinib, like sorafenib, is a multikinase inhibitor and cutaneous epithelial proliferations, but the used for kidney and liver cancers: it is associated classification of Gutzmer fits the aim of the with bullous manifestation and HFSR, which can investigation better. EGFRI (such as cetuximab) also be used as a marker of drug efficacy;18 and MEK inhibitors (such as selumetinib and inflammatory has also been trametinib) showed papulopustular rash with a observed with these two drugs.18,19 Other suppurative folliculitis in 83%, 93%, and 80% of the multikinase inhibitors in addition to HFSR also patients on therapy, respectively.12 induce skin changes, such as facial erythema and subungual splinter haemorrhages.20 RAF inhibitors HAND-FOOT SYNDROME AND such as vemurafenib were also associated with a variety of cutaneous epithelial proliferations MULTIKINASE INHIBITORS (, , verruca vulgaris, actinic keratosis, keratoacanthoma, and Hand-foot syndrome (HFSR) is one of the most squamous cell carcinoma).12 common skin reactions, occurring in 30-60% of patients in therapy with EGFRI erlotinib and BRAF inhibitors can lead to the development of tyrosine kinase inhibitor sorafenib.12-14 The HFSR and cutaneous keratinocytic neoplasms, often requires cessation or reduction of the for which patients should be closely monitored. dose of sorafenib therapy. Although the specific Finally, MEK/ERK inhibitors induce similar skin mechanisms underlying the sorafenib-induced toxicities to EGFRI, such as papulopustular HFSR are unknown, vascular endothelial growth rashes, skin xerosis and paronychia.19-21 Multikinase factor receptor (VEGFR) was reported to be inhibitors used in haematology, such as imatinib,

40 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 41 dasatinib and nilotinib, frequently cause skin cream may be beneficial in the reduction of toxicity, such as exfoliative dermatitis, associated itching and irritation.32 To reduce the risk of with fever18 and frequently with oedema. The severe acute radiation skin reaction some authors phosphoinositide 3-kinase (PI3K)/serine-threonine suggest that it can be useful to stop smoking protein kinase Akt pathway is a vital transduction during RT because smoking is an independent risk cascade that is connected with many essential factor for ARSR.24 cellular activities, such as growth and survival. PI3K inhibitor BKM120 and AKT inhibitor MK2206, Among the skin reactions it can be useful to signal used in patients with ovarian cancer, produced the associated with Phenytoin maculopapular eruptions.12 and Cranial radiation Therapy (EMPACT) syndrome. Phenytoin is commonly used as an antiepileptic DAMAGE AND EGFR medication for seizure prophylaxis in patients with brain metastases;33 it can, rarely, cause side-effects Paronychia and periungual pyogenic granuloma- when associated with radiotherapy. The EMPACT like lesions are observed in 10-30% of patients syndrome is characterised by erythematous receiving EGFRI therapy, developing after 2 or macular eruption on the scalp within the radiation more months of drug exposure. Paronychia is field in patients under phenytoin therapy; that characterised by oedematous inflammation of usually dramatically extends after a few days to the nail folds and usually affects the first digits. involve extensive areas of the face, trunk and Periungual pyogenic granuloma-like lesions extremities. Significant mucocutaneous blistering are characterised by easily bleeding, friable and desquamation with conjunctival suffusion vascular tissue overgrowth on lateral nail folds.22 can also develop.33 The pathogenesis of the The pathogenesis of paronychia is due to the EMPACT syndrome is still unclear. Studies in traumatic conflict between the thin tissues mice have shown that brain radiation can induce around the nail and the nail itself. In fact, changes the increase of TNF-α, TNF-β, ICAM-1, and in growth and differentiation of the nail are cytokines that could induce cellular autoimmunity. responsible for the retention of squama in the Moreover, radiation can alter the metabolism of nail folds, which act as foreign bodies, causing an phenytoin and anticonvulsant drugs. Normally, inflammatory reaction.23 phenytoin and other anticonvulsants induce microsomal cytochrome P450 3A (CYP3A) and RADIATION THERAPY AND SKIN produce oxidative intermediates that are later REACTION detoxified by epoxide hydrolase. In the case of therapy with phenytoin/phenobarbital and Up to 60% of patients with cancer receive radiation therapy, a deficiency of this enzyme can radiotherapy treatment. One of the main side- develop. Oxidative intermediates, which cannot effects of this treatment is an acute skin reaction, be metabolised, have direct toxicity for cells, which may range in severity from a mild and/or they can bind cell macromolecules and erythema to very severe radiodermatitis. Different behave as haptens. These mechanisms can treatments are proposed.24-28 Skin radiotherapy stimulate a new immune response and be (RT) reactions can be divided into acute and responsible for skin manifestations. Fabbrocini chronic. Radiation-induced acute skin reactions et al.33 described two interesting cases of are traditionally assessed using the Radiation EMPACT syndrome, caused by the combination of Therapy Oncology Group (RTOG) toxicity phenobarbital and cranial radiotherapy. criteria.24-31 To treat severe acute radiation skin reactions (ARSR) such as radiodermatitis, the CONCLUSIONS data show that, among the topical products analysed, calendula, corticosteroids, topical sodium In these last years, new cancer therapies have led hyaluronate, urea, and allantoin have shown to the increase of anticancer therapy success, significant protective effects.25 In the expert but several skin reactions have emerged. These opinion from the Cancer Care Ontario’s Supportive negatively impact on the quality of life of these Care Guidelines Group (SCGG) the use of a plain, patients. The dermatologist plays a critical role non-scented, lanolin-free hydrophilic cream may in the management of these adverse effects. be helpful in preventing radiation skin reactions. A strong relationship between dermatologists In addition, a low dose (i.e. 1%) corticosteroid and oncologists is important to make the best

40 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 41 decisions for patients and to choose anti-toxicity • HFSR occurred in 30-60% of patients in therapy interventions with minimal side-effects. During with EGFRIs erlotinib and sorafenib. and after radiation therapy it is particularly necessary to have a close follow-up in order to • Paronychia and periungual pyogenic granuloma- identify and monitor precancerous lesions occurring like lesions could be observed in patients receiving in these patients. EGFRI therapy. • It is necessary to pay attention to cranial Take-Home Messages: radiation therapy and neuroleptic drugs such as • New chemotherapeutic agents increase survival, phenobarbital and phenytoin that can cause skin but can lead to several skin reactions, worsening reaction such as EMPACT syndrome. the quality of life of patients. • Hydration, antimicrobial, sterile tissue, protective • The EGFRI (such as cetuximab, panitumumab, ointment, and specific dermocosmetological erlotinib, and gefitinib) showed increasing skin treatments can reduce the side-effects of chemo toxicity, causing widespread skin dryness and the and radiotherapy. papulopustular follicular rash.

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