Clinical and Translational Oncology (2019) 21:556–571 https://doi.org/10.1007/s12094-018-1953-x SPECIAL ARTICLE Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: a national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology C. Grávalos1 · O. Sanmartín2 · A. Gúrpide3 · A. España4 · M. Majem5 · H. J. Suh Oh6 · I. Aragón7 · S. Segura8 · C. Beato9 · R. Botella10 Received: 3 July 2018 / Accepted: 11 September 2018 / Published online: 3 October 2018 © The Author(s) 2018 Abstract Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at spe- cific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Der- matological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management. Keywords Targeted therapies · Antiangiogenic drugs · Immune checkpoint inhibitors · MTOR inhibitors · Anti-EGFR · Dermatological toxicity Introduction the development of drugs aimed at molecular targets. Targets of particular interest include EGFR (epidermal growth factor Recent progress in the understanding of cancer biology, receptor), HER-2, RAS, BRAF, MEK, KIT, RET, mTOR processes involved in carcinogenesis and neoangiogenesis, (mammalian target of rapamycin), and VEGFR (vascular the tumor/stroma relationship, proliferation, and invasion, endothelial growth factor receptor) 1, 2, and 3. These new signaling pathways and the immune response has enabled 6 * C. Grávalos Dermatology Department, Complejo Hospitalario cgravalos@telefonica.net Universitario de Pontevedra, Pontevedra, Spain 7 1 Medical Oncology Department, Complejo Hospitalario Medical Oncology Department, Hospital Universitario 12 de Universitario de Huelva, Huelva, Spain Octubre, Avenida de Córdoba km 5.4, 28041 Madrid, Spain 8 2 Dermatology Department, Hospital del Mar, Barcelona, Dermatology Department, Instituto Valenciano de Oncología, Spain Valencia, Spain 9 3 Medical Oncology Department, Hospital Universitario Medical Oncology Department, Clínica Universitaria de Virgen Macarena, Sevilla, Spain Navarra, Pamplona, Spain 10 4 Dermatology Service, Instituto de Investigación Sanitaria La Dermatology Department, Clínica Universitaria de Navarra, Fe, Valencia, Spain Pamplona, Spain 5 Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2019) 21:556–571 557 therapies include tyrosine kinase inhibitors (TKI), monoclo- Classification of targeted therapies nal antibodies, and cancer immunotherapies. and immunotherapies, and mechanism The dermatological effects they cause seem to be more of action of cutaneous toxicity common than those produced by conventional cytostatics and have specific clinical and pathological features [1, 2]. The cancer treatment scene has been revolutionized by EGFR inhibitors are routinely used to treat advanced malig- the advent of new targeted therapies and immunotherapy nancies such as colorectal cancer and lung cancer. Because (Table 1). One of their most common side effects is cutane- of their mechanism of action and the targets they attack, they ous toxicity, the features of which differ according to each are very often associated with the development of derma- drug’s mode of action. tological adverse effects, which need to be understood and managed [3, 4]. However, it must be borne in mind that other drugs, directed against targets other than EGFR, also cause Targeted therapies cutaneous toxicity. Symptoms and esthetic issues can both have a major EGFR inhibitors impact on patients’ quality of life. Patients’ personal, social, and workplace relationships can be affected. As with con- The most important EGFR inhibitors belong to the following ventional chemotherapy, the dermatological side effects of major therapeutic classes: targeted therapies can cause dose reductions and delays, or even treatment discontinuation. Accurate diagnosis of these • Monoclonal antibodies: cetuximab, panitumumab, and adverse effects is, therefore, necessary, and in many cases necitumumab; therapeutic measures to reduce their severity and duration • Tyrosine kinase inhibitors: must be introduced as soon as possible [5, 6]. Preventive measures should be applied whenever they exist. Also, mul- – EGFR TKIs (gefitinib, erlotinib, and osimertinib); tidisciplinary assessment by dermatologists and medical – Dual EGFR and HER-2 TKIs (lapatinib and afatinib); oncologists is key to caring for these patients. • Multikinase inhibitors (vandetanib). This article reviews the dermatological toxicity associ- ated with the most commonly used TKIs, monoclonal anti- bodies, and immunotherapies, together with the clinical Antiangiogenic drugs features, diagnosis, and therapeutic management involved with each of them. The two main classes of antiangiogenic drugs are: Table 1  Classification of targeted therapies and immunotherapies Targeted therapies EGFR inhibitors Monoclonal antibodies against EGFR: cetuximab, necitumumab, and panitumumab EGFR-specific TKIs: erlotinib, gefitinib, and osimertinib Dual EGFR and HER-2 kinase inhibitors: lapatinib, afatinib Less specific multi-kinase inhibitors: vandetanib KIT and BCR-ABL inhibitors Imatinib, dasatinib, ponatinib, nilotinib, and bosutinib Antiangiogenic agents Monoclonal antibodies against VEGFR: bevacizumab, ramucirumab, and afliber- cept Non-selective antiangiogenic agents: sorafenib, sunitinib, pazopanib, regorafenib, axitinib, lenvatinib, cabozantinib, and nintedanib RAS-RAF-MEK-ERK pathway inhibitors BRAF inhibitors: vemurafenib and dabrafenib MEK inhibitors: cobimetinib, selumetinib, and trametinib mTOR inhibitors: sirolimus, everolimus, and temsirolimus Hedgehog pathway inhibitors Vismodegib Immunotherapy Anti-PD-1 Nivolumab, pembrolizumab Anti-PD-L1 Atezolizumab, durvalumab, avelumab Anti-CTLA-4 Ipilimumab, tremelimumab CTLA-4 cytotoxic T-lymphocyte antigen 4, EGFR epidermal growth factor receptor, mTOR mammalian target of rapamycin, PD-1 programmed death 1, PD-L1 programmed death-ligand 1, TKI tyrosine kinase inhibitor, VEGFR vascular endothelial growth factor receptor 13 558 Clinical and Translational Oncology (2019) 21:556–571 • Monoclonal antibodies (bevacizumab, aflibercept, and The underlying mechanism by which these drugs cause ramucirumab); papulopustular eruption or xerosis cutis is not clear. • Non-selective multikinase inhibitors (sorafenib, suni- tinib, pazopanib, regorafenib, axitinib, lenvatinib, cabo- Anti‑EGFR drugs zantinib, and nintedanib). EGFR is mainly expressed and activated in basal keratino- Multikinase inhibitors characteristically act via several cytes and in the outer root sheath of hair follicles [7]. pathways, e.g. the platelet-derived growth factor receptor Arrested hair follicle growth and differentiation as a conse- (PDGFR), c-KIT, fibroblast growth factor receptor (FGFR), quence of therapy can cause mechanical breakage of the hair RET, and VEGF pathways. The cutaneous toxicity seen with follicle, generating hyperkeratosis and follicular plugging multikinase inhibitors reflects the promiscuity of these mol- [8]. Anti-EGFR drugs can also affect cytokine production, ecules, because it derives from their activity on receptors resulting in leukocyte chemotaxis and infiltration into the other than the VEGF receptors. skin [9], as well as changes in the skin microflora, giving rise to an inflammatory reaction [10]. KIT, PDGFR, and BCR‑ABL TKIs Papulopustular eruption The most important drugs in this class are imatinib, dasat- inib, ponatinib, nilotinib, and bosutinib. Anti-EGFR drug-related papulopustular eruption is char- acterized by the presence of pruritic papules and pustules, typically distributed in seborrheic areas: The scalp, the face, MAPK inhibitors (RAS‑RAF‑MEK‑ERK pathway) behind the ears, in the mid-chest region, and on the shoul- ders and upper third of the back (Fig. 1a, b). It differs from Mitogen-activated protein kinase (MAPK) inhibitors can be acne in the absence of comedones and the presence of asso- divided into three drug classes: ciated functional symptoms, such as a burning sensation, • BRAF inhibitors (vemurafenib, dabrafenib, and pruritus or pain. Its location in a highly visible area like the face has a major impact on the patient’s emotional and encorafenib); • MEK inhibitors (trametinib, cobimetinib, and bini- social life. It develops during the first and second weeks of therapy and peaks between weeks 4 and 6. The eruption metinib); • PI3K-AKT-mTOR pathway inhibitors (sirolimus, everoli- tends to resolve in approximately 8 weeks, leaving erythema and post-inflammatory inflammation (Fig. 1a, b). mus, and temsirolimus). Treatment for this condition will depend on the sever- ity (Table 2). Any therapeutic management must always be Hedgehog pathway inhibitors accompanied by general recommendations: Avoid soaps and perfumes, moisturize the skin daily, and apply pho- The main representative of this class of inhibitors is toprotection measures (avoid exposure to the midday sun, vismodegib. wear appropriate clothing, and use a sunscreen with a high UVA + UVB protection factor). For treating localized papu- Immune checkpoint inhibitors lopustular lesions, clindamycin 1% lotions or emulsions and moderately to highly potent topical corticosteroids are rec- The main immune checkpoints are cytotoxic T-lymphocyte ommended. In more extensive cases (grade 2 toxicity), oral antigen 4 (CTLA-4), programmed death-ligand 1 (PD-L1), antibiotics such as doxycycline or minocycline are used. In and programmed death 1 (PD-1). Inhibitors for each are as recalcitrant cases, some authors have documented the useful- follows: ness of oral retinoids, although xerosis and photosensitiv- ity may worsen in some individuals [11]. Patients who also • Anti-CTLA-4 (ipilimumab and tremelimumab); have seborrheic dermatitis of the scalp may benefit from • Anti-PD-1 (nivolumab and pembrolizumab); shampoos containing ciclopirox olamine 1.5%, ketoconazole • Anti-PD-L1 (atezolizumab, durvalumab, and avelumab). 2%, pyrithione zinc 1%, selenium sulfide, coal tar 0.5% or salicylic acid 3–5% preparations. The eruption caused by anti-EGFR drugs is initially Papulopustular eruption and xerosis cutis sterile, but it is not uncommon for it to be superinfected by Staphylococcus aureus, occasionally S. aureus resistant Both papulopustular eruption and xerosis cutis can occur to methicillin (MRSA), tetracycline or clindamycin. Her- after anti-EGFR drugs or mTOR inhibitors are used. pes simplex virus infections are rarely encountered [12]. 13 Clinical and Translational Oncology (2019) 21:556–571 559 Fig. 1  Papulopustular eruption on the trunk and arms of a patient cancer (c), Xerosis cutis with skin of an ichthyosis-like appearance in treated with cetuximab for colorectal carcinoma (a, b). Eczematous a patient treated with everolimus (d) eruption in a patient treated with gefitinib for non-small-cell lung Faced with a recalcitrant or atypical eruption, or one that or twice daily, and tetracycline 500 mg twice daily. In all lasts longer than 8 weeks, bacterial cultures and virological cases, prophylactic treatment has reduced the incidence of tests are recommended, to rule out superinfection and insti- grade 2 or grade 3 eruptions [18]. Some groups recommend tute specific treatment [13]. To prevent secondary infection, phytomenadione (vitamin K) as a topical therapy to prevent some authors recommend 10-minute baths in dilute bleach acneiform eruption [19]. (a quarter of a cup of household bleach in a bathtub) [13]. The severity of papulopustular eruption has been linked Xerosis and pruritus to greater overall survival [14–16], with a 60% decrease in the risk of death according to a recent meta-analysis [17]. Xerosis cutis occurs in up to 35% of patients treated with The prophylactic role of tetracyclines has been examined anti-EGFR drugs [20]. Deregulation of epidermal differen- in four clinical trials, and the following are recommended: tiation during anti-EGFR therapy gives rise to an abnormal minocycline 100 mg once daily, doxycycline 100 mg once stratum corneum and poor sebaceous gland function, which 13 560 13 Table 2  Grading and treatment of papulopustular eruptions, xerosis, and pruritus caused by anti-EGFR agents and mTOR inhibitors adapted from NCI CTCAE v4.03 Grade 1 Grade 2 Grade 3 Grade 4 Papulo- Papules and/or pustules < 10% BSA with Papules and/or pustules 10–30% BSA, Papules and/or pustules > 30% BSA, with Papules and/or pustules covering any % pustular or without pruritus or pain symptoms with or without pruritus or pain symp- or without pruritus or pain symptoms; BSA with or without pruritus or pain eruption toms; associated psychosocial impact limited ADL; local superinfection, oral symptoms; associated life-threatening and limited IADL antibiotic indicated extensive bacterial superinfection of lesions requiring iv antibiotic Topical antibiotic: clindamycin 1% lotion As for grade 1 plus doxycycline or mino- As for grade 2 plus oral corticosteroids Refer to hospital dermatology consultant or emulsion 1–2 times daily; moderately cycline 100 mg every 12 h (10–30 mg/day); consider oral isotreti- to highly potent topical corticosteroids noin in recalcitrant cases 1–2 times daily (e.g. hydrocortisone 1–2.5% face, triamcinolone acetonide 0.1% body) Xerosis 10% BSA, no erythema or pruritus 10–30% BSA with erythema or pruritus; > 30% BSA, with pruritus and limited limited IADL ADL Emollients, urea 5–10% creams Emollients, topical corticosteroids (highly Emollients, topical corticosteroids (highly potent) potent), antihistamines Pruritus Mild or localized pruritus Severe or generalized; intermittent; scratch Severe or generalized; constant; limits damage (papules, excoriations, licheni- ADL or sleep; oral corticosteroids and fication, scabs); limited IADL; oral immunosuppressants indicated treatment indicated Emollients, urea 5–10%, lauromacrogol Emollients, topical corticosteroids (highly Emollients, topical corticosteroids (highly 400 3%, topical corticosteroids (highly potent), oral antihistamines potent), oral antihistamines, oral corti- potent) costeroids ADL basic activities of daily living, BSA body surface area, IADL instrumental activities of daily living, iv intravenous, NCI CTCAE The National Cancer Institute Common Terminology Crite- ria for Adverse Events Clinical and Translational Oncology (2019) 21:556–571 Clinical and Translational Oncology (2019) 21:556–571 561 results in dry skin [20]. Elderly patients with a history of the extremities, neck, face, and scalp. Grading and treatment atopic eczema, and individuals previously treated with cyto- strategies are similar to those recommended for anti-EGFR toxic agents, are most likely to develop xerosis. It presents drug-induced eruption (Table 2) [22, 23]. Another similar- as dry, desquamative skin, with an itching sensation. It is ity to anti-EGFR drugs is that the presence of mucocutane- particularly located in areas simultaneously or previously ous toxicity has been associated with a better prognosis in affected by papulopustular eruption. Xerosis can progress patients with metastatic renal cell carcinoma treated with to chronic asteatotic eczema, with erythematous, desqua- everolimus [24]. mative plaques on the trunk and extremities (Fig. 1c). It can sometimes be superinfected by S. aureus and, more rarely, by herpes simplex virus 1 [10]. Acral erythema Treatment for this condition will depend on its severity and extent (Table 2). It essentially involves not applying any Differences between acral erythema caused irritant products to the skin (soaps, perfumes), using oils by targeted therapies and by conventional and detergent-free hygiene products, showering in lukewarm chemotherapy water, and applying emollient creams daily to help rebuild the skin barrier. Like conventional chemotherapy, targeted therapies often Pruritus is suffered by 18–55% of patients on anti-EGFR affect the skin on the palms of the hands and the soles of therapy, and the risk is highest with panitumumab [21]. the feet. However, there are important differences between Pruritus tends to be associated with papulopustular lesions, acral erythema caused by targeted therapies and by chemo- xerosis cutis or asteatotic eczema. Other factors, such as therapy, as summarized in Table 3. Acral erythema induced concomitant medication, comorbidities or the underlying by conventional chemotherapy is a dose-dependent reac- malignancy itself, can influence the presence of pruritus. In tion, caused by direct epidermal cytotoxicity. It manifests cases of mild to moderate pruritus, topical corticosteroids, with erythema, edema, fissuring, and blistering [25]. With emollient preparations containing antipruritic substances, conventional chemotherapy, palmar-plantar involvement and oral antihistamines can be used. Severe pruritus requires is often associated with other cutaneous lesions grouped oral treatment with antihistamines and corticosteroids, and together under the term “toxic erythema of chemotherapy” sometimes other drugs with an antipruritic effect, such as [26]. In contrast, TKI-induced hand-foot syndrome mani- antidepressants, anticonvulsants and aprepitant [21]. fests with hyperkeratotic lesions on the palms and soles that are more severe at pressure points. Although this too is a mTOR inhibitors dose-dependent reaction, the pathogenic mechanism has not been fully explained [27]. The hand-foot syndrome caused The inflammatory cutaneous eruptions that occur as a con- by multikinase inhibitors shows no significant association sequence of using these drugs are seen in up to 25% of with other cutaneous eruptions. patients on everolimus (< 1% grade ≥ 3) and up to 46% of those on temsirolimus (3% grade ≥ 3) [22]. Morbilliform, Epidemiology eczematous, and papulopustular eruptions can occur, some- times in combination with xerosis (Fig. 1d) and pruritus. Hand-foot syndrome is the most common of the cutaneous Papulopustular cutaneous eruption occurs during the first adverse events caused by TKIs. Table 4 lists the drugs most 2 weeks of therapy. It mainly affects the trunk, followed by often responsible for hand-foot syndrome [27–30]. Table 3  Differences between multikinase inhibitor-induced hand-foot syndrome and acral erythema caused by conventional chemotherapy Hand-foot syndrome Acral erythema Common causative agents Regorafenib, cabozantinib, sorafenib, axitinib, sunitinib, Docetaxel, paclitaxel, liposomal doxorubicin, capecit- vemurafenib, pazopanib abine, fluorouracil, vinorelbine Pathogenic mechanism VEGFR and PDGFR blockade, difficulty repairing Directly cytotoxic to epidermis and eccrine glands microtrauma Site of lesions Palms and soles Palms and soles, occasionally dorsum of hands and feet Clinical features Hyperkeratotic lesions at pressure points Erythema, edema, fissuring, blistering Histopathology Acanthosis, hyperkeratosis, ballooning degeneration of Cell-poor interface dermatitis, epidermal atrophy, the epidermis, subepidermal blisters keratinocyte necrosis, subepidermal blisters with epidermal necrosis PDGFR platelet-derived growth factor receptor, VEGFR vascular endothelial growth factor receptor 13 562 Clinical and Translational Oncology (2019) 21:556–571 Table 4  TKIs responsible for hand-foot syndrome Drug Targets Overall incidence of hand- Incidence of hand-foot foot syndrome (%) syndrome as DLT (%) Regorafenib [30, 36] VEGFR-1, 2 and 3; TIE-2; FGFR-1; PDGFR-α, β; c-KIT; 60.5 20.4 RET; RAF; MAPK Cabozantinib [26, 27] VEGFR-2; c-MET; RET; c-KIT; FLT3; TIE-2 35.3 9.5 Sorafenib [29, 35] VEGFR-2 and 3; PDGFR; ARAF; BRAF; CRAF; FLT3 33.8 8.9 Axitinib [25] VEGFR-1, 2, and 3 29.2 9.6 Sunitinib [29] VEGFR-2; PDGFR; c-KIT; FLT3 18.9 5.5 Vemurafenib [28] BRAF 8.7 2.0 Pazopanib [27] RAF; VEGFR-2 and 3; PDGFR-β; c-KIT; FLT3; RET 4.5 1.8 DLT dose-limiting toxicity, FGFR fibroblast growth factor receptor, MAPK mitogen-activated protein kinase, PDGFR platelet-derived growth factor receptor, VEGFR vascular endothelial growth factor receptor Pathogenesis (blisters, bleeding, edema or hyperkeratosis) hindering eve- ryday activities; and grade 3 entails painful severe cutaneous The pathogenic mechanism of hand-foot syndrome is lesions that make self-care impossible. unknown, although it has been linked to VEGFR and PDGFR blockade. It is possible that a defect may occur in Treatment vascular microtrauma repair, which would explain the ten- dency for lesions to be located at sites subjected to friction The tendency should be towards personalized, multidisci- [31]. Accordingly, the higher incidence of hand-foot syn- plinary treatment, involving the medical oncologist, derma- drome in patients on regorafenib, which uniquely inhibits the tologist, podiatrist, and nursing staff. Currently, there are endothelium-specific TIE-2 receptor (essential in vascular no controlled clinical trials available that demonstrate the remodeling), supports the importance of vascular compe- advantages of one treatment over another [33]. Preventive tence in the pathogenesis of this syndrome [30]. measures are important, such as using suitable footwear (padded and exerting no pressure), podiatric care, good Clinical features hygiene, applying emollient creams, and avoiding contact with anything hot [34]. Gentle keratolytics, such as urea 10% This is a dose-dependent reaction that occurs in the first or salicylic acid 5%, can be used on hyperkeratotic lesions. 2–4 weeks of therapy and increases in severity towards the Erosive or blistered lesions can be treated with hydrocolloid second and third months of therapy. The clinical features dressings. Highly potent topical corticosteroids (clobetasol usually tend to abate gradually as treatment continues [27, propionate 0.05%) can be used in cases of grade 2 or 3 sever- 30]. The lesions are located at pressure points on the palms ity [34]. Pain is treated with non-steroidal anti-inflamma- and soles, although they can affect other areas subjected to tory drugs or gamma-aminobutyric acid (GABA) agonists. friction, such as the knuckles or the sides of the feet. These Patients with grade 2 or 3 toxicity tend to require treatment lesions consist of hyperkeratotic plaques situated on an ery- discontinuations or dose adjustments according to the pro- thematous background, which may even blister in the most tocol for each drug. severe cases. Clinical features include pain and discomfort, such as paresthesia, a burning sensation, and reduced heat tolerance. Multikinase inhibitor‑induced Although hand-foot syndrome is not life-threatening, the exanthematous reactions severity of the discomfort can seriously impair patients’ quality of life, and it is a frequent cause of dose reductions Multikinase inhibitor drugs often give rise to dose-depend- or early treatment discontinuation. ent rashes during the first few weeks of therapy [29, 35–37]. The severity grading for hand-foot syndrome according Unlike the papulopustular eruption seen with anti-EGFR to the Common Terminology Criteria for Adverse Events drugs, these eruptions are unrelated to efficacy. Multikinase (CTCAE) is the same as for palmar-plantar erythrodyses- inhibitor-induced rashes are not well characterized in the thesia caused by conventional chemotherapy. Three grades literature and are usually described as non-specific rashes. are recognized [32]: Grade 1 means the presence of minimal They consist of diffuse mild eruptions of a morbilliform, skin changes (erythema, edema or hyperkeratosis) without eczematous or lichenoid nature, and tend to resolve spon- associated pain; grade 2 means painful cutaneous lesions taneously despite continued therapy (Fig. 2). They must be 13 Clinical and Translational Oncology (2019) 21:556–571 563 Fig. 2  Sorafenib-induced hand-foot syndrome. Hyperkeratotic lesions on an erythematous background located above pressure points (a, b). Sunitinib-induced rash and desquamative maculopapular rash distributed on the trunk (c, d) distinguished from other much less common, more serious If symptomatic treatment elicits a good response, therapy eruptions related to drug hypersensitivity, such as erythema can be allowed to continue. The accompanying symptoms multiforme, hypersensitivity syndrome, exanthematous tend to be pruritus and, occasionally, a pricking sensation. pustulosis, Stevens-Johnson syndrome or toxic epidermal Symptomatic treatment with oral antihistamines and mod- necrolysis. These have all been described occasionally in the erately potent topical corticosteroids is usually sufficient. past with one multikinase inhibitor or another. Multikinase inhibitor-induced rash is very common. It occurs in 20–30% of patients on sorafenib, regorafenib EGFR and BRAF inhibitor‑induced or imatinib therapy, 10–20% of patients on sunitinib, and abnormalities of the hair follicle and nail 5–10% of those on pazopanib therapy. It arises during the apparatus first 6–8 weeks of treatment and consists of mild eruptions (grade 1–2) involving less than 30% of the body surface area. Normal EGFR expression in the epidermis, eccrine glands, The lesions are mainly distributed on the trunk and the tops and hair follicles can encourage development of the PRIDE of the limbs. In most cases, the eruptions are eczematous and complex (papulopustules, paronychia, regulatory abnor- become morbilliform in appearance. Less often, they can malities of the hair follicle, pruritus and dry skin) [38] dur- present as lichenoid lesions. Generally, these eruptions are ing therapy with EGFR inhibitors. The onset of pustular mild (grade 1–2) and do not require withdrawal of the drug. acneiform folliculitis without comedones, sometimes with 13 564 Clinical and Translational Oncology (2019) 21:556–571 pruritus, occurs on the scalp, face, and trunk in over 50% [4, 10, 38], with substantial morbidity [20], with fissuring of cases (Fig. 3a), especially during cetuximab and panitu- of the heels (Fig. 3c) or fleshy parts of the digits (Fig. 3d) mumab therapy, when it is seen in up to 100% of cases [10]. 4–8 weeks after therapy with the inhibitor begins [10]. This abnormality is usually more severe with the administra- Another side effect related to drugs that inhibit EGFR, tion of monoclonal antibodies than with TKIs, and it devel- albeit uncommon, is the onset of nail abnormalities ops a week after treatment starts. Although most eruptions 4–8 weeks after therapy starts. These take the form of fra- are grade 1 or 2, higher severity tends to be associated with gility, onychoschizia, onychorrhexis or onycholysis. Only a better tumor response to therapy [4, 10, 38]. 10–15% of cases may develop paronychia (Fig. 3e), some- Cultures obtained from the lesions are usually negative times with S. aureus superinfection [10]. but increased expression of ­p27Kip1 in follicular lesions has been demonstrated [39]. These lesions, in turn, might be due to deregulation of pathways involving IL-1 [40]. Adminis- Pigmentation changes tering benzoyl peroxide, metronidazole or clindamycin, or with the administration of targeted adding tetracyclines, oral isotretinoin, or even stopping the therapies anti-EGFR drug are the treatment regimens that tend to be used most [4, 10, 38]. Pigmentary changes are commonly seen with the admin- EGFR inhibitors have also been associated with elonga- istration of targeted therapies and are often characteristic. tion (trichomegaly) (Fig. 3b) or fragility of the eyelashes, Essentially, they consist of depigmentation of the hair and, and with more brittle, finer, wavy, and fragile hair [41]. to a lesser extent, the skin or its appendages. The c-KIT BRAF inhibitors, such as vemurafenib, can cause alopecia protein is involved in melanocyte physiology, regulating in up to 36% of cases [42]. Last, xerosis cutis may develop melanogenesis and melanocyte proliferation, migration, Fig. 3  EGFR inhibitors can cause acneiform folliculitis on the head and trunk (a), elongated eyelashes (trichomegaly) with possibly increased eyebrow growth (b), fissures on the heels (c) and fleshy parts of the digits (d), and increased periungual granulation tissue with inflammation (e) 13 Clinical and Translational Oncology (2019) 21:556–571 565 and survival [43]. Imatinib can cause cutaneous hypopig- (Fig. 4b, c) [22]. RAF inhibitors (sorafenib, vemurafenib, mentation or depigmentation in up to 40% of patients, most dabrafenib, and regorafenib) can induce dynamic changes commonly those with a high phototype [44]. In some cases, in pre-existing naevi or trigger the development of eruptive bluish pigmentation of the oral cavity may be observed [45]. naevi (Fig. 4d). Dermatological surveillance is necessary in Cutaneous depigmentation may be localized or diffuse. It this context, because cases of de novo primary melanomas develops after several weeks of therapy and usually disap- have been reported in patients treated with BRAF inhibitors pears when treatment ends. In some cases, worsening of [50]. pre-existing vitiligo, or even hyperpigmentation, has been described (Fig. 4a) [46]. Nilotinib and dasatinib can also cause pigmentary changes, but less frequently [47]. Impaired healing due to antiangiogenic Sunitinib is a mixed TKI that can produce depigmenta- drug use tion of the hair, eyebrows or eyelashes after several weeks of therapy. This effect is characterized by alternating depig- Inhibition of angiogenesis interferes with normal skin home- mented and pigmented zones on the same hair shaft, corre- ostasis. Among other complications, this can give rise to sponding to weeks of therapy and rest periods, respectively. delays or difficulties in wound healing. Drugs that inhibit It is also common for a yellowish coloration to develop, VEGF or VEGFR have the potential to cause these compli- especially on the facial skin and oral mucosa. These changes cations. Bevacizumab, an anti-VEGF antibody, is associated usually resolve when treatment ends [48]. with a higher incidence of surgical wound complications The multikinase inhibitor vandetanib can induce the onset (dehiscence and delayed healing). The incidence varies of blue-gray macules measuring a few millimeters (blue according to the context in which it is used. It is advisable dots), predominantly in perifollicular regions of the face and to stop treatment with this drug at least 6–8 weeks before trunk. They tend to persist or recur with maintenance ther- surgery and to wait until 4 weeks after surgery before resum- apy [49]. Pigmentary changes (hyperpigmentation or depig- ing it [51]. The risk of complications with mTOR inhibitors mentation) have also been described with immunotherapies is not negligible either. It is, therefore, advisable to stop ther- (interferon, ipilimumab, nivolumab, pembrolizumab), MEK apy 7–10 days beforehand and to wait for at least 3 weeks inhibitors, and other multi-kinase inhibitors, e.g. pazopanib after the intervention before resuming it. The risk seems to Fig. 4  Worsening of pre-existing vitiligo (a), immunotherapy-induced vitiligo and depigmentation (b, c), and BRAF inhibitor-induced eruptive naevi (d) 13 566 Clinical and Translational Oncology (2019) 21:556–571 be lower with TKIs. The recommendation is to stop them Cutaneous lesions caused by BRAF and MEK 24–48 h before surgery and to wait 3–4 weeks before resum- inhibitors ing them [52]. In any case, good perioperative management, bearing in mind the elimination half-life of each drug, is In pivotal trials conducted with vemurafenib, a BRAF inhib- essential to avoid these complications [53]. itor, a high percentage of patients developed side effects, mainly of a cutaneous nature (92–95%) [28]. Nevertheless, most of these effects are mild or moderate, and relatively easy to manage if well understood. Very few cases require Neutrophilic dermatosis modification or discontinuation of therapy. The occurrence or severity of these side effects has not been correlated with The onset of various neutrophilic dermatoses has been treatment efficacy. described with the use of targeted therapies. TKIs, such as The cutaneous side effect of greatest concern is the imatinib, nilotinib or dasatinib, have been linked to cases onset of skin tumors, specifically squamous cell carcino- of Sweet’s syndrome, neutrophilic eccrine hidradenitis, and mas (Fig. 5a) and, in many cases, a well-differentiated vari- neutrophilic panniculitis [54]. Pyoderma gangrenosum has ant of these with very little metastatic potential, called a also been linked to TKIs, EGFR inhibitors, and drugs such keratoacanthoma. These tumors generally appear between as ipilimumab or rituximab, among others [55]. Cases of weeks 2 and 36, most commonly between weeks 12 and neutrophilic eccrine hidradenitis and neutrophilic pannicu- 18. They have been reported in 20–30% of patients [22]. litis have also been reported in patients on BRAF inhibitors Surgical treatment for these tumors is usually simple. The (vemurafenib, dabrafenib). In most cases, treatment discon- administration of oral retinoids has been shown to reduce tinuation tends not to be necessary [56]. their frequency [57]. Their occurrence seems to be due to Fig. 5  A patient with squamous cell carcinoma of the upper lip, keratosis pilaris, and plantar keratoderma secondary to vemurafenib therapy (a, b, and c, respectively). Reactivation of psoriasis in a patient on pembrolizumab therapy (d) 13 Clinical and Translational Oncology (2019) 21:556–571 567 paradoxical stimulation of the MAPK pathway in BRAF Cutaneous lesions caused by cancer wild-type cells [58]. This stimulation is especially impor- immunotherapy tant in cells that, because of sun exposure, already harbor mutations in RAS, the first kinase in this pathway. Other In the past few years, progress in the understanding of BRAF inhibitors developed subsequently, such as dab- regulatory mechanisms governing the immune response rafenib, cause cutaneous side effects, including squamous has led to the development of monoclonal antibodies that cell carcinomas, at a lower rate [59]. Introducing dual inhi- deactivate inhibitory receptors expressed by T cells. Drugs bition of the MAPK pathway with coadministered BRAF that stimulate the immune response by inhibiting CTLA-4 and MEK inhibitors has achieved a substantial reduction (ipilimumab), PD-1 (nivolumab, pembrolizumab) or in the frequency at which these tumors occur, probably by PD-L1 have thus appeared. However, the anticancer effect inhibiting the paradoxical stimulation described above, by of these drugs is accompanied by a number of cutaneous means of MEK inhibitor-induced blockade of the pathway and systemic side effects related to immune stimulation. downstream of BRAF [60]. The onset of both atypical mel- In this class, cutaneous side effects are the most common, anocytic lesions and melanomas of low thickness has also and they also tend to be the first to appear. Although their been documented. These have been attributed to the same severity seems to be correlated with treatment efficacy, paradoxical MAPK pathway stimulation effect [61]. their absence does not imply lack of response. In general, Despite the above, the most common cutaneous mani- they are reversible if treated promptly, and the administra- festation is a maculopapular rash (64–75% of cases), often tion of either systemic corticosteroids or anti-TNF drugs poorly described [28]. Of particular note is the follicular does not counteract the anticancer effect [70]. The most accentuation shown by the lesions in some cases, taking common cutaneous side effects are the same with either on the appearance of keratosis pilaris [22] (Fig. 5b). Other anti-CTLA-4 or anti-PD-1 drugs: maculopapular rash, pru- patients develop a rash composed of erythematous papules ritus, and vitiligo. They occur more often and are more located on the chest, face, and upper limbs. Biopsy has severe with ipilimumab than with anti-PD-1 drugs. demonstrated the existence of acantholysis and suprabasal In the case of ipilimumab, and unlike the situation with dyskeratosis, findings consistent with Grover’s disease (or anti-PD-1 drugs, cutaneous side effects depend on the transient acantholytic dyskeratosis) [62, 63]. These lesions drug dose. The most common side effect is maculopapu- have been attributed to paradoxical MAPK pathway activa- lar rash (47–68%) [62]. It tends to occur 2–5 weeks after tion in normal keratinocytes, causing decreased expression therapy begins. Severe, life-threatening reactions, of the of the protein sarco/endoplasmic reticulum ­Ca2+-ATPase Stevens-Johnson syndrome, toxic epidermal necrolysis or type 2 isoform (SERCA2), also involved in Darier’s disease, DRESS syndrome type, have been reported at a frequency which shares histological features in common with Grover’s of less than 1% [70]. Pruritus can occur on its own, or disease [63]. in the context of the above-mentioned rash, and may be Photosensitivity is another common side effect of vemu- severe enough to require dose reduction. Dermatomyosi- rafenib (35–63% of patients) [28]. This drug stimulates tis, Sweet’s syndrome, pyoderma gangrenosum, and sar- erythrocyte 5-aminolaevulinic acid synthase (ALAS), rais- coidosis have been described during anti-CTLA-4 therapy, ing porphyrin levels in red blood cells [64]. Photobiology albeit uncommonly [71–74]. tests have shown the photosensitivity to be due to a height- As far as the most common reactions related to anti- ened reaction to ultraviolet rays (UVA), with a decrease PD-1 drugs are concerned, the maculopapular rash often in the UVA minimal erythema dose [64, 65]. Other less acquires lichenoid features (lesions with a dark red tone common side effects are: palmar-plantar erythrodysaesthe- and intense residual hyperpigmentation). A biopsy con- sia (8–10% of patients) [28]; palmar-plantar keratoderma firms lichenoid histology [75, 76]. On the other hand, (6–60% of patients), which can cause substantial discomfort achromic lesions resembling vitiligo have often been in daily life [22] (Fig. 5c); alopecia due to telogen effluvium; described. Unlike vitiligo, however, they tend to adopt and changes in the appearance of the hair, ranging from turn- a patchy distribution, occur more often in light-exposed ing gray to becoming curly [66]. areas, and do not display the Koebner phenomenon [77]. One uncommon but very interesting side effect already An ever-increasing number of publications describe mentioned above is the onset of neutrophilic dermatoses patients who were diagnosed with pemphigoid after com- during the administration of BRAF inhibitors. There have mencing anti-PD-1 therapy [78]. Last the triggering of been reports of lobular panniculitis, Sweet’s syndrome, and psoriasis flare-ups has also been linked to this drug class, neutrophilic eccrine hidradenitis [67–69]. in most cases in patients with a history of this disease [79, Side effects related to MEK inhibitors (trametinib, cobi- 80] (Fig. 5d). metinib) are less complex. The most common are papulopus- tular rashes (77–89% of patients) and xerosis (30%) [22, 62]. 13 568 Clinical and Translational Oncology (2019) 21:556–571 Grading cutaneous toxicity in cancer at grade 2. If it persists, or reaches grade 3 or above, the patients on targeted therapies drug should be discontinued until the condition improves. and immunotherapy, and dose adjustments In the case of the RAF inhibitors vemurafenib and dab- rafenib, the onset of cutaneous squamous cell carcinomas New cancer treatments, including immunotherapy, cause a and new primary melanomas is managed by monitoring range of cutaneous toxicities that can lead to dose changes these new lesions and removing them surgically, with no or discontinuation of various drugs. The constant addition need for dose modification. of new substances and their combinations, especially in With the mTOR inhibitors everolimus and temsirolimus, clinical trials, poses a challenge, in terms of both grading given the risk of dehiscence at the suture site, it is recom- toxicities and managing them with specific dermatological mended that therapy be discontinued 7–10 days prior to treatment. Notable scales for grading cutaneous toxicity surgery, and resumed not less than 3 weeks afterwards [52]. include the Common Terminology Criteria for Adverse Last, during immunotherapy, the most common cutane- Events (CTCAE), Version 4.03 [32, 81], produced by the ous toxicities are maculopapular rash, pruritus, and viti- National Cancer Institute (NCI) and, more recently, the ligo. For clinical practice, it is suggested that grade 1 and Multinational Association of Supportive Care in Cancer mild grade 2 toxicities should be managed with supportive (MASCC) EGFR Inhibitor Skin Toxicity Tool (MESTT) measures, and immunotherapy can continue. In the event of [82]. grade 3 or highly symptomatic grade 2 toxicities, the recom- The CTCAE and MESTT scales grade dermatological mendation is to discontinue therapy temporarily until the toxicities from 1 to 5. As a general rule, a grade 1 toxicity symptoms become mild or have disappeared. It is then pos- is asymptomatic or involves few symptoms, which only sible to resume it, once the risks and benefits have been dis- requires diagnostic and clinical observation, and needs no cussed with the patient. With grade 4 toxicities, the therapy specific treatment. Grade 2 or moderate toxicity requires needs to be withdrawn permanently and the patient assessed non-invasive, local treatment. Grade 3 is severe, and the urgently by a dermatologist [88]. patient must be admitted to hospital. Grade 4 requires Once the existence of cutaneous toxicity of grade 2 or urgent treatment for a life-threatening condition, and above has been confirmed, the patient should be referred to Grade 5 means the patient died from the adverse effect. the dermatology department, to commence specific treat- The dermatological toxicity most often seen with targeted ment to improve the symptoms. Follow-up should take place. therapies relates to anti-EGFR drugs. It is caused by EGFR In the event of deterioration, the patient should be admitted inhibition in the skin, and the most common form is papu- to hospital and/or managed specifically as appropriate [81]. lopustular eruption [83, 84]. With immunotherapies, der- mal toxicity occurs in 40–45% of patients, normally between weeks 3 and 6 of therapy [85, 86]. Whether to adjust or delay Conclusions the dose or discontinue treatment is specified in the pre- scribing information for each drug. In general, we describe It is common for dermatological toxicities to occur while the steps to be taken according to drug class and the most cancer patients are being treated with targeted therapies. representative toxicities. For EGFR inhibitors, the dose Their onset may cause dose reductions and/or delays in treat- should be adjusted after the onset of cutaneous toxicity of ment, thus compromising patient survival. Also, this toxicity grade 3 or above, or intolerable grade 2 toxicity. In these has a significant impact on patients’ quality of life and can cases, treatment should be discontinued temporarily until affect their personal, social, and workplace relationships. the toxicity subsides to grade 1 or 2, respectively. It should Cutaneous toxicity is most common with EGFR inhibi- then be resumed at a lower dose [87]. tors, but it is not confined to this drug class. It also occurs Monoclonal antibodies against VEGF/VEGFR cause with the use of TKIs, PDGFR, and BCR-ABL inhibitors, delayed healing. The most representative drug of this class is antiangiogenic drugs such as the monoclonal antibodies bev- bevacizumab. Withdrawal is recommended 6–8 weeks prior acizumab and ramucirumab, MAPK inhibitors, and immune to planned surgery, followed by reintroduction 4 weeks after checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/ the operation. In the antiangiogenic drug class, in the case PD-L1 drugs. of multikinase inhibitors, it is recommended that therapy be The dermatological syndromes most often associated discontinued 24–48 h prior to surgery, and 3–4 weeks should with these therapeutic targets are as follows: papulopustular elapse before treatment resumes [52]. In all cases, therapy eruption, the onset of which, in the case of anti-EGFR drugs, should stop until the wound is completely healed. is related to greater overall survival; xerosis, and pruritus, Hand-foot syndrome is also common and limiting with sometimes combined with the above; hand-foot syndrome; this drug class. Dose reduction is recommended if it occurs rashes, often linked to multikinase inhibitors, and unrelated to efficacy in this case; abnormalities of the hair follicle 13 Clinical and Translational Oncology (2019) 21:556–571 569 and nail apparatus, linked to anti-EGFR drugs; pigmentary 6. Peuvrel L, Dreno B. Dermatological toxicity associated with tar- changes to the skin and its appendages; impaired healing geted therapies in cancer: optimal management. Am J Clin Der- matol. 2014;15:425–44. due to antiangiogenic drug use; and neutrophilic dermatoses. 7. 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Cytokine regulation by epidermal growth cutaneous toxicity, to optimize the delivery of therapy, and factor receptor inhibitors and epidermal growth factor recep- to improve patient survival. tor inhibitor associated skin toxicity in cancer patients. Eur J Cancer. 2014;50:1855–63. Acknowledgements The authors are grateful for the editorial assis- 10. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cuta- tance of Fernando Sánchez-Barbero of HealthCo (Madrid, Spain) in neous side effects of epidermal growth factor receptor inhibi- the production of this manuscript. SEOM and AEVD are grateful for tors: clinical presentation, pathogenesis, and management. J Am financial support for this project in the form of unrestricted grants Acad Dermatol. 2007;56:317–26. from AstraZeneca, Avène, Boehringer Ingelheim, Pierre Fabre, Roche 11. Chiang HC, Anadkat MJ. Isotretinoin for high-grade or Farma, La Roche Posay. refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions. J Am Acad Dermatol. 2013;69:657–8. Compliance with ethical standards 12. Eilers RE Jr, Gandhi M, Patel JD, Mulcahy MF, Agulnik M, Hens- ing T, et al. Dermatologic infections in cancer patients treated Conflict of interest The authors declare that, when writing and revis- with epidermal growth factor receptor inhibitor therapy. J Natl ing the text, they did not know the names of the companies that provid- Cancer Inst. 2010;102:47–53. ed financial support for this project, so this support has not influenced 13. Pugliese SB, Neal JW, Kwong BY. Management of dermatologic the content of this article. complications of lung cancer therapies. Curr Treat Options Oncol. 2015;16:50. Ethical approval The study has been performed in accordance with the 14. Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huber- ethical standards of the Declaration of Helsinki and its later amend- man M, Karp D, et al. Determinants of tumor response and sur- ments. This article does not contain any studies with human partici- vival with erlotinib in patients with non—small-cell lung cancer. pants or animals performed by any of the authors. J Clin Oncol. 2004;22:3238–47. 15. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Informed consent All patients gave informed consent for the publica- Santoro A, et al. Cetuximab monotherapy and cetuximab plus tion of their images that illustrate this article. irinotecan in irinotecan-refractory metastatic colorectal cancer. New Engl J Med. 2004;351:337–45. 16. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Open Access This article is distributed under the terms of the Crea- Siu LL. 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