Management of dermatologic adverse events from cancer therapies: recommendations of an expert panel

Cury-Martins, Jade; Eris, Adriana Pessoa Mendes; Abdalla, Cristina Martinez Zugaib; Silva, Giselle de Barros; Moura, Veronica Paula Torel de; Sanches, Jose Antonio

doi:10.1016/j.abd.2020.01.001

Jade Cury-Martins ^** Corresponding author. E-mail:jadecury@yahoo.com.br (J. Cury-Martins).

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0001-9741-4311

Adriana Pessoa Mendes Eris

Dermatology Clinic, Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brazil

Skin Cancer Unit, A.C. Camargo Cancer Center, São Paulo, SP, Brazil

http://orcid.org/0000-0001-8044-8232

Cristina Martinez Zugaib Abdalla

Dermatology Unit, Hospital Sírio-Libanês, São Paulo, SP, Brazil

http://orcid.org/0000-0002-7489-3679

Giselle de Barros Silva

Dermatology Unit, Centro Paulista de Oncologia, São Paulo, SP, Brazil

http://orcid.org/0000-0002-9329-8883

Veronica Paula Torel de Moura

Oncology Center, Hospital Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0003-1566-1752

Jose Antonio Sanches

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0002-5709-092X

* Corresponding author. E-mail:jadecury@yahoo.com.br (J. Cury-Martins).

Authors' contribution

Jade Cury Martins Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Adriana Pessoa Mendes Eris: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Cristina Martinez Zugaib Abdalla: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Giselle de Barros Silva: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Veronica Paula Torel de Moura: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Jose Antonio Sanches: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Conflicts of interest

None declared.

Dermatologic toxicity	Most frequent agents	Management	Level of evidence
Hyperpigmentation		-Photoprotective measures -Bleaching agents	IV IV
Diffuse	Busulfan ("tan" appearance); methotrexate; procarbazine, capecitabine
Flagellate	Bleomycin
Serpentine supravenous	5-FU, docetaxel, vincristine, vinorelbine
Areas of pressure, flexural, under occlusive dressings	Ifosfamide, thiotepa, hydroxyurea, cisplatin, docetaxel
Palms and soles	Hydroxyurea, doxorubicin, capecitabine
Palmar creases	Ifosfamide, cyclophosphamide bleomycin, busulfan, doxorubicin
Mucous membranes	Cyclophosphamide (gingiva), busulfan, doxorubicin, cisplatin, capecitabine
Nail changes		General measures to all patients: reduction of contact to water, use of cotton gloves beneath plastic or rubber gloves for any wet work, avoidance of any damaging procedure (e.g.: aggressive manicuring), and hydration with thick emollients	IV
Onycholysis	Taxanes, cyclophosphamide doxorubicin, capecitabine, etoposide	Prevention: frozen gloves and socks during infusion (depending on the agent and type of infusion)	IIA
		Treatment:
		-Avoiding traumas (e.g.: keeping nails short) and humidity	IV
		-If green discoloration: topical antibiotic (tobramycin or ciprofloxacin eye drops)	IV
Paronychia	Taxanes, etoposide, capecitabine	-Topical corticosteroids -If secondary infection is suspected, culture guided antibiotics	IV IB
Nail pigmentation	5-FU, taxanes, hydroxyurea, cyclophosphamide, doxorubicin, capecitabine	Might be diffuse or banding/streaking. No treatment needed.
Hand-foot syndrome (HFS)	Capecitabine, doxorubicin, citarabine, 5-FU, taxanes	Prevention:
		-regional cooling during chemotherapy infusion	IB
		-nonsteroidal anti-inflammatory agent	IA
		-use thick cotton gloves and/or socks; urea based emollients; avoid irritants and tight clothing and shoes; avoid extremes of temperature, pressure and friction	III
		Treatment:
		-potent topical steroid	III-IV
		-for relief of symptoms, cool compresses or emergence of hands and feet on cool water, topical anesthetics and NSAIDs	III-IV
		-Dose reduction or treatment interruption is sometimes necessary	III-IV
PATEO syndrome	Docetaxel	See measures for HFS above
Chemotherapy-induced alopecia	Cyclophosphamide, doxorubicin, irinotecan and taxanes	Prevention: scalp cooling devices	I
		Treatment:
		-Topical Minoxidil 2%	IB
		-Topical minoxidil 5%, biotin containing oral supplements	IV
		-Topical bimatoprost (for eyelashes)	IIA

Drug class	Agents	Dermatologic toxicities	Management	Level of evidence
EGFR inhibitors	-Monoclonal antibodies: cetuximab and panitumumab -TKI specific for EGFR: erlotinib and gefitinib -Less specific multikinase inhibitors: vandetanib	Papulopustular eruption (starts on the first 2 weeks)	Prevention:
			-Systemic antibiotics for the first 6-8 weeks (tetracyclines), sunscreen	IB
			Treatment:
			-Low potency topical steroids	III
			-Systemic antibiotics (tetracyclines)	IB
			-Systemic isotretinoin (low doses)	III
			-Culture-driven antibiotics if secondary infection	IB
		Xerosis	-Limited shower time, use of gentle cleansers (pH-neutral soaps or syndets), regular use of emollients	III
		Xerosis	-Topical steroid if eczematous lesions	III
		Paronychia and pyogenic granuloma like lesions	Prevention:
			-Systemic antibiotics (tetracyclines)	IB
			-Antiseptic solutions	III
			Treatment:
			-Topical steroids	III
			-Systemic antibiotics (tetracyclines)	III
			-Culture-driven antibiotics if secondary infection	IB
		Fissures	Protective coverings (hydrocolloid, biological or cyanoacrylate glue), barrier creams (petroleum jelly, zinc oxide cream) and thick emollients	IIB
		Hair changes	-Nonscarring alopecia: topical minoxidil	IB
			-Inflammatory and scarring alopecia: topical steroids	III
			-Trichomegaly: eyelash trimming	III
			-Hypertrichosis: laser hair reduction	IB
KIT and BCR-ABL inhibitors	Imatinib, nilotinib, dasatinib	Exanthema (rash)	Topical steroids or short courses of oral steroids	III
KIT and BCR-ABL inhibitors	Imatinib, nilotinib, dasatinib	Hypopigmentation	Reversible after treatment interruption	III
Antiangiogenic agents	-Selective VEGFR inhibitors: bevacizumab and ranibizumab Non-selective multikinase inhibitors: sorafenib, pazopanib, sunitinib	Hand-foot skin reaction	Prevention:
			-Use thick cotton gloves and/or socks; urea based emollients; avoid irritants and tight clothing and shoes; avoid extremes of temperature, pressure and friction	III
			-Pretreatment evaluation with a podiatrist with callosity chopping and the use of orthopedic shoe inserts when needed	III
			-Urea based emollients	IB
			Treatment:
			-Keratolytic agents	III
			-Topical corticosteroids	III
			-Potent topical steroid	III
			-For relief of symptoms, cool compresses or emergence of hands and feet on cool water, topical anesthetics and NSAIDs	III
			-Hydrocolloid dressings?	IB
		Pigmentary changes	-Hypopigmentation of hair and skin (pazopanib and sunitinib), yellow discoloration of skin (sunitinib) - reversible after discontinuation	III
		Hair and scalp	-Seborrheic dermatitis-like rash: topical steroids	III
		Hair and scalp	-Non-scarring alopecia: topical minoxidil	IV
RAF inhibitors	Vemurafenib and dabrafenib	Exanthema (rash)	-Oral antihistamines, topical or short courses of systemic steroids	III
		Exanthema (rash)	^* * NSAID, nonsteroidal anti-inflammatory drug. Temporary treatment interruption might be necessary
		Photosensitivity	Prevention: photoprotective measures	IIB
			Treatment: topical or short courses of systemic steroids	III
			^* * NSAID, nonsteroidal anti-inflammatory drug. Mostly vemurafenib, UVA-induced	III
		Keratosis pilaris like eruption	Keratolytics and emollients, gentle skin care	III
		Seborrheic dermatitis-like	Topical steroids	III
		Hand-foot skin reaction	See above (antiangiogenic agents)
		Keratoacanthomas and squamous cell carcinomas	-Frequent dermatological monitoring	III
			-If few lesions: surgical excision	III
			-If multiple lesions: 5-FU, systemic retinoids or photodynamic therapy	IIA/B
			^* * NSAID, nonsteroidal anti-inflammatory drug. Association with a MEKi decreases lesions	IIA/B
		Warts and verrucal keratoses	-Destructive or surgical measures	III
		Warts and verrucal keratoses	-Topical treatments: keratolytics, 5-FU, imiquimod	III
MEK inhibitors	Cobimetinibe, trametinibe, selumetinibe	Papulopustular eruption	See EGFR inhibitors above
		Xerosis
		Paronychia
		Exanthema (rash)	-Oral antihistamines, topical or short courses of systemic steroids	III
mTOR inhibitors	Rapamycin, everolimus, sirolimus	Stomatitis	Antiseptic washes, topical steroids and anesthetics	IV

Drug class	Agents^* * Dual checkpoint blockade (anti-CTLA-4 + anti-PD1) is related to a higher grade of adverse events, including dermatologic toxicities. Case reports for severe irAE are available with the use of other immunomodulatory agents.	Dermatologic toxicities	Management	Level of evidence
"Checkpoint" inhibitors	-CTLA-4 inhibitors: ipilimumab -PD-1 inhibitors: nivolumab, pembrolizumab -PD1l inhibitors: atezolizumab	Exanthema (rash)	-Mild (<30% BSA): oral antihistamines, topical steroids	IV
			-Moderate (>30% BSA): oral steroids (1-2 mg/kg); hold immunotherapy	IV
			-Severe (SSJ/TEN or necrotic, bullous or hemorrhagic complications): systemic steroid (1-2 mg/kg); permanently discontinue immunotherapy	IV
		Pruritus	Prevention:
			Limited shower time, use of gentle cleansers (pH-neutral soaps or syndets), regular use of emollients	IV
			Treatment:
			-Oral antihistamines	IV
			-Topical or oral steroids	IV
			-GABA agonists (pregabalin, gabapentin)	IV
		Oral toxicity -Lichenoid lesions -Dry mouth	Topical steroids and anesthetics, good oral hygiene	IV
		Vitiligo	No definitive treatment	IV
		Others:	Only case reports on the literature
		-Lichenoid eruptions
		-Sarcoidosis
		-Auto-immune blistering diseases (bullous pemphigoid)
		-Psoriasis

[1] * Corresponding author. E-mail:jadecury@yahoo.com.br (J. Cury-Martins).

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Abstract