Retinoids for prevention and treatment of actinic keratosis

Ianhez, Mayra; Fleury Junior, Luiz Fernando Fróes; Miot, Hélio Amante; Bagatin, Edileia

doi:10.1590/abd1806-4841.20131803

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Review • An. bras. dermatol. 88 (4) • Aug 2013 • https://doi.org/10.1590/abd1806-4841.20131803 copy

Retinoids for prevention and treatment of actinic keratosis^* * Study carried out at the Federal University of Goiás (UFGO), the São Paulo State University - Júlio de Mesquita Filho (UNESP) and the Federal University of São Paulo (EPM -UNIFESP) - São Paulo (SP), Brazil.

Retinoides para a prevenção e tratamento das queratoses actínicas

Authorship SCIMAGO INSTITUTIONS RANKINGS

Actinic keratosis is a common cause of dermatological consultations and it presents a strong association with squamous cell carcinoma. Many substances are used for treatment and prevention, such as retinoids. Nevertheless, many studies on retinoids emphasize their application in treating and preventing non melanoma skin cancers. In this article, we reviewed studies about systemic and topical retinoids used with immunocompetent patients and organ transplant recipients with actinic keratosis, as primary or secondary outcomes. The majority of these papers pointed to a reduction in actinic keratosis count after treatment with retinoids. However, studies need to be better-defined in order to address the lack of a standardized dose, the absence of control groups, the low number of patients and short follow-up periods. Blind, randomized and controlled clinical trials with adequate sample sizes, specifically focused on actinic keratosis, are needed to clarify the real benefit of topical and/or oral retinoids. Comparison of efficacy and safety between oral and topical retinoids in the prevention and treatment of non-melanoma skin cancers and actinic keratosis is an essential pre requisite to establish new strategies to control these conditions.

Chemoprevention; Isotretinoin; Keratosis; Actinic; Retinoids; Tretinoin

Retinoids	Examples	Administration route
First generation (non-aromatic)	Tretinoin	Topical
	Isotretinoin	Topical and systemic
	Alitretinoin	Systemic

Second generation (mono-aromatic)	Etretinate	Acitretin
	Systemic	Systemic

Third generation (poly-aromatic)	Adapalene	Topical
	Tazarotene	Topical
	Bexarotene	Systemic

Skin lesions	Author (year)	Retinoids
AK/SCC	Kelly (1991)²⁶	Etretinate; acitretin; acitretin
	Bavinck (1994)²⁷
	De Sevaux (2003)²⁸
AK / BCC	Bollag (1970)²⁹; Hughes (1998)³⁰	Tretinoin etretinate
AK / warts	Euvrard (1992)³¹	Tretinoin
AK / warts/SCC	Rook (1995)²⁵	Tretinoin x etretinate + tretinoin
AK / BCC/SCC	Majewski (1994),³² Yuan (1995)³³ Euvrard (1998),³⁴ George (2002),³⁵McNamara(2002)³⁶	Isotretinoin + calcitriol acitretin; adapalene; acitretin; acitretin
AK / warts/BCC/SCC	Shuttleworth (1988),³⁷ McKenna (1999)³⁸	Etretinate; acitretin
AK alone	Moriarty (1982),¹⁸ Kligman (1991),³⁹ Misiewicz (1991),⁴⁰ Alizerai (1994),⁴¹ Moglia (1997),⁴² Campanelli (2002),⁴³ Smit (2002),⁴⁴ Smit (2004)⁴⁵	Etretinate; tretinoin 0.05%; Ro-14-9706 x tretinoin 0.05%; isotretinoin 0.1%; retinoid fenretinide; retinaldehyde 0.05%; tretinoin 0.02% x calcipotriol; acitretin

Author (year)	Study design Nº patients	Drug and treatment duration	Results
Moriarty (1982)18	Cross-over, open, randomized, controlled; 50 immunocompetent patients	Etretinate 5mg 3x/day versus placebo, 2months, after, the groups were swapped for 2 more months (placebo x etretinate)	84% of the etretinate group had complete or partial response compared to 5% in the placebo group
Shuttleworth (1988) 37	Cases series 6 transplanted patients	Etretinate 1mg/kg/day, 6months	"Almost" complete resolution of neoplastic and pre-neo-plastic lesions in 4 patients, partial response in 1 patient
Kelly (1991)26	Cases series 4 transplanted patients	Etretinate 50mg/day, 8-13months	AKs were not counted but they became less severe after treatment
Bavinck (1995)27	Double-blind, randomized, controlled 44 transplanted patients	Acitretin 30mg/ day versus placebo, 6 months	13.4% of patients in the acitretin group saw decreases in the number of AKs, while in the placebo group, 28.2% of the patients saw increases
Majewski (1994)32	Cases series 4 immunocompetent patients	Isotretinoin 0.4-0.5mg/kg/day + calci-triol 0.5-1µg, 12months, approximately	Patient 1- complete clearance; Patients 2 and 3- AK regression about 50 to 80%; Patient 4 - regression of 40% of AKs in number and size
Yuan (1995)33	Cases series 15 transplanted patients	Acitretin 10-50mg/day, 6-12 months	The number of skin cancers decreased in 4 of the 6 patients. All warts and AKs had improvement in all patients (without counting)
Rook (1995)25	Open, non-randomized, controlled 11 transplanted patients	Group 1= 7 patients (tretinoin 0.025% to 0.05% according to tolerance) + (etretinate 10mg/day or alternate days), 6 months according to improvement in AKs Group 2= 4 patients (tretinoin 0.025 to 0.05%, according to tolerance)	Both groups obtained a decrease in the number of AKs and an improvement in the number of Langerhans cells. Four patients in the combined group obtained almost 50% regression of AKs while 2 in the tretinoin group obtained improvement, after six months
Hughes (1998)30	Cases series 15 immunocompetent patients	Etretinate,18 month follow-up 1st month - 1.5mg/kg/day 2nd and 3rd months - 0.75mg/kg/day	Only 12 patients with AKs completed the study, with an average reduction in the number of AKs before and after treatment of 12.73 to 5.82
McKenna (1999)38	Cases series, 16 transplanted patients	Acitretin 0.3mg/kg/day, 5 years	There was significant improvement in warts and AKs, but they were not counted
George (2002)35	Cross-over, open, randomized controlled 23 immunocompetent patients	Group 1: Acitretin 25mg/day (variable) + placebo, 12months Group 2: Placebo + Acitretin 25mg/day (variable), 12months	In the acitretin group, complete clearance or reduction in number of AKs occurred in all patients, except one. In the placebo group, there was an increase of 50% in the number of AKs in 3 patients and 6 remained with no significant change
McNamara (2002)36	Cases series 5 transplanted patients	Acitretin 10 or 25mg/day, 10-24 months	AKs seemed to be in varying degrees of resolution with treatment but they were not counted
De Sevaux (2003)28	Open, randomized controlled 26 transplanted patients	Acitretin Group 1: 0.4mg/kg/ day, 12 months Group 2: 0.4mg/kg/ day, 3 months + 0.2mg/kg/ day, 9 months	Significant reduction in number of AKs in both groups after 2 months, but no difference between the groups at any particular point
Smit (2004)45	Cases series 33 transplanted patients	Acitretin: up to 0.4mg/kg/ day, 3months (biopsy of AKs)	Reduction of 44% in epidermal thickness due to stratum corneum, no difference in expression of p53 and Ki67 and an increase in the expression of K13 and K19 after treatment with acitretin

Author (year)	Study design Nº patients	Drug and treatment duration	Results
Bollag (1970)29	Case series 60 immunocompetent patients	Tretinoin 0.1% and 0.3% cream, 2x/day, in AKs and lx/day, occlusive in BCCs, 3 to 8 weeks	44 patients showed total or more than 50% of regression of the AKs. Tretinoin 0,3% showed higher rates of regression, as well as the face, compared to the upper limbs
Purcell (1986)46	Double-blind, non-randomized, controlled; 24 immuno-competent patients (8 drop out)	Tretinoin 0.05% ointment x placebo, 12months	There was no statistically significant difference between the groups in relation to the number of AKs
Kligman (1991)39	Double-blind, controlled 1265 immunocompetent patients (multicentered)	Tretinoin 0.05% x tretinoin 0.1% x placebo ointment, up to 15 months	The most effective treatment for reducing AKs was 0.1% tretinoin, applied twice daily (P.001). An excellent response was observed in 73% of tretinoin-treated patients compared with only 40% of placebo
Misiewicz (1991)40	Double-blind, randomized, controlled, 25 immunocom-petent patients	Ro 14-9706 x tretinoin 0.05% ointment, 16 weeks	Decrease of 37.8% in AK numbers with Ro 14-9706, while with tretinoin, the decrease was 30.3%. There was no difference between the two drugs, although Ro 14-9706 was better tolerated
Euvrard (1992)31	Double-blind, randomized, controlled, 22 transplanted patients	Tretinoin 0.05% ointment x placebo, 3 months	Reduction of 45% versus 23% of AKs in the tretinoin 0.05% group versus placebo, respectively
Alizerai (1994)41	Double-blind, randomized, placebo-controlled 100 immunocompetent patients	Isotretinoin 0.1% ointment, 2x/day x placebo, 24 weeks	66% of the patients with isotretinoin versus 45% of the patients with placebo had a partial or complete response, whereas 34% of patients with isotretinoin versus 55% of patients with placebo had no response or worsening on the face
Rook (1995)25	Open, non-randomized, controlled 11 transplanted patients	Group 1= 7 patients (tretinoin 0.025% to 0.05% according to tolerance) + (etretinate 10mg/day or alternate days), 6 months according to AK improvement, Group 2= 4 patients (tretinoin 0.025 to 0.05%, according to tolerance)	Both groups obtained a decrease in the number of AKs and an improvement in the number of Langerhans cells. Four patients in the combined group obtained almost 50% of regression of AKs, while 2 in the tretinoin group obtained improvement, after six months
Moglia (1997)42	Case series 18 immunocompetent patients	Retinoid fenretinide 2x/day, 3months	Complete and partial regression was observed in 56% and 44% of patients, respectively
Euvrard (1998)34	Randomized, controlled 40 transplanted patients	Adapalene 0.1% x adapalene 0.3%, 6 months	Reduction of 32% versus 21% in AKs number with concentrations of 0.3% and 0.1% respectively
Campanelli (2002)43	Case series 61 immunocompetent patients	Retinaldehyde 0.05%, 6-142 months	37% of the patients aged over 60 and 10% between 41-60 years developed AKs during the treatment. Retinaldehyde alone does not appear to have prophylactic effects on the development of AKs
Smit (2002)44	Open, non-randomized, controlled, 13 immunocom-petent patients	Group 1: Tretinoin 0,02%	There were no significant differences in clinical, histological and immunohistochemical parameters between the four different therapies during a 6-week treatment period.
		Group 2: calcipotriol
		Group 3: both
		Group 4: emollient
		All 2x/day, 6 weeks

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[1] MAILING ADDRESS: Mayra Ianhez, Universidade Federal de Goiás, Ambulatório de Dermatologia/ Hospital das Clínicas, Primeira Avenida s/n, Setor Leste Universitário, 74605-020 - Goiânia - GO, Brazil, E-mail: ianhez@hotmail.com

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Retinoids for prevention and treatment of actinic keratosis* * Study carried out at the Federal University of Goiás (UFGO), the São Paulo State University - Júlio de Mesquita Filho (UNESP) and the Federal University of São Paulo (EPM -UNIFESP) - São Paulo (SP), Brazil.

Retinoides para a prevenção e tratamento das queratoses actínicas

Retinoids for prevention and treatment of actinic keratosis^* * Study carried out at the Federal University of Goiás (UFGO), the São Paulo State University - Júlio de Mesquita Filho (UNESP) and the Federal University of São Paulo (EPM -UNIFESP) - São Paulo (SP), Brazil.