EFFICACY AND SAFETY OF INGENOL MEBUTATE IN THE TREATMENT OF ACTINIC KERATOSIS − A SYSTEMATIC REVIEW AND META-ANALYSIS
Abstract
Introduction: Actinic keratosis is the most common premalignant lesion. The therapeutic approach to patients with multiple lesions involves field-directed treatment.
Objective: To evaluate the efficacy and safety of ingenol mebutato, a new drug treatment for topical field-directed treatment of actinic keratosis.
Design: Systematic review and meta-analysis of randomized controlled trials (RCTs) trials.
Data sources: Medline and Cochrane Library (June 2014).
Study selection: Two reviewers independently searched for studies and retrieved their characteristics and data estimates.
Data synthesis: Random-effects meta-analysis. Heterogeneity was assessed with the I2 test.
Results: Six trials (n = 1,492) versus placebo were included. The odds of a patient experiencing complete removal of the lesions was 17 (95%CI: 9 to 31, I2 = 0%) and 8.5 (95% CI: 5 to 15, I2 = 0%) times higher, compared to placebo, in the face/scalp and trunk/extremities, respectively. The incidence of adverse events related to treatment was higher in the group of mebutato ingenol (+23%, 95%CI: 11 to 35%), with no differences between groups in the discontinuation rate due to adverse events.
Conclusions: Mebutato of ingenol is efficacious in the treatment of actinic keratosis. Compared to other field-directed treatments available in Portugal, its therapeutic value comes from the favourable safety profile and tolerability, simplicity and short duration of the treatment regimen and the possibility of different treatment to injuries according to anatomical location (individualization of therapy). Future studies should directly compare the different therapeutic options and evaluate the effectiveness of the same in the real world.
Downloads
References
Rosen T, Lebwohl MG. Prevalence and awareness of actinic keratosis: Barriers and opportunities. J Am
Acad Dermatol. 2013; 68(1 Suppl 1):S2-9.
Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000; 42(1 Pt 2):23-4.
Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy
over treatment. A patient-oriented perspetive. Arch Dermatol. 1991; 127(7):1029-31.
Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma.
Dermatol Surg. 2007; 33(9):1099-101.
Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis").
J Am Acad Dermatol. 2000; 42(1 Pt 2):11-7.
Röwert-Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H. et al. Actinic keratosis is an early
in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007; 156 Suppl 3:8-12.
Williams H, Svensson A, Diepgen T, Naldi L, Coenraads PJ, Elsner P, et al; European Dreamt-Epidemiology Network (EDEN). Epidemiology of skin diseases in Europe. Eur J Dermatol. 2006; 16(2):212-8.
Lucas R, McMichael T, Smith W, Armstrong B. Solar ultraviolet radiation- global burden of disease from
solar ultraviolet radiation- WHO report. 2006. Report No.: Environmental Burden of Disease Series N 13.
Massa A, Alves R, Amado J, Matos E, Sanches M, Selores M, et al.. Ata Med Port. 2000; 13(5-6):247-54.
de Berker D, McGregor JM, Hughes BR; British Association of Dermatologists Therapy Guidelines
and Audit Subcommittee. Guidelines for the management of actinic keratoses. Br J Dermatol. 2007;
(2):222-30.
Stockfleth E, Terhorst D, Braathen L, Cribier B, Cerio R, Ferrandiz C, et al., on behalf of the European
Dermatology Forum. European Dermatology Forum. [Online]; 2010 [consultado: 2012 10 25.
Disponível em: http://www.euroderm.org/images/stories/guidelines/guideline_Management_Actinic_
Keratoses-update2011.pdf.
Stockfleth E, Ferrandiz C, Grob JJ, Leigh I, Pehamberger H, Kerl H; European Skin Academy. Development
of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008; 18(6):651-9.
European public assessment report (EPAR) do Picato®. [consultado em 2/07/2014] Disponível em: http://
www.ema.europa.eu/docs/pt_PT/document_library/EPAR_-_Product_Information/human/002275/
WC500135327.pdf.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700.
Altman DG, Sterne JAC. Chapter 8: assessing risk of bias in included studies. In: Higgins JPT, Green S.
eds. Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. [consultado em 2/07/2014]. Disponível em: http://handbook.cochrane.org/.
Cochrane Review Manager Software. Version 5.2. [consultado em 2/07/2014]. Disponível em: http://tech.cochrane.org/Revman.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ.
; 327:557-60.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7:177-88.
Berman B, Goldenberg G, Hanke CW, Tyring SK, Werschler WP, Knudsen KM, et al. Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results. J Drugs Dermatol. 2014; 13(6):741-7.
Neidecker MV, Davis-Ajami ML, Balkrishnan R, Feldman SR. Pharmacoeconomic considerations in treating actinic keratosis. Pharmacoeconomics. 2009; 27(6):451-64.
Tinghög G, Carlsson P, Synnerstad I, Rosdahl I. Societal cost of skin cancer in Sweden in 2005. Acta Derm Venereol. 2008; 88(5):467-73.
Australian Institute of Health and Welfare. Health system expenditures on cancer and other neoplasms
in Australia, 2000-01. Canberra: AIHW; 2005.
Serup J, Lindblad AK, Maroti M, Kjellgren KI, Niklasson E, Ring L, et al. To follow or not to follow
dermatological treatment--a review of the literature. Acta Derm Venereol. 2006; 86(3):193-7.
Ceilley RI, Jorizzo JL. Current issues in the management of actinic keratosis. J Am Acad Dermatol. 2013; 68(1 Suppl 1):S28-38.
Lebwohl M, Shumack S, Stein Gold L, Melgaard A, Larsson T, Tyring SK. Long-term follow-up study of
ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol. 2013; 149(6):666-70.
Bettencourt MS. Use of ingenol mebutate gel for actinic keratosis in patients in a community dermatology practice. J Drugs Dermatol. 2014; 13(3):269-73.
Gupta AK, Paquet M, Villanueva E, Brintnell W. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012 Dec 12;12:CD004415.
Gupta AK, Paquet M. Network meta-analysis of the outcome 'participant complete clearance' in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013; 169(2):250-9.
Jorizzo J, Dinehart S, Matheson R, Moore JK, Ling M, Fox TL, et al., Vehicle-controlled, double-blind,
randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol. 2007; 57(2):265-8.
Alomar A, Bichel J, McRae S, Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol. 2007; 157(1):133-41.
All articles in this journal are Open Access under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
