A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe

Stefan Vegter, Keith Tolley, Stefan Vegter, Keith Tolley

Abstract

Background: Several treatments are available for actinic keratosis (AK) on the face and scalp. Most treatment modalities were compared to placebo and therefore little is known on their relative efficacy.

Objectives: To compare the different treatments for mild to moderate AK on the face and scalp available in clinical practice in Europe.

Methods: A network meta-analysis (NMA) was performed on the outcome "complete patient clearance". Ten treatment modalities were included: two 5-aminolaevulinic acid photodynamic therapies (ALA-PDT), applied as gel (BF-200 ALA) or patch; methyl-aminolevulinate photodynamic therapy (MAL-PDT); three modalities with imiquimod (IMI), applied as a 4-week or 16-week course with 5% imiquimod, or a 2-3 week course with 3.75% imiquimod; cryotherapy; diclofenac 3% in 2.5% hyaluronic acid; 0.5% 5-fluorouracil (5-FU); and ingenol mebutate (IMB). The only data available for 5% 5-FU was from one small study and was determined to be too limited to be reliably included in the analysis. For BF-200 ALA and MAL-PDT, data from illumination with narrow-band lights were selected as these are typically used in clinical practice. The NMA was performed with a random-effects Bayesian model.

Results: 25 trials on 5,562 patients were included in the NMA. All active treatments were significantly better than placebo. BF-200 ALA showed the highest efficacy compared to placebo to achieve total patient clearance. BF-200 ALA had the highest probability to be the best treatment and the highest SUCRA score (64.8% and 92.1%), followed by IMI 5% 4 weeks (10.1% and 74.2%) and 5-FU 0.5% (7.2% and 66.8%).

Conclusions: This NMA showed that BF-200 ALA, using narrow-band lights, was the most efficacious treatment for mild to moderate AK on the face and scalp. This analysis is relevant for clinical decision making and health technology assessment, assisting the improved management of AK.

Conflict of interest statement

Competing Interests: The research was funded by Biofrontera, Germany. The authors have no other conflict of interests that are directly relevant to the content of this paper.

Figures

Figure 1. Flow-chart of study selection.
Figure 1. Flow-chart of study selection.
Figure 2. Treatment network for the NMA.
Figure 2. Treatment network for the NMA.
Figure 3. Absolute clearance rates (bars ±…
Figure 3. Absolute clearance rates (bars ± SE; left axis) and ranking according to the probability to be the best treatment (yellow dots; right axis) and the SUCRA score (yellow squares; right axis).

References

    1. Flohil SC, van der Leest RJT, Dowlatshahi EA, Hofman A, de Vries E, et al. (2013) Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol 133: 1971–1978.
    1. Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, et al. (2009) Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer 115: 2523–2530.
    1. Marks R, Rennie G, Selwood TS, Hospital A (1988) Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1: 795–797.
    1. Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, et al. (2013) The natural history of actinic keratosis: a systematic review. Br J Dermatol 169: 502–518.
    1. Glogau RG (2000) The risk of progression to invasive disease. J Am Acad Dermatol 42: 23–24.
    1. Salasche SJ (2000) Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42: 4–7.
    1. Warino L, Tusa M, Camacho F, Teuschler H, Fleischer AB, et al. (2006) Frequency and cost of actinic keratosis treatment. Dermatol Surg 32: 1045–1049.
    1. De Berker D, McGregor JM, Hughes BR (2007) Guidelines for the management of actinic keratoses. Br J Dermatol 156: 222–230.
    1. Stockfleth E, Kerl H (2006) Guidelines for the management of actinic keratoses. Eur J Dermatol 16: 599–606.
    1. Jansen JP, Crawford B, Bergman G, Stam W (2008) Bayesian meta-analysis of multiple treatment comparisons: an introduction to mixed treatment comparisons. Value Heal 11: 956–964.
    1. Ades AE, Sculpher M, Sutton A, Abrams K, Cooper N, et al. (2006) Bayesian methods for evidence synthesis in cost-effectiveness analysis. Pharmacoeconomics 24: 1–19.
    1. Caldwell DM, Ades AE, Higgins JPT (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331: 897–900.
    1. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23: 3105–3124.
    1. Gupta a K, Paquet M (2013) 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 169: 250–259.
    1. Gupta A, Paquet M, Villanueva E, Brintnell W (2012) Interventions for actinic keratoses (Review). Cochrane Database Syst Rev
    1. Piacquadio DJ, Chen DM, Farber HF, Fowler JF, Glazer SD, et al. (2004) Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 140: 41–46.
    1. Pariser D, Loss R, Jarratt M, Abramovits W, Spencer J, et al. (2008) Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study. J Am Acad Dermatol 59: 569–576.
    1. Szeimies R-M, Matheson RT, Davis Sa, Bhatia AC, Frambach Y, et al. (2009) Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study. Dermatol Surg 35: 586–592.
    1. Szeimies R-M, Radny P, Sebastian M, Borrosch F, Dirschka T, et al. (2010) Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study. Br J Dermatol 163: 386–394.
    1. Dirschka T, Radny P, Dominicus R, Mensing H, Brüning H, et al. (2012) Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol 166: 137–146.
    1. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, et al. (2007) A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 157 Suppl 34–40.
    1. Gupta AK, Davey V, Mcphail H (2005) Evaluation of the effectiveness of imiquimod and 5-fluorouracil for the treatment of actinic keratosis: Critical review and meta-analysis of efficacy studies. J Cutan Med Surg 9: 209–214.
    1. University of Bristol, School of Social and Community Medicine. Mixed Treatment Comparisons. (2013). Available: .
    1. Salanti G, Ades aE, Ioannidis JPa (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64: 163–171.
    1. Salanti G, Higgins JPT, Ades aE, Ioannidis JPa (2008) Evaluation of networks of randomized trials. Stat Methods Med Res 17: 279–301.
    1. Ooi T, Barnetson RS, Zhuang L, McKane S, Lee JH, et al. (2006) Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. Br J Dermatol 154: 72–78.
    1. Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF (2004) Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol 140: 813–816.
    1. Gebauer K, Brown P, Varigos G (2003) Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol 44: 40–43.
    1. Stockfleth E, Kerl H, Zwingers T, Willers C (2011) Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol 165: 1101–1108.
    1. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, et al. (2010) Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62: 582–590.
    1. Hauschild a, Stockfleth E, Popp G, Borrosch F, Brüning H, et al. (2009) Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies. Br J Dermatol 160: 1066–1074.
    1. Greiner R, Batscheider A, Eheberg D, Gohlke A, Pfiffner C, et al. (2013) Methodological Challenges in Comparing Topical Therapies in Dermatology in the Absence of Head to Head Studies. Value in Health 16: A608.
    1. Brown MB, Jones SA (2005) Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol 19: 308–318.
    1. Seed MP, Brown JR, Freemantle CN, Papworth JL, Colville-Nash PR, et al. (1997) The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan. Cancer Res 57: 1625–1629.
    1. Freemantle C, Alam CA, Brown JR, Seed MP, Willoughby DA (1995) The modulation of granulomatous tissue and tumour angiogenesis by diclofenac in combination with hyaluronan (HYAL EX-0001). Int J Tissue React 17: 157–166.
    1. Alam CA, Seed MP, Willoughby DA (1995) Angiostasis and vascular regression in chronic granulomatous inflammation induced by diclofenac in combination with hyaluronan in mice. J Pharm Pharmacol 47: 407–411.
    1. White SJ, Wright CG, Robinson KS, Meyerhoff WL (1995) Effect of topical hyaluronic acid on experimental cholesteatoma. Am J Otolaryngol 16: 312–318.
    1. Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, et al. (2004) Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 50: 714–721.
    1. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, et al. (2012) Ingenol mebutate gel for actinic keratosis. N Engl J Med 366: 1010–1019.
    1. Szeimies R-M, Gerritsen M-JP, Gupta G, Ortonne JP, Serresi S, et al. (2004) Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51: 547–555.
    1. Armoškaitė V, Ramanauskienė K, Briedis V (2011) Selection of the Optimal Pharmaceutical Form of 5-Aminolevulinic Acid and Its Application in the Treatment of Oncologic Diseases. Mededicina (Kaunas) 47 (Suppl) 49–55.
    1. Stanley MA (2002) Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 27: 571–577.
    1. Kaur RR, Alikhan A, Maibach HI (2010) Comparison of topical 5-fluorouracil formulations in actinic keratosis treatment. J Dermatolog Treat 21: 267–271.
    1. Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, et al. (2005) Indirect comparisons of competing interventions. Health Technol Assess 9: 1–,
    1. Hadley G, Derry S, Moore RA (2006) Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol 126: 1251–1255.
    1. Falagas ME, Angelousi AG, Peppas G (2006) Imiquimod for the treatment of actinic keratosis: A meta-analysis of randomized controlled trials. J Am Acad Dermatol 55: 537–538.
    1. Gupta AK (2002) The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 70: 30–36.
    1. Wilson ECF (2010) Cost effectiveness of imiquimod 5% cream compared with methyl aminolevulinate-based photodynamic therapy in the treatment of non-hyperkeratotic, non-hypertrophic actinic (solar) keratoses: a decision tree model. Pharmacoeconomics 28: 1055–1064.
    1. Muston D, Downs A, Rives V (2009) An economic evaluation of topical treatments for actinic keratosis. J Dermatolog Treat 20: 266–275.
    1. Morton C, Campbell S, Gupta G, Keohane S, Lear J, et al. (2006) Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 155: 1029–1036.
    1. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, et al. (2002) Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study. J Am Acad Dermatol 47: 258–262.
    1. Dirschka T, Radny P, Dominicus R, Mensing H, Brüning H, et al. (2013) Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol 168: 825–836.
    1. Korman N, Moy R, Ling M, Matheson R, Smith S, et al. (2005) Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 141: 467–473.
    1. NCT00828568. A Therapeutic Equivalence Study of Two Imiquimod Cream 5% Treatments for Patients With Actinic Keratosis. .
    1. Jorizzo J, Dinehart S, Matheson R, Moore JK, Ling M, et al. (2007) 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 57: 265–268.
    1. Alomar a, Bichel J, McRae S (2007) 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 157: 133–141.
    1. Weiss J, Menter A, Hevia O, Jones T, Ling M, et al. (2002) Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis 70: 22–29.
    1. Jorizzo J, Stewart D, Bucko A, Davis SA, Espy P, et al. (2002) Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis. Cutis 70: 335–339.
    1. Wolf JE, Taylor JR, Tschen E, Kang S (2001) Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40: 709–713.
    1. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, et al. (2002) Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146: 94–100.
    1. Solaraze gel: Diclofenac Sodium 3% - package insert.
    1. NCT00700063. A Multicenter Study to Evaluate the Safety and Efficacy of PEP005 Topical Gel When Used to Treat Actinic Keratoses on the Head (Face or Scalp). .
    1. Hanke CW, Beer KR, Stockfleth E, Wu J, Rosen T, et al. (2010) Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 62: 573–581.

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