The Importance of Medication Adherence in the Treatment of Actinic Keratosis: An Expert Consensus Panel
Main Article Content
Keywords
actinic keratosis, actinic keratoses, AK, topical treatment, patient reported outcomes, skin cancer, pre-cancer, squamous cell carcinoma, SCC
Abstract
Background: Actinic keratosis (AK) is one of the most common dermatologic diagnoses. While there are several treatment options, many topical therapies have poor adherence due to duration of treatment and local skin reactions (LSRs).
Objective: To review the available literature on the most commonly used patient-administered field-directed therapies for AK and create consensus statements on the role of medication adherence in improving AK outcomes.
Methods: A literature search of PubMed was completed for English-language original research articles reporting efficacy, safety, and tolerability data for 5-FU, diclofenac gel, imiquimod cream, and tirbanibulin. Once the articles were selected, they were distributed to a panel consisting of seven dermatologists with extensive expertise in managing AKs. Each panelist reviewed the articles and assigned them a level of evidence based on Strength of Recommendation Taxonomy (SORT) criteria. The panelists then met to review and discuss the studies and created consensus statements on the management of AKs and the importance of medication compliance. A modified Delphi process was used to approve the adoption of each statement.
Results: The literature search produced 1,326 articles that met search criteria. After screening these articles for relevance and applying the inclusion criteria, 17 articles were chosen to be reviewed by the panel and assigned a level of evidence based on SORT criteria. The panel then created six consensus statements that received a unanimous vote for adoption.
Conclusion: While there are several options for the treatment of AK, there is little consensus on a standard of care. Clearance rates for the most common topical field therapies vary significantly but are also difficult to directly compare due to differences in methodology for measuring and assessing outcomes. Overall, it is clear that an efficacious, tolerable, and convenient treatment for AKs is critical to optimal adherence and management and, given the results of recent studies, tirbanibulin may be the best topical option for meeting these criteria.
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3. Siegel JA, Korgavkar K, Weinstock MA. Current perspective on actinic keratosis: a review. Br J Dermatol. 2017;177(2):350-358. doi:10.1111/bjd.14852
4. Landis ET, Davis SA, Taheri A, Feldman SR. Top dermatologic diagnoses by age. Dermatol Online J. 2014;20(4):22368. Published 2014 Apr 16.
5. Willenbrink TJ, Ruiz ES, Cornejo CM, Schmults CD, Arron ST, Jambusaria-Pahlajani A. Field cancerization: Definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol. 2020;83(3):709-717. doi:10.1016/j.jaad.2020.03.126
6. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237-247. doi:10.1016/j.jaad.2017.08.059
7. Muzic JG, Schmitt AR, Wright AC, et al. Incidence and Trends of Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma: A Population-Based Study in Olmsted County, Minnesota, 2000 to 2010. Mayo Clin Proc. 2017;92(6):890-898.
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11. Dessinioti C, Pitoulias M, Stratigos AJ. Epidemiology of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2022;36(1):39-50. doi:10.1111/jdv.17709
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13. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957-966. doi:10.1016/j.jaad.2012.11.037
14. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523-2530. doi:10.1002/cncr.24284
15. Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. doi:10.1111/bjd.12420
16. Dianzani C, Conforti C, Giuffrida R, et al. Current therapies for actinic keratosis. Int J Dermatol. 2020;59(6):677-684. doi:10.1111/ijd.14767
17. Cornejo CM, Jambusaria-Pahlajani A, Willenbrink TJ, Schmults CD, Arron ST, Ruiz ES. Field cancerization: Treatment. J Am Acad Dermatol. 2020;83(3):719-730. doi:10.1016/j.jaad.2020.03.127
18. Goldenberg G. Treatment considerations in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:12-16. doi:10.1111/jdv.14152
19. Blauvelt A, Kempers S, Lain E, et al. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. N Engl J Med. 2021;384(6):512-520. doi:10.1056/NEJMoa2024040
20. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):548-556.
21. Hsu C-C, Sandford BA. The Delphi technique: making sense of consensus. Practical assessment, research & evaluation 2007;12:1-8.
22. Heppt MV, Dykukha I, Graziadio S, Salido-Vallejo R, Chapman-Rounds M, Edwards M. Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. J Clin Med. 2022;11(6):1654. Published 2022 Mar 16. doi:10.3390/jcm11061654
23. Rajkumar JR, Armstrong AW, Kircik LH. INDIVIDUAL ARTICLE: Safety and Tolerability of Topical Agents for Actinic Keratosis: A Systematic Review of Phase 3 Clinical Trials. J Drugs Dermatol. 2021;20(10):s4s4-s14. doi:10.36849/JDD.M1021
24. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol. 2006;126(6):1251-1255. doi:10.1038/sj.jid.5700264
25. Pomerantz H, Hogan D, Eilers D, et al. Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. JAMA Dermatol. 2015;151(9):952-960. doi:10.1001/jamadermatol.2015.0502
26. Askew DA, Mickan SM, Soyer HP, Wilkinson D. Effectiveness of 5-fluorouracil treatment for actinic keratosis--a systematic review of randomized controlled trials. Int J Dermatol. 2009;48(5):453-463. doi:10.1111/j.1365-4632.2009.04045.x
27. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol. 2002;146(1):94-100. doi:10.1046/j.1365-2133.2002.04561.x
28. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019;380(10):935-946. doi:10.1056/NEJMoa1811850
29. 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):250-259. doi:10.1111/bjd.12343
30. Kempers S, DuBois J, Forman S, et al. Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results. J Drugs Dermatol. 2020;19(11):1093-1100. doi:10.36849/JDD.2020.5576
31. Yavel R, Overcash JS, Cutler D, Fang J, Zhi J. Phase 1 Maximal Use Pharmacokinetic Study of Tirbanibulin Ointment 1% in Subjects With Actinic Keratosis. Clin Pharmacol Drug Dev. 2022;11(3):397-405. doi:10.1002/cpdd.1041
32. Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest. 2017;127(1):106-116. doi:10.1172/JCI89820
33. Berman B, Grada A, Berman DK. Profile of Tirbanibulin for the Treatment of Actinic Keratosis. J Clin Aesthet Dermatol. 2022;15(10 Suppl 1):S3-S10.
34. Dao DD, Sahni VN, Sahni DR, Balogh EA, Grada A, Feldman SR. 1% Tirbanibulin Ointment for the Treatment of Actinic Keratoses. Ann Pharmacother. 2022;56(4):494-500. doi:10.1177/10600280211031329
35. Dlott AH, Di Pasqua AJ, Spencer SA. Tirbanibulin: Topical Treatment for Actinic Keratosis. Clin Drug Investig. 2021;41(9):751-755. doi:10.1007/s40261-021-01068-9
36. Eisen DB, Dellavalle RP, Frazer-Green L, Schlesinger TE, Shive M, Wu PA. Focused update: Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2022;87(2):373-374.e5. doi:10.1016/j.jaad.2022.04.013
37. Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2021;85(4):e209-e233. doi:10.1016/j.jaad.2021.02.082
38. Yeung H, Baranowski ML, Swerlick RA, et al. Use and Cost of Actinic Keratosis Destruction in the Medicare Part B Fee-for-Service Population, 2007 to 2015. JAMA Dermatol. 2018;154(11):1281-1285. doi:10.1001/jamadermatol.2018.3086
39. Marks R. Freckles, moles, melanoma and the ozone layer: a tale of the relationship between humans and their environment. Med J Aust. 1989;151(11-12):611-613. doi:10.5694/j.1326-5377.1989.tb139626.x
40. Lucas, R.; McMichael, T.; Smith, W.; Armstrong, B. Solar Ultraviolet Radiation: Global Burden of Disease from Solar Ultraviolet Radiation; Environmental Burden of Disease, Series; no., 13; Prüss-Üstün, A., Zeeb, H., Mathers, C., Repacholi, M., Eds.; World Health Organization: Geneva, Switzerland, 2006.
41. Green A., Battistutta D.: Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer 1990; 46: pp. 356-361.
42. Navarrete-Dechent C, Marghoob AA, Marchetti MA. Contemporary management of actinic keratosis. J Dermatol Treat. 2019;32:572–4.
43. Marks R., Foley P., Goodman G., Hage B.H., Selwood T.S.: Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986; 115: pp. 649-655.
44. Marks R., Rennie G., Selwood T.S.: Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1: pp. 795-797.
45. Czarnecki D., Meehan C.J., Bruce F., Culjak G.: The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg 2002; 6: pp. 207-209.
46. Mittelbronn M.A., Mullins D.L., Ramos-Caro F.A., Flowers F.P.: Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol 1998; 37: pp. 677-681.
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May 20, 2023
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Zakria, D., Armstrong, A., Berman, B., Del Rosso, J., Lebwohl, M., Schlesinger, T., & Rigel, D. (2023). The Importance of Medication Adherence in the Treatment of Actinic Keratosis: An Expert Consensus Panel. SKIN The Journal of Cutaneous Medicine, 7(3), 752–763. https://doi.org/10.25251/skin.7.3.1
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Clinical Management Recommendations
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