Actinic Keratosis: Rationale and Management

Dermatology and Therapy

Volumn 4, Issue 1, 2014, Pages 11-31

  Dodds, Annabel ^a   Chia, Alvin ^b   Shumack, Stephen ^c  

^a St George Dermatology and Skin Cancer Centre   (Australia)

^b PRINCE OF WALES HOSPITAL   (Australia)

^c UNIVERSITY OF SYDNEY   (Australia)

Author keywords

5 Fluorouracil; Actinic keratosis; Cryosurgery; Dermatology; Diclofenac; Field cancerization; Imiquimod; Ingenol mebutate; Photodynamic therapy

Indexed keywords

AMINOLEVULINIC ACID; AMINOLEVULINIC ACID METHYL ESTER; DICLOFENAC; FLUOROURACIL; HYALURONIC ACID; IMIQUIMOD; INGENOL MEBUTATE; PLACEBO; PROTEIN P53; RESIQUIMOD; RETINOIC ACID; SALICYLIC ACID;

ACTINIC KERATOSIS; COMPARATIVE STUDY; CONTACT DERMATITIS; CORTICOSTEROID THERAPY; CRYOSURGERY; CRYOTHERAPY; DEPIGMENTATION; ERYTHEMA; GENE INACTIVATION; GENE MUTATION; GENETICS; HUMAN; META ANALYSIS (TOPIC); MULTIPLE CYCLE TREATMENT; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHOTODYNAMIC THERAPY; PRACTICE GUIDELINE; PRIORITY JOURNAL; PRURITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SKIN DISEASE; SWELLING; SYSTEMATIC REVIEW (TOPIC); ULTRAVIOLET IRRADIATION; UNSPECIFIED SIDE EFFECT; VIRAL SKIN DISEASE; XEROSIS;

EID: 84915795403     PISSN: 21938210     EISSN: 21909172     Source Type: Journal    
DOI: 10.1007/s13555-014-0049-y     Document Type: Review

References (133)

1. Samrao A, Cockerell J. Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. Am J Dermatol. 2013;14:273–7.
2. Stockfleth E. The paradigm shift in treating actinic keratosis: a comprehensive strategy. J Drugs Dermatol. 2012;11(12):1462–7.
3. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000;42(1 Pt 2):4–7.
4. Franceschi S, Levi F, Randimbison L, La Vecchia C. Site distribution of different types of skin cancer: new aetiological clues. Int J Cancer. 1996;67(1):24–8.
5. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin and Chemoprevention Trial. Cancer. 2009;115(11):2523–30.
6. Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. J Am Acad Dermatol. 2013;68(1 Suppl 1):S10–9.
7. Roewert-Huber J, Stockfleth E, Kerl H. Pathology and pathobiology of actinic (solar) keratosis—an update. Br J Dermatol. 2007;157(Suppl 2):18–20.
8. Marks R, et al. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol. 1986;115(6):649–55.
9. Brougham NDLS, Dennett ER, Cameron R, Tan ST. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol. 2012;106:811–5.
10. Brantsch KD, Meisner C, Schonfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9(8):713–20.
11. Mourouzis C, Boynton A, Grant J, et al. Cutaneous head and neck SCCs and risk of nodal metastasis: UK experience. J Craniomaxillofac Surg. 2009;37(8):443–7.
12. Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single institution cohort study. JAMA Dermatol. 2013;149(5):541–7.
13. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1(8589):795–7.
14. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42(1 Pt 2):23–4.
15. Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT. From keratinocyte to cancer: the pathogenesis and modelling of cutaneous squamous cell carcinoma. J Clin Invest. 2012;122(2):464–72.
16. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer. 1990;46(3):356–61.
17. Rigel DS, Gold LFS. The importance of early diagnosis and treatment of actinic keratosis. J Am Acad Dermatol. 2013;68(1 Suppl 1):S1.
18. Simon JC, et al. Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenic antigen-presenting cells. Induction of specific clonal anergy in CD4+ T helper 1 cells. J Immunol. 1991;146(2):485–91.
19. Yoshikawa T, et al. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans. J Invest Dermatol. 1990;95(5):530–6.
20. Mortier L, et al. Progression of actinic keratosis to squamous cell carcinoma of the skin correlates with deletion of the 9p21 region encoding the p16(INK4a) tumor suppressor. Cancer Lett. 2002;176(2):205–14.
21. Kanellou P, Zaravinos A, Zioga M, Stratigos A, Baritaki S, Soufla G, Zoras O, Spandidos DA. Genomic instability, mutations and expression analysis of the tumour suppressor genes p14(ARF), p15(INK4b), p16(INK4a) and p53 in actinic keratosis. Cancer Lett. 2008;264(1):145–61.
22. Timares L, Katiyar SK, Elmets CA. DNA damage, apoptosis and Langerhans cells—activators of UV-induced immune tolerance. Photochem Photobiol. 2008;84:422–36.
23. Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. J Am Acad Dermatol. 2010 Jan;68(Iss 1, Supp 1):PA1–A4, S10–S19.
24. Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumour promotion. J Investig Dermatol Symp Proc. 1996;1:136–42.
25. Jiang W, Ananthaswamy HN, Muller HK, Kripke ML. p53 protects against skin cancer induction by UV-B radiation. Oncogene. 1999;18(29):4247–53.
26. Wang L, Eng W, Cockerell CJ. Effects of ultraviolet irradiation on inflammation in the skin. Adv Dermatol. 2002;18:247–86.
27. Hruza LL, Pentland AP. Mechanisms of UV-induced inflammation. J Invest Dermatol. 1993;100:35S–41S.
28. Lober BA, Lober CW, Accola J. Actinic keratosis is squamous cell carcinoma. J Am Acad Dermatol. 2000;43(5 Pt 1):881–2.
29. Heaphy MR Jr, Ackerman AB. The nature of solar keratosis: a critical review in historical perspective. J Am Acad Dermatol. 2000;43(1 Pt 1):138–50.
30. Lebwohl MG, Rosen T, Stockfleth E. The role of human papillomavirus in common skin conditions: current viewpoints and therapeutic options. Cutis. 2010;86(5):Suppl 1–11 (quiz suppl 12).
31. Jackson S, Harwood C, Thomas M, et al. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev. 2000;14:3065–73.
32. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol. 2000;42(1 pt 2):11–7.
33. Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of disease progression. Arch Dermatol. 2010;146(3):288–93.
34. Neto PD, Alchorne M, Michalany N, Abreu M, Borra R. Reduced P53 staining in actinic keratosis is associated with squamous cell carcinoma: a preliminary study. Indian J Dermatol. 2013;58(4):325.
35. Marks R. Epidemiology of non-melanoma skin cancer and solar keratoses in Australia: a tale of self-immolation in Elysian fields. Australas J Dermatol. 1997;38(Suppl 1):S26–9.
36. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol. 1994;131(4):455–64.
37. Stockfleth E, Terhorst D, Braathen L, et al., Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratosis—update 2011. Available from: http://bestpractice.bmj.com/best-practice/monograph/616/diagnosis/guidelines.html. Accessed August 25 2013.
38. Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skin cancer and solar keratoses, II: analytical results of the South Wales skin cancer study. Br J Cancer. 1996;74:1308–12.
39. Holmes C, Foley P, Freeman M, Chong AH. Solar keratosis: epidemiology, pathogenesis, presentation and treatment. Australas J Dermatol. 2007;48(2):67–74.
40. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queensland community. J Invest Dermatol. 2000;115(2):273–7.
41. Marks R, Ponsford MW, Selwood TS, Goodman G, Mason G. Non-melanotic skin cancer and solar keratoses in Victoria. Med J Aust. 1983;2:619–22.
42. Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skin cancer and solar keratoses, I: methods and descriptive results of the South Wales skin cancer study. Br J Cancer. 1996;74:1302–7.
43. Euvrard S, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33(2 Pt 1):222–9.
44. Kaufman R. The concept of field cancerization. Melanoma Res. 2010;20:e13–4.
45. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium: clinical manifestations of multicentric origin. Cancer. 1953;6(5):963–8.
46. Basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in Australia. Cancer Council Australia and Australian Cancer Network, Sydney; 2008.
47. Stockfleth E, Karl H, Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratosis. Eur J Dermatol. 2006;16(6):599–606.
48. De Berker D, McGregor JM, Hughes BR, British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for the management of actinic keratosis. Br J Dermatol. 2007;156(2):222–30 (erratum in Br J Dermatol 2008;158(4):873).
49. Berman B, Bienstock L, Kuritzky L, Mayeaux EJ, Tyring SK, Primary Care Education Consortium, Texas Academy of Family Physicians. Actinic keratoses: sequelae and treatments. Recommendations from a consensus panel. J Fam Pract. 2006;55(5):Suppl 1–8.
50. 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.
51. Balkrishnan R, et al. Predictors of treatment choices and associated outcomes in actinic keratoses: results from a national physician survey study. J Dermatol Treat. 2006;17(3):162–6.
52. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43(9):687–92.
53. Kafmann R, Spelman L, Weightman W, Reifenberger J, Sziemies RM, Verhaeghe E, et al. Multicenter intraindividual randomized trial of topical methyl aminolevulinate-photodynamic therapy vs cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol. 2008;158:994–9.
54. McIntyre WJ, Downs MR, Bedwell SA. Treatment options for actinic keratoses. Am Fam Physician. 2007;76:667–71.
55. Berman B, Bienstock L, Kuritzky L, Mayeaux EJ Jr, Tyring SK. Actinic keratoses: sequelae and treatments. Recommendations from a consensus panel. J Fam Pract. 2006;55:1–8.
56. Hantash BM, Stewart DB, Cooper ZA, Rehmus WE, Koch RJ, Swetter SM. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch Dermatol. 2006;142(8):976–82.
57. Winton GB, Salache SJ. Dermabrasion of the scalp as a treatment for actinic damage. J Am Acad Dermatol. 1986;14(4):661–8.
58. Dillaha CJ, et al. Further studies with topical 5-fluorouracil. Arch Dermatol. 1965;92(4):410–7.
59. Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses. I. Effect on DNA synthesis in vivo. Arch Dermatol. 1970;101(2):132–9.
60. Kaur RR, Alikhan A, Maibach HI. Comparison of topical 5-fluorouracil formulations in actinic keratosis treatment. J Dermatol Treat. 2010;21(5):267–71.
61. Rhavar M, Lamel SA, Maibach HI. Randomized, vehicle-controlled trials of topical 5-fluorouracil therapy for actinic keratosis treatment: an overview. Immunotherapy. 2012;4(9):939–45.
62. Yentzer B, Hick J, Williams L, Inabinet R, Wilson R, Camacho FT, Russell GB, Feldman SR. Adherence to a topical regimen of 5-fluorouracil, 0.5%, cream for the treatment of actinic keratoses. JAMA Dermatol. 2009;145(2):203–5.
63. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E. 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. 2007;157(Suppl 2):34–40.
64. Labandeira J, et al. Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration. Dermatol Surg. 2004;30(4 Pt 1):517–20.
65. Robins P. Pulse therapy with 5-FU in eradicating actinic keratoses with less than recommended dosage. J Drugs Dermatol. 2002;1(1):25–30.
66. Berman B, Cohen DE, Amini S. What is the role of field directed therapy in the treatment of actinic keratosis? Part 2: commonly used field-directed and lesion-directed therapies. Cutis. 2012;89(6):294–301.
67. Clark RA, Huang SJ, Murphy GF, et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med. 2008;205(10):2221–34.
68. Meyer T, et al. Induction of apoptosis by Toll-like receptor-7 agonist in tissue cultures. Br J Dermatol. 2003;149(Suppl 66):9–14.
69. Schon MP, Schon M. Imiquimod: mode of action. Br J Dermatol. 2007;157(Suppl 2):8–13.
70. Uhlenhake EE. Optimal treatment of actinic keratoses. Clin Interv Ageing. 2013;8:29–35.
71. Gupta AK, Cooper EA, Abramovits W. Zyclara (imiquimod) cream, 3.75%. Skinmed. 2010;8:227–9.
72. Lebwohl M, et al. 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. 2004;50(5):714–21.
73. Lee PK, Harwell WB, Loven KH, et al. Long term clinical outcomes following treatment of actinic keratosis with imiquimod 5% cream. Dermatol Surg. 2005;31(6):659–64.
74. Korman N, et al. 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. 2005;141(4):467–73.
75. Szeimies RM, et al. 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. 2004;51(4):547–55.
76. Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol. 2002;47(4):571–7.
77. Chen K, et al. Short-course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Australas J Dermatol. 2003;44(4):250–5.
78. Ulrich C, Busch JO, Meyer T, et al. Successful treatment of multiple actinic keratoses in organ transplant patients with topical 5% imiquimod: a report of six cases. Br J Dermatol. 2006;155(2):451–4.
79. Hanke CW, Beer KR, Stockfleth E, Wu J, Rosen T, Levy S. 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. 2010;62(4):573–81.
80. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. 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. 2010;62(4):582–90.
81. Haddican M, Goldenberg G. Update on the treatment of actinic keratoses. Wayne PA: Bryn Mawr Communications III LLC; 2012. Available from: http://bmctoday.net/practicaldermatology/pdfs/PD0612_SF_AKs.pdf. Accessed August 30, 2013.
82. Foley P, et al. A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes. J Drugs Dermatol. 2011;10(12):1432–8.
83. Hadley J, et al. Results of an investigator-initiated single-blind split-face comparison of photodynamic therapy and 5% imiquimod cream for the treatment of actinic keratoses. Dermatol Surg. 2012;38(5):722–7.
84. Serra-Guillen C, Nagore E, Hueso L, Llombart B, Requena C, Sanmartin O, Botella-Estrada R, Guillen C. A randomized comparative study of tolerance and satisfaction in the treatment of actinic keratosis of the face and scalp between 5% imiquimod cream and photodynamic therapy with methyl aminolaevulinate. Br J Dermatol. 2011;164(2):429–33.
85. Stockfleth E, Sterry W, Carey-Yard M, Bichel J. Multicentre, open-label study using imiquimod 5% cream in one or two 4-week courses of treatment for multiple actinic keratoses on the head. Br J Dermatol. 2007;157(Suppl 2):41–6.
86. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol. 2006;126(6):1251.
87. Ulrich C, Bichel J, Euvrard S, et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol. 2007;157(Suppl 2):25–31.
88. Szeimies RM, Bichel J, Ortonne JP, et al. A phase II dose-ranging study of topical resiquimod to treat actinic keratosis. Br J Dermatol. 2008;159(1):205–10.
89. Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: evidence for growth suppression by inhibiting COX-2 expression. Int J Cancer. 2000;86(5):667–71.
90. Maltusch A, Rowert-Huber J, Matthies C, Lange-Asschenfeldt S, Stockfleth E. Modes of action of diclofenac 3%/hyaluronic acid 2.5% in the treatment of actinic keratosis. J Dtsch Dermatol Ges. 2011;9(12):1011–7.
91. Martin GM, Stockfleth E. Diclofenac sodium 3% gel for the management of actinic keratosis: 10+ years of cumulative evidence of efficacy and safety. J Drugs Dermatol. 2012;11(5):600–8.
92. Pirard D, Vereecken P, Melot C, Heenan M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Arch Dermatol Res. 2005;297(5):185.
93. Nelson C, et al. Phase IV, open-label assessment of the treatment of actinic keratosis with 3.0% diclofenac sodium topical gel (Solaraze). J Drugs Dermatol. 2004;3(4):401–7.
94. Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol. 2003;44(1):40–3.
95. Berlin JM, Rigel DS. Diclofenac sodium 3% gel in the treatment of actinic keratoses post cryosurgery. J Drugs Dermatol. 2008;7(7):669–73.
96. Nelson C, Rigel D. Long-term follow-up of diclofenac sodium 3% in 2.5% hyaluronic acid gel for actinic keratosis: one year evaluation. J Clin Aesthet Dermatol. 2009;2(7):20–5.
97. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B. 1990;6:143–8.
98. Stritt A, Merk HF, Braathen LR, von Felbert V. Photodynamic therapy in the treatment of actinic keratosis. Photochem Photobiol. 2008;84(2):388–98.
99. Braathen LR, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56:125–43.
100. Christensen E, et al. Guidelines for practical use of MAL-PDT in non-melanoma skin cancer. J Eur Acad Dermatol Venerol. 2010;24:505–12.
101. De Berker D, McGregor JM, Hughes BR, British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for the management of actinic keratoses (published correction in Br J Dermatol. 2008;158:873). Br J Dermatol. 2007;156:222–30.
102. Fritsch C, et al. Preferential relative porphyrin enrichment in solar keratoses upon topical application of delta-aminolevulinic acid methylester. Photochem Photobiol. 1998;68(2):218–21.
103. Pariser DM, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol. 2003;48(2):227–32.
104. Togsverd-Bo K, et al. Intensified photodynamic therapy of actinic keratoses with fractional CO2 laser: a randomized clinical trial. Br J Dermatol. 2012;166(6):1262–9.
105. Wiegell SR, Haedersdal M, Philipsen PA, Enk CD, Wulf HC. Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomised, controlled, single-blinded study. Br J Dermatol. 2008;158(4):740–6.
106. Wiegell SR, Haedersdal M, Eriksen P, Wulf HC. Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomised clinical trial. Br J Dermatol. 2009;160(6):1308–14.
107. Dirschka T, Radny P, Dominicus R, et al. 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. 2012;166(1):137–46.
108. Hauschild A, Stockfleth E, Popp G, et al. Optimisation of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies. Br J Dermatol. 2009;160:1066–74.
109. Serra-Guillen C, Hueso L, Nagore E, Vila M, Llombart B, Requena Caballero C, Botell-Estrada R, Sanmartin O, Alfaro-Rubio A, Guillen C. Comparative study between cold air analgesia and supraorbital and supratrochlear nerve block for the management of pain during photodynamic therapy for actinic keratoses of the frontotemporal zone. Br J Dermatol. 2009;161(2):353–6.
110. Halldin CB, Paoli J, Sandberg C, Gonzalez H, Wennberg AM. Nerve blocks enable adequate pain relief during topical photodynamic therapy of field cancerization on the forehead and scalp. Br J Dermatol. 2009;160(4):795–800.
111. Rosen RH, Gupta AK, Tyring S. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 2012;66(3):486–93.
112. Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004;64:2833–9.
113. Siller G, et al. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol. 2009;50(1):16–22.
114. Anderson L, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009;60(6):934–43.
115. Lebwohl M, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010–9.
116. 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.
117. Serra-Guillen C, et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. J Am Acad Dermatol. 2012;66(4):e131–7.
118. Jorizzo JL, et al. A randomized, double-blinded, placebo-controlled, multicenter, efficacy and safety study of 3.75% imiquimod cream following cryosurgery for the treatment of actinic keratoses. J Drugs Dermatol. 2010;9(9):1101–8.
119. Van der Geer S, Krekels GA. Treatment of actinic keratoses on the dorsum of the hands: ALA-PDT versus diclofenac 3% gel followed by ALA-PDT. A placebo-controlled, double-blind, pilot study. J Dermatol Treat. 2009;20(5):259–65.
120. Jorizzo J, Weiss J, Vamvakias G. One-week treatment with 0.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double blind, vehicle controlled, long-term study. J Drugs Dermatol. 2006;5(2):133–9.
121. Gupta AK et al. Interventions for actinic keratoses. Cochrane Database Syst Rev 2012;Issue 12. Art. No:CD004415. doi:10.1002/14651858.CD004415.pub2.
122. Stockfleth E, Kerl H, Zwingers T, Willers C. 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. 2011;165(5):1101–8.
123. Marrero GM, Katz BE. The new fluor-hydroxy pulse peel. A combination of 5-fluorouracil and glycolic acid. Dermatol Surg. 1998;24(9):973–8.
124. Ondo AL, Padilla S, Miedler JD, et al. Treatment-refractory actinic keratosis successfully treated using simultaneous combination topical 5-fluorouracil cream and imiquimod cream: case control study. Dermatol Surg. 2012;38(9):1469–76.
125. Price NM. The treatment of actinic keratoses with a combination of 5-fluorouracil and imiquimod creams. J Drugs Dermatol. 2007;6(8):778–81.
126. Jeffes EW 3rd, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol. 2000;1(3):167–79.
127. Amini S, Viera MH, Valins W, Berman B. Nonsurgical innovations in the treatment of nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2010;3(6):20–34.
128. Weinstock MA, Bingham SF, Digiovanna JJ, Rizzo AE, Marcolivio K, Hall R, Eilers D, Naylor M, Kirsner R, Kalivas J, Cole G, Vertrees JE, Veterans Affairs Topical Tretinoin Chemoprevention Trial Group. Tretinoin and the prevention of keratinocyte carcinoma (basal and squamous cell carcinoma of the skin): a veterans affairs randomized chemoprevention trial. J Invest Dermatol. 2012;132(6):1583–90.
129. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132(5):1497–500.
130. Huyke C, Laszczyk M, Scheffler A, Ernst R, Schempp CM. Treatment of actinic keratoses with birch bark extract: a pilot study. JDDG J Dtsch Dermatologischen Ges. 2006;4:132–6.
131. Campione E, Diluvio L, Paterno EJ, Chimenti S. Topical treatment of actinic keratoses with piroxicam 1% gel: a preliminary open-label study utilizing a new clinical score. Am J Clin Dermatol. 2010;11(1):45–50.
132. Berman B, Amini S. Pharmacotherapy of actinic keratosis: an update. Expert Opin Pharmacother. 2013;13(13):1847–71.
133. Stockfleth E, Ferrandiz C, Grob JJ, et al. Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008;18(6):651–9.