Among the most commonly diagnosed skin lesions, actinic keratoses (AKs) are often described as rough, scaly epidermal growths typically less than 1cm in size occurring in clusters on sun-exposed skin such as the face, scalp, and forearms.1 Ahead, we explore the relative benefits of a number of both lesion-directed and field therapies.

Common Treatment Options

Cryotherapy. Cryotherapy is the most common treatment of choice for actinic keratosis. Liquid nitrogen is usually either sprayed or directly placed with a cotton swab to each lesion.2 In a study of more than 1,000 lesions treated with liquid nitrogen using the spray technique, a cure rate of 98.8 percent was achieved with follow-up ranging from one to 8.5 years.3 Duration of spray treatment has a significant effect on cure rates, with one to five seconds of spray treatment associated with a 39 percent cure rate compared to lesions treated for greater than 20 seconds having a 83 percent cure rate.4 Common side effects of cryotherapy include hypopigmentation, hyperpigmentation, scarring, and infection.5

Curettage and Electrodesiccation. Curettage and electrodesiccation is generally preferred for hyperkeratotic actinic keratoses6 and for immunocompromised patients with AKs.7 Side effects are similar to treatment with cryotherapy and include hypopigmentation, hyperpigmentation, scarring, and infection.5

Fluorouracil. Since the 1960s, topical 5-fluorouracil (5-FU) (Efudex, Valeant) has been used to treat AKs and skin cancers. The mechanism of action for 5-FU involves decreased production of thymidylate synthetase leading to a reduction in DNA synthesis and cell death. Topical 5-FU is available as a cream or solution in 0.5% to 5% concentrations. Common side effects of 5-FU include application site reactions such as erythema, pain erosion, edema, and dryness.8,9

Once-daily 0.5% 5-FU cream has been shown to be more effective than twice-daily 5% 5-FU cream over a four-week treatment course.10 Another study found a four-week treatment regimen to be optimal for 0.5% 5-FU.11

One study showed that a one-week treatment duration of 0.5% 5-FU followed by cryotherapy for facial AKs resulted in 30 percent of patients having complete clearance compared to eight percent of patients who received vehicle followed by cryotherapy.12 Another study examined the efficacy of combining 70% glycolic acid with 5-FU showed a 92 percent reduction in the number of actinic keratoses compared to a 20 percent reduction with the chemical peel treatment alone.13

Imiquimod. Topical imiquimod (Aldara) cream acts as a toll-like receptor-7 agonist to strengthen the immune response to destroy abnormal keratinocytes. In 2004, imiquimod 5% cream was approved as a 16-week regimen for the treatment of AKs. Imiquimod 3.75% cream was approved in 2010 for the treatment of AKs on the face and balding scalp, and is now available in a metered-dose pump with 9.4 mg of the active drug dispensed with each pump. One to two pumps are applied once nightly for two weeks of treatment, followed by a two-week rest period, followed by another two weeks of treatment. Imiquimod 3.75% cream offers the advantages of a shorter total treatment duration and the ability to treat a larger area compared to imiquimod 5% cream (200cm2 versus 25cm2, respectively).14

In one study, 35.6 percent of patients treated with imiquimod 3.75% cream on the face or scalp had complete clearance of AK lesions eight weeks post-treatment.15 In another study, 40.5 percent of patients treated with imiquimod 3.75% who had complete clearance eight weeks post treatment maintained complete clearance for an additional 12 months.16

Jorizzo et al., found 59.5 percent of patients whose actinic keratoses were treated with cryotherapy plus imiquimod 3.75% achieved complete clearance of those lesions 20 weeks post-treatment in comparison to 29.8 percent of patients treated with cryotherapy alone.17

Diclofenac. Diclofenac sodium (Solaraze, PharmaDerm) 3% topical gel has been used for more than 10 years to treat AKs. This nonsteroidal anti-inflammatory agent inhibits cyclo-oxygenase 2 (COX-2).18 Upregulation of the COX-2 enzyme is believed to support tumor growth by promoting angiogenesis and inhibiting apoptosis.19 The vehicle for diclofenac includes hyaluronic acid, which helps maintain the active ingredient in the targeted area of the epidermis.20

In a double-blinded study, 195 subjects who had at least five AKs were randomized to receive diclofenac sodium 3% topical gel for 30 days, diclofenac sodium 3% topical gel for 60 days, 2.5% hyaluronan gel for 30 days, or hyaluronan gel for 60 days. All four groups applied 0.5 grams twice daily of their assigned treatment within a total area of 15cm2. At 90-days follow-up, the 60-day treatment arm had a statistically significant reduction of actinic keratoses compared to the 60-day placebo group (4.9 to 2.5, P=0.009). Adverse events for subjects receiving 30 days or 60 days of the active medication included pruritus, paraesthesia, rash, edema, and contact dermatitis.21

A retrospective case series analysis of recurrent AKs after cryotherapy alone, showed combining cryotherapy after a 12-week course of diclofenac sodium 3% topical gel improved clearance rates and reduced recurrence.22

Photodynamic Therapy. Photodynamic therapy (PDT), FDA approved in 1999 for the treatment of nonhyperkeratotic AKs on the face and scalp, involves applying 5-aminolevulinic acid (ALA) or methyl 5-aminolevulinate (MAL) topically. These agents then undergo conversion to a photosensitizer protoporphyrin IX in abnormal keratinocytes. Free radicals are then produced after light activation, which results in targeted tissue destruction.23

In one study, 27 patients with at least three AKs on the face or scalp had ALA applied for four hours. In each patient, separate AKs were randomized to receive different light doses using a filtered high-pressure metal halide lamp. One month post-treatment, the complete clearance rate was 88.5 percent, 92.3 percent, and 80.8 percent for light doses of 70J/cm2, 100J/ cm2, or 140J/cm2, respectively.24 Another study, involving the treatment of 198 actinic keratoses with a single session of MAL-PDT, demonstrated a 93 percent complete response rate for thin lesions and a 70 percent complete response rate for thicker lesions three-months post-treatment.25

Retinoids. As early as the 1980s, there was evidence to support the use of retinoids in the treatment of actinic keratoses. 26,27 A more recent study evaluated the use of the synthetic retinoid, adapalene gel (Differin, Galderma) 0.1% and 0.3%, in comparison to vehicle twice daily for nine months in 83 subjects with a reduction of 0.5 and 2.5 actinic keratoses for the 0.1% and 0.3% formulations, respectively, with an increase of 1.5 actinic keratoses for the group treated with vehicle gel (P<0.05).28

Ingenol Mebutate. Ingenol mebutate (Picato, LEO Pharma) is a natural ingredient found in the sap of the plant Euphorbia peplus. The mechanism of action is two-fold involving cellular necrosis as well as neutrophil-mediated antibody-dependent cellular cytotoxicity of residual cells.29 In a phase IIa, randomized, double-blind, vehicle-controlled study, ingenol mebutate gel 0.05% was applied for two days to actinic keratoses located on the arms, shoulders, face, and scalp with 71 percent (53/75) of these lesions demonstrating complete clearance at day 85. There were no treatmentrelated serious events reported and no patient discontinued because of an adverse event.29 In a phase IIb, randomized, double-blind, vehicle-controlled study, 57.9 percent (33/57) of patients treated with ingenol mebutate gel 0.025% for three days and 43.6 percent (24/55) of patients treated with the ingenol mebutate gel 0.05% for two or three days had complete clearance at day 57 of the non-facial actinic keratoses that were identified and treated at baseline. There were no treatment-related serious events and no patient withdrew because of an adverse event.30 In a study by Lebwohl et al, complete clearance for AKs on the face and scalp treated with ingenol mebutate 0.015% for three days was 42.2 percent at the eight-week follow-up visit.31

T4 Endonuclease Liposome Lotion. T4 endonuclease, a DNA repair enzyme, has been formulated into a liposomal lotion that helps its delivery into keratinocytes. This investigational agent has recently been found to lower the occurrence of AKs in subjects with xeroderma pigmentosa.32

Conclusion

The most compelling reason to effectively treat AKs is to prevent their possible malignant transformation. A multitude of therapies old and new are available, offering clinicians and their patients more options when previous therapies have been ineffective.

Dr. Haddican has no conflicts to disclose. Dr. Goldenberg has served as a consultant or speaker for AbbVie, Bayer, Genentech, LEO Pharma, and Medicis.

  1. Fitzgerald, D.A. Cancer precursors. Semini Cutan Med Surg. 1998;17:108-111.
  2. Lubritz RR. Cryosurgery. Clin Dermatol. 1987;5:120-7.
  3. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol. 1982;7:631–632.
  4. 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;43:687–692.
  5. Mcintyre, WJ, Downs MR, Bedwell SA, Treatment options for actinic keratoses. Am Fam Physician. 2007;76:667-667.
  6. Freeman RG, Knox JM, Heaton CL. The treatment of skin cancer. A statistical study of 1,341 skin tumors comparing results obtained with irradiation, surgery, and curettage followed by electrodesiccation. Cancer. 1964;17:535–358.
  7. Ng J, Chong A, Foley P. Destructive management of skin cancers in organ transplant recipients. Cancer Treat Res. 2009;146:447-460.
  8. Ceilley RI. Mechanisms of action of topical 5-fluoriuracil: review and implications for the treatment of dermatological disorders. J Dermatol Treat. 2012; 23:83-89
  9. 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;48:453–463.
  10. Loven K, Stein L, Furst K, et al . Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther. 2002; 24:990–991.
  11. Jorizzo J, Stewart D, Bucko A, et al . Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis. Cutis. 2002;70:335–339.
  12. Jorizzo J, Weiss J, Furst K, et al. 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. 2004;140:813–816.
  13. Marrero GM, Katz BE. The new fluor-hydroy pulse peel. A combination of 5-fluorouracil and glycolic acid. Dermatol Surg. 1998;24:973-978.
  14. Gupta AK, Cooper EA, Abramovits W. Zyclara (Imiquimod) Cream, 3.75%. Skinmed. 2010;8227-8229.
  15. 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;62:582-590.
  16. Hanke CW, Swanson N, Bruce S, Berman B, Kulp J, Levy S. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp via daily dosing with imiquimod 3.75% or 2.5% cream. J Drugs Dermatol. 2011;10:165-170.
  17. Jorizzo JL, Markowitz O, Lebwohl MG, 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;9:1101-1108.
  18. Buckman SY, Gresham A, hale P, et al. COX-2 expression is induced by UVB exposure in human skin: Implications for the development of skin cancer. Carcinogenesis. 1998;19:723-729.
  19. Subbaramaiah K, Zakim D, Weksler BB, Dannenberg AJ. Inhibition of cyclooxygenase: a novel approach to cancer prevention. Proc Soc Exp Biol Med 1997;216:201-10.
  20. Fecker LF, Stockfleth E, Braun FK et al. Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac/ hyaluronic acid correlates with downregulation of c-FLIP. J Invest Deramatol. 2010;130:2098-2109.
  21. 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. 2003;146:94-100.
  22. Mastrolonardo M. Topical diclofenac 3% gel plus cryotherapy for treatment of multiple and recurrent actinic keratoses. Clin Exp Dermatol. 2009;34:33-35.
  23. Hsi RA, Rosenthal DI, Glatstein E. Photodynamic therapy in the treatment of cancer: current state of the art. Drugs. 1999;57:725–734.
  24. Radakovic-Fijan S, Blecha-Thalhammer U, Kittler H, Honigsmann H, Tanew A. Efficacy of 3 different light doses in the treatment of actinic keratosis with 5–aminolevulinic acid photodynamic therapy: a randomized, observer-blinded, intrapatient, comparison study. J Am Acad Dermatol. 2005;53:823–827.
  25. Tarstedt M, Rosdahl I, Berne B, Svanberg K, Wennberg AM. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)–PDT in actinic keratosis of the face and scalp. Acta Derm Venereol. 2005;85:424–428.
  26. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: a double blind controlled study. Br J Dermatol. 1987;116:549-552.
  27. Peck GL. Topical tretinoin in actinic keratosis and basal cell carcinoma. J Am Acad Dermatol. 1986;15:829–835
  28. Kang S, Goldfarb MT, Weiss JS, et al. Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial. J Am Acad Dermatol. 2003;49:83.
  29. Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM. 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;50:16-22.
  30. Anderson L, Schmieder GJ, Werschler WP, 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;60:934-43.
  31. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010-1019.
  32. Yarosh D, Klein J, O'Connor A, et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet 2001; 357:926-929.