Aesthetic Medicine Chest

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.

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