Actinic Keratosis: Current Therapies and Insights Into New Treatments

May 2019 | Volume 18 | Issue 5 | Supplement Individual Articles | 161 | Copyright © May 2019

Peter W. Hashim MD MHS,a Tinley Chen BA,a Darrell Rigel MD,c Neal Bhatia MD,e Leon H. Kircik MDa,b,d

aThe Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY bIndiana University School of Medicine, Indianapolis, IN cRonald O. Perelman Department of Dermatology, NYU School of Medicine, New York, NY dPhysicians Skin Care PLLC, Louisville, KY eTherapeutics Clinical Research, San Diego, CA

The duration of freezing is tied to treatment efficacy. In a prospective study of 90 patients with a total of 421 AKs, the overall clearance rate at 3-month follow-up was 67.2% [SEM = +/-3.5%; 95% confidence interval (CI) = 60.4–74.1%], and longer freeze times were associated with improved responses.29 A clearance rate of 39% was achieved in lesions treated with a freeze time 5 seconds, and 83% with a freeze time >20 seconds. However, longer durations of freezing may result in greater discomfort and risks of localized cutaneous reactions, such as hypopigmentation.

Surgical Management

Surgical therapies, such as shave excision or curettage with electrodessication, are typically reserved for hyperkeratotic lesions. The advantage of acquiring a histopathologic specimen (eg, when concern arises for SCC) must be weighed against the increased risk of scarring.Dermabrasion has also been used to treat actinic damage, most commonly on the forehead or bald scalp.30 The technique utilizes a handheld device to manually abrade the skin and remove affected epidermal cells. In a study of 23 patients, dermabrasion led to 96% clearance at 1-year post-treatment, with clearance rates diminishing to 54% at 5 years post-treatment.31 Wide areas of actinic damage can be covered with the technique, but pain control measures are commonly required.

Photodynamic Therapy

Photodynamic therapy (PDT) is based on the application of a photosensitizer to the treatment area, exposure to a particular wavelength of light, and the resulting formation of oxygen species that are toxic to atypical keratinocytes. The most commonly used photosensitizers are 5-aminolevulinic acid (ALA) and, outside the US, methyl aminolevulinate (MAL). These agents serve as precursors to protoporphyrin IX, which accumulates in the target cells during the incubation period. When exposed to the appropriate wavelength of light, protoporphyrin IX transforms into reactive oxygen species, resulting in apoptosis of the neoplastic cells. Protoporphyrin IX has absorption peaks at 404–420 nm (blue light) and 635 nm (red light), which is the basis for the light sources used in treatment regimens with ALA and MAL, respectively.32 The phototoxic reaction of PDT is associated with the local skin reactions of erythema, crusting, burning, and/or pruritus, which typically resolve within 10 days.There are many regimens for treatment with PDT, including variations on the incubation time of the photosensitizer. The ideal conversion of exogenous porphyrins to protoporphyrin IX occurs after two hours of incubation, and efficacy studies have supported at least a two-hour incubation period for optimal lesion reduction.33

Daylight PDT

In contrast to conventional PDT, daylight PDT utilizes ambient visible light in order to activate the photosensitizer. Prior to treatment, an organic, broad-spectrum sunscreen is applied to all sun-exposed areas. MAL cream is then applied to the treatment area, and the patient is exposed to daylight within 30 minutes. The duration of daylight exposure is typically 2 hours, during which protoporphyrin IX and ROS are formed.34 Afterwards, the MAL cream is rinsed off to avoid further phototoxic reaction, and patients are instructed to spend the remainder of the day indoors.Daylight PDT has demonstrated favorable comparisons to conventional PDT in clinical trials.35,36 In an Australian study of 100 subjects with AKs of the face and/or scalp, subjects underwent a single treatment of both daylight PDT and conventional PDT using a split-face design.36 At 12-week follow-up, the clearance rate of mild lesions with daylight PDT was non-inferior to conventional PDT (89.2% vs 92.8%, respectively; 95% CI -6·8 to -0·3). However, pain scores were significantly lower with daylight PDT relative to conventional PDT (0.8 vs 5.7 on a 10-point scale; P less than .001).Similar outcomes were observed in a European split-face study of 108 subjects with AKs of the face or scalp, during which subjects underwent a single treatment with both daylight PDT and conventional PDT.35 At 12-week follow-up, the response rate with daylight PDT was non-inferior to conventional PDT (70% vs 74%, respectively; 95% CI [-9.5; 2.4). Importantly, daylight PDT was effective in both sunny and cloudy conditions and was associated with better pain scores than conventional PDT (0.7 vs 4.4 on a 10-point scale; P less than .001).


Imiquimod is a toll-like receptor-7 agonist that causes the activation of several cellular proteins, including nuclear factor-kappa B (NF-?B).37 Increases in NF-?B lead to the release of pro-inflammatory cytokines and induction of the innate and cellular immune response. This heightened immune response is directed against antigens expressed by atypical keratinocytes, leading to lesion destruction where imiquimod has been applied.Topical imiquimod originally came to market as a 5% cream, which is applied twice weekly for up to 16 weeks. In a meta-analysis of 5 trials involving 1293 subjects, complete clearance was achieved in 50% of patients.38 The most common adverse events were erythema (27%), scabbing or crusting (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%). In addition to local skin irritation, imiquimod may also produce