Current Concepts in the Management of Actinic Keratoses

Actinic keratoses (AKs) are characterized by the proliferation of atypical keratinocytes confined to the epidermis (Figure 1) and are induced by UV exposure.1-3 They represent part of the biologic continuum between photodamage and invasive squamous cell carcinoma (SCC).2

Figure. Actinic keratoses are characterized by the proliferation of atypical keratinocytes confined to the epidermis.

AKs are often referred to as a premalignant lesions because of their observed progression into SCC measured at a transformation rate of approximately 0.6% at 1 year and 2.57% over a 4-year time span.4 Ackerman and Mones,2 based on clinical, histologic, cytology, and molecular mutations, concluded that AKs represent a “squamous cell carcinoma, superficial type.” Validating their conclusions regarding the nature of AKs, the recently published guidelines for the treatment of AKs5 concluded that the term that could be applied to AKs was “in situ squamous cell carcinoma, type actinic keratosis.” In some regions or countries, the term solar keratosis is frequently used. Nomenclature aside, the clinician is left with the concept that this superficial malignancy should be treated as it is currently not possible to predict which AK lesion will evolve into invasive SCC.

AKs presenting on a background of photodamage skin are referred to as field cancerization.6 Therapeutic approaches to AKs involve a wide array of treatments ranging from destructive modalities such as cryotherapy, electrodesiccation and curettage, ablative carbon dioxide laser treatments, dermabrasion, and chemical peels to topical field therapies such as 5-fluorouracil (5-FU), imiquimod, ingenol mebutate (IM), diclofenac, and photodynamic therapy (PDT).5

The challenge in treating field cancerization using field therapies has involved reluctance on the part of treating physicians and their patients to undergo treatments that are often lengthy in their downtime due to cosmetically unacceptable side effects that can last weeks to months. Patient adherence with field therapy is often an issue due to these side effects. Treating physicians are often reluctant to prescribe treatments that require an in-office time-consuming pretreatment consultation regarding the side effects that often result in unwanted patient calls and return office visits. Consequently, metrics of prescribing habits of treating physicians demonstrate that more than 90% of patients with diffuse actinic damage who are candidates for a field therapy leave the office following cryotherapy alone without a prescription for a field therapy.7

Challenged by the need to deliver field therapies that maximize efficacy, maintain safety, minimize patient downtime, and improve adherence, new drugs have been developed and current therapeutic regimens have been modified. This article discusses the benefits and limitations of several new approaches using new and established field therapies.

5-Fluorouracil
5-FU is the oldest and most widely used of the commercially available topical field therapies. It has a predictable side effect profile involving the development of erosions and early ulceration of AKs by the end of the first week of treatment. The erosions and ulcerations worsen with continuing treatment beyond 1 week. Most treatment regimens involving the various concentrations of 5-FU require treatments lasting 4 weeks with corresponding AK clearance rates of 80% to 90%.5,8 However, in phase 3 studies involving 2 parallel clinical study groups with a total of 95 patients, 0.5% 5-FU (Carac) and 0.5% 5-FU when applied daily for 1 week resulted in a median reduction of AKs of 78.5% and 69.5%, respectively when measured 30 days posttreatment.9,10

Importantly from a patient adherence issue, the treatment irritation severity level was described as mild and was associated with a shorter recovery period in comparison to the 2- and 4-week study treatment arms whose side effects were described as moderate in severity and had longer treatment durations and recovery times. Thus, it is possible when prescribing 5-FU to avoid lengthy treatment downtimes by using a shorter but still effective treatment period.

Imiquimod
Imiquimod is a toll-like receptor 7 agonist that stimulates the innate arm of the cutaneous immune system.11 Since the development of imiquimod as a field therapy for the treatment of AKs in nonimmunocompromised individuals, its evolution has undergone changes in drug concentrations and dosing regimen frequency and duration. Its introduction in the United States was as a 5% cream applied twice weekly for 16 weeks to actinically damaged skin of the face.12,13 The 5% cream dosing regimen was modified and approved in the European Union as a 3 times weekly application for 4 weeks followed by a 4-week rest period followed by a second cycle of 3 times weekly applications for 4 weeks.8

The most recent step in the dosing evolution of imiquimod in nonimmunocompromised patients involves 2.5% or 3.75% imiquimod cream used once daily during a treatment cycle of 2 weeks on, followed by 2 weeks with no treatment and 2 weeks on, with the cream applied to the entire face and balding scalp.14,15 Individual AK median clearance rates from the pivotal phase 3 trials involving the face and scalp were 80%. However, from an adherence standpoint, cosmetic downtime during and after treatment still remains a significant challenge from a patient perspective and is often in excess of 6 weeks when treating the face.

The next step in the evolution of imiquimod to treat field cancerization may involve its use as a chronic field therapy. It is widely accepted that actinic damaged skin (ie, field cancerization) is a chronic cutaneous disease with the potential to evolve into invasive SCC. Despite this awareness and the chronic nature of AKs, treating clinicians continue to “spot” treat actinically damaged skin using cryotherapy and in the majority of situations underutilize field therapy. Even when field therapies are used, AK recurrence rates post-field therapy are disappointingly high 1-year posttreatment and in the range of 50%.16  

To augment our use of field therapies, patient counselling often involves recommending the use of sunscreen, protective clothing, sun avoidance, the use of a topical retinoid, and oral vitamin B3 (nicotinamide) 500 mg twice a day.5,17,18 While the implementation of these preventive measures is important, active field therapy for treating field cancerization is episodic, usually undertaken only a few times a year, and results in unacceptable recurrence rates.

Ideally a field therapy regimen should include ongoing treatment on a daily or weekly basis. Additionally, it should involve no ongoing patient cosmetic downtime that would interrupt therapy and have an excellent efficacy and safety profile. To that end, a regimen of chronic imiquimod immune stimulation to achieve sustained long-term AK clearance in nonimmunocompromised patients has been studied.16,19 Initial insight into the potential of imiquimod as a chronic field therapy option was provided by a proof of concept study in which 15 patients were treated once weekly with 5% imiquimod for 6 months.19

The treatments were well tolerated and a qualitative reduction in AKs resulted.

Building on the notion that chronic immune stimulation using imiquimod long term (ie, greater than 1 year) could reduce AKs and be well tolerated, a proof of concept study16 was initiated in 30 patients. Immunocompromised and autoimmune disease patients were excluded. The regimen involved an initial application of 3.75% imiquimod daily to the entire face for 1 week. This was followed by a 2-week rest period after which 3.75% imiquimod was applied once weekly to the entire face indefinitely. The patients are being followed clinically and photographically for recurring AKs and skin cancer. It has been observed that patients are experiencing a marked reduction in the incidence of new and recurrent AKs as well as nonmelanoma skin cancer.

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Ingenol Mebutate
IM was initially derived from Eurphobia peplus, a common weed found around the world.20 Development of IM into a commercial product for the treatment of AK led to the development and approval of 2 concentrations of IM: 0.015% applied daily for 3 consecutive days for the treatment of AKs of the face and scalp and 0.05% daily for 2 consecutive days for the treatment of AKs of the trunk and extremities.21 Data from the pivotal trials demonstrated significant and sustained clearance of AKs with little/no issues of hypopigmentation/hyperpigmentation or scarring. The pivotal clinical trials that led to IM’s FDA approval limited the treatment area to 25 cm2. While the efficacy and safety data from these pivotal trials is excellent, the limited approved field treatment area of 25 cm2 has proved to be a stumbling block in treating larger surface areas with the limited quantity of drug approved in the dosing regimen.

This led to the evaluation of the safety and efficacy of 7 concentrations of IM applied for 2 or 3 days in order to determine the maximum tolerated dose when applied to the full face, full balding scalp, or chest (up to 25 cm2). Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Adverse events were mild to moderate, peaking the day after last application and resolving in 2 weeks, with complete clearance rates at 8 weeks of 21.3% and 39.1%, respectively.22

Modifications of the structure of IM led to the development of the IM derivative ingenol disoxate for the treatment of AKs on the face or up to 250 cm2 on the trunk. In a phase 2, randomized, double-blind, vehicle-controlled trial, patients were randomized 1:1:1:1 to ingenol disoxate 0.018%, 0.012%, 0.006% gel, or vehicle for 2 consecutive days. The results showed a reduction in AK count from baseline at week 8 when compared with vehicle for all doses of ingenol disoxate gel (0.018%, 79.0%; 0.012%, 73.4%; 0.006%, 69.7%; and vehicle, 42.3%; P < .001). Local skin responses peaked at day 3 for all doses, rapidly declined, and reached mild levels at week 2. Most adverse events were mild or moderate in intensity, and were most commonly application site pain/pruritus.23

Photodynamic Therapy
PDT requires the presence of a photosensitizer, an activating wavelength of light, and oxygen. Commercially available prodrugs 5-aminolevulinic acid (5-ALA or ALA) and methyl-aminolevulinic acid (MAL), when applied to the skin, bypass the rate limiting step in heme synthesis and result in the preferential accumulation within AKs of the photosensitizer protoporphyrin IX (PpIX). PpIX can be activated by selective wavelengths of light resulting in PDT. ALA-PDT, using a 20% ALA solution (Levulan), was FDA approved for the treatment of AKs in the United States in 2000.24 MAL-PDT, using a 16.8% MAL cream (Metvix), was FDA approved in the United States. Although it is no longer marketed in the United States, it is widely used throughout Europe and other areas of the world.25,26 Recently, a 10% ALA gel (Ameluz), utilizing a nano-emulsion technology to deliver ALA into the skin, was FDA approved in the United States.27,28

Twenty percent ALA-PDT has undergone an evolution in both incubation and blue light exposure times since its pivotal trials to make it more convenient,29,30 and also to decrease the treatment associated pain.31,32

The FDA approved protocol involves ALA application to the skin of the face or scalp followed by a 14- to 18-hour incubation followed by blue light activation. The inconvenience of a 14- to 18-hour incubation led to more convenient shorter incubation periods between 1 and 3 hours.29,30 A recent publication examined the safety and efficacy of the shorter incubation periods.33 Individual AK median clearance rates of 35.7% (1-hour incubation), 50% (2-hour incubation), and 56.3% (3-hour incubation) were reported following 1 treatment. A second treatment 8 weeks later resulted in a 78.6%, 76.5%, and 80% median reduction in AKs for the 1-, 2- and 3-hour incubation periods.

The researchers concluded that 2 treatments separated by at least 8 weeks are required in the majority of patients in order to achieve clearance rates in the 80% range. Despite the shortening of the incubation periods, more than 60% of patients experienced moderate/severe pain during the procedure.33

Thus, while shortening the incubation periods resulted in greater patient and physician convenience, the procedure still remained quite painful.

The concept that PDT could be made painless originated from the practice of daylight-mediated PDT.34 Daylight-mediated PDT was developed as a method for using sunlight as the activating light source. This minimizes the time patients spend for in-office treatments, limits crowding of waiting rooms, limits PDT’s use of treatment rooms and staff, and eliminates the need to purchase expensive light sources. The treatment involves applying MAL, incubating in the office for 30 minutes prior to applying sunscreen, and walking outdoors for 90 or 150 minutes. The study showed a mean AK clearance rate of 75% for both exposure times when measured 3 months later. Importantly, more than 90% of the study patients treated experienced little or no discomfort during the daylight-mediated PDT.

The scientific rationale provided to explain the lack of pain during daylight-mediated PDT is that the shortened incubation period prior to light activation does not permit the accumulation of PpIX inside the targeted AK cells. It is postulated that accumulated intracellular PpIX has the potential to diffuse into surrounding tissue containing cutaneous nerves which become inflamed during light activation.34,35

While the development of daylight-mediated PDT provides many advantages, its use is restricted by weather conditions. This and other limitations led to the development of in-office painless PDT.31 This method invokes the same concept that shortened incubation periods prior to light activation minimizes the accumulation of PpIX in the target tissue and hence the ability of PpIX to diffuse into surrounding tissue and inflame cutaneous nerves during PDT. The protocol involves a 15-minute incubation using a 20% ALA solution followed by continuous blue light activation for 60 minutes. Split face studies involving 3 patients confirmed equivalent AK clearance for 15- vs 75-minute ALA incubation of approximately 50%; however, pain scores for the 15-minute incubation were 0/10 vs 7/10 for the 75-minute incubation. Clinical experience using this protocol in more than 100 patients during 121 painless procedures, many involving 7 to 10 days of pretreatment with 5-FU or imiquimod, validated the painless nature of the protocol. Additional studies are needed to optimize both incubation times and light exposure duration and intensity. A comprehensive review of PDT can be found in a recent consensus paper.32

The recent FDA approval of a novel formulation of 10% ALA in a nano-vesicle formulation (Ameluz) has provided an additional PDT option.27,28 The application protocol involves lightly abrading the lesion, applying the gel and letting it dry for 10 minutes and covering it with a light blocking dressing, incubating for 3 hours, and activating with an approved red light source (RhodoLED).27 The pivotal phase 3 trials demonstrated more than 80% and 90% median individual lesion clearance following 1 and 2 PDT treatments, respectively.27

Additionally, in a comparator trial with MAL,28 the 10% ALA gel demonstrated equivalent efficacy to MAL following 1 or 2 PDT treatment sessions using both narrowband and broadband light sources. In both protocols, nearly 50% of patients experienced severe erythema, edema, and pain. The likely next step to reduce treatment discomfort is to evaluate the 10% ALA gel using both daylight mediated and in-office painless PDT protocols.

In summary, the evolution of new therapeutic protocols involving currently available field therapies along with the development of new field therapies for the treatment of AKs has led to increased patient convenience and compliance while maintaining efficacy and safety.

Dr Martin is in private practice in Kihei, HI.

Disclosure: Dr Martin in a consultant, speaker, on the ad board of Ortho Dermatologics, LLC (formerly Valeant) and DUSA Pharmaceuticals, Inc, he is a consultant for Aqua Pharmaceuticals, and is on the ad board for LEO.

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34. Weigell, SR, Fabricius, S, Stender LM, et al. A Randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol. 2011;164(5):1083-1090.
35. Wiegell SR, Wulf HC, Szeimies RM, et al. Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology. J Eur Acad Dermatol Venereol. 2012;2(6):673-679.