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-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 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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