Actinic Keratosis: Update on Field Therapy

| October 1, 2014
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Gary Goldenberg, MD; Marcel Perl, MD
Dr. Goldenberg is from Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, New York; Dr. Mercel is from Icahn School of Medicine at Mount Sinai, New York, New York

Disclosure: Dr. Goldenberg is an investigator for, a consultant for, and receives honoraria from Leo, Valeant, and PharmaDerm. Dr. Perl reports no relevant conflicts of interest.

Abstract
Actinic keratosis is widely considered a field disease that is rarely limited to a single clinically apparent lesion. Field-directed therapies, such as ingenol mebutate, imiquimod, and photodynamic therapy, aim to treat not only clinically visible lesions, but also subclinical disease that is thought to exist along the same continuum as actinic keratosis and squamous cell carcinoma. These field treatments have shown efficacy compared to placebo as well as in long-term follow-up studies when compared to lesion-directed cryotherapy alone. Field therapy in combination with lesion-directed treatment will allow the practitioner to further optimize efficacy as well as patient preference and convenience. As the incidence of nonmelanoma skin cancer continues to rise, these treatment modalities provide new options to halt the progression of actinic keratosis, and thereby reduce the incidence of nonmelanoma skin cancer and its burden on our healthcare system.  (J Clin Aesthet Dermatol. 2014;7(10):28–31.)

Actinic keratoses (AKs) are common cutaneous lesions associated with chronic exposure to ultraviolet (UV) radiation. AK presents as a scaly, erythematous papule or plaque and is considered the earliest clinically recognizable manifestation of squamous cell carcinoma (SCC) that is capable of transforming into squamous cell carcinoma in situ and invasive squamous cell carcinoma.[1–4]  Fair skin, cumulative sun exposure, immunosuppression, and age increase the risk of AK.[5,6] AK is the second most common diagnosis seen by dermatologists in the United States, with the direct cost of therapy estimated at more than $1 billion per year with indirect costs nearing $300 million.[7]  The prevalence of AK was reported at 11 to 25 percent in 20081 with 5.2 million patient visits occurring annually for AK during the period 2000 through 2003.[8]

Historically, AK was considered a distinct, pre-malignant lesion. In recent years, however, more evidence is accumulating that AKs are part of a continuum of disease, on a spectrum between subclinical photodamaged skin and SCC.[4] Indeed, molecular analyses have revealed that AK and SCC have a similar genetic profile, including alterations in p53, p16INK4a, MYC, and epidermal growth factor receptor.[2,4,9] The risk of progression of AK to SCC (invasive or in situ) is considered to be low, but highly variable.[10] The risk of developing SCC increases with the number of AKs, with a relative risk of one percent in individuals with five or fewer AKs compared to 20 percent among patients with greater than 20 lesions.[1,9,11] Additionally, 60 percent of SCCs were shown to arise from prior AKs, with other estimates ranging from 25 to 80 percent.

Thus, a small proportion of AKs will progress to SCC, but currently it is not possible to predict which lesions will progress and which will not. There are no distinct clinical boundaries between AK and invasive SCC, and we know that there is high inter-observer variation among experienced dermatologists.[1,11,12] SCC has a metastatic risk of two to five percent to regional lymph nodes or more distant sites.[13,14] It is accepted that the presence of AK is a biomarker of risk for SCC, and while histologically there is usually clear differentiation, AK must be treated to avoid possible morbidity and mortality associated with SCC.[1,3]

Treatment Options
AKs are largely treated, and there are many options available. The selection of treatment reflects many considerations, including distribution, number and thickness of lesions, as well as past history of treatment and recurrence. Patient preference with respect to convenience of therapy, tolerance of side effects, and treatment cost are critical considerations. Lesion-directed treatments include cryotherapy, laser therapy, curettage, and dermabrasion. Efficacy is variable and depends on technique; cryotherapy has no standard guidelines for use, and clearance rates of 39 to 98.8 percent have been reported.[15] One prospective, multicenter study (n=90) found that longer freeze duration increased response to therapy.[16] Complete response at three months was 39 percent for freeze times of five seconds or less, 69 percent for five seconds or more, and 83 percent for freeze times of 20 seconds or longer.

Field-directed Therapy
AK is widely considered a field disease that is rarely limited to a single clinically apparent lesion.[2] Field-directed therapy aims to treat not only clinically visible lesions, but also subclinical lesions within the treatment area, lesions thought to exist along the same continuum as AKs and SCCs.

Imiquimod. Topical imiquimod cream acts as a toll-like receptor-7 agonist and inhibits tumor proliferation by modifying the immune response and promoting apoptosis. A meta-analysis of five randomized trials found that imiquimod 5%, applied two to three times weekly for 12 to 16 weeks, demonstrated complete clearance of AKs in 50 percent of patients.[17] A more recent 3.75% formulation was approved for the treatment of AKs on the entire face or balding scalp, with daily application for two two-week treatment cycles (“2 weeks on, 2 weeks off, 2 weeks on”). In a randomized trial following this regimen, 3.75% imiquimod demonstrated complete clearance in 36 percent of patients, compared to six percent under placebo.[18]

Two studies assessed the efficacy of imiquimod 3.75% and cryotherapy. In a randomized, multicenter study, patients with 10 or more AKs received cryotherapy and applied either 3.75% imiquimod (n=126) or placebo cream (n=121) to the entire face daily for two two-week cycles.19 Median AK reduction (86.5% vs. 50%, p<0.0001) and complete clearance (30.2% vs. 3.3%, p<0.0001) of the treatment area were greater in the cryotherapy/imiquimod versus the cryotherapy/placebo group. When assessing only individual lesions treated with cryotherapy, median AK reduction (100% vs. 80%, p=0.0008) and complete clearance (59.5% and 29.8% p< 0.001) remained higher in lesions treated with both cryotherapy and imiquimod.

A trial of 20 patients assessed cryotherapy and imiquimod for treatment of multiple hypertrophic AKs.[20] Following cryotherapy, the subjects were randomized to apply imiquimod 3.75% cream for two two-week cycles to either upper extremity, with the opposite extremity undergoing cryotherapy alone. Combination therapy resulted in significant reduction of hypertrophic AKs at the eight-week follow-up compared to cryotherapy alone (P<0.0094).

Ingenol mebutate. Ingenol mebutate, approved for the treatment of AK in January 2012, induces necrosis and produces a neutrophil-mediated, antibody-dependent cellular cytotoxicity (ADCC) of residual disease cells.[21–23] This dual mechanism of action causes rapid lesion necrosis taking place over the course of hours, followed by ADCC, whose lasting effect allows for short duration of therapy.[24] Perhaps most importantly, this short duration of treatment may not only decrease the burden of treatment, but also improve patient adherence.
Ingenol mebutate offers patients field treatment in two or three days depending on distribution and was evaluated in four multicenter, randomized trials.[25] Two of these studies (combined n=547) compared the 0.015% formulation of ingenol mebutate to vehicle gel when applied daily for three days to a 25cm2 area of face and scalp. Ingenol mebutate demonstrated higher complete (42.4% vs. 3.7%, p<0.001) and partial (63.9% vs. 7.4%, p<0.001) clearance rates compared to vehicle. The two studies (n=458) comparing 0.05% ingenol mebutate to vehicle applied for two days to a 25cm2 area of trunk and extremities showed higher complete (34.1% vs. 4.7%, p<0.001) and partial (49.1% vs. 6.9%, p<0.001) clearance rates in subjects treated with ingenol mebutate.

Ingenol mebutate was also assessed in combination with cryotherapy.[26] Three weeks following cryotherapy, subjects were randomized to apply vehicle (n=162) or 0.015% ingenol mebutate (n=167) daily for three days. Ingenol mebutate gel significantly improved complete clearance versus vehicle gel at 11 weeks (60.5% vs. 49.4%, p=0.04) and 12 months (30.5% vs. 18.5%, p=0.01). Treatment with ingenol mebutate was well-tolerated with no related adverse effects at 12 months.

Photodynamic therapy. Photodynamic therapy (PDT) is United States Food and Drug Administration (FDA) approved for lesion-directed therapy, but is used as a field therapy by most dermatologists off-label. PDT utilizes a topical photosensitizer, such as aminolevulinic acid (ALA) or methyl-aminolevulinate (MAL), to produce reactive oxygen species that mediate selective destruction of abnormal cells.[27,28] PDT with ALA, for treatment of AKs on the face and scalp, was assessed in a trial using shorter, potentially more convenient incubation times than previously indicated.[29] Subjects were randomized to one of five groups; ALA for one, two, or three-hour incubation followed by broad-area PDT, vehicle only with broad-area PDT, or two-hour incubation with ALA followed by PDT for spot treatment only. Subjects were evaluated at 8, 12, and 24 weeks for AK reduction of clinical, but not subclinical lesions, with treatment repeated at Week 8 if AKs remained. Pre-treatment with ALA was found to have similar efficacy for the one-hour (78.6%), two-hour (76.5%), and three-hour (80.0%) incubation times, with all ALA study arms superior to vehicle (7.1%) at the primary 12-week endpoint. Additionally, a higher proportion of patients treated with broad-area treatment versus spot treatment remained clear from Week 12 to Week 24.

A randomized trial of PDT, comparing pre-treatment with ALA to vehicle, also assessed the effect of occlusion on efficacy.[30] Subjects were randomized to apply ALA or vehicle to both dorsal hands/forearms, with each subject placing one extremity under occlusion for three-hour incubation prior to blue light PDT. At 12 weeks, the median clearance rate was 88.7 percent for extremities treated with ALA under occlusion, 70.0 percent for ALA without occlusion, 16.7 percent for vehicle under occlusion, and 5.6 percent for extremities treated with vehicle without occlusion. These findings confirmed the efficacy of PDT and elucidated a potentially important role for occlusion. The safety profile in this study was favorable and consistent with previously reported side effects of the therapy.[31]

Long-term follow-up studies are important since AK is a chronic disease. A 12-month study of patients who initially achieved complete clearance with ingenol mebutate at eight weeks found sustained clearance rates of 46.1 percent (face or scalp, 0.015% formulation, n=100) and 44.0 percent (trunk or extremities, 0.05% formulation, n=71) at one year.[32] Long-term follow-up of patients who showed initial clearance with imiquimod 5% (n=26), 5-fluorouracil (n=24), and cryosurgery (n=25), found sustained clearance of treatment field in 73, 33, and 4 percent of subjects, respectively (p<0.01).[33] Lastly, among patients who showed complete clearance three months after initial PDT with BF-200 ALA  (Biofrontera Bioscience GmbH, Leverkusen, Germany) (n=192), 59.2 percent were found to have sustained clearance of the treatment area at 12-month follow-up.[34]

While the discussed treatments show variable long-term efficacy, significant recurrence is nonetheless evident with all treatment modalities. Observation and maintenance is burdensome for patients and healthcare alike, magnifying the importance of such factors as duration, convenience, and efficacy of treatment, not only in adherence to therapy in the short term, but as part of long-term follow-up as well. As the incidence of nonmelanoma skin cancer (NMSC) continues to rise,2 these new treatment modalities provide new options to halt the progression of AK, and thereby reduce the incidence of NMSC and its burden on our healthcare system.

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