[LITERATURE
REVIEW]
Actinic Keratosis Update on Field Therapy GARY GOLDENBERG, MD; bMARCEL PERL, MD
a a
Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, New York; b Icahn School of Medicine at Mount Sinai, New York, New York
ABSTRACT Actinic keratosis is widely considered a field disease that is rarely limited to a single clinically apparent lesion. Fielddirected 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 followup 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.)
ctinic 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
A
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.
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. ADDRESS CORRESPONDENCE TO: Gary Goldenberg, MD, Icahn School of Medicine, 1428 Madison Ave, New York, NY 10029; E-mail: [email protected] 28
[October 2014 • Volume 7 • Number 10]
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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
REVIEW]
Actinic Keratosis Update on Field Therapy GARY GOLDENBERG, MD; bMARCEL PERL, MD
a a
Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, New York; b Icahn School of Medicine at Mount Sinai, New York, New York
ABSTRACT Actinic keratosis is widely considered a field disease that is rarely limited to a single clinically apparent lesion. Fielddirected 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 followup 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.)
ctinic 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
A
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.
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. ADDRESS CORRESPONDENCE TO: Gary Goldenberg, MD, Icahn School of Medicine, 1428 Madison Ave, New York, NY 10029; E-mail: [email protected] 28
[October 2014 • Volume 7 • Number 10]
28
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
