Journal of the Dermatology Nurses' Association:
Actinic Keratosis: A Review of Therapeutic Options
Berlin, Joshua M.
Joshua M. Berlin, MD, Dermatology Associates PA of the Palm Beaches, Boynton Beach, FL.
The author declares no conflicts of interest.
Correspondence concerning this article should be addressed to Joshua M. Berlin, MD, Dermatology Associates PA of the Palm Beaches, 10301 Hagen Ranch Rd., Ste. D-930, Boynton Beach, FL, 33437. E-mail: firstname.lastname@example.org
ABSTRACT: Actinic keratoses are some of the most widely encountered lesions in dermatology practices. They represent the second most common reason for patients to visit a dermatologist. There are many different approaches available to treat actinic keratoses, and the dermatology nurse plays a pivotal part in educating patients about their choices. The purpose of this article is to review how these different treatments work and to address potential advantages and disadvantages of each.
In most dermatology practices, patients present with precancerous actinic keratosis on a daily basis. The dermatology nurse plays an important role in helping to explain to patients the various treatment options available. This article will review the mechanism of action as well as some of the comparative advantages and disadvantages associated with these treatments.
Cryotherapy with the use of liquid nitrogen is one of the most common methods of treatment for actinic keratoses. Liquid nitrogen can be applied either via a cryospray, cryoprobe, or cotton tip. When liquid nitrogen makes contact with the skin, the temperature of the treated area is lowered to −50°C. The mechanism of action involves direct cellular freezing as well as vascular stasis occurring after thawing. The duration of freezing time for actinic keratosis is dependent on the morphology of the particular lesion with thicker hyperkeratotic lesions requiring up to 30 seconds of treatment and thinner lesions being eradicated after a 5- to 7-second freeze time. Cryotherapy is extremely effective with cure rates of up to 98% being achieved (Lubritz & Smolewski, 1982). It is important to advise patients that they will likely feel mild pain while the procedure is performed and will be left with erythema, crust formation, and even blister formation in some instances. A potential long-term sequelae is hypopigmentation of the skin, which can be especially prevalent in darker complected individuals. An important limitation of cryosurgery to convey to patients is that it only treats discrete lesion and not subclinical actinic keratosis, which can be found in wide photodamaged areas. Less common destructive measures to treat actinic keratoses include curettage, medium-depth chemical peels with 35% trichloroacetic acid and Jessner’s solution, and ablative lasers such as the carbon dioxide and erbium:yttrium-aluminum-garnet laser.
In contrast to cryotherapy, topical therapies have the advantage of not only treating individual lesions but also treating the subclinical areas of sun-damaged skin that are not yet apparent. A hallmark of topical treatment for actinic keratoses for the past 50 years has been 5-fluorouracil (5-FU). The mechanism of action involves its ability to interfere with the synthesis of nucleic acids through its metabolite, 5-fluorodeoxyuridylic acid, which inhibits thymidylate synthase (Menter, Vamvakias, & Jorizzo, 2008). This inhibition is significant as thymidylate synthase catalyzes conversion of deoxyuridine 5-monophosphate to the deoxyribonucleic acid (DNA) compound thymidine 5-monophosphate (Eaglestein, Weinstein, & Frost, 1970). By interfering with DNA synthesis, 5-FU clears actinic keratoses as these lesions have neoplastic keratinocytes that have a higher rate of DNA synthesis than normal skin. Another proposed mechanism of action involves the incorporation of fluorouracil into ribonucleic acid, which interferes with ribonucleic acid synthesis (Eaglestein et al., 1970).
There are a variety of regimens employed by dermatologists to use 5-FU in the management of actinic keratoses. One of the most commonly used methods is continuous once- or twice-daily application over a period of 2–3 weeks. The efficacy associated with 5-FU has been reported up to 75% (Kurwa, Yong-Gee, Seed, Markey, & Barlow, 1999). Major limitations associated with this treatment are complaints of erythema, pruritus, and pain. These troublesome adverse events often result in premature discontinuation of the product or noncompliance, which affects efficacy of clearance. In addition, crusting and scabbing of the skin can occur in the immediate posttreatment period adversely affecting the patient’s cosmetic appearance. The resulting noncompliance stresses the importance of dermatological nursing education at the time of prescribing the product, either through verbal explanation, photographs of patients during treatment and posttreatment, or written handouts for patients to review and decide if the treatment is appropriate for their lifestyle.
Imiquimod 5% cream was initially approved by the U.S. Food and Drug Administration in 1997 for the treatment of external genital and perianal human papillomavirus infection (Berlin, 2010). It subsequently gained approval for the treatment of nonhyperkeratotic, nonhypertrophic actinic keratoses in 2004. The finding of human papillomavirus DNA in 60.4% of actinic keratoses versus 4.7% in controls in a study by Iftner et al. helps explain its effectiveness in both of these disease states (Iftner et al., 2003). In addition, imiquimod activates innate immune cells through the toll-like receptor 7 pathway, which increases cytokine production (Gaspari, 2007). When applied, imiquimod functions as an immunomodulator. Specifically, lesional levels of interferon alpha, beta, and gamma are increased along with lesional levels of tumor necrosis factor alpha. These and other cytokines activate natural killer and cytotoxic T-cells resulting in a localized immune response against the target cells (Weinberg, 2006). Although imiquimod 5% cream has shown a median reduction in precancerous lesions as high as 86% compared with baseline, it is accompanied with adverse events such as scabbing, erythema, and flaking in as many as 73% of patients (Korman et al., 2005). Given these high rates of side effects, a study was performed to examine the efficacy at a lower strength of 3.75% in an attempt to mitigate adverse events in patients (Swanson et al., 2010). In this study, patients were treated with a once-daily application cyclically for 2 weeks followed by a 2-week period of rest and concluded with an additional 2-week treatment period. The results found comparable efficacy with an 81.8% median reduction in lesion count with a lower degree of adverse events. This cyclical regimen is presently how it is most commonly prescribed under the brand name of Zyclara cream (Valeant Pharmaceuticals). In choosing this type of therapy, it is important to ensure the 6-week cycle is compatible with a patient’s lifestyle. As mentioned above, erythema, edema, crusting, and scabbing are common side effects of topical imiquimod therapy. As with most topical medications, it is important that the patient be instructed in proper application techniques to ensure proper use and decrease the likelihood of adverse events. The dermatology nurse should be proficient in relaying the expected and adverse effect of using this modality. In addition to the local cutaneous side effects, the nurse should also inform the patient that topical imiquimod therapy has also been associated with generalized flu-like symptoms including malaise, fever, and headache.
Diclofenac sodium available commercially as Solaraze Gel is a nonsteroidal anti-inflammatory agent whose mechanism of action involves its ability to inhibit cyclooxygenase (COX)-2 (Merk, 2007). The COX-2 enzyme is oversynthesized in actinic keratoses and catalyzes the synthesis of prostaglandins. The resulting inhibition of COX-2 decreases the byproducts of arachidonic acid and thereby hinders tumor angiogenesis (Weinberg, 2006). An initial study by Rivers and McLean assessed the efficacy of diclofenac sodium in hyaluronic acid in a study of 27 patients (Rivers & McLean, 1997). This study showed compelling results with a complete response found in 81% of patients at 1 month. Because of these findings, a larger randomized, double-blind placebo-controlled study was undertaken by Wolf et al. In this study, 96 patients with at least five discrete actinic keratoses located on the face, scalp, arms, or hands were treated with either the inactive gel vehicle, hyaluronic acid, or diclofenac sodium in hyaluronic acid twice daily for 90 days (Wolf, Taylor, Tschen, & Kang, 2001). The authors found that 79% of patients reported complete or partial clearance of actinic keratoses in patients receiving diclofenac sodium in hylaruronic acid. The medication is reasonably well tolerated with less erythema and crusting noted than with other topical medications. A subsequent study investigated the use of diclofenac sodium in hyaluronic acid to treat actinic keratoses after cryosurgery (Berlin & Rigel, 2008). The purpose of this study was to see if sequential therapy led to a higher overall cure rate than that seen with each individual therapy. The authors concluded that a synergistic effect occurred with the combination of cryotherapy followed by diclofenac sodium in hyaluronic acid as the mean number of target lesions reduced from 8.9 to 1.1. A postulated reason for the synergy between these two treatment regimens is that both clinically apparent actinic keratoses as well as subclinical lesions can be treated. An important drawback about this therapy to discuss with patients is the twice-a-day dosing regimen over 2 months.
Compared with many of the other topical treatments for actinic keratoses, topical diclofenac sodium has a rather mild initial cutaneous response. For this reason, it is important for the dermatology nurse to be able to educate the patient on the expected treatment course. This is especially important in patients who may have used 5-FU in the past and are expecting a similar reaction. These patients are more likely to discontinue therapy prematurely because they do not think that the medicine is working. It is often just as important for the nurse to tell the patient what not to expect as it is to tell the patient what to expect.
One of the most recent treatments available to treat actinic keratoses is ingenol mebutate available commercially as Picato gel. This new treatment is purified and extracted from the sap of the plant Euphorbia peplus, and its mechanism of action involves its ability to cause cellular necrosis through disruption of the plasma membrane and mitochondria (Ogbourne et al., 2004). In addition, ingenol mebutate stimulates neutrophil-mediated and antibody-dependent cellular cytotoxicity to eradicate any residual diseased cells (Challacombe et al., 2006).
A recent study examined the 12-month recurrence rates associated with patients treated with ingenol mebutate gel 0.015% daily for 3 consecutive days for actinic keratoses on the face or scalp and ingenol mebutate gel 0.05% daily for 2 consecutive days for actinic keratoses on the trunk or extremities (Lebwohl et al., 2013). The authors found that sustained lesion reduction rates compared with baseline were 87.2% for the face or scalp and 86.8% for the trunk or extremities.
The convenient once-daily dosing for 2 days for the trunk and extremities and 3 days for the face and scalp makes this therapeutic agent a favorite of many patients.
With ingenol mebutate, patient education and instruction is especially important. Currently, ingenol mebutate is approved to treat an area of 5.0 cm × 5.0 cm. The medication is dispensed in two or three single-use tubes, depending on the area to be treated as described above. The dermatology nurse must be able to educate the patient on the importance of using the entire contents of the tube, but only in the assigned treatment field. The patient who attempts to treat an entire scalp or arm will likely end up with an inadequate therapeutic effect. Ingenol mebutate, like most of the other topical treatments for actinic keratoses, is associated with significant erythema, edema, crusting, and scabbing. Again, patient education is the key to maximizing the patient’s therapeutic response while minimizing any adverse events.
PHOTODYNAMIC THERAPY (PDT)
The use of topical 5-aminolevulinic acid (5-ALA) in combination with either blue light (400–450 nm) or red light (640 nm) has become an increasingly popular choice for patients and physicians alike in the treatment of actinic keratoses. It was initially approved by the U.S. Food and Drug Administration for the treatment of nonhyperkeratotic actinic keratoses in 2000 (Gold, 2008; Zheng, 2005). After application, 5-ALA penetrates the stratum corneum and is absorbed by actinic keratoses, pilosebaceous units, and nonmelanoma skin cancer cells (Gold, 2008). Once the prodrug 5-ALA is absorbed, it is converted into its active drug, protoporphyrin IX, which can be detected in the epidermis 4 hours after application (Peng et al., 1997). The active drug can then peakly absorb with exposure to either blue light, known as the Soret band, or red light (Tschen, et al., 2006). Once activated, reactive oxygen intermediates such as singlet oxygen are created that result in apoptosis and vascular endothelial damage (Kennedy, Pottier, & Pross, 1990). Studies have shown lesion cure rates ranging from 70% to 90% (Jeffes et al., 1997). In general, the face and scalp respond better than the trunk and extremities with thinner actinic keratoses showing improved clinical outcomes compared with thicker, hyperkeratotic lesions (Jeffes et al., 2001). Three majors factors affecting the efficacy of PDT are light fluence, tissue oxygen tension, and thickness of the stratum corneum (Silapunt, Goldberg, & Alam, 2008). A study by Robertson and Rees in 2010 showed significant variations in the thickness of the stratum corneum layers of the face and forearm, 6.3 and 10.9 micrometers, respectively. The thicker stratum corneum of areas on the arms and trunk may inhibit the penetration of ALA further into the epidermis and attenuate its therapeutic efficacy.
Before starting a patient on PDT, it is important to exclude patients with a history of hepatic diseases, photosensitivity disorders, or porphyria as well as elucidating any prior history of herpes simplex virus. In patients with a history of herpes simplex virus flaring with ultraviolet light exposure, prophylactic antiviral therapy should be initiated before therapy.
Before initiating PDT, it is important to document the lesions being treated, and preoperative photography can be useful to assess the final result. Although the technique was initially approved with application of the photosensitizer 14–18 hours before exposure to the light source, most practitioners apply the 5-ALA 1–3 hours before irradiation to reduce the associated pain experienced by patients. In addition, most patients note feelings of warmth or a burning sensation when exposed to the light source that can be mitigated with fans and use of ice packs. At the conclusion of treatment, the irradiated area will appear edematous and erythematous. Although the pain level is dramatically decreased when the light source is turned off, some patients may require postoperative pain control with the use of nonsteroidal anti-inflammatory agents or acetaminophen. The phototoxic effects of PDT, including pain, burning, itching, crusting, erythema, and blisters, are considered normal and desired effects of the therapy. These effects may take several weeks to fully resolve, but pain medication is only typically needed for 7–10 days after procedure. Postprocedure sun and/or light exposure can make these effects considerably worse. Therefore, it is imperative that the dermatological nurse stress the importance of avoiding sun exposure and exposure to strong artificial light sources for at least 48 hours after treatment. As total sun or light avoidance may be impractical for many patients, it is important to instruct the patient on the proper use of sunscreens (i.e., sun protection factor 30 or higher with ultraviolet A and B protection, reapply every 2 hours) and of photo protective clothing options. The patient should also be told that it may take several weeks for the treated lesions to heal entirely.
Actinic keratoses are a common problem encountered in dermatology practice across the world every day. Although the physician has the ultimate responsibility of determining the treatment modality most appropriate for an individual patient, the success of the treatment often depends as much on patient instruction and education as on product selection. The dermatology nurse’s ability to convey the proper application instructions and techniques and the planned course of treatment and explain and differentiate between expected and unexpected side effects is invaluable to a successful outcome.
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Actinic Keratosis; Squamous Cell Carcinoma; 5-Fluorouracil; Ingenol Mebutate; Cryotherapy; Photodynamic Therapy
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