Actinic keratoses (AKs) are evolving, malignant cutaneous neoplasms. AKs can be treated with physical or destructive methods and with topical therapies. This article is the first in a 2-part series that will review current topical therapeutic options for AKs. Several topical treatment options offer some significant benefit for the alleviation of these lesions. Therapies include 5-fluorouracil, imiquimod, diclofenac, colchicine, and retinoids. The first part of this review will focus on topical 5-fluorouracil and imiquimod.
Actinic keratoses (AKs), also known as solar keratoses, senile keratoses, squamous cell carcinoma in situ (solar keratotic type), and keratinocytic intraepidermal neoplasia, are the most common neoplastic skin lesions detected in individuals with Fitzpatrick skin type I or II. These lesions are the third most common reason a patient visits a dermatologist.1 AKs were described first in 1898 by Dubreuilh2 at the Third International Congress of Dermatology. AKs appear as papules in a vast spectrum of sizes, shapes, colors, and other characteristics. Their size and shape can range from a well-circumscribed, single millimeter papule to an irregularly shaped lesion that can span several centimeters. These neoplasms can be flesh colored, red, or pigmented and also can scale or become hyperkeratotic.
AKs can occur anywhere the skin is exposed to chronic sun radiation. The most common sites for these lesions are the face, ears, scalp, neck, forearms, and hands. Chronic, repetitive UV exposure results in repetitive cycles of DNA damage. Eventually, these cycles of damage and repair spawn a significant unrecoverable error. The DNA lesion most likely responsible for these neoplasms is the p53 and/or ras proto-oncogene mutation.3 Multiple studies have shown that the p53 mutation is present in 53% of AKs and in 69% to 90% of squamous cell carcinomas (SCCs).3,4
The Australian population has the highest prevalence of AKs (approximately 40%).5 In the United States, a population study revealed that the relationship between the prevalence of AK and overexposure to the sun ranged from 23.3% to 36.7% in men and 18.6% to 34.1% in women, with low and high UV exposure, respectively.6 An individual's population of AKs is a dynamic balance between the appearance of new lesions and the spontaneous resolution of a percentage of the existing ones. Annual rates of incidence and resolution are as high as 48% and 26%, respectively.7 Further, the current literature reflects that 60% to 99% of all SCCs arise from AKs. Subsequently, the overall annual incidence of an AK transforming into SCC is 0.075% to 0.096%.8 When these data are extrapolated, the 10-year incidence rate for developing SCC in a patient with an average AK burden is 10.2%.9
To combat this very common lesion, a host of topical preparations has been investigated. Therapies include 5-fluorouracil, imiquimod, diclofenac, colchicine, and retinoids. This first part of the review will focus on topical 5-fluorouracil and imiquimod (Table 1).
5-Fluorouracil A mainstay for the treatment of AKs for many years, topical 5-fluorouracil has been the focus of a multitude of studies (Table 2).10-14 The main mechanism of action is well understood and entails the topical formulation undergoing ribosylation and phosphorylation after entering cells, resembling a natural nucleotide. Fluorouracil then binds to thymidylate synthase, using the cofactor 5,10-methylene tetrahydrofolate. As a result, thymidylate synthase is inhibited and cannot convert deoxyuridine nucleotides to thymidine nucleotides. The depletion of thymidine leads to reduced synthesis of DNA.15 This agent acts selectively to cause cell death in the actinic lesions but not in the normal skin. It is not clear whether normal cells simply absorb less fluorouracil than AK cells or whether the absorption is the same in both without producing equal effects on both cell types.16-18
Among the earlier studies of 5-fluorouracil for the treatment of AKs is a double-blind investigation by Simmonds10 comparing the 1% and 5% formulations. Sixteen patients applied the 1% cream to one side of their face and the 5% cream to the other side and then were evaluated at 7-day intervals. Results indicated that for half of patients—when both sides of the face were affected equally at the start of treatment—both creams produced equal results.10 Although the most common fluorouracil cream formulations used have been the 1% and 5% strengths, recently, a relatively new 0.5% cream has garnered much attention.11
Levy et al11 performed an in vitro study involving the penetration of three 0.5% fluorouracil creams (formulations A, B, and C), using a microsphere delivery system and one commercially available 5% fluorouracil cream administered every 3 hours for 24 hours on full-thickness human cadaver skin. The three 0.5% cream formulations differed in the method of incorporating fluorouracil within the vehicle base, and a preservative was present only in formulation A. Total absorption was defined as the sum of the amount of cumulative flux through the skin over 24 hours plus the amount retained in the skin at 24 hours. Findings indicate that the flux through the skin of the 5% fluorouracil formulation was 20 to 40 times greater than that of the 0.5% fluorouracil formulation. A greater percentage of absorbed fluorouracil was retained in the skin after 24 hours with the 0.5% formulation (86%–92%) than with the 5% formulation (54%)(P<.001).11
Another study by Levy et al12 used a different methodology; systemic exposure was evaluated via plasma and urine fluorouracil concentrations following topical application of fluorouracil in patients with a minimum of 3 AKs.12 Patients were randomized to receive 1-g doses of either 0.5% or 5% fluorouracil cream. Treatment regimens were consistent with prescribing regimens: once daily for the 0.5% fluorouracil cream and twice daily for the 5% fluorouracil cream for up to 28 days. After determining the pharmacokinetics, measurable fluorouracil plasma concentrations were identified in 3 patients treated with the 0.5% cream and in 9 patients treated with the 5% cream.12 Despite the one-tenth difference in drug concentration among formulations, the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one fortieth that of the 5% fluorouracil group.12
In a single-blind study, Loven et al13 investigated the efficacy and tolerability of 0.5% fluorouracil cream compared with 5% fluorouracil cream. Patients with a balanced number of AKs on each side of their face were treated with the 0.5% cream on one half of their face once daily and the 5% cream on the other half twice daily for 4 weeks, or to the point when treatment became intolerable. Both the total clearance of AKs and the incidence of any adverse event were not found to be significantly different between the 2 groups. However, the majority of patients in the study preferred the 0.5% to the 5% cream (P=.003), secondary to the once-daily treatment schedule, less irritation, and ease of product application.13
In a similar study examining the efficacy of 0.5% fluorouracil in a randomized, double-blind, vehicle-controlled trial, Weiss et al14 reported a significant reduction in the number of AKs with the 0.5% cream. Treatment duration consisted of 1, 2, or 4 weeks, with a percentage reduction in the number of AKs from baseline of 78.5%, 83.6%, and 88.7%, respectively (P<.001). Total lesion clearance occurred in 26.3%, 19.5%, 47.5%, and 3.4% of patients in the 1-, 2-, and 4-week fluorouracil and vehicle groups, respectively. Facial irritation was experienced by patients in the 1- and 2-week groups and appeared to increase during the entire treatment period. Patients in the 4-week group noted only a slight increase in irritation beyond the second week. Irritation returned to baseline levels 15 to 17 days after completion of therapy, regardless of the duration of application.14 Further supporting that the topical 0.5% fluorouracil cream may be more cost-effective is a study conducted by Gupta,19 comparing the other 2 strengths (5% and 1%). Results suggest that 0.5% fluorouracil cream may be more cost-effective than the higher concentrations in a patient with multiple AKs, most likely due to the once-daily regimen.19
In all the studies reviewed, the most common side effects from treatment were mild to moderate facial irritation associated with erythema, dryness, and burning. Few serious adverse events have been reported with topical fluorouracil use and include allergic contact dermatitis20 and a single case of inflammatory colitis following topical application of a 5% formulation for a basal cell carcinoma of the scalp.21 This individual had a severe deficiency of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in fluorouracil breakdown. It is thought that this is the only case of a life-threatening toxicity in a patient receiving topical 5-fluorouracil.21
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Imiquimod
Another medication currently used to treat AKs is imiquimod. This drug has been approved by the US Food and Drug Administration as a therapy for external genital warts.15 However, there are increasing numbers of case reports and reviews that show the efficacy of topically applied imiquimod for off-label conditions, such as molluscum contagiosum, basal cell carcinoma,22 SCC, Bowen disease, human papillomavirus infections,23-26 vulvar intraepithelial neoplasms,25 and AK27,28-31 (Table 3).