Actinic keratosis (AK) is regarded as a lesion on a continuum of progression to squamous cell carcinoma (SCC).1 Studies have estimated that 44% to 97% of SCCs were associated with AK lesions either in contiguous skin or within the same histologic section and that AK lesions progress to SCCs at a rate of 0.6% at 1 year.2 In 1993-1994 there were 3.7 million reported office visits for AK lesions, while in 2002 alone there were 8.2 million office visits.3,4 As the burden of disease from AKs has increased, so has the associated costs from office-based visits, treatments, and subsequent surveillance.
There are a number of highly effective approaches to AK treatment that are based on several factors such as the number of and extent of the lesions, history of skin cancer, provider practice characteristics (eg, location, appointment availability), patient preferences, cost, and tolerability. Cryosurgery is the most commonly used lesion-directed modality in the treatment of individual AKs based on its effectiveness and relative ease of use. Cryosurgery alone has been shown to have a success rate of 67% on AK lesions.5 Patients often experience erythema, edema, pain, and crusting at treated sites; there also is potential for ulceration, scarring, hypopigmentation, hyperpigmentation, and secondary infection, but these effects are less common. Recurrence may be an indicator of treatment-resistant lesions or new lesions appearing in the field.
A field-directed approach with topical 5-fluorouracil (5-FU) may be preferred in patients with a history of substantial photodamage, AKs that are resistant to cryosurgery, or multiple AKs. Field-directed treatments address multiple AKs simultaneously and treat subclinical lesions. Fluorouracil is a common therapy for AKs that often is implemented by dermatologists due to its efficacy and well-understood mechanism of action. Fluorouracil inhibits thymidylate synthase during DNA synthesis, thereby halting cellular proliferation. 5-Fluorouracil cream 0.5% has been approved for 1-, 2-, and 4-week treatment periods. In one study, resolution of AK lesions was greatest in the 4-week treatment group; however, side effects also were greatest in this group.6 Patients commonly may experience a range of local reactions including erythema, pruritus, erosions, ulcerations, scabbing, crusting, and facial irritation. For patients with substantial photodamage and AKs, a robust response can lead to perceived adverse events (AEs) and considerable downtime, possibly affecting patient satisfaction and treatment compliance.7
Many alternative and combination approaches have been studied to decrease AEs and improve compliance and efficacy in the treatment of AKs. In this study, we examined the efficacy and perceived side effects of cryosurgery and 5-FU cream 0.5% combination therapy in the treatment of AKs.
This single-blind, single-center, comparator cream–controlled pilot study was parallel designed with a balanced randomization (1:1 frequency). The study protocol and consent form were approved by the Wake Forest University Health Sciences institutional review board (Winston-Salem, North Carolina). Participants were 18 years or older with 8 clinically typical, visible, and discrete AK lesions on the face (forehead and temples) or balding scalp. Typical inclusion and exclusion criteria were observed. No other topical agents or therapies were permitted to be applied to the affected areas at least 4 weeks prior to treatment, depending on the treatment modality.
During the screening (baseline) visit, eligible participants provided informed consent, baseline lesion counts and investigator global assessments (IGAs) were performed, and cryosurgery was administered to all visible AK lesions in the study areas. Participants returned at weeks 3, 4, 8, and 26. Three weeks following cryosurgery, participants were randomized according to standard randomization tables into 1 of 2 treatment groups to receive once-daily treatment with either 5-FU cream 0.5% or a moisturizing comparator cream. The cream was applied at bedtime to the affected sites for 1 week. Randomization was investigator blinded, but participants and the study administrators were not blinded. Participants were instructed to record their treatment compliance in daily diary entries, which were reviewed at week 4 using the medication tolerability assessment rating for burning, stinging, and ulceration. Investigator global assessment, IGA of improvement, lesion counts, and quality of life (QOL) survey responses were gathered at weeks 3, 8, and 26. The IGA measured the overall severity of AK disease involvement on a 6-point scale (clear; very severe). The IGA of improvement measured the overall improvement from baseline on a 6-point scale (clear; worse). Adverse events were measured at each visit.
The primary end point was 100% clearance of all AK lesions at the end of the study (week 26) relative to the baseline AK lesion count. Secondary end points included comparisons between the groups for the number of participants with greater than 75% reduction of baseline lesion counts at the end of the study as well as differences at each visit in medication tolerability assessments, QOL measures, IGA improvement scores, and medication adherence based on diary entries at week 4.
An intention-to-treat analysis was performed. The number of participants with 100% or greater than 75% clearance of AK lesions by specified time points were compared using relative risks and risk differences with Poisson regression analysis log and identity link functions, respectively, to obtain robust error variance 95% confidence intervals. Medication tolerability assessment, QOL, and IGA improvement scores were compared between the 2 groups using the Mann-Whitney U test. The significance level was set at α=.05. All analyses were performed using SAS data analysis software.
