Assessing clinically meaningful end points for the management of actinic keratosis with diclofenac 3% gel.

Actinic keratosis (AK) is an early stage of evolving skin cancer and may be classified as a squamous cell carci-noma (SCC) in situ, which originates from keratinocytes and appears on areas of skin exposed to sunlight, such as the face and arms. It is a common condition in the general population, with prevalence increasing with age and cumulative sun exposure. The American Academy of Dermatology estimates that 60% of predisposed individuals aged 40 years and over have at least one AK lesion (1). The ultimate treatment goal is to prevent progression to SCC (2). Recent insights into the relationship between cyclo-oxygenase-2 (COX-2) and carcinogenesis have provided a rationale for the topical use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AK. The most studied of these, diclofenac 3% gel (Solaraze TM 3% gel; Shire Pharmaceuticals Contract Ltd, Basingstoke, UK), is thought to have an effect on AK via selective COX-2 inhibition (3) and regulation of cell proliferation and apoptosis, although the exact mechanisms of action remains to be determined. The hyaluronic acid vehicle is a key component in this topical treatment. It has been shown to be capable of delivering twice as much diclofenac to the epidermis over a 24-h period than an aqueous control or sodium carboxymethyl, and to enhance the localization and retention of diclofenac in areas of inflammation within the epidermis (4, 5). A series of clinical studies have provided evidence for the use of topical diclofenac 3% gel for the treatment of AK (6–10). Two randomized, double-blind, parallel group, multicenter studies (Study A (7) and Study B (8)) have compared the effect of 0.5g bid diclofenac 3% gel vs. placebo (hyaluronic acid gel alone) for up to 90 days in patients with AK. The primary efficacy variables were the proportion of patients achieving a target lesion number score (TLNS) or a cumulative lesion number score (CLNS) equal to zero, where TLNS refers to the number of lesions identified at baseline, and CLNS refers to any new lesions appearing during the treatment phase plus remaining target lesions. In Study A, 50% of patients receiving diclofenac 3% gel achieved complete resolution of all target lesions (TLNS=0), compared with 20% in the placebo group (p <0.001), at the 30-day follow-up visit after the end of the 90-day treatment period (7). A similar difference was observed for CLNS (CLNS = 0) between the active and placebo groups (47% and …