THERAPEUTICS BJD British Journal of Dermatology Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial K. Gebauer, S. Shumack* and P.S.J. Cowen  Fremantle Dermatology, 6160 Fremantle, WA, Australia *St George Hospital, Sydney, NSW, Australia  Monash Medical Centre, Clayton, Vic., Australia Correspondence Kurt Gebauer. E-mail: kurt@fremantledermatology.com.au Accepted for publication 20 February 2009 Key words actinic keratosis, dose–response relationship, drug, imiquimod, randomized controlled trial Conflicts of interest This study was funded by 3M Pharmaceuticals, Saint Paul, MN, U.S.A. K.G., S.S. and P.S.J.C. were investigators for this study and were compensated for their efforts. DOI 10.1111/j.1365-2133.2009.09260.x Summary Background Clinical studies in cutaneous conditions other than actinic keratosis (AK) have revealed that the safety and efficacy profile of imiquimod is influenced by dosing frequency. Objectives To evaluate dosing frequency response of imiquimod 5% for treatment of AK. Methods This was a phase II, multicentre, randomized, double-blind, placebo- controlled study. Adults with ‡ 10 but £ 50 clinical AKs, one of which was histologically confirmed, were randomized (4 : 1) to 2–6 packets of imiquimod or placebo cream applied to the dorsum of the forearms and hands once daily 2, 3, 5 or 7 times per week for 8 weeks. The primary endpoint was complete clear- ance of AKs in the treatment area at 8 weeks post-treatment. Results One hundred and forty-nine (94 men and 54 women) white subjects, with a mean ± SD age of 71 ± 10Æ2 years, were enrolled. Twenty-eight subjects (18Æ8%) discontinued from study: 0%, 3Æ1%, 6Æ9%, 30Æ0% and 33Æ3% withdrew for local skin reactions or adverse events in the combined placebo, and in the imiquimod 2, 3, 5 or 7 times per week groups, respectively. Seven serious adverse events occurred; none was related to the study drug. Median baseline lesions ranged from 38 to 40 for the treatment groups. Complete clearance was achieved in 0%, 3Æ2%, 6Æ9%, 3Æ3% and 6Æ7% of subjects, and partial clearance (‡ 75% lesion reduction) in 0%, 22Æ6%, 24Æ1%, 20Æ0% and 36Æ7% of sub- jects for the placebo and imiquimod 2, 3, 5 or 7 times per week regimens, respectively. Conclusions Imiquimod 5% applied more frequently than 3 times per week to AKs was not well tolerated. Complete clearance rates were low; however, partial clearance rates increased with increased dosing frequency (P =0Æ002). Actinic keratoses (AKs) are common dysplastic cutaneous lesions, especially prevalent among populations with fair skin types, that arise as a consequence of chronic exposure to solar ultraviolet (UV) radiation. 1 AKs have been regarded as prema- lignant lesions; some propose that AK should be considered as incipient squamous cell carcinoma (SCC) as the two share similar cytological and molecular abnormalities. 2 Others point out that although AKs may be on the continuum to the devel- opment of SCC, AKs are distinct by histology and have a benign clinical behaviour. 3 The estimated risk for an individ- ual AK to progress to invasive SCC is relatively low. 4 Most people with AKs, however, have multiple lesions, so the cumulative risk is not insignificant. 5 It has been estimated that of the AKs that might develop into SCC, the time to progres- sion may be as short as 2 years. 6 As it is not possible to deter- mine which AK may progress to SCC, treatment of AKs in general has been proposed by some. 6–8 Others, however, do not recommend universal treatment, pointing out that there is a lack of adequate evidence that preventive treatment actually decreases the risk of subsequent malignancies. 9 Treatments for AK include procedures administered by healthcare provid- ers such as surgical excision, cryotherapy, curettage with or Ó 2009 The Authors Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp897–903 897