WAIKOLOA, Hawaii — The next generation of imiquimod therapy for actinic keratoses will offer a simpler, more convenient regimen that is easier to tolerate than the available 5% cream, according to Dr. Brian Berman, professor of dermatology at the University of Miami.
A 3.75% topical formulation of imiquimod has been designed for once-daily treatment. The new formulation received marketing approval in Canada earlier this year but is investigational in the United States. Called Zyclara (Graceway Pharmaceuticals), it is used in cyclic fashion over a 6-week period: 2 weeks on, 2 weeks off, and 2 weeks on.
The 5% imiquimod formulation (Aldara, Graceway Pharmaceuticals) isn't supposed to be applied to an area greater than 25 cm2. The 3.75% formulation, however, can be used to treat the full face or balding scalp, he said at the annual Hawaii Dermatology Seminar sponsored by the Skin Disease Education Foundation.
As part of four clinical trials, a 2.5% and a 3.75% formulation of imiquimod cream were evaluated in two regimens. Reponses were measured in a total of 969 patients, each having 5-29 facial and scalp actinic keratoses (AKs) with up to 1 mm of hyperkeratosis.
Trial participants were randomized to receive either 2.5% or 3.75% imiquimod cream or placebo. Patients were further randomized to either a schedule of 3-weeks-on/3-weeks-off/3-weeks-on therapy or to the 2-2-2 regimen. Outcomes were best with 3.75% imiquimod on the 2-2-2 cycle.
After the first 2 weeks of treatment with the 3.75% cream given on the 2-2-2 regimen, subclinical AK lesions became apparent in 85% of patients. At 8 weeks post-treatment, their AK lesion count was reduced by nearly 82%. The placebo group had a 25% decrease in lesion count at 8 weeks.
An earlier study of 5% imiquimod cream, applied twice weekly for 16 weeks, resulted in an 83% median decrease in AKs.
The complete clearance rate was nearly 36% with 3.75% imiquimod on a 2-2-2 schedule, compared to 6.3% with placebo. The partial clearance rate, defined as at least 75% clearance of AKs, was slightly over 59% with 3.75% imiquimod and nearly 23% with placebo.
The efficacy of 3.75% imiquimod on the 3-3-3 cycle was comparable, but the rate of treatment-related adverse events was nearly twice as great, and the number of unscheduled rest periods was more than doubled.
Favorable outcomes also were impressively durable. Among patients who were completely cleared at 8 weeks post-treatment, the median number of AKs was zero at 6 months and 1 at 1 year.
Following cryotherapy, the 1-year sustained clearance rate is typically in the low single digits, he observed.
Audience members asked Dr. Berman's preferences for treating AKs in his own practice. He replied that his favorable clinical trial experience would make 3.75% imiquimod, if it is made available in the United States, his first-line treatment for AKs on the balding scalp, face, and ears. He has relied upon topical 5-FU for AKs on the arms, since these lesions tend to be quite hyperkeratotic. Given the good responses to 3.75% imiquimod in the numerous trial patients with mildly hyperkeratotic AKs, Dr. Berman said he would be equally likely to turn to topical 5-FU or imiquimod 2-2-2 cycle therapy for lesions on the arms.
He also discussed important new developments in the pathogenesis of AKs and squamous cell carcinomas--and how imiquimod counters this process.
Among its multiple immunomodulatory effects, topical imiquimod activates toll-like receptor-7, NFkappaB, and Th1 lymphocytes that have antiviral and antitumor activities.
Investigators at Dongguk University in Kyongju, Korea, recently identified a new major player in the development of AKs and squamous cell carcinoma: the Forkhead box p3 (Foxp3) positive cell. These cells infiltrate and surround AKs and squamous cell carcinomas, where they induce immune suppression and ultimately immune tolerance to the tumor. Foxp3-positive T regulatory cells do so through direct cell-to-cell contact and by elaborating the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta (Yonsei Med.J. Dec. 31, 2008; 49:942-8).
"The good news is in vivo application of imiquimod to squamous cell carcinomas of the skin blocks these two immunosuppressive agents--IL-10 and TGF-beta--reversing the immune suppression. This obviously has a sanguine effect on removing AKs as well," Dr. Berman explained.
The Zyclara studies were funded by Graceway Pharmaceuticals. Dr. Berman, an investigator in the trials, is on the company's speakers' bureau and advisory board. He holds similar positions with 3M, Doak, PharmaDerm, Peplin, and Neutrogena.
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