Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Alabama Dermatology Society Summer Symposium

Sandestin, Florida / June 24-27, 2010

As reported by Dr. Neil Fenske, Professor and Chair, Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, a new study shows that imiquimod 3.75% cream following cryosurgery enhances treatment efficacy and represents a breakthrough in treating actinic keratoses (AKs). “This study shows that using imiquimod following cryosurgery enhances efficacy of treatment and can be a useful adjunct to cryosurgery,” he told delegates here during the scientific sessions.

AKs are cutaneous neoplasms caused by prolonged ultraviolet radiation (UVR) exposure and are the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC). They are the second most common reason for visits to dermatologists (Fenske et al. J Drugs Dermatol 2010;9(5 Suppl):S45-S49).

Cryosurgery, which destroys or removes diseased or abnormal tissue by freezing with liquid nitrogen, is currently the standard AK therapy. As the most commonly used treatment, cryosurgery was thought to have a high cure rate of approximately 99% (Lubritz RR, Smolewski SA. J Am Acad Dermatol 1982;7(5):631-2). This number has been questioned, however, and more recently, a cure rate of approximately 67% has been established. Increasing freeze time enhances efficacy, but results in greater discomfort and increased risk of post-treatment hypopigmentation, which many patients do not accept (Thai et al. Int J Dermatol 2004;43(9):687-92). Although effective, cryosurgery does not target the skin surrounding clinically apparent AKs, which is exposed to the same UVR damage and which can result in field cancerization. Subclinical AKs may progress to clinical AKs or even SCC.

Field-directed therapies are increasingly seen as viable adjuncts to lesion-directed treatment because they are non-invasive, potentially reduce the risk of scarring, target difficult-to-treat locations, reduce cost, resolve subclinical field cancerization and deliver secondary cosmetic benefit. Common field-directed treatments include 5-fluorouracil (5-FU), imiquimod, diclofenac, topical and systemic retinoids, chemical peels, laser resurfacing and modified photodynamic therapy (PDT). Other lesion-targeted treatments include curettage, electrosurgery and conventional PDT.

Promising Results

The study presented here assessed the efficacy of lesion-directed cryosurgery followed by field-directed imiquimod 3.75% therapy in treating AK in adults. Subjects underwent cryosurgery for part of their lesions and then were randomized to imiquimod 3.75% or placebo cream—applied to the full face once daily—for two two-week cycles separated by a two-week no-treatment interval.

Median lesion reductions were 86.5% and 50% (P<0.0001) for total AKs, 100% and 80% (P=0.0008) for cryosurgery-treated AKs, and 83.3% and 22.2% (P<0.0001) for non-cryosurgery-treated AKs for imiquimod and placebo groups, respectively (Figure 1). Additionally, 30.2% and 3.3% (P<0.0001) of participants had complete clearance for total AKs, 59.5% and 29.8% (P<0.0001) for cryosurgery-treated AKs, and 34.1% and 5% (P<0.0001) for non-cryosurgery treated AKs for imiquimod and placebo groups, respectively. Treatment was well tolerated and more effective than placebo in reducing total AKs, cryosurgery-treated AKs and non-cryosurgery-treated AKs. Local skin reactions occurred more frequently in the imiquimod-treated group and a higher percentage of patients suffered from severe-grade local skin reactions (34.9% vs.1.7% placebo).

According to one of the study’s authors, Dr. Joseph Jorizzo, Professor of Dermatology, Wake Forest University, Winston-Salem, North Carolina, and Adjunct Professor of Dermatology, Weill Cornell Medical Center, New York City, “The opportunity of combining cryosurgery with a field treatment is the optimal way to manage the ongoing problem of AKs.” Dr. Jorizzo confirmed that using liquid nitrogen to destroy AKs by freezing them is an excellent treatment modality, especially for getting rid of thicker lesions. But he added, “If a dermatologist only destroys lesions, he or she will be destroying lesions at every single interval when patients come in for treatment. Adding an approach that addresses field cancerization is a way to make progress with the patient’s treatment. In addition to the destructive treatment of cryosurgery, the patient obtains the added benefit of clearing a percentage of the evolving lesions, which is a more comprehensive way to manage the problem.”

Figure 1.

Dr. Fenske stated that using imiquimod 3.75% cream as sequential treatment to cryosurgery is an easier way to expand treatment to the entire affected area. “In this study, imiquimod helped to unmask clinically occult lesions and is one of the best drugs for bringing clinically occult lesions to the surface. Cycle therapy is also easier for patients to endure because of the rest period, simplified dosing frequency and shorter duration of treatment.” According to Dr. Fenske, every patient deserves consideration for field therapy. “Field therapy needs to be offered to every patient as an adjunct to cryotherapy. The concept of field cancerization cannot be denied.”

Sustained Complete Clearance

Another presented study evaluated 12-month sustained complete clearance of AKs after treatment with imiquimod 2.5% or 3.75% cream. Overall, complete clearance of AKs for at least 12 months (entire face or balding scalp) was sustained in =40% of participants who had complete clearance after treatment with imiquimod 3.75% cream.

In both the US and Europe, current AK treatment regimens using imiquimod 5% cream entail non-intuitive dosing frequencies, long treatment durations and treatment of only a small area (25 cm2) (Lebwohl et al. J Am Acad Dermatol 2004;50(5):714-21, Korman et al. Arch Dermatol 2005;141(4):467-73, Jorizzo et al. J Am Acad Dermatol 2007;57(2):265-8). Moreover, the 5% daily formulation is not sufficiently well tolerated (Gebauer et al. Br J Dermatol 2009;161(4):897-903).

Four phase III, placebo-controlled studies were undertaken using lower dosages of imiquimod (2.5% or 3.75%). Imiquimod and placebo creams were applied daily to the full face or balding scalp (treatment area >25 cm²) using two two-week or three-week cycles and separated by a two- or three-week non-treatment period, respectively (Swanson et al. J Am Acad Dermatol 2010;62(4):582-90, Hanke et al. J Am Acad Dermatol 2010;62(4):573-81). Both formulations of the cream proved more efficacious than placebo and were well tolerated as a daily regimen.

For those who were sustained clearance failures, median AK counts (recurrent or new) in the treatment area were 4, 3 and 3 for the placebo, 2.5% and 3.75% cohorts, respectively, in two-week subjects and 6, 2 and 2 in three-week participants.

Given the large number of baseline AKs prior to treatment (higher numbers of lesions increase the probability of recurring lesions) as well as the larger treatment area involved (larger area increases probability for new lesions), the =40% sustained clearance at 12 months for the 3.75% formulation was encouraging.

Summary

Cryosurgery is an effective and widely implemented treatment for AKs. Newer understanding of AKs is that they exist in an area of field cancerization: the tissue around AK lesions has also been exposed to UVR and may be histologically altered. Treating subclinical lesions in addition to visible AK is a more comprehensive approach to treatment. Sequential treatment with imiquimod has been shown to enhance the efficacy of cryosurgery and to be well tolerated. The 3.75% formulation administered daily as a two-week on/off/on (2/2/2) regimen resulted in an 86.5% median lesion reduction. Complete clearance of AKs was sustained for at least 12 months after treatment with the 3.75% cream in =40% of patients. Given the large number of AKs prior to treatment and the larger treatment area, this result is noteworthy.