Efficacy and Safety of Ingenol Mebutate 0.015% Gel 3 Weeks After Cryosurgery of Actinic Keratosis: 11-Week Results

February 2014 | Volume 13 | Issue 2 | Original Article | 154 | Copyright © February 2014

Brian Berman MD PhD,a Gary Goldenberg MD,b C. William Hanke MD,c Stephen K. Tyring MD PhD,d Wm Philip Werschler MD,e Kim Mark Knudsen PhD,f Joana Goncalves MD,g Thomas Larsson Dr Med Sci,h Torsten Skov MD PhD,i and Neil Swanson MDj

aDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
bDepartment of Dermatology, Mount Sinai School of Medicine, New York, NY
cDermatologic Surgery, Laser and Skin Surgery Center of Indiana, Carmel, IN
dDepartments of Microbiology and Immunology, Dermatology and Internal Medicine, University of Texas Health Science Center, Houston, TX
eDepartment of Medicine/Dermatology, University of Washington School of Medicine, Seattle, WA
fBiostatistics and Data Management, LEO Pharma A/S, Ballerup, Denmark
gLEO Pharma Inc, Parsippany, NJ
hCentre of Excellence Scientific Affairs, LEO Pharma A/S, Ballerup, Denmark
iMedical Department, LEO Pharma A/S, Ballerup, Denmark
jDepartment of Dermatology, Oregon Health and Science University, Portland, OR

INTRODUCTION: Cryosurgery is the most common treatment for actinic keratosis (AK) in the United States. Efficacy with cryosurgery is variable, and is a modality for treating individual, visible lesions while failing to treat subclinical lesions.
METHODS: FIELD Study 1 (NCT01541553) is a phase 3, multicenter, randomized, double-blind study that evaluated the short- (11-week) and long- (12-month) term efficacy and safety of sequential AK treatment using cryosurgery with liquid nitrogen followed by ingenol mebutate gel, versus cryosurgery followed by vehicle.
RESULTS: Overall, 329 patients were randomized to ingenol mebutate 0.015% gel (n=167) or vehicle (n=162) 3 weeks after cryosurgery. Baseline characteristics were balanced across groups. At week 11, complete clearance rate (100%) in the treatment area was higher for ingenol mebutate gel compared with vehicle (60.5% vs 49.4%, respectively; P=.04). Mean percentage reduction in number of AKs versus baseline was also numerically higher for ingenol mebutate gel (82.7% vs 75.6%). A general reduction from baseline lesion count was observed 3 weeks after cryosurgery. Treatment after cryosurgery was well tolerated.
CONCLUSIONS: Short-term (11-week) AK clearance rates on the face or scalp with ingenol mebutate gel after cryosurgery were higher than with cryosurgery alone.

J Drugs Dermatol. 2014;13(2):154-160.


Actinic keratosis (AK) is considered by some as the earliest stage of squamous-cell carcinoma. It is capable of progressing to in situ or invasive squamous-cell carcinoma, and is prevalent in older, light-skinned populations worldwide.1 AK is estimated to affect 11–50% of the population aged 40 years and older in the United States and Australia.2 Within Europe, the prevalence rate in this age group ranges from 11 to 25%.3,4
In the United States, approximately 58 million people are estimated to have AK, resulting in treatment costs of more than $1 billion.5 Cryosurgery is the most common treatment for AK in the US.6-8 However, although cryosurgery can effectively treat individual targeted lesions, recurrence rates are high, and the procedure fails to address field cancerization of perilesional skin.9
An enhanced understanding of the pathophysiologic changes leading from AK to malignancy has led to a new focus on the importance of combining treatments that remove individual lesions with field therapies that treat the entire actinically damaged field.10 AK treatment strategies that include both lesionand field-directed therapies to treat visible as well as subclinical lesions have demonstrated improved rates of clearance and lower recurrence rates.11-15 However, current topical pharmacologic field therapies, such as 5-fluorouracil, imiquimod, and diclofenac, must be used for several weeks or months and cause localized inflammation, often leading to erythema, burning, and ulceration, which impact on quality of life and possibly on adherence to therapy.
Ingenol mebutate gel16 is a novel topical agent for field-directed treatment of AK that requires only 2 or 3 days of application depending on the area treated.17-19 Ingenol mebutate is approved in the United States, Canada, the European Union, Australia, and other countries for the treatment of AKs located on the face, scalp, trunk, and extremities.17-19 Ingenol mebutate eradicates AK by