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
Abstract
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.
INTRODUCTION
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
