Download Imiquimod 5% cream for the treatment of actinic keratosis

Imiquimod 5% cream for the treatment of actinic
keratosis: Results from two phase III,
randomized, double-blind, parallel group,
vehicle-controlled trials
Mark Lebwohl, MD,a Scott Dinehart, MD,b,c David Whiting, MD,d
Peter K. Lee, MD, PhD,e Naji Tawfik, MD, PhD,f,g Joseph Jorizzo, MD,h
James H. Lee, MD, PhD,i and Terry L. Fox, MSi
New York, New York; Little Rock, Arkansas; Dallas, Texas; Minneapolis and
St Paul, Minnesota; Indianapolis and Evansville, Indiana; and
Winston-Salem, North Carolina
Background: The immune system plays a critical role in the development and pathogenesis of actinic
keratosis (AK). Imiquimod has been shown to stimulate the cutaneous immune response and be effective
for the treatment of nonmelanoma skin cancers.
Objective: Two phase III, randomized, double-blind, vehicle-controlled studies evaluated the efficacy of
imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp.
Methods: A total of 436 participants at 24 centers in the United States and Canada were randomized to
either imiquimod 5% or vehicle cream. Study cream was applied one time per day, 2 days per week for 16
weeks. Clearance of AK lesions was clinically assessed at an 8-week posttreatment visit.
Results: The complete clearance rate was 45.1% for the imiquimod group and 3.2% for the vehicle group.
The difference in complete clearance rates (imiquimod minus vehicle) was 41.9% with a 95% confidence
interval of 34.9% to 49%. The partial (ⱖ75%) clearance rate was 59.1% for the imiquimod group and 11.8%
for the vehicle group. The difference in partial clearance rates (imiquimod minus vehicle) was 47.3% with
a 95% confidence interval of 39.5% to 55.1%. The median percent reduction in AK lesions was 83.3% for the
imiquimod group and 0% for the vehicle group. Local skin reactions were common. Severe erythema was
reported by 17.7% of participants who received imiquimod and 2.3% of participants who received vehicle.
Overall, imiquimod was very well tolerated.
Conclusion: Imiquimod 5% cream used 2 times per week for 16 weeks is an effective and well-tolerated
treatment for AK. (J Am Acad Dermatol 2004;50:714-21.)
From the Department of Dermatology, Mount Sinai School of
Medicine, New York, New Yorka; University of Arkansas for the
Medical Sciences, Little Rock, Arkansasb; Bressinck, Gibson,
Parker, Dinehart and Sangster Dermatology, Little Rock,
Arkansasc; Dallas Associated Dermatologistsd; University of
Minnesota Academic Health Center, Department of
Dermatology, Division of Clinical Research, Minneapolis,
Minnesotae; Indiana University School of Medicine,
Indianapolis, Indianaf; Welborn Clinic Research Center,
Evansville, Indianag; Wake Forest University School of Medicine,
Department of Dermatology, Winston-Salem, North Carolinah;
and 3M Pharmaceuticals, St Paul, Minnesota.i
Supported by 3M Pharmaceuticals, St Paul, Minnesota.
Disclosure: Drs Lebwohl, Dinehart, Whiting, P. Lee, Tawfik, and
Jorizzo have received support from 3M Pharmaceuticals for performing clinical trials. Drs Jorizzo and P. Lee have served as consultants for 3M Pharmaceuticals. Drs Lebwohl and Tawfik have
received speaking honoraria. Dr J. Lee and Mr Fox are employees
of 3M Pharmaceuticals.
714
A
ctinic keratoses (AK) are epidermal lesions
consisting of dysplastic keratinocytes that
generally occur in pale-skinned individuals
chronically exposed to UV radiation.1,2 As the incidence of nonmelanoma skin cancer increases, the
Portions of this information have been presented at the 62nd Annual Meeting of the American Academy of Dermatology, Washington, DC, February 6-11, 2004 and at ACADEMY 2003, Chicago,
Ill, July 25-29, 2003.
Accepted for publication December 1, 2003.
Reprint requests: Mark Lebwohl, MD, Department of Dermatology,
The Mount Sinai School of Medicine, 5 E 98 St, Box 1048, New
York, NY 10029-6574. E-mail: [email protected].
0190-9622/$30.00
© 2004 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2003.12.010
J AM ACAD DERMATOL
VOLUME 50, NUMBER 5
incidence of AK is also expected to increase
throughout the world.3 In the white-skinned population older than 40 years who live in the northern
hemisphere, the incidence of AK is estimated to
range from 11% to 25%, whereas in the whiteskinned population living in Australia, the incidence
is estimated to range from 40% to 60%.4,5
Histologically and clinically, there is a continuum
and a progression between AK and squamous cell
carcinoma (SCC) that makes reliable clinical distinction between the diseases difficult to determine; an
AK lesion that evolves into an invasive SCC lesion
can do so without displaying any distinguishing clinical features.6,7 Because it is impossible to predict the
point at which an individual AK lesion will evolve into
invasive SCC, some clinicians advocate the treatment
of all AK lesions. The most common current therapies
for the treatment of AK include cryosurgery, curettage
with or without electrosurgery, and topical 5-fluorouracil. Because the pathogenesis of AK involves suppression of the cutaneous immune response, a treatment that stimulates the immune response would also
be a potentially effective therapy.
Imiquimod 5% cream is currently available as
Aldara (3M Pharmaceuticals, St Paul, Minn) and is
indicated for the treatment of external genital warts.
It has been shown to stimulate the immune system
by activating antigen-presenting cells such as monocytes/macrophages and dendritic cells to produce
interferon and other cytokines and chemokines. Because of this unique mechanism, imiquimod has
been used for the treatment of AK. Published anecdotes and small pilot studies suggested imiquimod
would be an effective and well-tolerated treatment
option for AK.8-11
To confirm these preliminary findings, two large,
randomized, double-blind, parallel group, vehiclecontrolled trials were conducted to evaluate the efficacy and safety of topically applied imiquimod 5%
versus vehicle cream for the treatment of AK lesions
on the face and balding scalp. The two studies were
of the same size and design, and were carried out
concurrently at different study centers across the
United States and Canada to provide independent
confirmatory evidence of safety and efficacy.
METHODS
Study population
Eligible participants were otherwise healthy men
and women at least 18 years of age with 4 to 8
clinically diagnosed AK lesions located within a contiguous 25-cm2 treatment area on the face or balding
scalp, but not both. Participants were to be excluded
from the study if they had any condition in the
treatment area that could be exacerbated by treat-
Lebwohl et al 715
ment with imiquimod 5% cream or that would impair the examination of the treatment area. If a
participant had previously received treatment with
imiquimod 5% cream in the treatment area or had
any known allergies to any excipients in the study
cream, they were excluded. Participants were also
excluded from study participation if they had received any of the following treatments in the 6
months before treatment initiation: psoralen plus
UVA therapy; UVB therapy; laser abrasion; dermabrasion; or chemical peel. The use of moisturizers,
over-the-counter retinol products, or products containing ␣- or ␤-hydroxy acids in the treatment area
was prohibited. Throughout the study and in the 4
weeks before treatment initiation, the following
treatments were not allowed: prescribed topical retinoids; 5-fluorouracil; masoprocol; cryodestruction;
chemodestruction; surgical excision; photodynamic
therapy; curettage; interferon/interferon inducers;
cytotoxic drugs; drugs with major organ toxicity;
immunomodulators; immunosuppressive therapies;
oral corticosteroids; or topical steroids anywhere on
the head.
Enrollment for both studies began in September
2001, and all study procedures were completed by
August 2002. All study procedures and informed
consent documents received approval from an institutional review board or international ethics committee, and all enrolled participants signed informed
consent forms. The studies were conducted in compliance with the Code of Federal Regulations (CFR)
of the United States Food and Drug Administration
(21 CFR Part 56, Institutional Review Boards, and 21
CFR Part 50, Protection of Human Subjects) and the
International Conference on Harmonization guidelines.
Study design
Data from participants enrolled at 24 centers in
the United States and Canada were analyzed in two
phase III, randomized, double-blind, parallel group,
vehicle-controlled studies. The studies consisted of a
prestudy period, a 16-week treatment period, and an
8-week posttreatment period. Participants who discontinued from the treatment period were asked to
return for an assessment of their AK lesions 8 weeks
after their last dose of treatment.
At the prestudy visit, participants were screened
for eligibility; demographic information was collected; and clinical laboratory tests, vital sign measurements, and physical examinations were performed.
Enrolled participants were randomized to either imiquimod 5% or vehicle cream in a 1:1 ratio. The
randomization assignments were made according to
a computer-generated randomization schedule and
716 Lebwohl et al
were allocated at treatment initiation. Labels with
hidden disclosure panels were used to conceal treatment assignments from participants, investigators,
study staff, and the sponsor. Study cream was delivered as imiquimod 5% cream (Aldara, 3M Pharmaceuticals) or vehicle cream. The vehicle cream was
similar in appearance to imiquimod 5% cream, and
was of identical composition, with the exception of
the active ingredient.
Study cream was administered topically from a
single-use sachet that contained 250 mg of cream.
Participants applied study cream 1 time per day, 2
days per week for 16 weeks. Dosing days were a
minimum of 3 days apart (eg, Monday and Thursday), and participants were instructed to dose on the
same 2 days of the week for each week of treatment.
The 16-week treatment period was followed by an
8-week treatment-free follow-up period. Throughout the treatment and posttreatment periods, participants returned to the study centers for safety and
efficacy assessments at weeks 1, 2, 4, 6, 8, 10, 12, 16
(end of treatment), 20, and 24 (end of posttreatment).
Efficacy evaluation
The primary objective was to evaluate the efficacy
of imiquimod 5% cream compared with vehicle in
the treatment of AK lesions when the cream was
applied 2 times per week for 16 weeks. Efficacy was
evaluated by clinically counting and recording the
number of AK lesions present in the treatment area
at the treatment initiation; at weeks 4, 8, and 16; and
at 8-week posttreatment visit.
The primary efficacy variable was the complete
clearance rate, defined as the proportion of participants at the 8-week posttreatment visit with a count
of 0 clinically visible AK lesions in the treatment
area. The secondary efficacy variable was the partial
clearance rate, defined as the proportion of participants at the 8-week posttreatment visit with at least
a 75% reduction in the number of AK lesions
counted at baseline in the treatment area.
Safety evaluation
Safety was monitored at every study center visit
by photographing the treatment area and by reviewing adverse events, local skin reactions, and concomitant medication use. All safety data were tabulated separately by treatment group.
Adverse events. Spontaneous participant-reported adverse events were categorized as follows:
mild, the participant was aware of the signs and
symptoms, but the signs and symptoms were easily
tolerated; moderate, the signs and symptoms were
sufficient to restrict, but not prevent, usual daily
J AM ACAD DERMATOL
MAY 2004
activity for the participant; and severe, the participant was unable to perform usual daily activity.
Local skin reactions. Local skin reactions are
adverse events that commonly occur in the treatment area. Data regarding local skin reactions were
collected independently of other adverse events.
Before the studies began, 7 local skin reactions were
identified for assessment by the investigator at each
study visit. They were clinically categorized as erythema, edema, erosion/ulceration, scabbing/crusting, weeping/exudate, vesicles, or flaking/scaling/
dryness. The severity of each local skin reaction was
rated by a study investigator on a scale of 0 to 3,
where 0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽
severe.
Clinical laboratory tests. At the prestudy visit
and the week-16 (end-of-treatment) visit, hematology (hemoglobin, hematocrit, red blood cell,
white blood cell, and platelet counts) and serum
chemistry (random glucose, blood urea nitrogen,
creatinine, total bilirubin, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic
transaminase, lactate dehydrogenase, alkaline
phosphatase, potassium, sodium, calcium, chloride, total protein, albumin, phosphorous, and
cholesterol) laboratory parameters were assessed.
In addition, urine specimens were analyzed for
color/appearance, specific gravity, pH, protein,
glucose, and ketones; a microscopic examination
was also performed.
Skin quality assessments. At the treatment initiation and 8-week posttreatment visits, the investigator performed a skin quality assessment of each
participant’s treatment area. Described characteristics included skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation
(both hyperpigmentation and hypopigmentation),
degree of scarring, and atrophy. After visual, clinical,
and tactile examinations of the treatment area, the
investigator coded the intensity of each characteristic on a scale of 0 to 3, where 0 ⫽ none, 1 ⫽ mild,
2 ⫽ moderate, and 3 ⫽ severe. If, for example,
atrophy was coded as mild and then later coded as
severe, that skin characteristic would have increased
in intensity.
Statistical analysis
The primary data set analyzed was the intent-totreat data set, which was composed of combined
data from 24 study centers and included all randomized participants. For each study, the sample size
was based on having at least 90% power to detect a
minimum clinically meaningful difference in complete clearance rates of 14% for the vehicle group
versus 35% for the imiquimod group, with a type I
Lebwohl et al 717
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VOLUME 50, NUMBER 5
Fig 1. Participant accountability for combined twice weekly application studies.
error rate of 0.05. There were no interim analyses or
stopping rules.
Treatment groups were compared with respect to
the complete clearance rate by means of the Cochran-Mantel-Haenszel test, which adjusted for the effects of multiple study centers. These efficacy analyses were also done for the partial clearance rate.
Fisher’s exact tests were used to compare treatment
groups with respect to the incidence of adverse
events, and Wilcoxon’s rank sum tests were used to
compare treatment groups with respect to the most
intense local skin reactions experienced by the participants. The Cochran-Armitage test for trend examined the data for relationships between complete
clearance and maximum intensity of local skin reactions. For laboratory parameters, Wilcoxon’s signed
rank tests were used to assess the significance of
within-treatment shifts and within-treatment
changes from baseline and Wilcoxon’s rank sum
tests were used to compare treatment groups with
respect to change from baseline. For skin quality
assessments, Wilcoxon’s signed rank tests were used
to assess the significance of within-treatment
changes from baseline. For participant demographics, Fisher’s exact tests were used to compare treatment groups with respect to sex, race, and skin type;
analysis of variance was used to compare treatment
groups with respect to age. All statistical analyses
were performed using software (SAS, Version 8, SAS
Institute, Inc, Cary, NC).
RESULTS
Study population
Between the two studies, a total of 623 people
were screened and 436 (217 in one study and 219 in
the other) were enrolled. Violations of inclusion or
exclusion criteria were the most common reasons
for study ineligibility. Overall, 215 participants were
randomized to treatment with imiquimod 5% cream,
and 221 were randomized to treatment with vehicle
cream. Participant accountability is shown in Fig 1.
There were no significant differences between treatment groups for age, sex, race, or Fitzpatrick skin
type (Table I).
Efficacy
Imiquimod 5% cream was statistically significantly better than vehicle with respect to the complete clearance rate (P ⬍ .001). A complete clearance rate of 45.1% (97 of 215) was achieved by the
imiquimod group, whereas the vehicle group had a
complete clearance rate of 3.2% (7 of 221). The
difference in complete clearance rates (imiquimod
minus vehicle) was 41.9% with a 95% confidence
interval of 34.9% to 49%. When examined separately, the complete clearance rates were very similar between the two studies. One study showed
718 Lebwohl et al
J AM ACAD DERMATOL
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Table I. Summary of participant demographics
Variable
Sex
Female
Male
Age (y)
Mean [SD]
Range
Race
White
American Indian
Skin type (Fitzpatrick)
I-II
III-VI
No. of baseline lesions
Median (range)
Imiquimod 5% cream
(n ⴝ 215)
28 (13%)
187 (87%)
Vehicle cream
(n ⴝ 221)
P value
28 (12.7%)
193 (87.3%)
1.00
65.5 [9.8]
37-88
.26
215 (100%)
0 (0%)
220 (99.5%)
1 (0.5%)
1.00
125 (58.1%)
90 (41.9%)
113 (51.1%)
108 (48.9%)
.15
6 (4, 10)
6 (3, 9)
.53
66.6 [10.6]
39-88
complete clearance rates of 45.8% (49 of 107) and
2.7% (3 of 110) for the imiquimod and vehicle
groups, respectively; whereas in the second study
the complete clearance rates were 44.4% (48 of 108)
and 3.6% (4 of 111) for the imiquimod group and the
vehicle group, respectively.
Partial clearance rates were also significantly better for the imiquimod group than the vehicle group
(P ⬍ .001). The partial clearance rates for the imiquimod and vehicle groups were 59.1% (127 of 215)
and 11.8% (26 of 221), respectively. The difference
in partial clearance rates (imiquimod minus vehicle)
was 47.3% with a 95% confidence interval of 39.5%
to 55.1%. Like the complete clearance rates, the
partial clearance rates were very similar between the
two studies. One study showed partial clearance
rates of 59.8% (64 of 107) and 10% (11 of 110) for the
imiquimod and vehicle groups, respectively;
whereas in the second study the partial clearance
rates were 58.3% (63 of 108) and 13.5% (15 of 111)
for the imiquimod group and the vehicle groups,
respectively. Both efficacy and safety results were
comparable between the two studies, and for this
reason the remaining results will be presented as
combined data.
At the 8-week posttreatment visit, the median
percent reduction in the number of AK lesions
counted at baseline was 83.3% for the imiquimod
group and 0% for the vehicle group. Therefore, half
of the participants in the imiquimod group had at
least an 83.3% reduction in the number of AK lesions
counted at baseline.
During the treatment period, 48% (103 of 215) of
the imiquimod group and 33% (72 of 221) of the
vehicle group had an increase in AK lesion count
(above the baseline level) at one or more of the
defined AK lesion count collection visits during the
treatment period. In the imiquimod group, those
with complete clearance had a slightly higher rate of
increased AK lesion counts during the treatment
period compared with those without clearance: 52%
(50 of 97) of participants with complete clearance
experienced an increase in AK lesion count compared with 45% (53 of 118) of participants without
complete clearance.
For the imiquimod treatment group, statistically
significant (P ⬍ .05) trends were found for erythema, edema, erosion/ulceration, weeping/exudate, and scabbing/crusting; specifically, the complete clearance rate increased as the severity of these
local skin reactions increased. No relationships were
significant for the vehicle group.
Safety
Adverse events. Adverse events were reported
by 77.2% (166 of 215) of participants who received
imiquimod and 63.8% (141 of 221) of participants
who received vehicle.
During the study, 6% (13 of 215) of participants
treated with imiquimod and 6.3% (14 of 221) of
participants who received vehicle reported at least
one severe adverse event. Application site reactions
(adverse events in the treatment area that were not
predefined) were the most frequently reported adverse events and were reported by 33% (71 of 215)
of participants on imiquimod and 14.5% (32 of 221)
of participants on vehicle. Adverse events that were
probably or possibly related to study cream were
reported by 34.4% (74 of 215) of participants on
imiquimod and by 14.9% (33 of 221) of participants
on vehicle. The most commonly reported application site reactions that were possibly or probably
Lebwohl et al 719
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VOLUME 50, NUMBER 5
Table II. Application site reactions possibly or probably related to study drug that were reported by at least 1%
of participants in the twice weekly studies
Application site reaction*
Itching at target site
Burning at target site
Bleeding at target site
Stinging at target site
Induration at target site
Pain at target site
Tenderness at target site
Itching at remote site
Burning at remote site
Irritation at remote site
Imiquimod 5% cream
2 d/wk
(n ⴝ 215)
Vehicle cream
2 d/wk
(n ⴝ 221)
P value
44 (20.5%)
12 (5.6%)
7 (3.3%)
6 (2.8%)
5 (2.3%)
5 (2.3%)
4 (1.9%)
7 (3.3%)
4 (1.9%)
3 (1.4%)
15 (6.8%)
4 (1.8%)
1 (0.5%)
2 (0.9%)
3 (1.4%)
2 (0.9%)
3 (1.4%)
3 (1.4%)
0 (0.0%)
0 (0.0%)
⬍.001
.04
.04
.17
.50
.28
.72
.22
.06
.12
*Target site refers to the treatment area; remote site refers to the area surrounding the treatment area and beyond.
related to study cream are listed by type in Table II.
A total of 30 serious adverse events, including one
death, were reported by 10 participants who received imiquimod and 8 participants who received
vehicle. None of the serious adverse events were
judged as related to study cream. In addition, two
participants randomized to treatment with imiquimod had local skin reactions or adverse events in
the treatment or surrounding areas that were suggestive of bacterial infection. Skin culture results,
coupled with the signs and symptoms that prompted
the skin culture, led to a clinical diagnosis of bacterial infection for one participant (⬍1%).
During the treatment period, 7 (3%) of the 215
participants who received imiquimod and 2 (1%) of
the 221 participants who received vehicle discontinued because of adverse events. Of these adverse
events, 4 were considered to be possibly or probably related to treatment (3 incidences of application
site reactions, and 1 incident of flu-like symptoms).
All 4 events considered possibly or probably related
to treatment were experienced by participants who
received imiquimod. No participants who received
vehicle (0%) discontinued from the treatment period
as a result of the adverse event of application site
reaction, and no participants discontinued from the
posttreatment period because of application site
reactions.
Local skin reactions. Local skin reactions were
common and occurred in both treatment groups.
Erythema was experienced by 97.2% (209 of 215) of
participants in the imiquimod group and 93.6% (206
of 220) of participants in the vehicle group. Severe
local skin reactions were experienced by participants randomized to treatment with imiquimod and
by participants who received vehicle; the rate of
severe local skin reactions was higher in the imi-
Table III. Incidence of severe local skin reactions
Type of local skin reaction
Imiquimod 5%
cream 2 d/wk
(n ⴝ 215)
Vehicle cream
2 d/wk
(n ⴝ 220*)
Erythema
Scabbing/crusting
Flaking/scaling/dryness
Erosion/ulceration
Edema
Vesicles
Weeping/exudate
38 (17.7%)
18 (8.4%)
16 (7.4%)
5 (2.3%)
0 (0%)
0 (0%)
0 (0%)
5 (2.3%)
4 (1.8%)
7 (3.2%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
*One participant in the vehicle group did not have an assessment of
local skin reactions after treatment initiation; consequently the denominator is 220 rather than 221.
quimod group. The most common investigator-assessed severe local skin reactions were erythema,
flaking/scaling/dryness, and scabbing/crusting (Table III). The local skin reactions shown in Fig 2, B,
represent typical responses to imiquimod 5% cream
and were generally well tolerated. Two participants
who received imiquimod (1%) and no participants
on vehicle (0%) discontinued from the treatment
period because of local skin reactions. No participants discontinued from the posttreatment period
because of local skin reactions.
Clinical laboratory tests. Changes in hematology parameters, particularly in platelet counts and
hemoglobin, were observed that showed a significant difference within and between treatment
groups. In addition, statistically significant withintreatment shifts in hemoglobin values from baseline
to the end of treatment (relative to the reference
range) were observed for the imiquimod group. The
standard errors of these significance tests were small
as a result of the large sample sizes, thus, making it
720 Lebwohl et al
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MAY 2004
Fig 2. A, Baseline count of 4 actinic keratosis (AK) lesions in treatment area (an approximation
of the treatment area is outlined). B, Treatment area with 6 AKs, mild flaking/scaling/dryness,
and moderate erythema after 4 weeks of treatment. C, Complete clearance at 8 weeks
posttreatment (0 lesions).
possible to detect small differences as statistically
significant. None of the changes were considered
clinically meaningful as they were minor and without clinical sequelae.
Skin quality assessments. In general, 2 times
per week dosing with imiquimod 5% cream did not
increase the intensity of skin quality characteristics.
In particular, at the end of the study less intense
assessments of the characteristic skin surface (ie,
roughness/dryness/scaliness) were noted in participants who received imiquimod. Of the 205 participants randomized to treatment with imiquimod who
had both initiation and 8-week posttreatment skin
surface assessments, 114 (56%) had a decrease in
roughness/dryness/scaliness at 8 weeks posttreatment compared with baseline, and 3 (1%) had an
increase in roughness/dryness/scaliness (P ⬍ .001).
For the 210 participants on vehicle, 46 (22%) had a
decrease in roughness/dryness/scaliness at 8 weeks
posttreatment compared with baseline and 30 (14%)
had an increase (P ⫽.20).
DISCUSSION
Imiquimod 5% cream is an effective and welltolerated treatment option for AK lesions on the face
and scalp. The results confirm earlier study results
and published anecdotes that showed imiquimod
5% cream was an effective treatment for AK. The
benefits of treatment with topical imiquimod 5%
cream include complete clearance of AK lesions for
45.1% of participants and partial clearance (ⱖ75%
reduction in the number of baseline lesions) for
59.1% of participants.
According to this protocol, participants who experienced resolution of 7 out of 8 lesions were
considered treatment failures because they did not
achieve complete clearance; however, the partial
clearance of most of their lesions would be considered clinically meaningful by both patients and physicians. Half of the participants treated with imiquimod experienced at least an 83% reduction in the
number of AK lesions counted at baseline. An additional benefit of treatment with imiquimod was that
it effectively uncovered and treated subclinical lesions. In fact, more than half of participants treated
with imiquimod who experienced complete resolution of their AK lesions also experienced an increase
in their AK lesion count during the study. This increase in lesion count was most likely a result of the
appearance of subclinical lesions rather than the
formation of new AK lesions.
Most of the participants who received imiquimod
had local skin reactions and one third of them reported application site reactions. The side effects
were consistent with local stimulation of an immune
response. Even though erythema was experienced
by more than 97% of participants in the imiquimod
group, most participants denied accompanying discomfort. In fact, only 2.3% and 5.6% of the participants in the imiquimod treatment group reported
pain and burning at the treatment site, respectively.
Imiquimod has been shown to stimulate the immune system by activating antigen-presenting cells
such as monocytes/macrophages and dendritic cells
to produce interferon and other cytokines and chemokines. The activation of Langerhans cells has
been shown to increase the recognition of antigens
expressed by actinically damaged cells.12 In addition, cytokines produced by various immune regulatory cells (eg, macrophages, monocytes, Langerhans cells) have been shown to result in an influx of
lymphocytes into the epidermis, an up-regulation of
tumor cell surface markers so they can be more
readily recognized by these lymphocytes, and an
up-regulation of the apoptotic signaling pathway
leading to individual AK cell death.13 This immune
response was evident in the local skin reactions
experienced by participants treated with imiquimod.
The cutaneous immune response has been
shown to play an important role in the transformation of AK into invasive SCC.14 Therefore, the stim-
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VOLUME 50, NUMBER 5
ulation of the immune response by imiquimod could
potentially decrease the transformation rate of AK
into invasive SCC. Similarly, induction of a cellmediated response could theoretically decrease the
recurrence rate or the rate of new AK lesion formation in the treated areas.
Although the results of this study provide important information on an additional treatment option in
the management of AK, there are some limitations
that need to be addressed. The patient population
studied was selected to represent the typical patient
who presents to a dermatologist for treatment of AK
lesions. Patients with extensive disease were not
evaluated in this study and, therefore, extrapolation
of the complete and partial clearance rates may not
be valid for this patient population. Although the
study design was double blind, the pharmacodynamic effect of the imiquimod treatment likely increased the observation bias. However, this bias is
inherent in studies where there is an observable
pharmacodynamic response. Because the primary
objective of this study was to evaluate the efficacy of
imiquimod treatment, no long-term follow-up period was incorporated into this study. The long-term
safety and recurrence rate need to be evaluated in a
long-term follow-up study. Finally, patient-centered
outcomes were not collected and need to be addressed in future studies.
In conclusion, the results of this study demonstrate that imiquimod 5% cream is an effective and
safe treatment for AK. Imiquimod 5% cream is a
topical, patient-applied product that offers both the
patient and clinician a unique therapeutic approach.
We thank Nanda Gosala, MD, for medical monitoring;
Mary Owens, MD, for editorial contributions; Scott McKane for statistical analyses support; and Áine Skow for
manuscript preparation.
The following are principal investigators who participated in the study: Scott Dinehart, MD (coordinating investigator); Mark Lebwohl, MD (coordinating investigator); Donald Belsito, MD; Robert Brown, MD; Charles
Dugan, MD; Richard Fitzpatrick, MD; Scott Fosko, MD;
Lebwohl et al 721
Glenn Goldman, MD; William Harwell, MD; Joseph
Jorizzo, MD; Richard Langley, MD; Peter Lee, MD, PhD;
Nicholas Lowe, MD; David McDaniel, MD; Ida Orengo,
MD; Yves Poulin, MD; Ronald Rapini, MD; Leonard
Swinyer, MD; David Tashjian, MD; Naji Tawfik, MD, PhD;
John Toole, MD; Jeffrey Weinberg, MD; David Whiting,
MD; and Paul Yamauchi, MD, PhD.
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