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http://jst.sciedupress.com Journal of Solid Tumors 2019, Vol. 9, No. 1
ORIGINAL ARTICLE
Actinic keratosis prevention – A double-blind,
half-face interventional study with a topical treatment
Elisabetta Sorbellini1, Barbara Marzani2, Daniela Pinto2, Fabio Rinaldi∗1
1International Hair Research Foundation, Milan, Italy
2Giuliani S.p.A. R&D, Milan, Italy
Received: September 19, 2018 Accepted: November 18, 2018 Online Published: November 29, 2018
DOI: 10.5430/jst.v9n1p1 URL: https://doi.org/10.5430/jst.v9n1p1
ABS TR ACT
Actinic keratosis (AK) is a chronic and recurrent disease and in this double-blind, half-face, placebo controlled study we attempted
to examine the efficacy of a topical treatment containing 2,4,6-octatrienoic acid and anthraquinone knipholone for the prevention
of new AK lesion formations. New lesion onset was detected with methyl-5-aminolevulinic acid and Wood’s lamp after 6 months
of treatment (T1) and 12 months after treatment end (T2). Absence of new lesion at T1, was 86.11% in active treatment side
while 77.78% in placebo side. At T2 the percentage was higher in skin treated with active product (83.33%) compared to placebo
(63.89%). Taking into consideration the number of new lesions during the study period, at T1 the new AK lesions were not
statistically significantly influenced by the treatments, while at T2, AK lesions were detected in 30.55% of placebo-treated area
while in the contralateral part the lesions were 13.89%. The reduction induced by active treatment was statistically significant.
The product containing 2,4,6-octatrienoic acid and anthraquinone knipholone is effective in reducing new AK lesion formation in
subjects with a history of AKs.
Key Words: Actinic keratosis prevention, Actinic keratosis lesion onset, 2,4,6-octatrienoic acid, Anthraquinone knipholone
1. INTRODUCTION
Actinic keratosis (AK) is the most common diagnosed in
the outpatient setting
[1]
and the most common in situ can-
cerous skin lesion
[2]
characterized by intraepithelial atypical
proliferations of keratinocytes.[3]
Clinically, the lesions are presented as erythematous or flesh-
colored, multiple, palpable macules, papule or plaques with
a size from few millimeters to > 2 cm.
[4, 5]
Telangiectasia
and verrucous keratotic lesions could constitute other less
reported clinical presentations.
[4]
Mainly, AK lesions are
asymptomatic, but some subjects report discomfort, such as
burning sensation or itch.[6]
AK lesions can be classified, based on their appearances as
atrophic, hypertrophic, pigmented, proliferative, lichenoid,
acantholytic or Bowenoid.
[7]
One of the major concern about
this pathology is that any single AK lesion can evolve in in-
vasive squamous cell carcinoma (SCC) and it is not possible
to foresee the specific lesion progression. The situation is
further complicated by spontaneous remission or stabiliza-
tion. From an epidemiological point of view, data underline
AK prevalence in fair-skinned subjects and in high-level sun
exposure body areas. Even if probably underestimated, the
incidence of AK is reported to be 16%-25% in USA, while
> 20% in Europe.[8]
Studies of AK prevalence in Europe are limited, currently
few data ara available on Spain, Germany, Netherlands. Only
∗Correspondence: Fabio Rinaldi; Email: fabio.rinaldi@studiorinaldi.com; Address: International Hair Research Foundation, Milan, Italy.
Published by Sciedu Press 1
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two studies are available on Italian population where the
prevalence rates vary greatly. The first one reported an AK
prevalence of 1.4% with a higher incidence in Sicily and
Sardinia;
[9]
while the second one, hospital-based, reported a
prevalence of 27.4% in dermatology outpatients.[10]
Since skin area affected by AK is the chronically sun-exposed
area, chronic long-term solar radiation exposure represents
the major AK risk factor.
[11]
Other reported risk factors are
specific phenotypic characteristics such as Fitzpatrick skin
types I-III, photodamages (i.e. facial wrinkles), age and the
number of hours spent in the sun.
[12–14]
The last factor has
also a strong impact on public health for outdoor workers due
to their great occupational UV exposure. As a consequence,
some Countries are working on to find and adopt strategies
for decrease the potential incidence of this occupational dis-
ease.
Cumulative UV radiation induces DNA damage in ker-
atinocyte creating genetically unstable cells, inactivating
functional repair genes, such as p53, and inducing oxidative
stress through the reactive oxygen species (ROS) production.
UV-damages not only can give rise to AK, but represent also
the common risk factor in progression of AK to SCC.
[15]
Although this risk is considered relatively low and uncertain,
the range is up to 0.53% in subjects with a history of non-
melanoma skin cancer, while the rate of lesion regression
after one year is 15%-63% and the recurrence rate of lesions
between 15%-53%.[16]
AK-derived photodamage can be extended from the le-
sional area to surrounded zone affected by subclinical al-
terations.
[17]
The concept of “field cancerization” describes
the area of molecular alterations observed in a chronical
photodamage skin with several foci of non-melanocytic cu-
taneous neoplasm.
[18]
All stages of AK progression can be
present: from UV-damage keratinocytes, subclinical lesions
(non-visible, non-palpable), early or late clinical lesions, and
eventually SCCs.
[18]
After the surgery for the primary AK
lesion, the imperative clinical action is addressed to treat
the entire field cancerization in order to reduce the lesion
recurrences and prevent new lesion development.
[18]
Many
effective field-directed therapeutic options are available but
the side effects, such as inflammation risk, scarring, dyschro-
mia can potentially decrease patient treatment adherence.
As a consequence, there is a growing need for novel preven-
tive strategies.The aim of this clinical study was to evalu-
ate the efficacy and tolerability of a topical cosmetic treat-
ment containing 2,4,6-octatrienoic acid and anthraquinone
knipholone in the prevention of new AK lesion onset. Le-
sions were monitored by means of fluorescence diagnosis
by coupling topical application of methyl ester of aminole-
vulinic acid (MAL) to Wood’s UV lamp with the aim to
detect occult areas of abnormal skin.
[3, 19, 20]
Previous pre-
clinical studies reported the capacity of 2,4,6-octatrienoic
acid to counteract photo-senescence in human fibroblast,
increasing the biological antioxidant potential and the ex-
pression and activity of antioxidant enzyme catalase.
Moreover, in UV-irradiated normal human keratinocytes
2,4,6-octatrienoic acid showed a protective effect against
UVA and UVB-induced damage and induction of DNA repair
mechanisms.
[21]
Anthraquinone knipholone from Bulbine
frutescens extract is also included in the topical formulation
as a selective inhibitor of leukotriene metabolism activated
by UV damage.[22]
2. MATERIALS AND METHODS
The study has been conducted according to the principles of
the Declaration of Helsinki and was performed in Milan on
subjects residing in Lombardy region, Italy.
2.1 Study population
Eligibility criteria for study participation included: male and
females 50 to 75 years of age with Fitzpatrick skin types I–III,
skin photodamage grade >3
[23]
with at least 1 treated AK
lesion in the past in sun-exposed area (scalp, face, decolletè)
but the absence of AK lesions at the study inclusion.
Subjects were excluded from the study if within the six
months before they received treatment interfering with the
evaluations: facial chemical peel, or any other resurfacing
procedure, botulinum toxin, facial fillers, immunosuppres-
sive or immunomodulation agents, oral retinoids. Subjects
were instructed to self-apply 1/day the 2 products on the half
face, not to use any facial products nor procedures during the
study.
2.2 Study design
In this double-blind placebo controlled trial, 36 eligible sub-
jects applied the active product (2,4,6-octatrienoic acid, an-
thraquinone knipholone and excipients) to one-half of their
face and placebo (excipients) to the opposite side, once daily
for six months.
Subjects were asked to continue their normal life style during
the study including the sun protection habits, and in case of
sun, exposition to report any sun burn or erythema event.
Moreover, during the study, a commercial sunscreen (Licht-
ena R
Dermosolari SPF 50+) was provided to all subjects.
Investigator assessments of new pre-cancerous lesions and
tolerance were conducted at Baseline (T0), after 6 months
of treatment (T1) and 12 months after treatment end (follow
up, T2). Digital photographs of the left and right sides, der-
2ISSN 1925-4067 E-ISSN 1925-4075
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matoscopic evaluation of the whole face were also taken at
all visits.
All subjects underwent diagnosis with photodynamic technic
with methyl-5-aminolevulinic acid (MAL) and Wood’s lamp.
MAL 5% was topically applied in occlusion condition for
30 minutes (modified by Cubeddu et al., 1999).
[19]
Then,
the use of Wood’s ultraviolet lamp permits the detection of
cutaneous lesions as pink fluorescence in the presence of
activated protoporphyrin IX from MAL. Prior treatment, the
patient skin photodamage and absence of pre-cancerous le-
sions were assessed by the examining physicians. Each side
was assessed separately.
2.3 Study endpoints
2.3.1 Efficacy
Investigator evaluations for the presence and new forma-
tion of pre-cancerous lesion on the left and right sides were
graded separately. The pre-cancerous lesions were graded us-
ing a noninvasive fluorescence diagnosis by means of MAL
5% and Wood’s lamp.[19]
2.3.2 Safety
Tolerance was assessed by investigators at T1 and T2 by
objective irritation parameters (including erythema, edema,
and scaling) on a four-point scale where 0 = none, 1 = mild,
2 = moderate, and 3 = severe; and the reporting of adverse
events.
2.3.3 Statistical analysis
All values were expressed as mean
±
standard error of mean
(SEM). Results were checked for normal distribution using
Shapiro-Wilk test before further analyses. Statistical differ-
ences between groups were carried out by Welch’s
t
-test,
using GraphPad Prism version 7.00 for Windows (GraphPad
Software, La Jolla California USA, www.graphpad.com).
p
–values equal to or less than .05 were considered signifi-
cant.
3. RES ULTS
36 subjects were enrolled in the study, 14 men and 22 women
(38.9% and 61.1%, respectively). The mean age was 61
±
6
years (see Table 1).
Table 1. Age and gender distribution in patients
Gender N Mean age (SEM)
Female 22 61.64 (6.40)
Male 14 61.57 (6.06)
All subjects concluded the study and no side effect was re-
ported by the patient or by physician evaluation by means of
objective irritation parameters.
After 6 months of treatment (T1), the clinical benefit, rep-
resented by absence of new lesion, in area treated with ac-
tive product was 86.11% (90.91% women and 78.57% men)
while the placebo side, the clearance was 77.78% (77.27% of
women and 71.43% of men). At follow-up, 12 months after
end of treatment (T2), the frequency of sustained cleared
lesions was higher in skin area treated with active product
(83.33% of subjects, 90.91% women and 71.43% men) com-
pared to placebo effect (63.89% of subject, 68.18% of women
and 57.14% of men) (see Table 2).
Table 2. Clinical benefit during the study period
Clearance rate
%
Sustained clearance rate
%
T1 T2
Active side
Men 78.57 71.43
Women 90.91 90.91
Total 86.11 83.33
Placebo side
Men 71.43 57.14
Women 77.27 68.18
Total 77.78 63.89
In particular, as regard the appearance of new lesions, after
6 months of treatment (T1), new AK lesions were present
in 25% of area treated with placebo (4 men and 5 women)
while, 13.89% in the face zone treated with active product
(3 men and 2 women). At T1 the mean (
±
SEM) number of
new AK lesion was not statistically significantly influenced
by the treatments. At T2, after 12 months from treatment end,
AK lesions were detected in 30.55% of placebo-treated side
(in 5 men and 6 women) while 13.89% in the contralateral
treated side (in 3 men and 2 women) (see Table 3).
Table 3. New lesion in the face area treated with active
product and contralateral part treated with placebo
Subjects with new lesion (number)
T1 T2
Active side
Men 3 3
Women 2 2
Total (%) 13.89 13.89
Placebo side
Men 4 5
Women 5 6
Total (%) 25 30.55
Published by Sciedu Press 3
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The AK mean (
±
SEM) number measured during the follow-
up in placebo area shown the disease progression, while
active treatment induced a statistically significant reduction
in the new AK formation (p< .05, see Figure 1).
Figure 1. Mean ±SEM of AK lesion detected at T1 (6
months of treatment) and T2 (12 months after the treatment
end) in 36 subjects treated half face with placebo and
contralateral half face with active product. ∗p< .05 active
treatment vs. placebo treatment.
4. DISCUSSION
AK is extremely frequent in dermatological clinical prac-
tice. AK treatment needs to reduce the risks of progression,
but complete lesion clearance is rarely achieved in real-life
practice.
[24]
Because of its chronicity, AK presents a high
recurrence rate despite the previous treatment received.
[8]
Recurrence of lesions was reported in 65% of subjects 1 year
after 5-Fluorouracil (5-FU) treatment;
[25]
a range from 17.4
to 39% of recurrence 1 year after Imiquimod treatment;
[25, 26]
while 54%-56% in Ingenol mebutate treated patients, after 1
year.[27]
In any case, field-directed treatments are essential to address
subclinical damage and reduce AK recurrence rates and po-
tentially reduce the risk of SCC development.[28–31]
The AK development is due to damages from chronic sun
exposure and because of its potential progression to invasive
squamous cell carcinoma, treatment and preventive measures
are required.
Some efforts have been done to prevent AK lesions and pro-
gression, the use of sunscreen is one of this measure. In a
randomized controlled trial, it was evaluated the regular use
of sunscreen and the new keratosis appearances in Australian
subjects during summer. The data showed that regular use
of sunscreen prevents the formation of new keratosis and
accelerate the remission of present lesions.
[32]
Another study
confirmed that regular application of sunscreen delays the
new lesion formation.[33]
However, sunscreen seems not able to reduce the BCCs
incidence,
[34]
so many other attempts are made for an alter-
native form of chemoprevention. Sunscreen use and patient
education are the first line prevention strategy, but not the
only. An interesting study was conducted by Elments and
colleague
[35]
in which the drug Celecoxib, an inhibitor of
cyclooxygenase,
[2]
was effective in SCC prevention, but not
in the modulation of new AK formation.
The Italian studies
[9, 10]
were preparatory for our investiga-
tion and in particular to subject selection: we decided to limit
our patient inclusion to a single Italian region, Lombardy, in
order to have a more homogeneous population in terms of
habits, general sun irradiation and lifestyles.
Due to the formulation characteristic, cosmetics can be used
in the management of AK lesions, i.e. the unappealing aspect
of the AK lesions can be improved by cosmetic emollients
with an effect on patient comfort by means of skin dryness
and roughness reduction.[36]
The cosmetic for its intrinsic nature is more easy to use: not
particular recommendations or indications are needed. Sun-
screen use is recommended by different Guidelines for the
AK prevention and management, but often the real consumer
use condition makes the photoprotection inefficacy due to:
the low amount product applied (with a significative reduc-
tion in sun protection, up to 25% of labeled SPF),
[37]
and low
compliance to this type of cosmetics.
Previous
in vivo
assays demonstrated the capacity of 2,4,6-
octatrienoic acid to protect and counteract UV-induced DNA
damage. Pre- or post-treatment with 2,4,6-octatrienoic acid
accelerate DNA repair decreasing cyclobutane-pyrimidine
dimers, 7,8-dihydro-8-oxoguanine, and levels of phosphory-
lated histone H2A.X, associated with the amount of DNA
double-strand breaks by UV radiation.[38]
The performed study shows that the use of a topical formu-
lation containing 2,4,6-octatrienoic acid and anthraquinone
knipholone for 12 months could help the reduction of new
AK lesions formation, decreasing also skin photo-aging in
treated subjects.
5. CONCLUSION
As a chronic disease, AK treatment need a long-term dis-
ease control and prevention. It is of primary importance to
find new products to delay the recurrence and new lesion
formation in the skin sun damaged areas.
In this double-blind trial, the product containing 2,4,6-
octatrienoic acid and anthraquinone knipholone is effective
in reducing new AK lesion formation in subjects with a his-
tory of AKs in “real life condition”.
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Further studies with longer follow up are necessary to con-
firm treatment prolonged efficacy.
Therefore, based on our experience, secondary prevention
by a cosmetic product should be extended in dermatological
practice to minimized the photo-induced skin damage and to
prevent recurrence in patients with a history of AK.
Patient regular monitoring, with at least a yearly consulta-
tion, can be performed by means of fluorescent detection by
Wood’s lamp and MAL (5%), an essential noninvasive diag-
nostic tool. This method is extremely helpful in permitting
the detection of otherwise occult areas of abnormal skin with
the advantage of
in vivo
tissue examination reducing the
biopsy need and it is well accepted by patients.
CON FLI CT S OF INTEREST DISCLOSURE
R.F. serves as a consultant for Giuliani S.p.A. P.D. and M.B.
are employed by Giuliani S.p.A.
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