Review

Treating skin cancer with topical

cream
Giuseppe Micali, Francesco Lacarrubba, Franco Dinotta,
Doriana Massimino & Maria Rita Nasca
1. Introduction University of Catania, Dermatology Clinic, Catania, Italy
2. Fluorouracil
Importance of the field: Topical pharmacotherapy is an approach to consider
3. Imiquimod
in selected skin cancers. Noninvasive, tissue-sparing, topical, self-administered
4. Diclofenac
treatments represent a highly desirable alternative option, both in aged and
5. Retinoids unhealthy patients who may be poor surgical candidates, as well as in rela-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13

6. Conclusions tively young subjects with lesions located on cosmetically sensitive areas wish-
7. Expert opinion ing to avoid disfiguring scars. This paper reviews and discusses the use of
topical pharmacotherapy in the treatment of skin cancer.
Areas covered in this review: This paper examines the existing literature and
updates current knowledge of topical pharmacotherapy for skin cancer using
fluorouracil, imiquimod, diclofenac and retinoids.
What the reader will gain: There is a gap between current and best practice in
that the use of pharmacotherapy in the treatment of skin cancer is only par-
tially known. The purpose of this paper is to provide an in-depth knowledge
on this topic; consequently, the readers should be able to consider new
strategies in their practice.
For personal use only.

Take home message: Topical pharmacotherapy represents an option for treat-

ment of actinic keratoses and selected basal cell carcinomas. Moreover, prelim-
inary reports indicate imiquimod to be effective for skin or mucosal cancers
such as Bowens disease, erythroplasia of Queyrat and lentigo maligna.

Keywords: cancer, diclofenac, fluorouracil, imiquimod, pharmacotherapy, retinoids, skin

Expert Opin. Pharmacother. (2010) 11(9):1515-1527

1. Introduction

Treatment of skin cancer includes several options such as surgery (conventional

excisional and Mohs micrographic surgery), physical therapy (electrodesiccation/
curettage, cryosurgery, CO2 laser and radiation therapy) as well as photodynamic
therapy (PDT) and pharmacotherapy, both topical and systemic. Regardless of
the approach, removal of the tumor, preservation of function and good cosmetic
outcome represent treatment end points [1,2].
Topical pharmacotherapy represents an option for treatment of both actinic ker-
atoses and select basal cell carcinomas (BCCs). Moreover, some topical treatments
are reported as useful for skin or mucosal cancers such as Bowens disease, erythro-
plasia of Queyrat and lentigo maligna. Indications for topical pharmacotherapy
include extensive, multifocal, multiple tumors, indistinct lesion boundaries, locali-
zation in cosmetically sensitive areas (e.g., face), history of hypertrophic scarring
and/or keloids, surgical risk factors (age, associated diseases) and patient preference
to avoid invasive procedures.
In this review, evidence from the literature on topical pharmacotherapy of skin
cancer with fluorouracil, diclofenac, imiquimod and retinoids are analyzed. Their
proper use and indication are summarized and discussed.

10.1517/14656566.2010.481284 2010 Informa UK Ltd ISSN 1465-6566 1515

All rights reserved: reproduction in whole or in part not permitted
 Treating skin cancer with topical cream
Article highlights.
. Topical pharmacotherapy offers effective alternative
treatments for skin cancer, although careful patient
selection is required to achieve the desired goal of
complete tumour clearance.
. Topical pharmacotherapy deserves first-line treatment
status for actinic keratoses, especially in consideration of
the field cancerization phenomenon.
. Imiquimod 5% cream represents the more versatile
agent: although FDA-approved for only actinic keratoses
and superficial basal cell carcinomas (BCCs), its
off-label use supported by numerous studies includes
nodular BCCs, Bowens disease, erythroplasia of Queyrat
and lentigo maligna, with excellent outcome.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
. An important issue that needs to be highlighted is the
frequent occurrence of moderate to severe application-
site irritation during imiquimod therapy; however, this
reaction is a good predictor of the therapeutic effect
and expert physicians can easily manage it without
further complications.
. Fluorouracil has demonstrated in controlled studies to be
effective in actinic keratoses and superficial BCCs.
. Diclofenac 3% gel in 2.5% hyaluronic acid (DHA),
whose efficacy is at present limited to actinic keratoses,
is considered a well-tolerated treatment by most
patients, with side effects at application sites
considerably lower compared with other treatments.
For personal use only.
This box summarizes key points contained in the article.
2. Fluorouracil
Topical fluorouracil is the most extensively studied topical
chemotherapeutic agent. As an antimetabolite and structural
analogue of thymidine, it hinders thymidylate synthetase
and interferes with DNA and RNA synthesis in dividing cells,
resulting in cell death [3-5].
Topical fluorouracil 5% is FDA-approved for the treat-
ment of actinic keratoses and superficial BCCs. Efficacy in
the treatment of Bowens disease has been reported [3].
2.1 Actinic keratoses
Topical effectiveness in the treatment of actinic keratoses was
first demonstrated in the 1960s [6], and subsequently con-
firmed by several open trials, dose-ranging studies and
randomized controlled trials (RCTs) [3-6].
Reduction in the number of actinic keratoses is achieved by
topical fluorouracil 5% twice daily for 2 -- 4 weeks, depending
on the treatment site and patient sensitivity. In two random-
ized trials, fluorouracil 5% cream applied twice daily for
3 weeks on the dorsum of the hands [7] and on the face [8]
resulted in a mean reduction in actinic keratoses of 70 and
78% respectively [7,8]. Less aggressive regimens are reported
in order to enhance patient tolerance and compliance. Less
frequent but more prolonged applications (only once or twice
a week for 6 -- 7 weeks), or lower potencies (1%, or dilution
to 0.5%), have been suggested as possible alternatives; but
1516 Expert Opin. Pharmacother. (2010) 11(9)
efficacy compared with standard formulations is unclear [9].
In some studies, fluorouracil 0.5% formulation is as effective
as fluorouracil 5% concentration, based on percentage reduc-
tion and complete clearance of actinic keratoses from
baseline [3,4,10-13]. Also, topical fluorouracil 0.5% achieves
good patient compliance owing to reduced frequency of
excessive skin reactions at application sites [10]. In a study of
207 subjects, a microsphere formulation of fluorouracil
0.5% applied once daily for 1, 2 or 4 weeks was more effective
than vehicle in achieving actinic keratose clearance (15, 37,
58 and 0%, respectively) [12]. In another similar double-blind,
multicenter, parallel-group study, in which 177 participants
were randomized to receive fluorouracil 0.5% once daily for
1, 2 or 4 weeks, patients achieved 100% clearance (26.3,
19.5 and 47.5%, respectively, vs 3.4% of controls) [14].
A recent systematic review including 13 RCTs, evaluated
fluorouracil short- and long-term efficacy at different dosing
regimens and compared these results with other available treat-
ments [5]. Fluorouracil 5% cream was effective in 49.0% of
patients and achieved 100% clearance of lesions, compared
with 34.8% of the 0.5% formulation. Moreover, treatment
with 5 and 0.5% resulted in an average reduction of 79.5
and 86.1%, respectively, in the number of lesions.
One randomized study compared the efficacy rates of
fluorouracil 5% (twice daily for 4 weeks), imiquimod 5%
(3 times/weeks for 4 -- 8 weeks) and cryosurgery (1 -- 2 courses)
in patients affected by actinic keratoses. Complete clinical
clearance at the end of the treatment was achieved by 96,
85 and 68% of patients, respectively [15]. In a 12-month
follow-up, 33% of subjects sustained clearance for fluorouracil,
73% for imiquimod, and only 4% for cryosurgery [15]. This
study also evaluated cosmetic outcome, reporting no significant
difference between fluorouracil and imiquimod after 3 months
of therapy; while at a 12-month follow-up, imiquimod
reported a better cosmetic profile than both fluorouracil and
cryosurgery in terms of scarring, atrophy and induration [5,15].
2.2 Basal cell carcinoma
Topical fluorouracil 5% cream was the first FDA nonsurgical
treatment approved for superficial BCCs, though few con-
trolled studies are published [3]. A double-blind, randomized
trial evaluated the effectiveness of fluorouracil 5% cream in
treating BCCs using two different vehicles designed to enhance
penetration and efficacy [16]. In this study, 13 subjects with
17 biopsy-proven BCCs were randomized to receive either fluo-
rouracil 5% in a phosphatidyl choline vehicle or fluorouracil
5% in a petrolatum-base. Treatments were applied twice a
day for 4 weeks and resulted in a 90% cure rate (9/10), both
clinical and histologic, for lesions treated with phosphatidyl
choline formulation, compared with a 57% cure rate (4/7) in
those treated with the petrolatum-based vehicle [16].
In a more recent, single-arm evaluation of 31 superficial
BCCs treated with fluorouracil 5% cream applied twice daily
for up to 8 -- 12 weeks, 90% of lesions showed complete
histologic clearance [17].

2.3 Bowens disease
Topical fluorouracil is successfully used for the treatment of
Bowens disease, particularly in cases of multiple lesions or
where lesions are located in areas difficult to treat with con-
ventional surgery. Twice-daily application of 5% fluorouracil
formulation is recommended for up to 8 weeks or longer to
provide satisfactory results with low recurrence rates [18,19].
In an open-label study, 24 subjects with 26 biopsy-
confirmed lesions of Bowens disease were treated with topical
fluorouracil 5% twice daily for up to 9 weeks. Complete clear-
ance was observed in 92% of subjects (24 of the 26 lesions),
with an average duration of follow-up at 55 months.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
Post-treatment biopsies were performed in 18/26 cases,
and 17 of the 18 histological specimens showed evidence of
resolution [20].
In a randomized trial comparing fluorouracil with PDT,
fluorouracil 5% cream applied once daily for 1 week and
twice daily for 2 -- 4 weeks resulted in a clearance rate of
48 versus 82% for PDT at 12-month follow-up [21].
Interestingly, some authors have noted an increased effec-
tiveness of fluorouracil when used in combination with
other therapeutic modalities (imiquimod, systemic retinoids,
cryotherapy and PDT) [18,19].
For personal use only.
2.4 Safety
Topical fluorouracil cream has an acceptable safety profile
based on RCT evidence. The most common adverse effects
reported during treatment include erythema, irritation, burn-
ing, dryness, pain, pruritus and hypo- or hyperpigmenta-
tion [3]. These symptoms typically present at the application
site within 5 -- 10 days of treatment initiation and progres-
sively improve as application frequency is reduced or treat-
ment is discontinued. Allergic contact dermatitis has been
reported [4]. Systemic toxicity is rare since fluorouracil absorp-
tion rate is low through fully keratinized skin. Fluorouracil
should not be used in women who are or may become
pregnant, since it is teratogenic and classified as pregnancy
category X.
3. Imiquimod
Imiquimod is an immune response modifier with antiviral,
antitumor and antiangiogenic activity, first approved by
the FDA in 1997 for topical treatment of external genital
and perianal warts, and later for actinic keratoses and
superficial BCCs.
The mechanism of action of imiquimod is primarily related
to its activity upon toll-like receptors (TLR) 7 and 8 of antigen-
presenting cells, which are involved in the modulation of both
innate and acquired immunity pathways [2,22-27]. Imiquimod,
by binding TLR-7, stimulates production and release of
several endogenous cytokines and chemokines, which, in
turn, enhance and perpetuate cell-mediated immune response
involving CD4+ and CD8+ T lymphocytes, resulting in
imiquimod antitumor and antiviral activity [22-24,28,29]. Recent
Expert Opin. Pharmacother. (2010) 11(9)
Micali, Lacarrubba, Dinotta, Massimino & Nasca
studies have suggested an additional TLR-independent func-
tion, related to the suppression of adenylyl-cyclase, which is
thought to be important for the control of viral infections and
tumors. Moreover, imiquimod may be involved in the produc-
tion of proapoptotic signalling in tumor cells via death receptor
pathways, including Fas receptor [30]. Several studies have
demonstrated imiquimod antiangiogenic property due to the
production of various cytokines and have provided evidence
for inhibition of pathological growth of new vessels [31].
There are several studies evaluating the efficacy of imiqui-
mod in the treatment of actinic keratoses, BCCs, Bowens
disease and lentigo maligna.
3.1 Actinic keratoses
Imiquimod is a topical FDA-approved treatment for face and
scalp actinic keratoses in immunocompetent individuals. It is
used as a 5% cream three times a week for 4 weeks. Additional
treatment may be required for those patients who do not
completely clear. The treatment site should not be cleansed
for at least 8 h after imiquimod application. Increasing the
dosing frequency to more than three times a week has been
associated with a concomitant increase in the number of
patients discontinuing the treatment because of excessive
application site irritation [32,33].
Multiple controlled studies have confirmed its short-
term efficacy in reducing the number of actinic kerato-
ses [32,34]. Overall clinical clearance rates from these studies
ranged from 45 to 57% in the imiquimod arm versus 2 to
15% in the placebo group, respectively [32].
In a meta-analysis study [35] including five RCTs, imiqui-
mod 5% cream was found to achieve complete clearance in
50% of patients compared with 5% in the placebo group.
In another meta-analysis study [36] consisting of four RCTs,
imiquimod 5% cream or vehicle was applied three times a
week for up to 16 weeks in two studies and 12 weeks in one
study, while the fourth study adopted a twice-weekly applica-
tion regimen for 16 weeks. The data showed complete clinical
and histologic (only two studies) clearance of actinic keratoses
ranging from 45 to 84% in patients treated with imiquimod
compared with 0 -- 7% in the vehicle groups (p < 0.0001).
In a third meta-analysis study [37] comparing topical
imiquimod with topical fluorouracil, a relatively higher effi-
cacy of imiquimod 5% than that of fluorouracil (0.5,
1 and 5%) has been demonstrated for actinic keratoses loca-
ted on face or scalp. The mean efficacy rate for each drug
was 70 12% for imiquimod compared with 52 18%
for fluorouracil.
Topical imiquimod long-term efficacy has been demon-
strated in one study in which 36 subjects were randomized to
receive either imiquimod or control vehicle (one application
3 times/week). Complete clinical and histologic clearance at
12 weeks was observed in 84% of the treatment group. Twelve
months after treatment, two subjects (8%) in the treatment
group reported clinical recurrence. The imiquimod group
was reviewed at a 2-year follow-up. Of these, 16% developed
1517
 Treating skin cancer with topical cream
new actinic keratoses after 18 months and 20% reported new
lesions after 24 months [38].
Recently, an RCT involving 20 subjects investigated
imiquimod efficacy and safety of a lower dosing regimen
(once-weekly applications for 24 weeks). Although the
imiquimod-treated group improved compared with the pla-
cebo arm, overall data showed a lower cure rate with placebo
(6.7%) compared with the active regimen [39].
Interestingly, clinical and histologic clearance correlates
with irritation at the application site, indicating a major role
of inflammation in imiquimods mechanism of action [36,38].
Imiquimod has been combined with other therapeutic
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
options (cryotherapy, fluorouracil), to increase efficacy [34].
A recent clinical trial [40], concluded favorably on the use of
5% imiquimod combined with fluorouracil as it was found to
increase clinical clearance and reduce recurrence rate of actinic
keratoses. Nevertheless, optimal frequency of application and
duration of treatment need further elucidation.
3.2 Basal cell carcinoma
Topical imiquimod 5% cream is licensed by the FDA for the
treatment of superficial BCCs. In a Cochrane Skin Group anal-
ysis including seven RCTs, imiquimod was found to be effec-
tive and safe in the treatment of both superficial and nodular
For personal use only.
BCCs, although response rates varied according to therapeutic
regimen and tumor type (superficial vs nodular) [41].
A European multicenter RCT [42] evaluating imiquimod
(7 times/week for 6 weeks) clinical efficacy versus vehicle con-
cluded that cure (based on both clinical and histologic clear-
ance) was achieved in 77 versus 6% of cases (p < 0.001) and
that histologic clearance occurred in 80 and 6% respectively
(p < 0.001).
Various imiquimod treatment regimens have been used
with positive outcomes. A multicenter 6-week dose-response
trial [43] evaluating different dosing schedules in 99 subjects
treated with imiquimod 5% cream showed higher histologic
clearance rates for twice-daily applications six times a week
(100%) compared with a less frequent dosing regimen (88,
73 and 70% for once-daily, 6-times-weekly and 3-times-
weekly regimens, respectively). Another RCT reported similar
results showing decreasing histologic clearance rates (100, 87,
81 and 52%) for less frequent applications (respectively twice-
daily, once-daily, 5 days/week and 3 days/week); clearance
rate for vehicle was 19% [44]. In one study designed to com-
pare five to seven applications a week for a 6-week period,
no statistical difference in clinical or histologic clearance was
noted between the two regimens [45]. Thus, five applications
a week is preferred, as it provides a balance of efficacy and
safety with minimal side effects. Similar results are supported
by a more recent, open-label clinical trial [46].
Topical imiquimod 5% in the treatment of nodular BCCs
has been investigated in several studies, showing poor efficacy
as a monotherapy compared with surgical excision, most
likely due to skin barrier effect and deeper localization of
tumor cells [26]. Two Phase II studies were conducted: a
1518 Expert Opin. Pharmacother. (2010) 11(9)
6-week, randomized, open-label, dose-response study evaluat-
ing four dosing regimens; and a 12-week, randomized, vehi-
cle-controlled, double-blind, dose-response study evaluating
four dosing regimens. Dosing once daily for 7 days/week
resulted in the highest clinical and histologic clearance rate,
with 25 (71%) of 35 and 16 (76%) of 21 subjects showing
clearance of their tumor in the 6- and 12-week studies, respec-
tively [47]. In another Phase III randomized study, imiquimod
as a monotherapy for nodular BCCs showed relatively poor
efficacy since residual tumor was found in 36% of treated
subjects [48].
The long-term outcome of topical imiquimod in the treat-
ment of superficial, nodular and infiltrative BCCs has been
evaluated in a 5-year follow-up, prospective, open-label study.
Clearance rates (100% for superficial BCCs, 75% for nodular
BCCs and 60% for infiltrative BCCs) demonstrate long-
term benefit, with only 2% recurrence, and confirm the previ-
ously published RCT on short-term imiquimod [49]. Similar
findings have been reported in a second 5-year, long-term,
follow-up study carried out in Europe on 182 subjects with
BCCs [50], showing an overall clinical complete clearance
rate at the end of the study of 77.9%.
Two studies comparing the use of topical imiquimod 5%
cream with and without occlusion in the treatment of superfi-
cial and nodular BCCs showed no significant difference for
early treatment failure in the two regimens [51].
The use of imiquimod has been evaluated in combination
with other treatment modalities in order to improve its effec-
tiveness in the treatment of nodular BCCs [32]. A double-
blind, vehicle-controlled study on 20 patients with nodular
BCCs evaluated the efficacy of curettage and electrodesicca-
tion followed by imiquimod in reducing the frequency of
residual tumor compared with curettage and electrodesicca-
tion alone [52]. The subjects were randomized to an imiqui-
mod (n = 10) or vehicle (n = 10) treatment group. After
8 weeks of treatment, only one subject treated with imiqui-
mod showed a residual tumor (10%) compared with four
treated with vehicle (40%). Similarly, in an open-label study,
17 subjects with a total of 34 nodular BCCs on the trunk
and limbs were treated with imiquimod following curettage
(without electrodesiccation). After 3 months, 32 of 34 treated
nodular BCCs (94%) showed no histologic evidence of resid-
ual tumor [53]. Two previous clinical trials investigating the
long-term histologic clearance obtained with postoperative
use of imiquimod 5% cream reported histologic clearance,
thus supporting imiquimod 5% as an adjunctive therapy after
surgical removal of the primary BCCs [54,55]. In one of these
open-label studies, initial treatment with curettage was fol-
lowed by once-daily application of imiquimod 5% cream
5 times/week for 6 weeks: all 17 treated nodular BCCs
(100%) showed no histological evidence of residual tumor
on the post-treatment excision [54]. In the other study,
a 36-month clinical experience on the use of imiquimod
5% cream (applications once a day, 5 days/week for 6 weeks)
following curettage of biopsy-confirmed nodular BCCs,

reported a clearance rate of 96% along with a satisfactory
cosmetic outcome [55].
A recent RCT evaluating the preoperative effectiveness of
imiquimod 5% cream applied nightly for 6 weeks with occlu-
sion to nodular BCC on the nose, in reducing the level of
Mohs stages, defect size, cost of Mohs surgery, and recon-
struction, indicated that imiquimod was not effective as a
neoadjuvant treatment in nodular BCCs [56].
Finally, some case reports have claimed positive responses
to topical imiquimod 5% in large superficial BCCs [57,58]
and multiple BCCs as observed in Gorlin syndrome [59,60].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
3.3 Bowens disease
Some RCTs have assessed imiquimod 5% cream efficacy and
safety in the topical treatment of Bowens disease. In a double-
blind, placebo-controlled trial, 31 subjects with biopsy-
proven Bowens disease were randomized to receive either
imiquimod 5% cream or vehicle, as a daily application for
16 weeks [61]. At the end of the study, 75% of treated subjects
showed both clinical and histologic resolution, with no relapse
during a 9-month follow-up period. By contrast, no improve-
ment was recorded in the placebo group. The presence of 25%
non-responders in the imiquimod-treated group was attrib-
uted to the presence of thick, hyperkeratotic lesions. Similar
For personal use only.
results were reported by several nonrandomized clinical trials
and case reports [19,62-64].
Finally, some studies show favorable evidence for the
use of topical 5% imiquimod in the treatment of erythro-
plasia of Queyrat [19,64,65]. Despite the absence of RCTs,
topical imiquimod is accepted as alternative therapy by
some practitioners. As such, imiquimod 5% has been success-
fully used 3 times a week for 4 weeks, followed by progres-
sive reduction in dosing to complete clinic resolution (at
8 weeks) [64,65].
3.4 Lentigo maligna
Imiquimod has been suggested as a possible alternative treat-
ment for lentigo maligna, although no RCTs establishing
its long-term efficacy, treatment schedule and regimen are
clearly defined.
The first reported case proposing the therapeutic role of
imiquimod in lentigo maligna dates back to 2000 [66]. Since
then, several uncontrolled studies and case reports have
favorably described the possible role of imiquimod 5% in
treating lentigo maligna and with clinical, dermatoscopic
and histologic resolution [67-73].
Naylor et al. reported a high rate of complete clinical and
histologic clearance and no relapses at 1-year follow-up in
80% of 28 patients, using daily topical imiquimod 5% cream
for 3 months [67]. Similar results are confirmed by a more recent
study of 48 subjects (37 complete responders, 11 no or partial
response) with a mean follow-up duration of 49 months [70].
However, despite these results, some authors have reported
discordance between clinical and histological clearance rates,
together with possible recurrence of the disease at the end of
Expert Opin. Pharmacother. (2010) 11(9)
Micali, Lacarrubba, Dinotta, Massimino & Nasca
the treatment [74], or the development of a more invasive mel-
anoma [71]. Interestingly, the use of topical imiquimod has
also been suggested as a preoperative treatment to reduce the
bulk of lentigo maligna before surgical removal, with
the intent of improving cosmetic outcome of the surgical
excision [72].
3.5 Safety
Topical imiquimod is generally well tolerated. However,
patients may experience moderate to severe application-site irri-
tation, which may occasionally extend beyond the application
site. Such reactions include burning, pruritus, pain, tenderness,
erythema, edema, vesicles, erosions, ulcerations, excoriations,
exudation and crusting (Figures 1, 2 and 3) [32]. Acute,
severe reactions require temporary discontinuation (generally
1 -- 2 weeks). Also, superficial scarring, pigmentary changes,
and, rarely, onset of other dermatoses (psoriasis, pemphigus
foliaceus, aphthosis, vitiligo, angioedema, eruptive epidermoid
cysts) have been reported [75-81]. Although systemic absorption
is low, influenza-like, gastrointestinal symptoms (fatigue, fever
and chills, arthralgias, myalgias, nausea, diarrhea) or induction
of nondermatologic disorders (chronic neuropathic pain, auto-
immune spondyloarthropathy) have also, though rarely, been
reported [26,82,83].
Sunlight exposure to the application site should be avoided
or minimized because imiquimod heightens sunburn suscepti-
bility; similarly, the concurrent use of sunscreen should be
encouraged. Safety of topical imiquimod during pregnancy
is not established and thus its use is not recommended. Ani-
mal studies have not shown clear evidence of teratogenicity
or fetotoxicity, but with FDA pregnancy category, contracep-
tion is generally recommended for women of childbearing age
while using topical imiquimod [84].
4. Diclofenac
The upregulation of arachidonic acid metabolism, due
to overexpression of cyclooxygenase enzymes (primarily
COX-2), may promote carcinogenic effects [85]. Thus, arach-
idonic acid metabolites have been shown to play a possible
role in promoting epithelial tumor growth by stimulating
angiogenesis, inhibiting apoptosis and increasing invasiveness
of tumor cells [86-89]. Several studies have shown NSAIDs to
be safe and effective for the treatment of precancerous lesions,
including actinic keratoses, apparently via COX-2 inhibition.
Also, they may play a role in preventing the development of
nonmelanoma skin cancers [3,85,87,88,90].
Diclofenac is a potent NSAID that acts as an inhibi-
tor of COX-2. Recently, additional mechanisms of action
have explained its therapeutic benefit by induction of
apoptosis, alteration of cell proliferation and inhibition of
angiogenesis [91].
Diclofenac 3% gel in 2.5% hyaluronic acid (DHA) is FDA-
approved for actinic keratoses and has also been demonstrated
to be effective in the treatment of Bowens disease.
1519
 Treating skin cancer with topical cream
4.1 Actinic keratoses
Several studies suggest DHA is a safe and effective topi-
cal therapy for actinic keratoses [3,9,33,91-97]. The FDA-
approved regimen consists of twice-daily applications for up
to 12 weeks.
Two vehicle-controlled studies have evaluated the effi-
cacy of twice-daily applications of DHA in actinic kera-
toses [93,96]. In one study of 48 subjects, DHA provided
total resolution in 33% of subjects (vs 10% of those treated
with vehicle) after 60 days of treatment [96]. In another study
of 120 subjects, DHA totally cleared target lesions in 50%
of subjects (vs 20% of those treated with vehicle) after
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
90 days [93].
In another Phase IV, open-label study, subjects were treated
twice daily with DHA for a period of 90 days with a follow-
up assessment at 30 days post-treatment. The rate of respond-
ers demonstrating actinic keratose clearance 75% were
78 and 85% after 90 and 120 days respectively [92].
As regards comparator studies, a randomized, open-
label, 12-week study of 49 subjects with actinic kera-
toses showed a complete response in 12% of subjects treated
with once-daily applications of DHA (vs 22% of subjects
treated with imiquimod 5% cream 3 times a week) [95]. In
another study, DHA (applied twice daily for 90 days) led
For personal use only.
to clearance of 89% of actinic keratose lesions (vs 98% of
those treated with 5-fluorouracil applied twice daily for
28 days) [97].
Because follow-up is limited to 30 days in these studies,
data on long-term efficacy of DHA for actinic keratose
progression and regression are still lacking and need to be
investigated more [9].
4.2 Bowens disease
So far, no RCTs have been reported on the evaluation of the
effectiveness of in the treatment of Bowens disease. Anedoc-
tal reports include two cases treated with DHA twice daily
for about 3 months with clinical and histological clearance
at the end of the treatment [98]. More recent reports on
five patients with histology-proven Bowens disease, showed
similar results with once-daily application for 8 weeks [61].
These preliminary findings support the use of DHA for
selected cases. However, additional investigations to define
optimum dosage regimens and long-term follow-up are
needed [19].
4.3 Safety
DHA is considered a well-tolerated treatment by most
patients, with mild irritant side effects at application sites
(considerably lower compared with other treatments, such as
fluorouracil and imiquimod) and a satisfactory cosmetic out-
come. However, pruritus and rash may occur [9]. Of note, its
use should be carefully considered in certain conditions, such
as in the case of positive history for bleeding diathesis, hepatic
dysfunction or known hypersensitivity to any component of
the medication [3,91,94].
1520 Expert Opin. Pharmacother. (2010) 11(9)
5. Retinoids
Retinoids are vitamin A derivatives that act by binding
nuclear receptors involved in gene transcription. As a conse-
quence, retinoids control cell proliferation and differentiation
and might potentially interfere with the tumor-promotion
phase of carcinogenesis by inducing apoptosis [4].
Among topical retinoids, tretinoin cream 0.05 -- 0.1% and
adapalene gel 0.1 -- 0.3% have been used in the treatment of
actinic keratoses.
5.1 Actinic keratoses
Topical tretinoin, approved by the FDA for the treatment
of the cutaneous manifestations of photo-aging, has been
used at varying concentrations as a single or combination
treatment for facial actinic keratoses, showing some efficacy
in reducing the number of lesions [4,9]. Different treatment
regimens have been proposed. In a comparative study, a
higher dose response, in terms of cure rate, has been
obtained with the 0.3% formulation (55%) compared
with the 0.1% formulation (35%) [9,99]. A multicenter study
on 1265 patients treated with tretinoin 0.05% or 0.1% or
vehicle for about 15 months indicated tretinoin 0.1% twice
daily to be the most effective treatment (p < 0.001). Over-
all, 73% of tretinoin-treated patients showed a reduction in
the total number of lesions, compared with 40% of the
vehicle group [4,100,101].
The efficacy and tolerability of isotretinoin 0.1% cream in
the treatment of actinic keratoses were evaluated in a double-
blind, parallel-group study on 100 subjects randomly assigned
to treatment with 0.1% cream or vehicle twice daily for
24 weeks to the face, the scalp and the upper extremities [102].
On the face, 66% of subjects treated with isotretinoin
achieved a > 30% reduction in lesion count compared with
45% of subjects treated with vehicle [102].
Interestingly, retinoids may enhance the effectiveness of
fluorouracil by improving its percutaneous absorption [4,101].
A double-blind, controlled study on 19 subjects applying fluo-
rouracil 5% cream to actinic keratoses on each arm twice daily,
followed by nightly application of tretinoin 0.05% cream to
one arm, and a control cream to the other, revealed after
3 months of treatment that the tretinoin-treated cohort had a
meaningful statistical improvement (p < 0.04) compared
with the control cohort [103].
In a prospective randomized, controlled study, 90 subjects
with actinic keratoses and photodamage were randomized
to either adapalene gel (0.1 or 0.3%) or vehicle, once daily
for 4 weeks, followed by twice-daily application up to
9 months [104]. Participants receiving adapalene gel 0.1 or
0.3% achieved a dose-dependent reduction in the number
of actinic keratoses. Overall, 62 and 66% of subjects in the
adapalene gel 0.1 and 0.3% groups, respectively, were consid-
ered to have shown clear, marked or moderate improvement
in actinic keratoses compared with 34% of those treated
with vehicle [104].

5.2 Basal cell carcinoma
Some studies have supported the efficacy of tazarotene, a
selective retinoic acid receptor (RAR) ligand, in reducing the
expression of retinoid-induced tumor suppressor and inhibit-
ing tumor cell formation in mouse models [105,106]. In one
clinical study including 30 subjects, topical tazarotene 0.1%
gel was applied once daily up for 20 weeks to treat multi-
ple superficial BCCs. Complete cure rate was achieved
in 58.5% of lesions after a mean 11-week duration of
treatment [107].
5.3 Lentigo maligna
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Aberdeen on 06/02/13
In one study, two elderly subjects with facial lentigo maligna
showed complete regression, both clinical and histopa-
thologic, after once-daily topical treatment with tazarotene
0.1% gel for 6 -- 8 months. After a follow-up period of
18 and 30 months, no recurrence was observed [108].
5.4 Safety
Topical retinoids may be responsible for mild to moderate
local side effects consisting of erythema, peeling, dryness,
burning and pruritus [101,104] that may lead to patient dis-
continuation or noncompliance. Retinoids may also induce
sun hypersensitivity, thus sun exposure to application site
For personal use only.
should be minimized, and the use of concurrent appropriate
sunscreens recommended.
6. Conclusions
Several studies have demonstrated the usefulness of topical
pharmacotherapy in the treatment of cutaneous malignancies.
Noninvasive, tissue-sparing, topical, self-administered treat-
ments represent a highly desirable alternative option, both
in aged and unhealthy patients who may be poor surgical can-
didates, as well as in relatively young subjects with lesions
located on cosmetically sensitive areas wishing to avoid
disfiguring scars.
7. Expert opinion
Topical pharmacotherapy offers effective alternative treat-
ments for skin cancer, although careful patient selection is
required to achieve the desired goal of complete tumor clear-
ance. Therapeutic response is related both to tumor type,
extension and localization, as well as to the ability of the
patient to be compliant. The advantages and disadvantages
for topical treatment available for skin cancers are summarized
in Table 1.
Undoubtedly, noninvasive topical pharmacotherapy
deserves first-line treatment status for actinic keratoses. Topi-
cal compounds containing fluorouracil 5 or 0.5%, imiquimod
5%, DHA 3% or tretinoin 0.1% have all demonstrated
efficacy in randomized trials with variable outcome rates.
Moreover, topical therapy may often be preferred to more
destructive or invasive treatments in the treatment of actinic
Expert Opin. Pharmacother. (2010) 11(9)
Micali, Lacarrubba, Dinotta, Massimino & Nasca
keratoses in consideration of the field cancerization phenom-
enon. This finding -- for example the presence of histologically
abnormal tissue surrounding an invasive squamous cell
carcinoma -- was first described in tumors of the upper gastro-
intestinal system in 1953 [109]. As actinic keratoses represent
the earliest, clinically detectable cutaneous lesions of multi-
focal, preneoplastic areas of dysplastic keratinocytes that
can extend beyond visible lesions, or that might appear years
later, the use of topical agents to promote reversal of neo-
plastic transformation in surrounding tissue may provide a
field effect on subclinical disease and contribute to the
prevention of further tumor development in adjacent
areas [110,111].
Fluorouracil, the first topical medication approved for
actinic keratoses, is also effective in treating BCCs and
Bowens disease. However, it provides cytotoxic action that
can also destroy adjacent tissues. Efficacy of fluorouracil is
dose-related and depends on skin-barrier penetration of the
applied formulation. Thicker, hypertrophic lesions may need
to be pretreated with keratolytic agents or gentle curettage.
Generally, patients who develop an intense inflammatory
reaction obtain a greater clinical response. The use of topical
fluorouracil without close clinical follow-up or histologic
confirmation of cure may lead to the persistence of invasive
tumors and their occult progression.
At this point in time, imiquimod 5% cream represents a
more versatile agent. Although FDA-approved only for actinic
keratoses and superficial BCCs, its off-label use includes
Bowens disease, erythroplasia of Queyrat and lentigo maligna,
with excellent outcome. Although there is an RCT for Bowens
disease, optimal dosage and duration of therapy for each off-
label use, as well as long-term efficacy, should be assessed
through additional RCTs. An important issue that needs to
be highlighted is the frequent occurrence of irritation during
imiquimod therapy, including burning, pruritus, pain, tender-
ness, erythema, edema, vesicles, erosions, ulcerations, excoria-
tions, exudation and crusting. As for fluorouracil treatment,
the ability to develop an inflammatory reaction to imiquimod
is a good predictor of the therapeutic effect, and expert
physicians can easily manage it without further complications.
DHAs efficacy is at present limited to actinic keratoses, in
which the overall clearance rate slightly lower than that of
fluorouracil and imiquimod. However, DHA, with better tol-
erability, may represent an alternative for those patients who
are not willing to tolerate the typical side effects associated
with fluorouracil and imiquimod. So far, no RCTs have
been carried out to evaluate DHA efficacy in other cutaneous
malignancies. However, some studies seem to support its use
in Bowens disease for selected cases and further investigation
is needed.
The cure rate of actinic keratoses seems to be lower for ret-
inoids compared with other topical treatments. Moreover, a
prolonged treatment (up to 15 months) is usually required.
Therefore, this treatment does not compare favorably with
more rapidly effective treatments for actinic keratoses.
1521
 Treating skin cancer with topical cream

Table 1. Topical treatments for skin cancers: advantages and disadvantages.

Indication Therapeutic options Advantages Disadvantages

Actinic keratoses Imiquimod 5%
Fluorouracil 0.5 -- 5%
Diclofenac 3% in 2.5%
hyaluronic acid
Retinoids
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Short and long-term efficacy
with high RR
Several recent RCTs available
Short and long-term efficacy
with high RR
Short-term efficacy with high RR
Recent RCTs available
Mild side effects
Short-term efficacy with moderate RR
Mild to severe side effects
at application site
High cost
Few recent RCTs available
Mild to severe side effects
at application site
Lack of data on long-term efficacy
Lack of data on long-term efficacy

Mild side effects

Basal cell carcinoma
Bowens disease
For personal use only.
Imiquimod 5% Short- and long-term efficacy with Mild to severe side effects
high RR for superficial BCC at application site
Short and long-term efficacy with High cost
moderate RR for nodular BCC
Several recent RCTs available
Fluorouracil 5% Short and long-term efficacy Limited RCTs available
with high RR Mild to severe side effects
at application site
Retinoids Some data of short-term efficacy with Lack of RCTs
moderate RR
Mild side effects
Imiquimod 5% Short-term efficacy with high RR Limited data on long-term efficacy
Recent RCTs available Mild to severe side effects
at application site

High cost
Fluorouracil 5% Short- and long-term efficacy Lack of RCTs
with high RR Mild to severe side effects
at application site
Diclofenac 3% in 2.5% Some data on short-term efficacy Lack of RCTs
hyaluronic acid with high RR
Mild side effects
Erythroplasia of Queyrat Imiquimod 5% Some data on short-term efficacy Lack of RCTs
with high RR Mild to severe side effects
at application site
High cost
Lentigo maligna Imiquimod 5% Some data on short-term efficacy Lack of RCTs
with high RR Mild to severe side effects
at application site
High cost
Retinoids Few data on short-term efficacy Lack of RCTs

High RR: 70%.

Moderate RR: 40 -- 69%.
BCC: Basal cell carcinoma; RCTs: Randomized controlled trials; RR: Resolution rate.

Of note, the preliminary results in treating BCCs and lentigo
maligna with retinoids have not been confirmed by
other studies.
Some of these treatments carry an individual response that
could be essential for achievement of clinical and histologic
cure. For example, both the inflammatory reaction and
therapeutic effects of imiquimod are not always dose-related,
and may vary among patients depending on an un-
predictable individual response. This implies that close
clinical supervision and clinical experience are essential for
accurate interpretation of outcome. In addition, for some
agents (e.g., fluorouracil and retinoids) standardized optimal
concentrations have not necessarily been assessed for each
possible indication or clinical use.
As the ultimate goal is to treat patients successfully with the
best risk-to-benefit treatment options, more controlled clinical
trials are necessary, as well as the development of new molecules
with enhanced efficacy and reduced side effects. The potential
of new applications is that they may be applied to a wide vari-
ety of cutaneous malignancies. Certainly, treatment of skin
tumors with immunomodulators is an important advance,
and industry and scientists are focusing on this and related

1522 Expert Opin. Pharmacother. (2010) 11(9)

 Micali, Lacarrubba, Dinotta, Massimino & Nasca

A. B.
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Figure 1. A. Small superficial BCC. B. Mild application-site reaction during IQ treatment: erythema, vesicles and erosions.

A. B.
For personal use only.

Figure 2. A. Nodular BCC. B. Moderate application-site reaction during IQ treatment: erythema, oedema, vesicles and
exudation.

A. B.

Figure 3. A. Large superficial BCC. B. Severe application-site reaction during IQ treatment: erythema, oedema, ulcerations,
exudation and crusting.

Expert Opin. Pharmacother. (2010) 11(9) 1523

 Treating skin cancer with topical cream
fields. In our opinion, future development should include other
immune response modifiers such as resiquimod, an analogue of
imiquimod that shows encouraging preliminary results for
actinic keratoses [112].
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Affiliation
Giuseppe Micali MD,
Francesco Lacarrubba MD, Franco Dinotta MD,
Doriana Massimino MD &
Maria Rita Nasca MD PhD
Author for correspondence
University of Catania,
Dermatology Clinic,
A.O.U. Policlinico -- Vittorio Emanuele,
Via Santa Sofia, 78 95123 Catania, Italy
Tel: +39 095 321705; Fax: +39 095 3782425;
E-mail: cldermct@nti.it
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