JEADV

DOI: 10.1111/jdv.12702

ORIGINAL ARTICLE

A prospective randomized exploratory study comparing the

efcacy of once-daily topical 0.5% 5-uorouracil in
combination with 10.0% salicylic acid (5-FU/SA) vs.
cryosurgery for the treatment of hyperkeratotic actinic
keratosis
J.-C. Simon,1,* R. Dominicus,2 L. Karl,3 R. Rodr
guez,4 C. Willers,4 T. Dirschka5
1

Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Leipzig, Germany
lmen, Germany
Proderma, Du

2
3

Private practice, Soest, Germany

Almirall, S.A., Barcelona, Spain
5
Faculty of Health, Private University of Witten-Herdecke, Witten and Centroderm clinic, Wuppertal, Germany
*Correspondence: J.-C. Simon. E-mail: jan.simon@uniklinik-leipzig.de
4

Abstract
Background Actinic keratoses (AKs) are clinically signicant and require therapy. Efcacy of low-dose (0.5%)
5-uorouracil with 10% salicylic acid (5-FU/SA) has been shown in randomized comparative trials of hyperkeratotic
lesions of various grades.
Objectives To evaluate the efcacy, tolerability and safety of low-dose 5-FU/SA topical solution vs. cryosurgery in
patients with moderate/severe (grade II/III) hyperkeratotic AKs (NCT01358851).
Methods In an exploratory, open, randomized study, patients with histologically conrmed moderate/severe hyperkeratotic AKs on the face/forehead or bald scalp received 6 weeks of once-daily topical 0.5% 5-FU/SA, or up to two cryosurgery treatments (3 weeks apart). Histological outcomes were determined from punch biopsies. Clinical, cosmetic and
tolerability outcomes were also assessed.
Results Sixty-six patients received treatment (33 per arm). The baseline total number of lesions was 266 (8.1/patient) in
the 0.5% 5-FU/SA and 263 (8.0/patient) in the cryosurgery group. Most (74.5%) lesions were grade II (grade III, 25.5%).
Mean change in lesion count from baseline to Day 98 was

5.2 and

5.7 lesions per patient for 0.5% 5-FU/SA and

cryotherapy groups respectively. Histological AK clearance rates on Day 98 were 62.1% and 41.9% respectively. At 6month posttreatment follow-up, recurrence of cleared lesions (no clinically visible lesions in treatment area) occurred in
39.4% of 0.5% 5-FU/SA and 84.8% of cryosurgery patients. Drug-related adverse events (AEs), including local skin
reactions considered severe by the investigator, were reported in 24.2% of 0.5% 5-FU/SA and 6.1% of cryosurgery
patients. All drug-related AEs were skin reactions.
Conclusions Although the study was not powered to explore statistical differences in clinical efcacy between treatments, a short (6-week) schedule of topical treatment with 0.5% 5-FU/SA achieved greater histological clearance and
lower recurrence of grade II/III hyperkeratotic AKs than cryosurgery. AE incidence across both treatment groups was relatively low and AEs were generally mild or moderate. Clinical trials.gov identier: NCT01358851.
Received: 18 February 2014; Accepted: 17 July 2014

Conicts of interest
Jan Simon has served as a speaker, consultant or advisory board member for Almirall, S.A, and has received research
grants from Almirall, S.A. Rolf Dominicus has no nancial interest in Almirall, S.A. Thomas Dirschka has served as a
speaker, consultant or advisory board member for Almirall, S.A, and has received research grants from Almirall, S.A. Lars
Karl has had no nancial interest in Almirall, S.A during the past 2 years. Rosario Rodr
guez and Christoph Willers are
employees of Almirall, S.A.

Funding sources
This study was sponsored by Almirall, S.A.

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modications or adaptations are made.

JEADV 2015, 29, 881889

Simon et al.

882

Introduction

Materials and methods

Actinic keratosis lesions (AKs) occur on chronically lightexposed adult skin (usually on the face and dorsa of hands) and
are common in fair-skinned people.1 An estimated 23% of people aged 60 years will have at least one AK.2 After the age of
70 years, AKs are estimated to affect 34% of men and 18% of
women.3 The highest prevalence rates occur in countries that are
equatorial and have large fair-skinned populations. For example,
AK rates of 55% in men and 37% in women have been
reported in Queensland, Australia, in a population of 30- to
69-year-olds.4
AKs can transform to invasive squamous cell carcinoma
(SCC), indicating that AKs are clinically significant, and that
therapy is necessary.1,5 The long-term effectiveness of treatments in reducing the recurrence of AKs is an important
consideration.
Most AKs are diagnosed based on clinical appearance, with
few being confirmed histologically6 despite similarities to
superficial BCC, Bowens disease and invasive SCC.7 Furthermore, once AKs have been treated, histological examination
enables the identification of subclinical, residual atypical cells
in the epidermis and is therefore a more reliable method
than clinical examination for predicting the recurrence of
lesions.810
Cryosurgery is a non-specific treatment option that uses
liquid nitrogen to disrupt and separate the epidermis from the
dermis, thereby destroying both atypical and normal cells. It is a
widely utilized technique for small, or a low number of, AKs.1,5,7
Historically, cryosurgery has been the treatment of choice for
focal lesions, despite the lack of standardization of treatment frequency, duration, intensity or temperature.8 Although there is
stronger evidence for its use in treating thin AKs, the British
Association of Dermatologists suggests that cryosurgery could be
used for hypertrophic lesions.7
Topical therapies, such as 3% diclofenac with 2.5% hyaluronic acid gel,11 5% 5-fluorouracil (5-FU) ointment,8 3.75%
or 5% imiquimod cream,11,12 0.015% or 0.05% ingenol
mebutate gel13 and photodynamic therapy,1416 may be used
for field-directed treatment for AKs.8,11 Therapy with lowdose (0.5%) 5-FU with 10% salicylic acid (5-FU/SA) offers
target-lesion-directed treatment and has demonstrated efficacy,
in terms of histological clearance and recurrence rates, for up
to 12 months posttreatment in randomized comparative trials
of various grades of hyperkeratotic lesions.1719 0.5% 5-FU/SA
is approved in Europe for the treatment of slightly palpable
and/or moderately thick hyperkeratotic mild or moderate AKs
(grade I/II). Here, we investigate the efficacy, tolerability and
safety of low-dose (0.5%) 5-FU/SA topical solution compared
with that of the widely used technique of cryosurgery in
patients with moderate/severe (grade II/III) hyperkeratotic
AKs in a Phase 2, randomized, controlled study.

JEADV 2015, 29, 881889

Study design

An exploratory, open, randomized, prospective, two-armed

Phase 2 study, conducted at four centres in Germany between
April 2011 and August 2012, compared 6-week treatment with
topical 5 mg/g (0.5%) 5-fluorouracil plus 100 mg/g (10%) salicylic acid (5-FU/SA) solution vs. cryosurgery (NCT01358851).
At the screening visit (after AK histology confirmation),
centres received a fax assigning each patient to a screening
number used to randomly allocate (1 : 1) each patient to
treatment. The randomization list was generated by the clinical
research organization (FOCUS Clinical Drug Development
GmbH, Neuss, Germany), using a validated SAS programme
(SAS Institute Inc., Cary, NC, USA). The observer (histologist
not involved in administering treatment) was blinded to treatment group.
Patients were assessed at baseline, 3 weeks, 6 weeks (end of
treatment), 14 weeks (posttreatment visit), and at 6 months
after stopping treatment (follow-up visit). The study was conducted in accordance with the Declaration of Helsinki and good
clinical practice guidelines. The protocol was approved by institutional review boards at each study centre and all patients provided informed consent.
Patients

Men or women were eligible for inclusion if they were aged

between 18 and 85 years, and were in good general health with
Fitzpatrick skin type I-IV and 4 but 10 clinically confirmed
hyperkeratotic AK target lesions of moderate/severe intensity
within the face/forehead or bald scalp (excluding eyelids, lips,
mucosa and concha), i.e. AK grade II and III according to Olsen
et al.20 Patients with lesions histologically diagnosed as AKs
grade I, II or III according to the criteria of R
owert-Huber
et al.21 were also eligible.
Lesions were photographed to document diagnoses. In addition, a photodynamic diagnosis of all areas to be treated was performed at the site of the co-ordinating investigator. Lesions were
discrete and quantifiable: > 1.0 cm apart, diameter 0.5 cm
and 1.5 cm. Treatment areas were 25 cm2. Lesions were
considered to be AKs if they presented as rough, crusted, fleshcoloured to reddish-brown papules, or with an adherent scale in
a field of sun-damaged skin.2224
Patients with controlled hypertension, type 2 diabetes mellitus,
hypercholesterolaemia and osteoarthritis were permitted to enrol
provided they were not taking any excluded medication. Patients
refrained from sunbathing and solarium use during the study. Application to the treatment areas of topical treatments, moisturizers, ointments or gels containing anti-ageing products, vitamin A, vitamin C
and/or vitamin E was not permitted during the study. Sunscreens not
containing vitamin E were allowed if not applied to treatment areas

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Low-dose 5-FU/SA for actinic keratosis

within the 24 h before a clinic visit. Women of childbearing potential

were instructed to use a highly effective method of contraception.
Exclusion criteria included: treatment for AKs in the target area
within 3 months preceding study start; known hypersensitivity
to 5-FU, salicylic acid or acetylsalicylic acid; patients receiving
immunosuppressive therapy or having inherited or acquired
coagulation defects; patients with evidence of clinically significant, unstable medical conditions (e.g. metastatic tumour and
immunosuppressive conditions). Patients were also excluded if
they had received topical retinoid, diclofenac or 5-FU products
within 6 weeks preceding the study, or topical steroids within
4 weeks preceding the study.

883

(MedDRA), version 14.1. Local skin reactions were recorded and

classified by severity. Only those classified by the investigator as
severe (incapacitating or preventing normal everyday activities)
were required to be reported as AEs, as the nature of the treatments meant that mild/moderate skin reactions were to be
expected. A serious AE (SAE) was defined as any AE that was life
threatening or resulted in death, hospitalization or significant
disability/incapacity.
Statistical evaluation

Patients randomized to 0.5% 5-FU/SA applied the solution once

daily for 6 weeks to each target lesion and approximately 0.5 cm
of the surrounding area to treat subclinical AK areas. The eyes,
nostrils, mouth, ears and mucosa were avoided. Dose reduction
to 3 days per week was allowed in the case of adverse events
(AEs). Prior to application of study drug, the skin was cleaned
with water (not soap).
Patients randomized to cryosurgery received one treatment
on Day 1. A second treatment was administered 3 weeks later if
the investigator considered it necessary. Double freezethaw
cryosurgery was performed using liquid nitrogen spray to
achieve a frozen rim 0.10.2 cm outside the marked outline of
the lesion. The decision on the timing of the freezethaw application was at the discretion of the study investigators.

It was planned to enrol approximately 70 patients to gain 60 evaluable patients (30 per study arm), achieving an estimated 95% confidence interval of 0.510.85 for the responder rate. A statistical
difference between the treatment groups was not sought owing to
the small sample size in this exploratory study. However, an inferential analysis (chi-squared test) was performed regarding lesion
recurrence data; this analysis should be interpreted with caution
since no adjustment for multiplicity was performed.
All efficacy analyses were completed on the full analysis set,
defined as all randomized patients receiving at least one dose of
study drug and with available data on any efficacy variable,
regardless of any protocol deviation or violation. Baseline and
demographic data were collated for the safety set, defined as all
patients treated with 5-FU/SA or cryosurgery. Missing values
were tabulated with their frequency but were not included in the
calculation of percentages.
Descriptive statistics were used for the number of AKs and
changes from baseline in AKs.

Efcacy and safety assessments

Results

Study treatment

The primary efficacy variable was the percentage of patients with

histological clearance of a predefined target lesion at 8 weeks
after completion of the 6-week 0.5% 5-FU/SA treatment or
14 weeks after first cryosurgery or, if performed, 11 weeks after
the second cryosurgery. A patient was defined as being histologically cleared when a biopsy of the predefined target lesion did
not reveal any microscopic sign of AKs.
Secondary efficacy end points included lesion counts, lesion
response at each study visit, AK clearance rate at Day 98 [complete and partial (> 75%), determined by clinical evaluation],
the physicians global assessment, cosmetic outcome and
patients assessment of clinical improvement.
Patients were screened 14 days but 28 days before study
start. Before and after treatment, a biopsy was performed on a
defined AK using a 3-mm biopsy punch. Visual inspections to
determine lesion size, counts, response to treatment and to
assess skin quality were performed during and after treatment.
Marker lesions previously selected for screening were photographed. Physicians and patients assessments of treatment were
performed posttreatment.
AEs occurring on or after Day 1 of treatment were recorded
using the Medical Dictionary for Regulatory Activities

JEADV 2015, 29, 881889

Patients

Between 12 and 27 patients were recruited at each of the four centres. Of 67 patients randomized, 66 received treatment (n = 33 in
each treatment group; one patient withdrew consent before receiving study medication). Fig. 1 shows patient disposition. The mean
age was 70.9 years; most patients were 65 years of age and male.
There were no clinically or statistically relevant differences in baseline characteristics between study groups (Table 1).
AKs

Overall, 25.8% of patients had AKs on the bald scalp as well as

face and forehead. Two-thirds of patients (44/66) had AKs on
the bald scalp and 59.1% (39/66) had AKs on the face and forehead. There were no significant differences in lesion location
between the treatment groups. Most (74.5%) AKs were grade II,
and 25.5% were grade III according to the criteria of Olsen
et al.20 (Table 2).
Treatment

The mean (standard deviation) duration of treatment for

patients who received 0.5% 5-FU/SA was 38.6 (9.0) days. Three

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Simon et al.

884

72
patients
screened

5-FU/SA
34 randomized

Cryotherapy
33 randomized

Treated
33 (97.1%)

Treated
33 (100.0%)

Safety population: 33 (97.1%)

Full analysis set: 33 (97.1%)
Per-protocol set: 26 (76.5%)

Safety population: 33 (100.0%)

Full analysis set: 33 (100.0%)
Per-protocol set: 31 (93.9%)

Completed study
33* (97.1%)

Completed study
32 (97.0%)

Withdrawn from study: 1 (2.9%)

Lost to follow-up: 0 (0.0%)
Consent withdrawn prior to
treatment: 1 (2.9%)

Withdrawn from study: 1 (3.0%)

Lost to follow-up: 1 (3.0%)
Consent withdrawn prior to
treatment: 0 (0.0%)

Completed follow-up
33 (100.0%)

Completed follow-up
31 (96.9%)

*Based on patients completing 14 weeks of study

5-FU/SA, 0.5% 5-fluorouracil/10.0% salicylic acid

Figure 1 Patient disposition.

(9.1%) patients stopped, and a further 3 (9.1%) temporarily discontinued treatment due to local skin reactions. Most patients
receiving cryosurgery (29/33; 87.9%) had a second administration within 3 weeks of the first cryosurgery.

second cryosurgery) was achieved by 62.1% of patients who

received 0.5% 5-FU/SA (18/33), and 41.9% of patients who
received cryosurgery (13/33) (Fig. 2). Examples of typical representative lesions before and after treatment are shown in Fig. 3.

Lesion clearance

Lesion recurrence

Histological clearance of predefined target AKs on Day 98 (i.e.

8 weeks after the end of treatment with 0.5% 5-FU/SA or
14 weeks after first cryosurgery, or, if performed, 11 weeks after

From study initiation to 6-month-posttreatment follow-up,

recurrence of cleared AKs (no clinically visible lesions in the
treatment area on Day 98) was reported in 39.4% (13/33) of

JEADV 2015, 29, 881889

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Low-dose 5-FU/SA for actinic keratosis

Table 1 Patient demographics

(safety set).
Demographic/
characteristic

0.5% 5-FU/SA
(n = 33)

and

885

baseline characteristics

Cryosurgery
(n = 33)

Sex
Male
Female

29 (87.9%)

29 (87.9%)

4 (12.1%)

4 (12.1%)

33 (100.0%)

33 (100.0%)

1.0000*

NA

Age, years
Mean (SD)
Range

70.6 (8.3)

71.3 (7.6)

5183

5385

0.7227

Age groups
< 65 years

9 (27.3%)

6 (18.2%)

65 years

24 (72.7%)

27 (81.8%)

0.3782

26.6 (3.7)

27.1 (3.8)

Range

18.735.5

19.039.9

0.5893

18.5 (4.2)

Range

829

6.9 (3.0)

0.1197

9 (27.3%)

14 (42.4%)

III: 1725

21 (63.6%)

19 (57.6%)

IV: 2530

3 (9.1%)

0 (0.0%)

0.1562*

3 (9.1%)

8 (24.2%)

AK II

26 (78.8%)

20 (60.6%)

AK III

4 (12.1%)

5 (15.2%)

18 (54.5%)

21 (63.6%)

0.7390

3.4 (3.9)

3.6 (3.6)

Total No. lesions

Grade II
Grade III
Patients with lesions
on bald scalp
Mean (SD) lesion
count

113

120

86 (76.1%)

91 (75.8%)

27 (23.9%)

29 (24.2%)

20 (60.6%)

24 (72.7%)

4.6 (4.1)

4.3 (3.4)

153

143

Grade II

113 (73.9%)

104 (72.7%)

Grade III

40 (26.1%)

39 (27.3%)

8.1 (1.2)

8.0 (1.1)

0.7083

Mean (SD)
lesion count

266

263

Grade II

199 (74.8%)

195 (74.1%)

Grade III

67 (25.2%)

68 (25.9%)

0.8368

0.2634*

*Fishers exact test.

t-test.
Chi-squared test.
Wilcoxon test.
AK, actinic keratosis; 5-FU/SA, 5-uorouracil with 10% salicylic acid; NA,
not applicable; SD, standard deviation.

patients receiving 0.5% 5-FU/SA and 84.8% (28/33) of patients

receiving cryosurgery (Fig. 4).
In patients with complete clinical clearance at 14 weeks posttreatment, 27.3% (3/11) of patients receiving 0.5% 5-FU/SA and
50.0% (4/8) of patients receiving cryosurgery reported recurrent
lesions at 6-month-post-treatment follow-up.
Lesion count

At baseline (before treatment), the mean number of lesions per

patient was similar in the 0.5% 5-FU/SA and cryosurgery treatment groups (8.1 and 8.0 lesions respectively). The mean
change from baseline to Week 14 was similar for both treatments ( 5.2 and 5.7 lesions per patient in the 0.5% 5-FU/SA
and cryosurgery groups respectively). At Day 98, 33.3% (11/33)
of patients in the 0.5% 5-FU/SA group had complete clearance
of all lesions compared with 25.0% (8/32) in the cryosurgery
group. Partial clearance (> 75% reduction) at Day 98 occurred

JEADV 2015, 29, 881889

Patients with lesions

on face and forehead

Percentages of severity grade were calculated over the total number of

lesions.
5-FU/SA, 5-uorouracil with 10% salicylic acid; SD, standard deviation.

Biopsy at baseline
AK I

Wilcoxon
test P-value

Total No. lesions

1022

Fitzpatrick skin type

II: 816

Cryosurgery
(n = 33)

All locations

Total skin type score

Mean (SD)

0.5% 5-FU/SA
(n = 33)

Total No. lesions

BMI, kg/m2
Mean (SD)

Characteristic

Mean (SD)
lesion count

Race
Caucasian

Table 2 Summary of baseline characteristics of actinic keratoses

(safety set)

in 51.5% (17/33) and 62.5% (20/32) for 0.5% 5-FU/SA and

cryosurgery respectively.
Physicians global assessment and patients assessment
of therapy

At 6 months follow-up, the proportion of patients with a very

good/good outcome according to physicians global assessment
scores was 84.9% (28/33) in the 0.5% 5-FU/SA group and 83.9%
(26/33) in the cryosurgery group. A total of 13/33 (39.4%)
patients in the 0.5% 5-FU/SA group and 7/33 (21.2%) patients
in the cryosurgery group had a physicians global assessment of
very good, defined as lesion clearance with no signs of AK.
Patients assessment of clinical improvement was rated as very
good/good by 81.8% of patients receiving 0.5% 5-FU/SA and
78.2% of patients receiving cryosurgery.
At Week 14, the proportion of patients who assessed themselves as having a good/very good cosmetic outcome was 84.9%
(28/33) for 0.5% 5-FU/SA vs. 81.3% (26/31) for cryosurgery. At
6-months follow-up, the proportion of patients with a good/
very good cosmetic outcome was 87.8% (29/33; very good rating, 24.2%) for 0.5% 5-FU/SA and 80.7% (25/31; very good
rating, 9.7%) for cryosurgery.
Safety and tolerability

An overview of local skin reactions and AEs from the start of

treatment to Day 98 is shown in Table 3. The most common

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Simon et al.

886

100

0.5% 5-FU/SA (All AK, n = 29; AKII, n = 14)

70
62.1%
57.1%

60

47.6%

50

Patients (%)

41.9%
40

*
Proportion of patients with
at least one recurrence

Cryosurgery (All AK, n = 31; AKII, n = 21)

0.5% 5-FU/SA
28/33 (84.8%)

Cryotherapy

**

80

22/31 (71%)

11/19 (57.9%)

60
40

13/33 (39.4%)
11/33 (33.3%)
5/21 (23.8%)

20
0

30

All lesions

Only AKII lesions

Only AKIII lesions

*P = 0.0001; **P = 0.0026; P = 0.0280

AK, actinic keratosis; 5-FU/SA, 5-fluorouracil with 10% salicylic acid

20

Figure 4 Recurrence of all actinic keratoses, grade II and grade III

lesions during the study (full analysis set) AK, actinic keratosis; 5FU/SA, 5-uorouracil with 10% salicylic acid.

10
0

All AK

AK II only

AK, actinic keratosis; AKII, AK grade II; 5-FU/SA,

5-fluorouracil with 10% salicylic acid

Figure 2 Histological clearance of a predened grade II/III AK at

the posttreatment visit (Week 14; full analysis set) AK, actinic keratosis; AKII, AK grade II; 5-FU/SA, 5-uorouracil with 10% salicylic
acid.

Table 3 Overview of adverse events from the start of treatment to

Day 98, including local skin reactions [n (%) patients; safety set]
Characteristic

0.5% 5-FU/SA
(n = 33)

Total AEs

13 (39.4%)

Cryosurgery
(n = 33)
8 (24.2%)

AEs related to study drug

8 (24.2%)

2 (6.1%)

SAEs

1 (3.0%)

0 (0.0%)

SAEs related to study drug

1 (3.0%)

0 (0.0%)

AEs leading to discontinuation

3 (9.1%)

0 (0.0%)

Local skin reactions

Erythema

Day 42
6-month FU

27 (81.8%)
14 (42.4%)

17 (51.6%)
6 (19.4%)

Scabbing/crusting

Day 42
6-month FU

24 (72.7%)
12 (36.4%)

22 (66.7%)
10 (32.3%)

Burning

Day 42
6-month FU

23 (67.9%)
1 (3.0%)

5 (15.2%)
0 (0%)

Pain

Day 42
6-month FU

2 (6.1%)
1 (3.0%)

10 (30.3%)
0 (0%)

Pruritus

Day 42
6-month FU

7 (21.2%)
2 (6.1%)

3 (9.1%)
2 (6.5%)

Maceration

Day 42
6-month FU

6 (18.2%)
0 (0%)

0 (0%)
1 (3.2%)

Vesicles

Day 42
6-month FU

3 (6.1%)
0 (0%)

5 (15.2%)
0 (0%)

Hypopigmentation

Day 42
6-month FU

5 (15.2%)
2 (6.1%)

2 (6.1%)
8 (25.8%)

Hyperpigmentation

Day 42
6-month FU

7 (21.2%)
4 (12.1%)

3 (9.1%)
4 (12.9%)

Screening

Post-treatment
Figure 3 Examples of typical representative lesions before
(screening) and after treatment (Visit 6) with 0.5% 5-uorouracil/
10% salicylic acid.

local skin reactions were erythema, scabbing/crusting and burning, mainly of mild to moderate intensity (Table 3). Erythema
occurred more often after treatment with 0.5% 5-FU/SA and

JEADV 2015, 29, 881889

AE, adverse event; 5-FU/SA, 5-uorouracil with 10% salicylic acid; FU,
follow-up, SAE, serious adverse event.

was observed for a longer duration than after cryosurgery. The

incidence of scabbing/crusting was similar for both treatment
groups. Burning was mainly observed during treatment with
0.5% 5-FU/SA (Table 3). Local skin reactions were most
prevalent at Day 21, reducing slightly by Day 42 and becoming
less common by Day 98. At the 6-month follow-up visit, the

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Low-dose 5-FU/SA for actinic keratosis

number of patients with local skin reactions was similar in both

treatment groups except for a slightly higher incidence of erythema in the 0.5% 5-FU/SA group and a slightly higher incidence of hypopigmentation in the cryosurgery group. Severe
local skin reactions were also reported as AEs.
Thirteen patients (39.4%) receiving 0.5% 5-FU/SA experienced 23 AEs, and eight patients (24.2%) in the cryosurgery
group experienced 12 AEs (Table 3). The most common AEs
were administration site and skin disorders [13 AEs (56.5%) for
0.5% 5-FU/SA; 5 AEs (41.7%) with cryosurgery]. Most AEs were
of mild/moderate intensity. Severe AEs were primarily application site reactions, reported in six patients (18.2%, 10 AEs)
receiving 0.5% 5-FU/SA and one patient (3.0%, 1 AE) receiving
cryosurgery.
Three patients in the 0.5% 5-FU/SA group interrupted
treatment for 416 days due to AEs, whereas a further three
patients were permanently discontinued due to local skin
reactions. In one of the patients who discontinued therapy,
application of 0.5% 5-FU/SA was stopped after 16 days of
treatment because all AKs had cleared. No other discontinuations occurred.
Drug-related AEs were reported in 24.2% (8/33, 13 AEs) of
patients receiving 0.5% 5-FU/SA and 6.1% (2/33, 2 AEs) of
patients receiving cryosurgery: all were skin reactions. The most
frequently reported drug-related AEs were burning sensation
(three patients in the 0.5% 5-FU/SA group) and application site
erythema/erythema (3 patients in the 0.5% 5-FU/SA group; all
severe intensity). All other drug-related AEs were reported by
single patients.
Overall skin quality improved in both treatment groups at
Day 98, and fewer patients in the 0.5% 5-FU/SA group had any
hyperpigmentation (15.1% vs. 25.0%) or hypopigmentation
(9.1% vs. 40.6%), compared with the cryosurgery group.

Discussion
This was the first exploratory open-label, randomized, controlled
Phase 2 study designed to compare a widely used treatment,
cryosurgery, with 6 weeks of treatment with once-daily 0.5% 5FU/SA in patients with moderate/severe (grade II/III) hyperkeratotic AKs. The sample size recruited was not powered to explore
statistical differences between treatments in terms of clinical
efficacy.
In patients with grade II/III AKs, 6 weeks of 0.5% 5-FU/
SA treatment was associated with a greater histological clearance rate (62%) than cryosurgery (42%) at Day 98. One
possible explanation for the greater clearance with 0.5% 5FU/SA compared with cryosurgery is that SA is a powerful
keratolytic agent and the formulation also included 8%
dimethyl sulfoxide, a known penetration enhancer.17
Together, these elements may permit deep penetration of 5FU into hyperkeratotic AKs, thereby enhancing its efficacy.17
In addition, 5-FU/SA was applied to a marginally larger area

JEADV 2015, 29, 881889

887

of perilesional skin than cryosurgery, which may have

enhanced clearance of clinically inapparent lesions in the 5FU/SA group.
Histology is recognized as a gold standard for proving efficacy, as posttreatment clinical clearance might not always indicate histological lesion clearance. A previous randomized,
placebo-controlled, double-blind study in patients with mild/
moderate (grade I/II) hyperkeratotic AKs who received 12 weeks
of 0.5% 5-FU/SA treatment (the currently licensed treatment
period for low-dose 5-FU/SA) reported histological lesion clearance in 72% of patients.17 A variety of histological clearance
rates have been reported for topical agents after different treatment durations and in patient populations with unspecified AK
grades, making it difficult to assess overall efficacy. The histological clearance rate after 4 weeks therapy was 67.0% with 5% 5FU ointment and 73.0% with 5% imiquimod.8 Histological
clearance rates in two randomized, vehicle-controlled studies
were 84.0% and 57.1% following 12 and 16 weeks of treatment
with 5% imiquimod respectively; AK grade was again unspecified.12,25
A significant aspect of AK therapy is the recurrence of lesions,
with reported recurrence rates following cryosurgery varying
greatly (1.279.0%) across studies, depending on the length of
the follow-up and the severity of the lesions.8,10,2628 In our
study, patients treated with 0.5% 5-FU/SA solution once-daily
had a > 2-fold lower incidence of lesion recurrence during the
study than patients who received cryosurgery (39.4% vs. 84.8%,
respectively; P = 0.0001). Cryosurgery is frequently used for
treating isolated, visible AKs; however, unlike field-directed topical therapies, it does not treat perilesional skin, which might
account for high recurrence rates.8,2931 In addition, cryosurgery
might not be suitable for thicker lesions, such as hyperkeratotic
lesions,32 owing to the inability of the technique to penetrate
deeper skin layers. A longer treatment time (1015 s) has been
proposed when performing cryosurgery for thicker or hyperkeratotic lesions.3335
Previously reported recurrence rates in a larger (n = 470)
study of 0.5% 5-FU/SA were 8.4% and 14.2% at 6 and
12 months, respectively, after the end of treatment.17,18 The AKs
in this previous study were located on the face/forehead or bald
scalp and were mild/moderate (grade I/II) only; 0.5% 5-FU/SA
was applied for up to 12 weeks.17 A shorter (4-week) treatment
schedule of 5% 5-FU ointment was associated with a 12-month
recurrence rate of 46.0%, vs. 27.0% in patients with unspecified
grades of AKs who received imiquimod cream.8 Up to 12 weeks
of imiquimod therapy was associated with a 10.0% 12-month
recurrence rate in patients with unspecified AK grade.25 The
inclusion of hyperkeratotic, higher-grade AKs in our study compared with these previous studies might account for the higher
lesion recurrence rate in our study. A high degree of hyperkeratosis might interfere with the penetration of field-directed topical treatments.17

2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.

Simon et al.

888

The incidence of AEs across both treatment groups in this

study was relatively low and AEs were generally mild/moderate
in intensity. AEs related to study drug were more common in
patients treated with 0.5% 5-FU/SA than cryosurgery (13 AEs vs.
2 AEs respectively). AEs reported for low-dose 5-FU/SA were
characteristic of those reported previously.17 We would have
expected patients who received cryosurgery to report pain, as a
recent study reported that pain associated with cryosurgery may
be significantly higher than that deemed to be appropriate,36 but
this was not the case in our patient population. In an earlier randomized, controlled study, cryosurgery was associated with local
adverse reactions in 26.0% of patients, with two patients discontinuing treatment because of pain.14 In contrast, other studies
have shown higher rates of cryosurgery-associated AEs (35
72%).15,16 Possible reasons for the disparity in AEs include the
small number of patients enrolled in our study, which might
have skewed any differences between the treatments in AE
occurrences, and the fact that the investigators in this study were
particularly experienced in performing cryosurgery, thereby
reducing the potential harmful effects of this unstandardized
technique.27 As expected with therapies for AK, local skin reactions were common although most had cleared at the 6-month
follow-up visit. Erythema and scabbing/crusting are among the
clinical features of AKs; therefore, it is possible that the relatively
large number of patients reporting these symptoms at the 6month visit may relate to any untreated or incompletely cleared
lesions.
Limitations of this study include the small patient population,
which somewhat restricts the conclusions that can be drawn for
the efficacy of 0.5% 5-FU/SA and cryosurgery. This Phase 2
study was started in April 2011, before 0.5% 5-FU/SA (Actikerall) received regulatory approval in Europe in 2011 for its 12week dosing schedule and indication for the topical treatment of
slightly palpable and/or moderately thick hyperkeratotic AKs
(grade I/II according to the 4-point scale of Olsen et al.20) in
immunocompetent adult patients. Thus, a reduced dosing schedule and small sample size, alongside the inclusion of more difficult-to-treat AKs, i.e. AKs grade III, may have contributed to the
results for 0.5% 5-FU/SA seen in our study differing from those
reported previously.

Conclusion
In this open-label, randomized, controlled study, topical
once-daily 6-week treatment of grade II/III hyperkeratotic
AKs with 0.5% 5-FU/SA was associated with greater histological clearance than cryosurgery. Furthermore, patients treated
with low-dose 5-FU/SA had a lower incidence of lesion
recurrence than patients treated with cryosurgery, most of
whom received two applications. In addition, low-dose 5-FU/
SA appeared to have good general tolerability and was well
accepted by both physicians and patients in terms of clinical
and cosmetic outcomes.

JEADV 2015, 29, 881889

Acknowledgements
Medical writing support was provided by Rhian Harper Owen
on behalf of Complete Medical Communications Ltd, funded by
Almirall, S.A.

Author contributions
Jan Simon contributed to the conception or design of the study,
data acquisition and data analysis and interpretation. Rolf Dominicus contributed to data acquisition as principal investigator
for this study. Thomas Dirschka contributed to the conception
or design of the study, data acquisition and data analysis and
interpretation. Lars Karl contributed to the conception, data
acquisition and data analysis. Rosario Rodr
guez and Christoph
Willers contributed to the interpretation of data.

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2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of the European Academy of Dermatology and Venereology.