10.5826/dpc.1302a151
Introduction:5-fluorouracil (5-FU) is one of the most effective topical treatments for actinic keratosis (AK). A new 4% formulation of 5-FU was recently approved in Europe.
Objectives:This study aimed at evaluating 4% 5-FU cream safety and effectiveness in a real-world setting.
Methods:Adult AK patients were retrospectively selected from the University of Campania Dermatology Unit database. Selection criteria included a diagnosis of non-hyperkeratotic, non-hypertrophic AK (Olsen grade I and II) of the face, ears, and/or scalp, treatment with 4% 5-FU once daily for 4 weeks, and at least 3 follow-up visits (4 and 8 weeks after treatment initiation, and 6 months after treatment end). The primary objectives were to evaluate AK lesions improvement at 8 weeks and relapse rate at 6 months. Patient-reported erythema and burning sensation intensity were also assessed at 4 weeks.
Results: Ninety-eight patients were included in this analysis (male/female 80/18, mean age 74.7 years). AK lesions improvement at 8 weeks resulted complete or significant in 74.5% and 20.4% of the patients, respectively. At 6 months, 65.3% of the patients did not show AK relapses. Burning sensation at 4 weeks was reported as light, moderate, or absent by 44.9%, 22.4%, and 31.6% of the patients, respectively. Erythema was reported as light, moderate, or absent by 37.8%, 51%, and 10% of the patients, respectively. Burning sensation and erythema disappeared gradually during follow-up. No other side effects were reported.
Conclusions:In this real-world study 4% 5-FU proved to be highly effective for AK lesions clearance with a favorable safety profile.
text/xml
2160-9381
2939
en
Giuseppe Argenziano
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
 safety
Real-World Experience with Topical 5-Fluorouracil 4% (40 mg/g) Cream for the Treatment of Actinic Keratosis
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-04-29
2022-10-27
2023-04-29
2023-06-05
e2023151
Dermatol Pract Concept
Introduction:5-fluorouracil (5-FU) is one of the most effective topical treatments for actinic keratosis (AK). A new 4% formulation of 5-FU was recently approved in Europe.
Objectives:This study aimed at evaluating 4% 5-FU cream safety and effectiveness in a real-world setting.
Methods:Adult AK patients were retrospectively selected from the University of Campania Dermatology Unit database. Selection criteria included a diagnosis of non-hyperkeratotic, non-hypertrophic AK (Olsen grade I and II) of the face, ears, and/or scalp, treatment with 4% 5-FU once daily for 4 weeks, and at least 3 follow-up visits (4 and 8 weeks after treatment initiation, and 6 months after treatment end). The primary objectives were to evaluate AK lesions improvement at 8 weeks and relapse rate at 6 months. Patient-reported erythema and burning sensation intensity were also assessed at 4 weeks.
Results: Ninety-eight patients were included in this analysis (male/female 80/18, mean age 74.7 years). AK lesions improvement at 8 weeks resulted complete or significant in 74.5% and 20.4% of the patients, respectively. At 6 months, 65.3% of the patients did not show AK relapses. Burning sensation at 4 weeks was reported as light, moderate, or absent by 44.9%, 22.4%, and 31.6% of the patients, respectively. Erythema was reported as light, moderate, or absent by 37.8%, 51%, and 10% of the patients, respectively. Burning sensation and erythema disappeared gradually during follow-up. No other side effects were reported.
Conclusions:In this real-world study 4% 5-FU proved to be highly effective for AK lesions clearance with a favorable safety profile.
Giuseppe Argenziano
2023/04/29
10.5826/dpc.1302a151
e2023151
Dermatology Unit, University of Campania, Naples, Italy
2160-9381
 safety
en
e2023151
Couch SM, Custer PL. Topical 5-fluorouracil for the treatment of periocular actinic keratosis and low-grade squamous malignancy. Ophthalmic Plast Reconstr Surg. 2012;28(3):181-183. DOI:10.1097/IOP.0b013e3182467c68. PMID: 22460673.
Real-World Experience with Topical 5-Fluorouracil 4% (40 mg/g) Cream for the Treatment of Actinic Keratosis
https://dpcj.org/index.php/dpc/article/download/2939/1982
                 Real-World Experience With Topical
             5-Fluorouracil 4% (40 mg/g) Cream for the
                   Treatment of Actinic Keratosis
       Giulia Briatico1, Gabriella Brancaccio1, Camila Scharf1, Eugenia Veronica Di Brizzi1,
           Sebastiano Pellerone1, Stefano Caccavale1, Caterina Mariarosaria Giorgio1,
               Enrico Maria Procaccini1, Elvira Moscarella1, Giuseppe Argenziano1


1 Dermatology Unit, University of Campania, Naples, Italy



Key words: actinic keratosis, 5-fluorouracil, treatment, efficacy, safety
Citation: Briatico G, Brancaccio G, Scharf C, et al. Real-world experience with topical 5-fluorouracil 4% (40 mg/g) cream for the treatment
of actinic keratosis. Dermatol Pract Concept. 2023;13(2):e2023151. DOI: https://doi.org/10.5826/dpc.1302a151
Accepted: November 30, 2023; Published: April 2023
Copyright: ©2023 Briatico et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Giulia Briatico, Dermatology Unit, University of Campania, Via Pansini, 5, 80131, Naples, Italy,
giuliabriatico@gmail.com




  ABSTRACT              Introduction: 5-fluorouracil (5-FU) is one of the most effective topical treatments for actinic keratosis
                        (AK). A new 4% formulation of 5-FU was recently approved in Europe.
                        Objectives: This study aimed at evaluating 4% 5-FU cream safety and effectiveness in a real-world setting.
                        Methods: Adult AK patients were retrospectively selected from the University of Campania Dermatol-
                        ogy Unit database. Selection criteria included a diagnosis of non-hyperkeratotic, non-hypertrophic AK
                        (Olsen grade I and II) of the face, ears, and/or scalp, treatment with 4% 5-FU once daily for 4 weeks,
                        and at least 3 follow-up visits (4 and 8 weeks after treatment initiation, and 6 months after treatment
                        end). The primary objectives were to evaluate AK lesions improvement at 8 weeks and relapse rate at
                        6 months. Patient-reported erythema and burning sensation intensity were also assessed at 4 weeks.
                        Results: Ninety-eight patients were included in this analysis (male/female 80/18, mean age 74.7 years).
                        AK lesions improvement at 8 weeks resulted complete or significant in 74.5% and 20.4% of the
                        ­patients, respectively. At 6 months, 65.3% of the patients did not show AK relapses. Burning sensation
                         at 4 weeks was reported as light, moderate, or absent by 44.9%, 22.4%, and 31.6% of the patients,
                         respectively. Erythema was reported as light, moderate, or absent by 37.8%, 51%, and 10% of the
                         patients, respectively. Burning sensation and erythema disappeared gradually during follow-up. No
                         other side effects were reported.
                        Conclusions: In this real-world study 4% 5-FU proved to be highly effective for AK lesions clearance
                        with a favorable safety profile.



Original Article | Dermatol Pract Concept. 2023;13(2):e2023151                                                                           1
Introduction                                                      AK treatment in various formulations, with concentrations
                                                                  ranging from 0.5 to 5% [8]. The 5% 5-FU cream efficacy
Actinic keratosis (AK) is a common skin disease caused            is supported by a substantial number of studies. In a net-
by chronic sun exposure [1]. Clinically, AK presents with         work meta-analysis published in 2019 by Wu et al, including
small, dry, erythematous, scaly and sometimes pigmented           11 studies and more than 2200 patients, 5% 5-FU was more
­papules [2]; these lesions result from abnormal proliferation    likely to be effective in AK lesions total clearance compared
of atypical epidermal keratinocytes and are located in chron-     with the association of 5-FU with salicylic acid, 3% di-
ically sun-exposed body areas such as the face, scalp, neck,      clofenac sodium, and cryosurgery (56.8% vs 37.5%, 6.6%,
hands, and forearms [1,2].                                        and 0.9%, respectively) [7]. 5% 5-FU resulted also more
    Italy shows one of the highest prevalence of AK world-        likely to be the most effective treatment among patients with
wide [2,3]. In a retrospective, observational study published     lesions reduction from baseline (98.6%).
in 2017, which enrolled 7,284 outpatients attending Italian          In a multicentre, single-blind, randomized trial published
general dermatology clinics, the overall mean prevalence          by Jansen et al in 2019, patients treated with 5% 5-FU
of AK was 27.4%, with a significantly higher rate in males        showed a significantly higher cumulative probability of re-
compared with females (34.3% versus 20.0%, respectively;          maining free from treatment failure at 12 months compared
P <0.001) [2]. The same study confirmed in the Italian pop-       with patients who received 5% imiquimod, methyl ami-
ulation the well-known, independent risk factors of AK,           nolevulinate PDT, or 0.015% ingenol mebutate (74.7% vs
i.e. older age, male gender, fair skin (Fitzpatrick phototypes    53.9%, 37.7%, and 28.6%, respectively; P ≤0.001) [9].
I-II), prolonged UV exposure for professional or recreational        Finally, according to a recent secondary analysis of a
reasons, and alcohol consumption [1,2].                           randomized clinical trial, 5% 5-FU seems to reduce long-
    AK is considered a precursor of invasive squamous cell        term SCC risk compared with other field-directed AK
carcinoma (SCC), a malignancy which can produce distant           ­treatments [10]. In this analysis, conducted on 624 patients
metastases [2,3]. The AK progression rate is highly variable      with AK, the 4-year risk of cutaneous SCC in the treated area
(from 0.025% to 20%) and increases with the number of             resulted lower in subjects who initially received 5% 5-FU
­lesions, being 11-fold higher in patients with >20 lesions       (2.2%) compared with imiquimod (5.8%), methyl amino-
[1,4]. Since it is impossible to predict lesions risk of trans-   levulinate PDT (3.6%), or ingenol mebutate (3.0%) [10].
formation based on their morphological features, a prompt            In 2020, the European Medicines Agency approved a
diagnosis and treatment of every AKs are essential to reduce      novel 4% 5-FU formulation for the treatment of Olsen grade
the risk of SCC [2,3,5]. Importantly, according to the “field     I or II AK [11,12]. The 4% formulation has a more conve-
cancerization” (FC) concept, treatment should also target         nient dosage compared with twice daily 5% 5-FU: it should
the skin surrounding AK lesions, where subclinical lesions        be applied once daily for a maximum of 4 weeks, potentially
with the potential of malignant transformation could be           improving treatment compliance [12,13].
present [6]. The cutaneous FC is due to chronic ultraviolet          In a multicenter, randomized, double-blind, ­parallel-
radiation exposure, which results in clonal proliferation of      group, phase III study conducted in 841 subjects with AK,
p53-­mutated fields, high burden of both clinical and sub-        4% 5-FU efficacy was similar to 5% 5-FU in terms of 100%
clinical actinic damage, and high risk of developing multiple     lesions clearance at 4 weeks (54.4% versus 57.9%, respec-
SCCs; these, in turn, are associated with relevant mortality,     tively), ≥75% lesions clearance at 4 weeks (80.5% versus
morbidity and high costs for national healthcare systems [6].     80.2%, respectively), and percentage change from baseline
    Given the need for an effective AK treatment, several         in AK lesions count (80.1% versus 79%) [11,13]. N
                                                                                                                  ­ otably,
therapeutic options have been developed. They include             4% 5-FU showed an improved safety profile compared
lesion-directed treatments, such as cryosurgery, curettage,       with 5% 5-FU, with a lower rate of adverse events leading
and excision surgery, which remove atypical keratinocytes         to treatment discontinuation (10.1% versus 14.9%, respec-
of every single lesion, and field-directed treatment, such as     tively) [11,13].
photodynamic therapy (PDT) and topical treatments, whose             These results were confirmed by a recently published
therapeutic action is extended to the whole FC [1].               ­network meta-analysis which included 75 randomized clini-
    5-fluorouracil (5-FU) is an antineoplastic drug commonly      cal trials [14]. In this analysis, 4% 5-FU was compared with
used as a topical, field-directed treatment for AK [7]. 5-FU is   5% formulation, placebo and several other topical treat-
a pyrimidine analogue, which irreversibly inactivates thymi-      ments for AK (diclofenac sodium, imiquimod, ingenol mebu-
dylate synthase, interfering with DNA synthesis and causing       tate, and PDT). The Surface Under the Cumulative RAnking
apoptosis of the high proliferative AK keratinocytes [1,8].       (SUCRA) values ranked 4% 5-FU as having the probabil-
It was the first drug for AK field-directed treatment and         ity of being the best treatment in achieving ≥75% clearance
its approval dates back to 1962 [3]. 5-FU is available for        of AK lesions, followed by 5% 5-FU (SUCRA 89.98 versus



2                                                                     Original Article | Dermatol Pract Concept. 2023;13(2):e2023151
88.95, respectively); moreover, 4% 5-FU ranked second,             Results
following 5% 5-FU, in the probability of being the best
treatment for complete AK lesions clearance (SUCRA 78.26           Overall, 98 patients satisfied the inclusion criteria and
versus 84.74). Notably, SUCRA values showed a lower risk           were selected for the study. Most of these patients were
of withdrawal due to adverse events associated with 4%             males (N = 80/98; 81%) and the mean age at first visit was
5-FU treatment compared with 5% 5-FU (SUCRA 70.89                  74.7 years. The mean number of follow-up visits resulted
versus 70.89 r­ espectively) [14].                                 slightly higher than the number required for the inclusion
                                                                   in the study (3.05 versus 3) since 5 patients required 1 or 2
                                                                   additional consultations because of side effects. The mean
Objectives
                                                                   follow-up duration in our sample was 212 days.
Due to 4% 5-FU formulation recent approval, real-world                According to the IGI scores, after 8 weeks from treat-
­evidence on this treatment in AK is lacking. This study aimed     ment initiation (4 weeks after the end of treatment) AK
to fill this gap, reporting the experience of an Italian Derma-    ­lesions were completely or significantly improved compared
tology Centre using 4% 5-FU to treat subjects with AK in           with baseline in the vast majority of the patients (74.5%
routine clinical practice.                                         and 20.4%, respectively; Figure 1). In only 4 ­patients the
                                                                   investigators graded the improvement as moderate or slight
                                                                   (4.1%) and 1 patient (1%) showed no change in AK se-
Methods
                                                                   verity. ­Moreover, no patient showed a worsening of the
This study was a retrospective analysis of the University          disease.
of Campania Dermatology Unit (Naples, Italy) patient da-              4% 5-FU treatment results were sustained during
tabase. Adult subjects with a diagnosis of grade I or II AK        follow-up, and 64 patients (65.3%) did not show AK
(based on the 4-point Olsen scale), localized on the face,         ­relapses at the 6 months visit.
ears, and/or scalp, consisting of visible and palpable lesions        Patients-reported burning sensation after 4 weeks from
neither hypertrophic nor hyperkeratotic, treated with 5-FU         treatment initiation was generally light (N = 43, 43.9%)
4% cream (Tolerak®, Pierre Fabre) once daily for 4 weeks           or moderate (N = 22, 22.4%; Figure 2A). Only 1 patient
from September 2021 to November 2021 were selected.                (1%) reported severe burning sensation, and 31 patients
Only patients with at least 3 follow-up visits were included:      (31.6%) did not report this adverse event. Similar results
the first and the second one after 4 and 8 weeks from treat-       were obtained for patients-reported erythema at 4 weeks
ment initiation respectively; the third one 6 months after the     (Figure 2B), which was generally graded as light (N = 37,
­second visit.                                                     37.8%) or moderate (N = 50, 51%). Only 1 patient (1%)
    The primary objective of the study was to evaluate the         reported a severe erythema, while 10 patients (10.2%) did
4% 5-FU cream efficacy in terms of AK lesions improve-             not report this adverse event.
ment at 8 weeks and relapse rate at 6 months. AK lesions              In patients with burning sensation and/or erythema, these
improvement is routinely assessed at our Centre with the           adverse events disappeared gradually during follow-up, and
7-point Investigator Global Improvement Scale (IGI; -2, sig-       they could be managed with moisturizing and/or topical
nificantly worse; -1, slightly worse; 0, no change; +1, slightly   ­antibiotics on the basis of the investigator clinical judgment.
improved; +2, moderately improved; +3, significantly im-           No other side effects were reported.
proved; +4, completely improved), and the availability of
this measurement was included in the patients’ selection
                                                                   Conclusions
criteria.
    The secondary objective was to evaluate the safety of          In our study, 4% 5-FU proved to be an effective and safe
4% 5-FU cream in terms of erythema and burning sensa-              topical treatment for adults with non-hyperkeratotic,
tion intensity at 4 weeks. These adverse events are routinely      non-hypertrophic AK (Olsen grade I and II) of the face, ears,
assessed at our Centre with the patient-reported Scale for         and/or scalp, in a real-world clinical setting. Almost the
Clinical Assessment (SCA; 0, absent; 1, light; 2, moderate;        totality of our patients (99%) showed a clinical improve-
3, severe); only patients with these measurements available        ment after 8 weeks from treatment initiation, which was
were selected.                                                     considered significant or complete in 94.4% of the cases
    Statistical analyses were performed with Software R.           (Figure 3). Moreover, although the natural course of AK is
­Descriptive statistics of the cohort are provided with con-       characterized by the recurrence of lesions, the clearance ob-
fidence intervals. Chi-squared test for categorical variables      tained with 4% 5-FU was sustained during follow-up, with
and the t-test for continuous variables were used. Statistical     more than 64% of the patients free from AK recurrences at
significance was set at P <0.05.                                   6 months [15].



Original Article | Dermatol Pract Concept. 2023;13(2):e2023151                                                                   3
                                        90

                                        80                                                                                                         *
                                                                                                                                                  74.5

                                        70

                          Patients, %   60

                                        50

                                        40

                                        30
                                                                                                                                     *
                                                                                                                                    20.4
                                        20

                                        10
                                                                                *                        *            *
                                                                                                        3.1
                                                     0            0             1                                     1
                                         0
                                                     -2           -1           0             +1        +2           +3            +4
                       IGI score               (Significantly (Sligthly   (No change)    (Sligthly (Moderately (Significantly (Completely
                                                   worse)      worse)                   improved) improved)      improved) improved)
                         n/N                        0/98        0/98         1/98          3/98       1/98         20/98         73/98

                       Figure 1. AK lesions improvement from baseline at 8 weeks.
                       Percentages of patients with AK lesion improvement assessed with IGI scale after 8 weeks from 8 weeks after
                       treatment initiation. Error bars show 95% CIs. *P <0.001.
                       AK = actinic keratosis; IGI = Investigator Global Improvement; CI = confidence interval.


                                             A. BURNING SENSATION                                                                  B. ERYTHEMA
                  60                                                                                    70


                                                                                                        60
                  50
                                                      43.9                                                                                       51.0
                                                                                                        50
                  40
                                         *                                                                                           37.8
    Patients, %




                                                                                          Patients, %




                                        31.6                                                            40
                  30
                                                                   *                                    30
                                                                  22.4
                  20
                                                                                                        20
                                                                                                                           *
                  10                                                                                                      10.2
                                                                                                        10
                                                                               *                                                                               *
                                                                              1.0                                                                             1.0
      0                                                                                       0
SCA score              0 (absent)                1 (light) 2 (moderate) 3 (severe)      SCA score               0 (absent)       1 (light) 2 (moderate) 3 (severe)
n/N                       31/98                   43/98        22/98       1/98         n/N                        10/98          37/98        50/98       1/98

Figure 2. Safety assessment at 4 weeks.
(A) Burning sensation assessed with SCA after 4 weeks from 4 weeks after treatment initiation.
(B) Erythema assessed with SCA after 4 weeks from 4 weeks after treatment initiation.
Error bars show 95% CIs. *P <0.001.
SCA = Scale for Clinical Assessment; CI = confidence interval.



         These results confirm previously published evidence on                                         4% 5-FU was well tolerated in our patient population,
5-FU, which is currently considered one of the most effective                             with no side effects reported other than erythema and burn-
topical treatments for AK lesion clearance based on several                               ing sensation. After 4 weeks of treatment, erythema was
randomized clinical trials and meta-analyses [7,9,13,14].                                 light or moderate in almost 90% of the subjects, and only
Furthermore, our study confirms that reducing 5-FU con-                                   1 ­patient graded it as severe. 31.6% of patients did not report
centration from 5% to 4% does not affect its efficacy, even                               any burning sensation, which was severe in only 1 patient.
when used in real-world clinical practice.                                                In all the patients both erythema and burning sensation were



4                                                                                                       Original Article | Dermatol Pract Concept. 2023;13(2):e2023151
          Figure 3. Effects of 4% 5-FU treatment.
          These pictures show 4 patients with diffuse AK of the scalp, forehead and/or face at baseline, treated for 4 weeks with
          4% 5-FU. They confirm the normal pattern of response to 4% 5-FU: at the end of treatment, the inflammatory response
          associated with 5-FU pharmacological action on dysplastic AK cells reaches its peak, characterised by mild-moderate
          erythema (and burning sensation); after 8 weeks from 8 weeks after treatment initiation, the inflammatory response is
          resolved, and AK lesion clearance is noticeable.
          (A) 86-year-old male patient; (B) 76-year-old male patient, (C) 67-year-old male patient; (D) 76-year-old male patient.
          5-FU = 5-fluorouracil.




Original Article | Dermatol Pract Concept. 2023;13(2):e2023151                                                                      5
limited to the acute phase and they gradually disappeared                          2020;83(3):709-717. DOI:10.1016/j.jaad.2020.03.126. PMID:
during follow-up, being managed, when needed, according                            32387665.
                                                                              7.   Wu Y, Tang N, Cai L, Li Q. Relative efficacy of 5-fluorouracil
to the investigator’s clinical practice.
                                                                                   compared with other treatments among patients with ac-
    These results are in line with the well-known 5-FU safety
                                                                                   tinic keratosis: A network meta-analysis. Dermatol Ther.
profile, which resulted to be favorable both in challenging                        2019;32(3):e12822. DOI:10.1111/dth.12822. PMID: 30638294.
patients (such as those immunosuppressed) and in sensitive                   8.    Reinehr CPH, Bakos RM. Actinic keratoses: review of clini-
skin areas (such as the periocular region) [16,17].                                cal, dermoscopic, and therapeutic aspects. An Bras Dermatol.
    This study has two limitations. First, its retrospective                       2019;94(6):637-657. DOI:10.1016/j.abd.2019.10.004. PMID:
                                                                                   31789244. PMCID: PMC6939186.
­design, with the lack of a placebo group to account for the
                                                                              9.   Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized
natural regression of AK lesions. Second, we did not include
                                                                                   Trial of Four Treatment Approaches for Actinic Keratosis. N Engl
patients who either suspended or discontinued the therapy,                         J Med. 2019;380(10):935-946. DOI:10.1056/NEJMoa1811850.
since our first aim was to evaluate the treatment response.                        PMID: 30855743.
This did not allow us to calculate the rate of treatment with-               10.   Ahmady S, Jansen MHE, Nelemans PJ, et al. Risk of ­Invasive
drawal. However, we are convinced that patient education                           Cutaneous Squamous Cell Carcinoma After Different
                                                                                   ­
                                                                                   ­Treatments for Actinic Keratosis: A Secondary Analysis of a
is crucial for achieving a satisfactory compliance to 5-FU
                                                                                    Randomized Clinical Trial. JAMA Dermatol. 2022;158(6):
treatment. Patients should be taught to consider erythema
                                                                                    634-640. DOI:10.1001/jamadermatol.2022.1034. PMID: 3547​
and burning sensation as normal and transient signs of 5-FU                         5852. P­ MCID: PMC9047727.
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after 4 weeks of treatment and then gradually resolving. In                         (Pierre Fabre Italia).
our study this simple strategy resulted in a low rate (5.1%)                 12.    Del Regno L, Catapano S, Di Stefani A, Cappilli S, Peris K. A
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                                                                                   Status and Future Directions [published correction appears
                                                                                   in Am J Clin Dermatol. 2022 Apr 22]. Am J Clin Dermatol.
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6                                                                                  Original Article | Dermatol Pract Concept. 2023;13(2):e2023151
