Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review

January 2022 | Volume 21 | Issue 1 | 60 | Copyright © January 2022

Published online December 30, 2021

Lindsey Mohney a, Rohan Singh a, Ayman Grada MD MSb, Steven R. Feldman MD PhDa,c,d

aCenter for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC
bResearch & Development, and Medical Affairs, Almirall (US), Malvern, PA
cDepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC
dDepartment of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC

Background: Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations.
Objective: To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence.
Methods: A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included.
Results: In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy.
Limitations: A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy.
Conclusion: Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment.

J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632


Actinic Keratosis (AK) is a recurring premalignant lesion that arises from prolonged and intermittent sun exposure.1 In the United States, AK is the second most frequent diagnosis made by dermatologists.2 Worldwide, the number of cases continues to rise, with the highest prevalence among countries with high levels of sunlight and populations with light skin tones.2,3 UV radiation from sunlight can induce dysplastic proliferation of keratinocytes, resulting in the formation of AK.3 AKs have a 0.025% to 16% chance of progression to cutaneous squamous cell carcinoma (cSCC).4 Individuals with a higher burden of AKs carry an increased risk of transformation.5 Due to the underlying risk for malignant transformation, AKs require treatment.4,5

Individual AKs are treated with lesion-directed therapy.6 For multiple AKs located in one area, field-directed therapy is the treatment of choice.6 Field-directed therapies include the FDA- approved topical agents 5-Fluorouracil (5-FU), imiquimod, diclofenac, tirbanibulin, and photodynamic therapy.7 Field cancerization is a term used to describe areas of skin affected by chronic UV radiation.8 The affected skin region can develop visible AKs and also harbor subclinical AKs. In order to effectively treat the entire region, field-directed therapy is required.9 5-FU 5% cream is thought to be a more effective field-directed therapy when compared to imiquimod cream, ingenol mebutate gel, and PDT, based on a single-blind study – but no comparative data available vs the recently FDA-approved tirbanibulin 1% ointment (2020).7,10 However, topical 5-FU requires multiple daily applications, long durations of treatment, and can cause severe cutaneous and systemic adverse effects.11 These factors decrease patient adherence and real-world effectiveness.11 A negative experience with topical treatment may prevent patients from seeking treatment for AK in the future.11,12,13