Calcipotriol and 5-Fluorouracil Combination Therapy for the Treatment of Actinic Keratosis in the Clinic: A Review Article

Abstract

This review examines the pharmacology, efficacy and safety, dosage and administration, and place in therapy of the combination of 5-fluorouracil (5-FU) and calcipotriol for the treatment of actinic keratosis. Currently, 5% 5-FU topical cream is approved for actinic keratosis treatment, while calcipotriol is indicated for plaque psoriasis in adults. The typical administration of 5-FU involves topical application twice daily for up to 4 weeks, whereas calcipotriol is applied in a thin layer once or twice daily as directed by a physician. Adverse effects of 5-FU are primarily localized, including skin irritation, ulceration, pruritus, erythema, crusting, and eczematous reactions due to minimal systemic absorption. Calcipotriol may cause burning, itching, and skin irritation. This review details clinical trials that investigate the innovative approach of combining topical 5-FU with calcipotriol for actinic keratosis treatment, highlighting the significant outcomes. Notably, the clinical trials indicate that all participants experienced either a reduction in lesion size or complete lesion clearance, with minimal adverse effects impacting treatment success. The combination of 5-FU and calcipotriol effectively treats actinic keratosis by enhancing the immune response and targeting cell overgrowth, while reducing local site reactions and the lengthy treatment time often associated with existing therapies.

Key Points

When combined, calcipotriol and 5-fluorouracil optimally activate CD4+-mediated immunity against actinic keratoses.

Calcipotriol and 5-fluorouracil have a 4-day application period with fewer local site reactions and minor adverse effects, compared with other current treatment options.

This combination therapy has the potential to inhibit the development of actinic keratosis lesions into squamous cell carcinoma.

Introduction

Actinic keratosis (AK) is a prevalent precursor to squamous cell carcinoma (SCC), which is a type of skin cancer that arises in sun-damaged skin [1]. Given the premalignant nature of AK and its 0.1% to up to 20% risk of developing into SCC, treatment is strongly recommended [1]. Current treatment options for AK include photodynamic therapy, cryotherapy, 5-fluorouracil (5-FU), imiquimod, diclofenac, and ingenol mebutate [1]. The choice of treatment is typically based on various AK features such as location, treatment-related factors (efficacy, tolerability, and burden), and patient characteristics and preferences. Topical agents such as creams, gels, and solutions are commonly used, as AK frequently occurs on sun-exposed areas such as the neck, shoulders, and hands, as well as contiguous regions like the face and scalp. Although not yet included in official treatment guidelines, the combination of 5-FU and topical calcipotriol has recently emerged as a promising novel treatment for AK owing to their synergistic effects and the short course of treatment. This review aims to provide a comprehensive understanding of the new topical combination therapy of calcipotriol and 5-FU on the treatment of AK lesions and offer recommendations for further studies.

Data Sources

A comprehensive literature search using PubMed was conducted using the terms actinic keratosis, calcipotriol, and 5-fluorouracil from January 2017 to March 2024. Additional data were obtained from manufacturer’s product labeling, Lexicomp, and current treatment guidelines of AK. The time frame for our data collection was 15 May to 28 June, 2024.

Pharmacology

5-Fluorouracil is a pyrimidine antimetabolite that is known to interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid to thymidylic acid [2]. Blocking DNA synthesis, 5-FU is able to prevent cell proliferation of fast-growing cells by causing cell death. Calcipotriol, in contrast, is a synthetic vitamin D₃ analog that regulates skin cell production and proliferation [3]. More specifically, calcipotriol binds to vitamin D receptors and inhibits keratinocyte proliferation and enhances keratinocyte differentiation.

Pharmacokinetics and Pharmacodynamics

In the 5% topical cream formulation of 5-FU, approximately 6% of the topical dose is systemically absorbed [4]. The time to peak effect is approximately 1 hour following application to the impacted site [5]. The onset of action of calcipotriol begins approximately after 2 weeks and marked improvement is typically seen after 8 weeks [6]. The absorption of calcipotriol cream and foam formulations when applied to psoriasis plaques is unknown. The ointment formulation once applied has approximately a 6% systemic absorption [5]. Calcipotriol is metabolized into inactive metabolites. When combined, there is a synergistic effect of calcipotriol and 5-FU treatment in optimally activating a CD4+ cell-mediated immunity against actinic keratoses and potentially cancers of the skin [4].

Efficacy and Safety

Multiple studies effectively evaluated the efficacy of a 4-day course in clearing AK lesions and reducing the incidence of SCC. 5-Fluorouracil is a cytotoxic medication that is already approved for the treatment of AK lesions by inhibiting cellular thymidylate synthase, leading to the disruption of DNA replication [7]. However, the purpose of the combination therapy with calcipotriol is to not only cause cell death by 5-FU but slow down the rapid production of skin cells through the use of the vitamin D analog and ultimately prevent the development of new lesions and by doing so, prevent the formation of SCC [8].

In a blinded cohort study involving participants from a randomized double-blind clinical trial, a 4-day course of topical calcipotriol combined with 5-FU was compared to a control group using vaseline plus 5-FU [8]. This study by Rosenberg et al. assessed the incidence of SCC and basal cell carcinoma following treatment at 1, 2, and 3 years after the trial. The combination treatment induced a tissue-resident memory T-cell formation against actinic keratoses and lowered the risk of SCC development. In this study, the combination therapy was applied to the face and scalp. This study suggests that by inducing the expression of thymic stromal lymphopoietin in the skin, calcipotriol synergizes with the cytotoxic effects of 5-FU and together leads to a robust CD4+ T-cell immunity against skin carcinogenesis [8]. In comparison to the control cohort, the test cohort remained SCC free over the 1500-day follow-up period (p = 0.0765) and had significantly fewer SCC on the face and scalp within 3 years (2 of 30) compared with the control group (11 of 40) [8]. Additionally, there were more epidermal tissue-resident memory T cells in the test cohort compared with the control group, indicating a more robust immune response [8].

In another clinical trial by Azin et al., participants either received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or vaseline plus 5-FU twice daily. The inclusion criteria consisted of participants containing four to ten clinically discrete and visible actinic keratoses within a 25-cm² contiguous area on the face, scalp, right upper extremity, and/or left upper extremity [9]. This study also utilized the presence of any hypertrophic AK as a means to assess the clearance of lesions compared to the control group. The definition of an AK was a ≥ 6-mm hyperkeratotic papule or plaque on the skin. The conclusion of this study was that the combination of calcipotriol and 5-FU demonstrated a significantly higher complete (62% vs 8%, p < 0.0001) and partial clearance (82% vs 11%, p < 0.0001) of AK lesions on all anatomical sites [9]. However, this study did not determine if the combination therapy can effectively prevent SCC.

A follow-up to the study by Cunningham et al. compared AK lesions on the face, scalp, and right/left upper extremities when calcipotriol plus 5-FU was applied compared to vaseline plus 5-FU twice daily for 4 consecutive days. Following the treatment, it was reported that the number of AK lesions when compared with the control group were reduced by 87.8% versus 26.2% on the face, 76.4% versus 5.7% on the scalp, and 68.8% versus 9.6% on the right upper extremity, and 79% versus 16.3% on the left upper extremity by week 8 (p < 0.0001) for all anatomical sites [10].

Additionally, a study was conducted observing calcipotriene 0.005% foam and 1% 5-FU cream after utilizing cryotherapy in the treatment of hyperkeratotic AK. This retrospective study by Moore et al. instructed participants to apply topical treatments off label in 3-week cycles for 5 nights on the face and 7 nights elsewhere, then off for 2 weeks and then repeated. The results from the group 3 leg (cryotherapy followed by calcipotriol plus 5-FU) demonstrated earlier and more significant AK reductions compared with either treatment alone [11].

All studies noted certain skin reactions, such as erythema centered around the AK lesions, following the combination treatment. Participants also noted a burning sensation and scaling/itching [10]. However, there were no reports of pain, scarring, pigmentary changes, or skin infection, in addition to no systemic side effects [12]. In the cryotherapy study, participants reported non-persistent redness, dryness, and itching but no pain, scaling, or blistering. Irritation appeared to resolve within each 3-week cycle [11].

The studies mentioned indicate that the 4-day twice-daily application of the combination therapy when compared to vaseline plus 5-FU are an effective and short course of treatment for the reduction and elimination of AK lesions. The limitations of these studies primarily revolve around the lack of data determining if this combination therapy can effectively prevent SCC. A summary of clinical trial results for the combination of calcipotriol and 5-FU on AK lesions is presented in Table 1.

Table 1.

Summary of clinical trial results for the combination of calcipotriol and 5-FU on AK lesions

Study	Study population	Number of participants	Intervention	Outcome
Rosenberg et al. [8]	Age range: 56–86 years Both male and female participants 4–15 AK lesions within a 25 cm2 area of the face, scalp, RUE and/or LUE	130 patients 64 participants in the calcipotriol + 5-FU arm 66 participants in the vaseline + 5-FU control arm	4-day course, twice-daily application of mixed equal parts of 0.005% calcipotriol ointment + 5% 5-FU cream immunotherapy (chemopreventive effect)	Treatment associated with long-lasting T-cell immunity in the skin against skin carcinogenesis
Azin et al. [9] and Cunningham et al. [10] (secondary analysis)	Age 51–88 years Both male and female participants 4–10 clinically discrete and visible AK lesions within a 25-cm2 contiguous area on the face, scalp, RUE and/or LUE	130 participants 64 participants in the calcipotriol + 5-FU arm (54 in secondary analysis) 66 participants in the vaseline + 5-FU control arm (52 in secondary analysis)	0.005% calcipotriol ointment plus 5% 5-FU cream twice daily treatment for 4 consecutive days Used the presence of hypertrophic actinic keratoses on the face as an inclusion criterion to assess the clearance rate	Study confirms high efficacy of calcipotriol plus 5-FU therapy and are comparable to other AK treatments Calcipotriol and 5-FU combination resulted in a specific induction of CD4+ T-cell immune response against AK lesions
Moore et al. [11]	Non-randomized, retrospective study	175 participants 50 participants in the cryotherapy 50 participants in the cryotherapy group followed by 1% 5-FU cream 50 participants in the cryotherapy group followed by 1% 5-FU cream and 0.005% calcipotriene foam 25 participants in the cryotherapy group followed by cyclic vitamin D3	Cryotherapy followed by either 1% 5-FU cream, 1% 5-FU cream and 0.005% calcipotriol foam, or cyclic vitamin D3 Applied topical treatments in 3-week cycles for 5 nights on the face and 7 nights elsewhere, off for 2 weeks, and then repeat	Addition of a vitamin D3 analog to 5-FU after cryotherapy may improve efficacy and accelerate onset of action through induction of antitumor T-cell immunity

5-FU fluorouracil, AK actinic keratosis, LUE left upper extremity, RUE right upper extremity

Dosage and Administration

The topical combination of calcipotriol plus 5-FU is for topical application only. The application can be used on the areas in which AK lesions are present such as the face, scalp, and upper/lower extremities. For this treatment, a 4-day twice-daily application course is recommended with a 5% strength of 5-FU cream and a 0.005% strength of calcipotriol ointment. For 5-FU, when applied to a lesion, a response occurs in a sequence that most often results in erythema, usually followed by vesiculation, desquamation, erosion, and re-epithelialization [2]. It is recommended to apply both creams in an amount sufficient to cover the lesions and to wear gloves while applying 5-FU and wash hands thoroughly after the application of both medications.

Relevance to Patient Care and Clinical Practice

Current guidelines for the treatment of AK recommend overall protection from ultraviolet light, and the topical application of imiquimod, 5-FU, and cryotherapy [1]. There are also conditional recommendations for the use of photodynamic therapy and diclofenac. The primary concern with the current treatment options is the length of treatment, severe local reactions, and ineffective AK clearance. Clinically, AK can be graded on a scale of mild (1) to severe (3), according to the three-level Olsen scale [1]. However, clinicians tend to view the area where the AK lesions are present and patient preference in terms of the burden of treatment.

The combination therapy of calcipotriol, a vitamin D₃ analog most commonly used for the treatment of plaque psoriasis, and 5-FU, which is approved for the treatment of AK, offer an innovative approach to treating AK lesions through their combined mechanisms. The synergistic effects of calcipotriol and 5-FU treatment work by activating a CD4+ cell-mediated immunity against actinic keratoses [10]. Because of the fact that actinic keratoses represent an early stage of the malignant transformation of keratinocytes and can progress to SCC, the use of these therapies is optimal in repressing this progression.

The short course of treatment and the minimal side-effect profile highlight the advantages of calcipotriol plus 5-FU for the treatment of patients with AK. The ultimate objective of this combination treatment is to prevent the development of SCC in addition to other skin cancers and provide a low burden treatment with a short course of therapy. Although approved cytotoxic therapies for AK demonstrate a long-term benefit in reducing AK lesions, their impact on preventing SCC from development still remains uncertain. However, because of the combination therapy’s ability to induce a T-cell-mediated immunity against AK, calcipotriol and 5-FU may have the potential to establish an antitumor immune memory in the skin, which in the long term could prevent the development of skin cancer [12]. More studies of the long-term effectiveness of preventing SCC will need to be conducted to support this theory.

The combination of calcipotriol and 5-FU is not commercially available, so it would require compounding by a pharmacist or specialty pharmacy. Calcipotriol and 5-FU are each available generically. Pricing for calcipotriol and 5-FU is shown in Tables 2 and 3, respectively.

Table 2.

Calcipotriene pricing (USA) [6]

Formulation	Strength	Cost
Cream (calcipotriene external)	0.0005% (per gram)	$6.75–$9.71
Foam (calcipotriene external)	0.005% (per gram)	$19.13
Foam (Sorilux external)	0.005% (per gram)	$16.95
Ointment (calcipotriene external)	0.005% (per gram)	$6.03–$6.88
Ointment (calcitrene external)	0.005% (per gram)	$6.38
Ointment (calcipotriene external)	0.005% (per mL)	$5.39–5.66

Table 3.

5-Fluorouracil pricing (USA) [5]

Formulation	Strength	Cost
Cream (Carac external)	0.5% (per gram)	$99.91
Cream (Efudex external)	5% (per gram)	$1.80
Cream (fluorouracil external)	0.5% (per gram)	$59.21
	5% (per gram)	$6.43–$9.62
Cream (Tolak external)	4% (per gram)	$1.20
Solution (fluorouracil external)	2% (per mL)	$7.56
	5% (per mL)	$11.13

Conclusions

5-Fluorouracil is a pyrimidine antimetabolite that interferes with DNA synthesis and, by doing so, prevents cell proliferation and causes cell death. Calcipotriol is a synthetic vitamin D₃ analog that regulates skin cell production and proliferation through regulating the immune system in the skin to reduce overgrowth. This 4-day and twice-daily course of calcipotriol plus 5-FU treatment can be applied to contiguous areas such as the face and scalp and to the upper extremities where AK lesions are present. The most commonly reported adverse effects include erythema, a burning sensation, and scaling/itching, yet no systemic side effects have been noted. The effect of calcipotriol inducing the expression of thymic stromal lymphopoietin in the skin combined with the cytotoxic effects of 5-FU leads to a robust CD4+ T-cell immune response against skin carcinogenesis.

Declarations

Funding

No external funding was received for the preparation of this article. Anthony J. Di Pasqua is supported financially by the Massachusetts College of Pharmacy and Health Sciences.

Conflicts of interest

Anna H. Dlott and Anthony J. Di Pasqua have no conflicts of interest that are directly relevant to the content of this article. Sara A. Spencer is an employee of Otsuka Pharmaceutical.

Ethics approval

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Consent to publication

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Availability of data and material

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Code availability

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Authors’ contributions

AHD: conceptualization, original draft preparation, reviewing, and editing; SAS: reviewing and editing; AJD: conceptualization, reviewing, and editing.