Has a topical combination treatment of fluorouracil (5-fluorouracil), imiquimod, and retinoic acid (Vitamin A acid) been used to treat actinic keratosis?

From the Guidelines

Yes, a topical combination treatment of fluorouracil, imiquimod, and retinoic acid has been used to treat actinic keratoses, as evidenced by the guidelines of care for the management of actinic keratosis 1. This combination approach, sometimes referred to as "combination field therapy," targets actinic keratoses through multiple mechanisms of action.

Key Points:

• The treatment typically involves sequential application of these agents rather than mixing them together.
• A common approach is to first use 5-fluorouracil cream (usually 5% or 0.5%) once or twice daily for 2-4 weeks, followed by a rest period, then imiquimod 5% cream applied 2-3 times weekly for 4-16 weeks, with tretinoin (retinoic acid) 0.05% cream sometimes used before, between, or after these treatments to enhance penetration and efficacy.
• This combination works because each medication targets actinic keratoses differently: fluorouracil disrupts DNA synthesis in rapidly dividing cells, imiquimod stimulates the immune system to target abnormal cells, and retinoic acid normalizes cell differentiation and can enhance penetration of the other medications.
• Patients should expect significant skin irritation, redness, crusting, and discomfort during treatment, and should use sun protection throughout the course of therapy.
• This aggressive approach is typically reserved for patients with multiple, recurrent, or resistant actinic keratoses, as supported by the conditional recommendations for combination therapy regimens 1.

Treatment Considerations:

• The guidelines conditionally recommend the use of diclofenac, based on lower quality of evidence than that of the evidence supporting strong recommendations for the use of 5-FU or imiquimod 1.
• The benefits of 5-FU treatment for AK were assessed as moderate or large, based on studies assessed field treatment with 5-FU 1.
• The use of topical 5-FU as a field treatment for AKs is strongly recommended, with imiquimod also being a recommended treatment option 1.

From the FDA Drug Label

INDICATIONS AND USAGE: Fluorouracil Cream USP is recommended for the topical treatment of multiple actinic or solar keratoses. 1.1 Actinic Keratosis Imiquimod Cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.

The FDA drug label does support the use of fluorouracil and imiquimod as individual topical treatments for actinic keratosis. However, there is no information in the provided drug labels that directly supports the use of a topical combination treatment of fluorouracil, imiquimod, and retinoic acid for this condition.

• The use of retinoic acid is not mentioned in the context of treating actinic keratosis in the provided drug labels.
• There is no direct evidence to support the combination of these three treatments for actinic keratosis 2, 3.

From the Research

Topical Combination Treatment for Actinic Keratosis

• The combination of 5-fluorouracil and imiquimod creams has been used to treat actinic keratosis, as reported in studies 4, 5.
• These studies demonstrate the effectiveness of this combination therapy in treating actinic keratosis, with one study showing that 48 out of 64 patients achieved complete clearing of their lesions after three months of treatment 5.
• Another study found that the combination of 5-fluorouracil and imiquimod creams may be an effective alternative therapeutic strategy for patients who have failed standard therapy for actinic keratosis 4.
• However, there is no evidence to suggest that retinoic acid (Vitamin A acid) is part of this combination treatment, although it is mentioned as a topical therapy option for actinic keratosis in general 6, 7.

Efficacy of 5-Fluorouracil and Imiquimod

• Studies have compared the efficacy of 5-fluorouracil and imiquimod in treating actinic keratosis, with one meta-analysis finding that imiquimod may have higher efficacy than 5-fluorouracil for lesions located on the face and scalp 7.
• Another study found that 5-fluorouracil appeared to be significantly more effective than imiquimod in the short-term, but not long-term, prevention of subsequent actinic keratosis lesions 8.

Treatment Regimens and Side Effects

• The treatment regimen for the combination of 5-fluorouracil and imiquimod creams typically involves applying both creams to the lesions daily for one week each month over the course of three months 5.
• Patients may experience an inflammatory response at the sites of their actinic keratosis lesions, as well as at subclinical sites with no apparent lesions, but this is usually confined to localized sites without involvement of the surrounding skin 5.