A Controlled Comparison Study of Topical Fluourouracil 5% Cream Pre-Treatment of Aminolevulinic Acid/Photodynamic Therapy for Actinic Keratosis
November 2015 | Volume 14 | Issue 11 | Original Article | 1241 | Copyright © 2015
Emil A. Tanghetti MD, Carolyn Hamann MBA, and Margo Tanghetti BS
Center for Dermatology and Laser Surgery, Sacramento, CA
INTRODUCTION: Topical Fluorouracil 5% cream (5-FU) and 20% aminolevulinic acid (ALA)/ photodynamic therapy (PDT) are both FDA approved
for the treatment of Actinic Keratosis (AK). We have studied the use of these 2 agents alone and in a sequential manner. We have also used a 5-FU re-challenge 3 months after treatment to highlight the efficacy of these treatments.
METHODS: This was an investigator-blinded randomized study in which 30 patients were randomized 1:1:1 into the following groups: Group 1 patients pretreated for 6-7 days with 5-FU, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J/cm2 with Blu-U device; Group 2 patients treated with 5-FU BID for 6-7 days and no ALA/PDT; Group 3 patients received no pretreatment, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J.cm2 with Blu-U device. Patients were seen at screening/baseline, treatment for ALA/PDT, 24 hours post treatment, 1 week post treatment and 3 months post treatment. All subjects were then given a re-challenge course of 5-FU for 6 days and reassessed.
RESULTS: AK counts in all groups were dramatically decreased and similar at 1 and 3 months post treatment. The re-challenge brought a significant difference with many subclinical lesions in the area of activity in the ALA and 5-FU alone groups.
CONCLUSIONS: All three arms appeared equal in treating visible AKs. These data strongly suggests a synergistic role of 5-FU with ALA/PDT over ALA/PDT or 5-FU alone in treating the subclinical lesions demonstrated on a 5-FU re-challenge. Treatment of these subclinical lesions should result in a longer remission. The data also suggests that a 5-FU re-challenge could be a clinical tool to judge the efficacy of treatment for AK if these subclinical lesions are proven to be an AK precursor.
J Drugs Dermatol. 2015;14(11):1241-1244.
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The use of multiple agents in combination for the treatment of acne and psoriasis has a long legacy in dermatology. For acne, there are combination products that include benzoyl peroxide, clindamycin, and/or topical retinoids that are FDA approved. In the treatment of psoriasis, there are topical vitamin D derivatives used in combination with topical steroids. These agents used together are not only more convenient, but also demonstrate enhanced efficacy over the single agents. There are many FDA approved agents currently available for the treatment of actinic keratoses. There are not any drugs used in combination that are approved by the FDA for this indication.
There are many ways to consider the relationship of topical agents to each other when they are used in combination for the treatment of actinic keratosis. This could simply be additive features that both drugs bring to the treatment by different mechanisms of action. There is also the potential for synergy, in which one of the treatment modalities enhances the other agent. It is useful to consider agents that can affect differentiation as a method of inducing synergy. Differentiation theory is predicated on the fact that cancer cells generally do not progress through the normal process of growth arrest, differentiation, and scheduled apoptosis thus avoiding programed cell death.1,2 Pharmacologic agents, such as methotrexate and 5-FU, might be used to redirect these aberrant pathways so that neoplastic cells mature and undergo apoptosis. Maytin and his colleagues were able to successfully demonstrate the enhancement of the effects of ALA/PDT by pretreatment with methotrexate.3 This agent is a competitive inhibitor of dihydrofolate reductase that is involved in folic acid metabolism. 5-FU is a suicide inhibitor or thymidylate synthase, also involved in the folic acid pathway. The wide availability, possible synergy, and FDA approval of both topical 5-FU and ALA/PDT for the treatment of actinic keratosis make them logical choices to use in combination.
Gilbert previously reported using topical 5-FU as a pretreatment for ALA/PDT using an IPL light source suggesting that there was enhancement of efficacy.4 Martin also did a pilot study with topical 5-FU pretreatment with ALA/PDT using a blue light source.5 These studies using short incubation periods are reflective of the current widespread use of truncated incubation periods with ALA/PDT in clinical practice. These abbreviated incubation periods appear to be associated with diminished efficacy with