Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis

Pomerantz, Hyemin; Hogan, Daniel J.; Eilers, David; Swetter, Susan M.; Chen, Shuo; Jacob, Sharon E.; Warshaw, Erin M.; Stricklin, George P.; Dellavalle, Robert P.; Sidhu-Malik, Navjeet; Konnikov, Nellie; Werth, Victoria P.; Keri, Jonette; Lew, Robert A.; Weinstock, Martin A.

doi:10.1001/jamadermatol.2015.0502

Cited by 90 publications

(85 citation statements)

References 31 publications

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“…Twice-daily application of 5% 5-FU cream for 4 weeks was found to reduce the number of actinic keratoses on the face and ears by 73% compared with 24% in the vehicle-treated group (31). The mean baseline number of actinic keratoses in this study was 11.1 in the 5-FU-treated group versus 10.7 in the vehicle-treated group (31). Imiquimod is a TLR7 agonist used for actinic keratosis treatment (32,33).…”

Section: Tslp Hla Class II and Cellular Stress Signal Synergism In mentioning

confidence: 60%

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

138

113

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Premalignant lesions of cutaneous squamous cell carcinoma (SCC) are identified clinically as actinic keratoses (12,13). Several field-directed treatments including 5-fluorouracil (5-FU), diclofenac, ingenol, and imiquimod have been approved for the treatment of sun-damaged skin with multiple actinic keratoses (13-15). However, the long treatment duration and the severity BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS.The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS.Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4 + T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration.CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4 + T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355. FUNDING. Not applicable (investigator-initiated clinical trial).

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Section: Tslp Hla Class II and Cellular Stress Signal Synergism In mentioning

confidence: 60%

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

138

113

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“…Topical therapies, such as 5‐FU, may prevent the development of new AKs. In a population with multiple prior KCs, a single month‐long course of topical 5‐FU was shown to reduce the number of AKs and subsequent AK treatments for > 2 years, and to reduce the number of new AKs (J.L. Walker, J.A.…”

Section: Chemoprevention Of Actinic Keratosesmentioning

confidence: 99%

Current perspective on actinic keratosis: a review

2016

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Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun-damaged skin. Yearly AK to SCC progression rates of 0·6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5-fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management.

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“…Topical chemical therapies (e.g. 5-fluorouracil) are also effective, but are associated with undesirable side effects including dryness, erythema, pain, or edema [2, 3]. Alternatively, photodynamic therapy (PDT) is a light-based treatment modality [4] which does not induce scarring or cumulative toxicity, allowing repeated treatments to the same areas [5–8].…”

Section: Introductionmentioning

confidence: 99%

Pre-treatment protoporphyrin IX concentration in actinic keratosis lesions may be a predictive biomarker of response to aminolevulinic-acid based photodynamic therapy

Kanick

Davis

Zhao

et al. 2015

Photodiagnosis and Photodynamic Therapy

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Background Although Aminolevulinic Acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy (PDT) is an effective FDA-approved therapy for actinic keratosis (AK), a substantial fraction of patients (up to 25%) do not respond to treatment. This study examined the feasibility of using pre-treatment measurements of PpIX concentration in AK lesions to predict response of ALA-PpIX PDT. Methods A non-invasive fiber-optic fluorescence spectroscopy system was used to measure PpIX concentration in patients undergoing standard-of-care ALA-PDT for AK. All patients provided assessments of pain at the time of treatment (n=70), and a subset reported pain and erythema 48–76 hours after treatment (n=13). Results PpIX concentration was significantly higher in lesions of patients reporting high levels of pain (VAS score ≥ 5) immediately after treatment vs. patients reporting pain scores below VAS=5 (p<0.022) (n=70). However, pain was not an exclusive indicator of PpIX concentration as many patients with low PpIX concentration reported high pain. In a subpopulation of patients surveyed in the days after treatment (n=13), PpIX concentration measured on the day of treatment was uncorrelated with pain-reported immediately after treatment (r=0.17, p<0.57), but positive correlations were found between PpIX concentration and patient-reported pain (r=0.55, p < 0.051) and erythema (r=0.58, p < 0.039) in the 48–72 hr following treatment. Conclusions These data suggest that in vivo optical measurements of PpIX concentration acquired before light delivery may be an objective predictor of response to ALA-PpIX PDT. Identification of non-responding patients on the day of treatment could facilitate the use of interventions that may improve outcomes.

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Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis

Abstract: clinicaltrials.gov Identifier:NCT00847912.

Cited by 90 publications

References 31 publications

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Current perspective on actinic keratosis: a review

Pre-treatment protoporphyrin IX concentration in actinic keratosis lesions may be a predictive biomarker of response to aminolevulinic-acid based photodynamic therapy

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