Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: Results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles

Hanke, C. William; Beer, Kenneth; Stockfleth, Eggert; Wu, Jason; Rosen, Theodore; Levy, Sharon

doi:10.1016/j.jaad.2009.06.020

Cited by 138 publications

(79 citation statements)

References 23 publications

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“…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). Unlike the direct effect of calcipotriol plus 5-FU treatment on adaptive immunity, the innate immune activation by imiquimod lacks tumor specificity.…”

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

confidence: 73%

“…Unlike the direct effect of calcipotriol plus 5-FU treatment on adaptive immunity, the innate immune activation by imiquimod lacks tumor specificity. Imiquimod (3.75%) treatment once daily for two 3-week treatment cycles led to an 80% median reduction in actinic keratosis counts on the face and scalp compared with 23.6% in the placebo group (32). Median baseline lesion counts in this trial were 9-10 (32).…”

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

confidence: 78%

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

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

132

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: 73%

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

confidence: 78%

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

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

132

113

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“…10 Partial, but not complete, clearance results from the current trial, investigating treatment in the trunk and extremities, compare well with two previous studies with imiquimod 2.5% and 3.75% that investigated a scalp/facial treatment area > 25 cm 2 . 18,19 In those studies, complete clearance rates were 30.6% and 35.6% for 2-week 18 and 25.0% and 34.0% for 3-week on/off/on treatment regimens. 19 Partial clearance rates were 48.1% and 59.4% 18 and 42.7% and 53.7%, 19 respectively.…”

Section: Discussionmentioning

confidence: 90%

“…18,19 In those studies, complete clearance rates were 30.6% and 35.6% for 2-week 18 and 25.0% and 34.0% for 3-week on/off/on treatment regimens. 19 Partial clearance rates were 48.1% and 59.4% 18 and 42.7% and 53.7%, 19 respectively.…”

Section: Discussionmentioning

confidence: 90%

Ingenol Mebutate 0.06% Gel for Field Treatment of Actinic Keratosis on 250 cm2 of Skin on Trunk and Extremities: A Randomized Dose-Finding Trial

Siegel

Tanghetti²,

Brody³

et al. 2017

J of Skin

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“…Yet, current treatment options are either not sufficiently effective or very painful or both, and thus cSCC has become a most prevalent lethal risk factor in heart and kidney transplant recipients [4]. Complete cure rates in large-size clinical studies are less than 70% with 5-fluoruracil (5-FU), diclofenac/hyaluronic acid [3], imiquimod [5] and photodynamic therapy using 5-aminolaevulinic acid followed by red light irradiation. Response rates are up to 91% when using methyl 5-aminolaevulinate as photosensitizer for minor to moderate lesions [6].…”

Section: Introductionmentioning

confidence: 99%

Improving Topical Non-Melanoma Skin Cancer Treatment: In vitro Efficacy of a Novel Guanosine-Analog Phosphonate

Laue

Zoschke²,

Do³

et al. 2014

Skin Pharmacol Physiol

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Actinic keratosis, a frequent carcinoma in situ of non-melanoma skin cancer (NMSC), can transform into life-threatening cutaneous squamous cell carcinoma. Current treatment is limited due to low complete clearance rates and asks for novel therapeutic concepts; the novel purine nucleotide analogue OxBu may be an option. In order to enhance skin penetration, solid lipid nanoparticles (SLN, 136-156 nm) were produced with an OxBu entrapment efficiency of 96.5 ± 0.1%. For improved preclinical evaluation, we combined tissue engineering with clinically used keratin-18 quantification. Three doses of 10^-3 mol/l OxBu, dissolved in phosphate-buffered saline as well as loaded to SLN, were effective on reconstructed NMSC. Tumour response and apoptosis induction were evaluated by an increase in caspase-cleaved fragment of keratin-18, caspase-7 activation as well as by reduced expression of matrix metallopeptidase-2 and Ki-67. OxBu efficacy was superior to equimolar 5-fluorouracil solution, and thus the drug should be subjected to the next step in preclinical evaluation.

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Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: Results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles

Cited by 138 publications

References 23 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

Ingenol Mebutate 0.06% Gel for Field Treatment of Actinic Keratosis on 250 cm2 of Skin on Trunk and Extremities: A Randomized Dose-Finding Trial

Improving Topical Non-Melanoma Skin Cancer Treatment: In vitro Efficacy of a Novel Guanosine-Analog Phosphonate

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