Actinic keratosis lesions were successfully and rapidly cleared with the use of a combination of a topical chemotherapy and an immune-system–activating compound among participants in a clinical trial, according to findings reported in the  Journal of Clinical Investigation.1

Actinic keratosis is characterized by rough, scaly patches on the skin, and if untreated, can develop into squamous cell carcinoma. The condition is common in older persons with fair complexions. Current standard treatment involves application of topical medication for up to 4 weeks, and patients may experience adverse effects such as pain, crusting, and susceptibility to infection.

Calcipotriol, an FDA-approved treatment for psoriasis, induces TSLP expression in the skin. Although overexpression of TSLP, an immune system activator, is associated with the allergic inflammation seen in asthma and eczema, researchers have noted that people with these allergic conditions appear to be less susceptible to skin cancer. In addition, the ability of TSLP to suppress skin cancer development has been noted in other studies; therefore, a team of researchers at the Massachusetts General Hospital (MGH) sought to investigate the potential of calcipotriol in patients with actinic keratosis.

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In experiments with a mouse model of skin cancer development, twice-weekly application of calcipotriol induced TSLP expression and delayed tumor development, with fewer and smaller tumors when they did develop. Furthermore, application on the ears of the mice produced an immune response that suppressed tumor development on their backs, suggesting a potential lasting systemic antitumor immune response.

However, clinically available concentrations of calcipotriol (0.005%) have limited effectiveness against actinic keratosis with no evidence of immune activation. The MGH team, therefore, hypothesized that the immune-activiting potential of calcipotriol ointment might be enhanced if it were added to the standard 5% fluorouracil (5-FU) cream used to treat actinic keratosis. To test their theory, the researchers conducted a double-blinded clinical trial. Participants with multiple actinic keratosis lesions were randomized to treatment with a combination of calcipotriol and 5-FU (65 patients) or 5-FU mixed with petroleum jelly (67 patients).

Participants applied the treatment to the entire affected sites twice a day for 4 days. (Treatment with 5-FU alone requires 7 or more days for a notable response.) Among the patients who received the treatment, inflammation indicating immune system activation was seen 1 day after treatment ended even in areas with lesions not clinically visible. These areas had a significant influx of lymphocytes, primarily T cells, at the lesion sites.

An overall reduction in lesions was seen in participants using the calcipotriol/5-FU combination. For example, facial lesions were reduced in participants using the treatment preparation compared with those using the control preparation (88% vs 26%, respectively). Response to conventional topical treatments is rarely seen with large hypertrophic lesions; however, patients with these lesions also saw a significant reduction in the size of their lesions with the treatment preparation. In addition, the treatment preparation was deemed more effective in 82% of participants who had undergone previous treatment for actinic keratosis.

“As both medications used in our trial are already available clinically, they could readily be used by dermatologists to treat actinic keratosis, particularly in patients for whom conventional treatments have failed,” says Shadmehr Demehri, MD, PhD, of the MGH Center for Cancer Immunology and the Cutaneous Biology Research Center, an assistant professor of Dermatology at Harvard Medical School, and senior author of this report.


1. Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Investigation. 2016 Nov 21. doi: 10.1172/JCI89820. [epub ahead of print]