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N Engl J Med. 2019 Mar 7;380(10):935-946. doi: 10.1056/NEJMoa1811850.

Randomized Trial of Four Treatment Approaches for Actinic Keratosis.

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From the Departments of Dermatology (M.H.E.J., J.P.H.M.K., N.K., A.H.M.M.A., P.M.S., N.W.J.K.-S., K.M.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), Maastricht University Medical Center, and the GROW School for Oncology and Developmental Biology (M.H.E.J., J.P.H.M.K., A.H.M.M.A., P.M.S., N.W.J.K.-S., K.M.) and the Department of Epidemiology (P.J.N.), Maastricht University, Maastricht, the Department of Dermatology, Zuyderland Medical Center, Heerlen (J.P.H.M.K., P.J.F.Q.), the Department of Dermatology, Catharina Hospital, Eindhoven (A.H.M.M.A., P.M.S.), and the Department of Dermatology, VieCuri Medical Center, Venlo (H.P.A.P.) - all in the Netherlands.



Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred.


We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm2, were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed.


A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented.


At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; number, NCT02281682.).


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