PracticeUpdate Dermatology May 2019

EDITOR’S PICKS 6

Four Treatment Approaches for Actinic Keratosis The New England Journal of Medicine Take-home message

" It is a deficiency of our healthcare system that this is the first paper that conducts rigorous and appropriate

• This study investigated the effectiveness of 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel in 624 patients with multiple actinic keratosis lesions. • Fluorouracil treatment showed the highest cumulative probability of remaining free from treatment failure compared with imiquimod, MAL-PDT, or ingenol mebutate at 12 months after the end of treatment. Jeffrey M. Wiisanen MD COMMENT By Martin Weinstock MD, PhD, Meghan E. Beatson BS and Angelica A. Misitzis MD A ctinic keratoses affect about 40 million Americans, are potential premalignant lesions, have been recognized and treated for decades, and consume large quantities of healthcare resources. Actinic insults resulting in actinic keratoses affect areas of skin – hence, the concepts of actinic neoplasia syndrome and field cancerization. Dermatologists must understand how different options compare for treating these conditions. It is a deficiency of our healthcare system that this is the first paper that conducts rigorous and appropriate randomization to compare the major treatment options for this condition. The way forward is to continue designing and executing studies like this one. Dr. Weinstock is Professor of Dermatology and Epidemiology at Brown University in Providence, Rhode Island. Ms. Beatson is Dermatoepidemiology Fellow at Brown University and an M.D. Candidate at George Washington University in Washington, DC. Dr. Misitzis is Dermatoepidemiology Research Fellow at Brown University in Providence, Rhode Island.

Abstract BACKGROUND Actinic keratosis is the most fre- quent premalignant skin disease in the white population. In current guidelines, no clear rec- ommendations are made about which treatment is preferred. METHODS 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 cm 2 , were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluo- rouracil 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 num- ber 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. RESULTS A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumula- tive probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confi- dence 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 haz- ard 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. CONCLUSIONS At 12 months after the end of treatment in patients with multiple actinic kera- tosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019 Mar 07;380(10)935-946, MHE Jansen, JPHM Kessels, PJ Nelemans, et al. www.practiceupdate.com/c/80651 randomization to compare the major treatment options for this condition. "

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