PracticeUpdate Dermatology February 2019

EDITOR’S PICKS 17

Effectiveness of Topical Fluorouracil vs Topical Imiquimod for the Treatment of Actinic Keratosis Journal of the American Academy of Dermatology Take-home message

• This community-based cohort study compared the effectiveness of 5-fluorouracil with imiquimod in the prevention of keratinocyte carcinoma (KC) in a real-world prac- tice setting. 5-Fluorouracil was associated with a statistically significant decrease in the overall risk of any KC (aHR, 0.86), but there were no significant differences in risk by tumor subtype (squamous cell carcinoma aHR, 0.89; basal cell carcinoma aHR, 0.87), or site-specific KC (aHR, 0.96). No significant differences in 2- or 5-year risk for KC were observed. • While 5-fluorouracil was more effective than imiquimod in reducing KC risk overall, no differences were observed in risk of subsequent site-specific KC in a real-world practice setting. InYoung Kim MD, PhD

Abstract BACKGROUND The most widely used topical agents for the field-based treatment of multiple actinic keratoses (AKs) are 5-fluorouracil and imiquimod, but their comparative effectiveness has not been assessed in a real-world setting. OBJECTIVE We compared the effectiveness of 5-fluorouracil and imiquimod in reducing risk for subsequent AKs in a large, integrated health care delivery system in northern California. METHODS In this cohort study, we identified adult health plan members who had an AK diag- nosed in 2007 and who subsequently filled a prescription for 5-fluorouracil or imiquimod (N = 5700). We followed subjects for subsequent AKs identified by the International Classification of Diseases codes and estimated the 2-year which are very common and consume sub- stantial resources. The best way to compare the efficacy of two treatments would be to conduct a randomized trial because ran- domization protects against confounding. Unfortunately, there are no randomized controlled trials evaluating the risk of sub- sequent keratinocyte carcinoma (KC) in patients treated with 5-fluorouracil versus imiquimod for AKs. The one randomized trial that looks at effective AK treatment on risk of a subsequent KC compared 5-fluoro- uracil with placebo found that 5-fluorouracil reduced SCC risk by 75%, but did not affect risk of subsequent basal cell carcinoma. 1 This study suggested that 5-fluorouracil reduced the risk of subsequent KC but did

(short-term) and 5-year (long-term) differences in cumulative risk while controlling for potential confounding by pretreatment variables. RESULTS 5-Fluorouracil reduced the short-term incidence of subsequent AKs (cumulative risk difference -4.54% [95% confidence interval, -7.91% to -1.17%]), but there was no statistically significant evidence of a long-term decreased risk (cumulative risk difference -1.43% [95% confi- dence interval, -3.43% to 0.05%]) compared with that with imiquimod. LIMITATIONS This is a retrospective study with limited ascertainment of all relevant potential confounding variables. CONCLUSION We found that 5-fluorouracil appeared to be significantly more effective than not evaluate the risk at 1 year, which was demonstrated by the randomized control trial, and instead looked at 2 and 5 years, at which point the randomized trial found no persistent effect. These results are in this respect different from the results of the more rigorous randomized trial. A key issue in these results is the possibility of confounding, and some key confounding factors were not well-controlled, such as number of prior KCs, which they controlled for only with a yes or no question. We also note that they found a weaker preventive effect when they looked at site-specific KC versus overall KC, even though one would predict that the stronger effect should be with site-specific KC if it were a real effect of the 5-fluorouracil or imiqui- mod. This observation might suggest that the differences they found were indeed

imiquimod in the short-term, but not long-term, prevention of subsequent AKs. A Real-World, Community- Based Cohort Study Comparing the Effectiveness of Topical Fluorouracil Versus Topical Imiquimod for the Treatment of Actinic Keratosis. J Am Acad Der- matol 2018 Apr 01;78(4)710-716, R Neugebauer,

KA Levandoski, Z Zhu, et al. www.practiceupdate.com/c/76316

COMMENT By Martin Weinstock MD, PhD, Meghan E. Beatson BS and Angelica A. Misitzis MD T his study is important because it is an early step to the investigation of the treatment of actinic keratoses (AKs),

due to confounding. For these reasons, more rigorous research is needed to clarify this important first analysis from community-based observational data. Reference 1. Weinstock MA, Thwin SS, Siegel JA, et al. Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial. JAMA Dermatol 2018;154(2):167-174. Dr. Weinstock is Professor of Dermatology and Epidemiology at Brown University in Providence, Rhode Island. Dr. Beatson is Dermatoepidemiology Fellow at Brown University and MD Candidate at George Washington University in Washington, DC. Dr. Misitzis is Dermatoepidemiology Research Fellow at Brown University in Providence, Rhode Island.

VOL. 3 • NO. 1 • 2019