Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial

Abstract

Importance: Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States.

Objective: To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma.

Design, setting, and participants: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years.

Interventions: Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization.

Main outcomes and measures: Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers.

Results: Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed.

Conclusions and relevance: A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma.

Trial registration: clinicaltrials.gov Identifier: NCT00847912.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Weinstock is employed by Brown Dermatology, Inc (Brown University Department of Dermatology’s faculty practice) in addition to his listed affiliations. Dr Weinstock served as a consultant to AbbVie, Castle, and Celgene. Dr Dellavalle receives editorial stipends from the Journal of Investigative Dermatology and the Journal of the American Academy of Dermatology and has received grant support from Pfizer Pharmaceuticals for an independent research grant to the University of Colorado (for development of patient decision).

Figures

Figure 1.. Randomization, Stratification, and Follow-up of Study Participants

Participants were recruited from May 2009 to September 2011 and included veterans with a history of at least 2 keratinocyte carcinomas in the past 5 years. Of 954 patients enrolled and randomized, 932 were included in the primary analysis: 468 in the fluorouracil group and 464 in the control group. HIPAA indicates Health Insurance Portability and Accountability Act.

Figure 2.. Proportion of Participants With SCC by Treatment Group

Participants who completed a 2- to 4-week course of topical fluorouracil, 5%, applied twice daily to the face and ears reduced the risk of SCC requiring surgery at those sites by 75% for 1 year. No effect was seen over 4 years. SCC indicates squamous cell carcinoma.