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

Educational Objective
To learn what a single course of topical fluorouracil can do for preventing new keratinocyte carcinoma in a high-risk population.
1 Credit CME
Key Points

Question  Can a single course of topical fluorouracil, 5%, prevent keratinocyte carcinoma?

Findings  In this randomized clinical trial of 932 veterans at high risk for keratinocyte carcinoma, a 2- to 4-week course of topical fluorouracil, 5%, applied twice daily to the face and ears reduced the risk for 1 year of squamous cell carcinoma (SCC) requiring surgery at those sites. No effect was seen on basal cell carcinoma (BCC) in year 1 or on SCC or BCC over 4 years.

Meaning  Effective chemoprevention of cutaneous SCC for a year is achievable with a single 2- to 4-week course of topical fluorouracil, suggesting a possible role for annual use in groups at very high risk.

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

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Article Information

Corresponding Author: Martin A. Weinstock, MD, PhD, Providence Veterans Affairs Medical Center, 830 Chalkstone Ave, Building 1, Room 514, Providence, RI 02908 (maw@brown.edu).

Accepted for Publication: July 27, 2017.

Published Online: January 3, 2018. doi:10.1001/jamadermatol.2017.3631

Author Contributions: Dr Weinstock had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Weinstock.

Acquisition, analysis, or interpretation of data: Weinstock, Thwin, Siegel, Marcolivio, Hogan, Eilers, Swetter, Chen, Jacob, Warshaw, Stricklin, Dellavalle, Sidhu-Malik, Konnikov, Werth, Keri, Robinson-Bostom, Means, Leader, Ringer, Lew, Ferguson, DiGiovanna, Huang, Shaw.

Drafting of the manuscript: Weinstock, Thwin, Siegel, Ringer, Means, Leader.

Critical revision of the manuscript for important intellectual content: Weinstock, Thwin, Siegel, Marcolivio, Hogan, Eilers, Swetter, Chen, Jacob, Warshaw, Stricklin, Dellavalle, Sidhu-Malik, Konnikov, Werth, Keri, Robinson-Bostom, Means, Leader, Ringer, Lew, Ferguson, DiGiovanna, Huang, Shaw.

Statistical analysis: Weinstock, Thwin, Siegel, Lew, Means, Leader, Shaw.

Obtained funding: Weinstock, Ferguson, Huang.

Administrative, technical, or material support: Weinstock, Siegel, Means, Leader, Ferguson, Huang, Ringer.

Study supervision: Weinstock, Marcolivio, Ferguson, Huang.

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).

Funding/Support: The study was supported in part by the Office of Research and Development Cooperative Studies Program, US Department of Veterans Affairs.

Role of the Funding/Sponsor: Design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication.

Study Group Members: Study Chairman’s Office: Martin A. Weinstock, MD, PhD (Chair), Kimberly Marcolivio, MEd (National Coordinator); Executive/Planning Committee: Martin A. Weinstock, MD, PhD; Suephy C. Chen, MD, MS; Robert P. Dellavalle, MD, PhD, MSPH; Erin M. Warshaw, MD, MS; John J. DiGiovanna, MD; Ryan Ferguson, ScD, MPH; Robert A. Lew, PhD; Robert J. Ringer, PharmD; Jean Yoon, PhD; Ciaran S. Phibbs, PhD; Ken Kraemer, MD; Grant D. Huang, MPH., PhD; Clinical Centers (Investigators): Daniel Hogan, MD; David Eilers, MD; Susan M. Swetter, MD; Suephy C. Chen, MD, MS; Sharon Jacob, MD; Laura Romero, MD; Erin M. Warshaw, MD, MS; George P. Stricklin, MD, PhD; Robert P. Dellavalle, MD, PhD, MSPH; Nellie Konnikov, MD; Victoria Werth, MD; Navjeet Sidhu-Malik, MD; Jonette E. Keri, MD, PhD; Clinical Centers (Coinvestigators): James W. Swan, MD; Kristin Nord, MD; Brian Pollack, MD, PhD; Stephen Kempiak, MD, PHD; Whitney High, MD; Nicole Fett, MD; Russell P. Hall III, MD; Javier Alonso-Llamazares, MD, PhD; Georgette Rodriguez, MD, MS; Clinical Centers (Study Coordinators): Lorine Sisler; Mary O’Sullivan, MSN, RN, NP; Sonya Wilson, RN; Madhuri Agrawal, RN; Debra Bartenfeld, RN; Keith Nicalo, RN; Deb Johnson, RN; Patricia Parks; Barbara Bidek, RN; Nancy Boyd, RN; Barbara Watson, RN; Dianne Wolfe, RN; Mark Zacheis, RN; Joyce Okawa, RN; Mary Ann Iannacchione, MSN; Jalima Quintero, RN; Clinical Centers (Unblinded Practitioners): Subbarayudu Cuddapah, MD; Karen Muller, NP; Vanessa Lichon, MD; Todd Anhalt, MD; Vista Khosravi, MD; Zakia Rahman, MD; Leslie Lawley, MD; Roberta McCoy, NP; Neal Foman, MD; Andrea Bershow, MD; John Zic, MD; Jami Miller, MD; H. Alan Arbuckle, MD; Linnea Hemphill, RN, NP; Mayumi Fujita, MD; David Norris, MD; Preethi Ramaswamy, MD; Jennifer Nevas, CRNP; Caroline H. Rao, MD; Allen J. Gifford, PA-C; Kelly A. Asher, PA-C; Adela Rambi G. Cardones, MD; Angela F. Richardson, MHS, PA-C; Carmen Adams Patrick, PA; Cooperative Studies Program Coordinating Center, MAVERIC: Louis Fiore, MD, MPH; Ryan E. Ferguson, ScD, MPH; Soe Soe Thwin, PhD, MS; Denis Rybin, PhD; Robert A. Lew, PhD; Clara E. Kebabian, MPH; Jennifer Pavao; Cooperative Studies Program Clinical Research Pharmacy Coordinating Center: Mike Sather, PhD; Carol Fye, MS; Robert J. Ringer, PharmD, BCNP; David Hunt, MS; Dermatopathologists: Leslie Robinson-Bostom, MD; Gladys Telang, MD; Caroline Wilkel, MD; Data and Safety Monitoring Board: Harley A. Haynes, MD (Chair); Maurice Alan Brookhart, PhD; Eliot N. Mostow, MD, MPH; Thomas Rector, PharmD, PhD.

Meeting Presentation: These results were presented orally at the Society for Investigative Dermatology 75th Annual Meeting; May 11-14, 2016; Scottsdale, Arizona.

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