Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial | Cancer Screening, Prevention, Control | JAMA Dermatology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Criscione  VD, Weinstock  MA, Naylor  MF, Luque  C, Eide  MJ, Bingham  SF; Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group.  Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial.  Cancer. 2009;115(11):2523-2530.PubMedGoogle ScholarCrossref
Werner  RN, Sammain  A, Erdmann  R, Hartmann  V, Stockfleth  E, Nast  A.  The natural history of actinic keratosis: a systematic review.  Br J Dermatol. 2013;169(3):502-518.PubMedGoogle ScholarCrossref
Lee  K, Weinstock  M.  Prospective quality of life impact of actinic keratoses: observations from the veterans affairs topical tretinoin chemoprevention trial.  Acta Derm Venereol. 2011;91(1):101-102.PubMedGoogle Scholar
Goldenberg  G, Perl  M.  Actinic keratosis: update on field therapy.  J Clin Aesthet Dermatol. 2014;7(10):28-31.PubMedGoogle Scholar
The Society for Investigative Dermatology and the American Academy of Dermatology Association. The Burden of Skin Diseases: 2005 [monograph on the Internet]. Falls Church, VA: The Lewin Group; 2005. http://www.lewin.com/~/media/Lewin/Site_Sections/Publications/april2005skindisease.pdf. Accessed December 10, 2014.
Warino  L, Tusa  M, Camacho  F, Teuschler  H, Fleischer  AB  Jr, Feldman  SR.  Frequency and cost of actinic keratosis treatment.  Dermatol Surg. 2006;32(8):1045-1049.PubMedGoogle Scholar
Perera  E, McGuigan  S, Sinclair  R.  Cost for the treatment of actinic keratosis on the rise in Australia [v2; ref status: indexed, http://f1000r.es/48f].  F1000 Res. 2014;3:184. PubMedGoogle Scholar
Hagele  TJ, Levender  MM, Davis  SA, Williford  PM, Feldman  SR.  Practice trends in the treatment of actinic keratosis in the United States: 0.5% fluorouracil and combination cryotherapy plus fluorouracil are underused despite evidence of benefit.  J Cutan Med Surg. 2012;16(2):107-114.PubMedGoogle Scholar
Nashan  D, Meiss  F, Müller  M.  Therapeutic strategies for actinic keratoses—a systematic review.  Eur J Dermatol. 2013;23(1):14-32.PubMedGoogle Scholar
Jorizzo  J, Stewart  D, Bucko  A,  et al.  Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis.  Cutis. 2002;70(6):335-339.PubMedGoogle Scholar
Weiss  J, Menter  A, Hevia  O,  et al.  Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks.  Cutis. 2002;70(2)(suppl):22-29.PubMedGoogle Scholar
Jorizzo  J, Weiss  J, Furst  K, VandePol  C, Levy  SF.  Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial.  Arch Dermatol. 2004;140(7):813-816.PubMedGoogle Scholar
Jorizzo  J, Weiss  J, Vamvakias  G.  One-week treatment with 0.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double-blind, vehicle-controlled, long-term study.  J Drugs Dermatol. 2006;5(2):133-139.PubMedGoogle Scholar
Korgavkar  K, Firoz  EF, Xiong  M,  et al; VAKCC Trial Group.  Measuring the severity of topical 5-fluorouracil toxicity.  J Cutan Med Surg. 2014;18(4):229-235.PubMedGoogle ScholarCrossref
Lee  KC, Lew  R, Weinstock  MA.  Improvement in precision of counting actinic keratoses.  Br J Dermatol. 2014;170(1):188-191.PubMedGoogle ScholarCrossref
Gupta  AK, Paquet  M, Villanueva  E, Brintnell  W.  Interventions for actinic keratoses.  Cochrane Database Syst Rev. 2012;12:CD004415.PubMedGoogle Scholar
Loven  K, Stein  L, Furst  K, Levy  S.  Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis.  Clin Ther. 2002;24(6):990-1000.PubMedGoogle ScholarCrossref
Chen  SC, Hill  ND, Veledar  E, Swetter  SM, Weinstock  MA.  Reliability of quantification measures of actinic keratosis.  Br J Dermatol. 2013;169(6):1219-1222.PubMedGoogle ScholarCrossref
Original Investigation
September 2015

Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial

Author Affiliations
  • 1Center for Dermatoepidemiology, Veterans Affairs (VA) Medical Center, Providence, Rhode Island
  • 2Department of Dermatology, Brown University, Providence, Rhode Island
  • 3Dermatology, Bay Pines VA Healthcare System, Bay Pines, Florida
  • 4Department of Internal Medicine (Dermatology), NOVA Southeastern University College of Osteopathic Medicine, Davie, Florida
  • 5Dermatology, Edward Hines Jr VA Hospital, Hines, Illinois
  • 6Dermatology, VA Palo Alto Health Care System, Palo Alto, California
  • 7Department of Dermatology, Stanford University Medical Center, Palo Alto, California
  • 8Dermatology, Atlanta VA Medical Center, Atlanta, Georgia
  • 9Department of Dermatology, Emory University, Atlanta, Georgia
  • 10Dermatology, VA San Diego Healthcare System, San Diego, California
  • 11Dermatology, Minneapolis VA Health Care System, Minneapolis, Minnesota
  • 12Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
  • 13Dermatology, Tennessee Valley Healthcare System, Nashville, Tennessee
  • 14Division of Dermatology, Vanderbilt University, Nashville, Tennessee
  • 15Dermatology, VA Medical Center, Denver, Colorado
  • 16Dermatology, Durham VA Medical Center, Durham, North Carolina
  • 17Department of Dermatology, Duke University, Durham, North Carolina
  • 18Dermatology, Boston VA Medical Center, Boston, Massachusetts
  • 19Dermatology, Philadelphia VA Medical Center, Philadelphia, Pennsylvania
  • 20Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania
  • 21Dermatology, Miami VA Hospital, Miami, Florida
  • 22Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami
  • 23VA Cooperative Studies Coordinating Center, Boston, Massachusetts
  • 24Department of Dermatology, Rhode Island Hospital, Providence
  • 25Department of Epidemiology, Brown University, Providence, Rhode Island
JAMA Dermatol. 2015;151(9):952-960. doi:10.1001/jamadermatol.2015.0502

Importance  Topical fluorouracil was demonstrated to be effective in reducing the number of actinic keratoses (AKs) for up to 6 months, but no randomized trials studied its long-term efficacy.

Objective  To evaluate the long-term efficacy of a single course of fluorouracil cream, 5%, for AK treatment.

Design, Setting, and Participants  The Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial was a randomized, double-blinded, placebo-controlled trial with patients from dermatology clinics at 12 VA medical centers recruited from 2009 to 2011 and followed up until 2013. Our study population comprised 932 veterans with 2 or more keratinocyte carcinomas in the 5 years prior to enrollment. The mean follow-up duration was 2.6 years in both treatment and control groups.

Interventions  Participants applied either topical fluorouracil cream, 5% (n = 468), or vehicle control cream (n = 464) to the face and ears twice daily for up to 4 weeks.

Main Outcomes and Measures  This study reports on AK counts and treatments, which were secondary outcomes of the VAKCC trial. Actinic keratoses on the face and ears were counted by study dermatologists at enrollment and at study visits every 6 months. The number of spot treatments for AKs on the face and ears at semiannual study visits and in between study visits was recorded.

Results  The number of AKs on the face and ears per participant was not different between the fluorouracil and control groups at randomization (11.1 vs 10.6, P > .10). After randomization, the fluorouracil group had fewer AKs compared with the control group at 6 months (3.0 vs 8.1, P < .001) and for the overall study duration (P < .001). The fluorouracil group also had higher complete AK clearance rates (38% vs 17% at 6 months) and fewer spot treatments at 6-month intervals, at study visits, and in between study visits during the trial (P < .01 for all). The fluorouracil group took longer to require the first spot AK treatment (6.2 months) compared with the control group (6.0 months) (hazard ratio, 0.69; 95% CI, 0.60-0.79). The number of hypertrophic AKs was not different between the 2 groups overall (P = .60), although there were fewer hypertrophic AKs in the fluorouracil group at 6 months (0.23 vs 0.41) (P = .05).

Conclusions and Relevance  Our results indicate that a single course of fluorouracil cream, 5%, effectively reduces AK counts and the need for spot treatments for longer than 2 years.

Trial Registration  clinicaltrials.gov Identifier:NCT00847912