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

Owing to the nature of the recruitment process, an exact number of the screened individuals could not be identified. The recruitment was done in several steps (ie, identifying patients scheduled for dermatology clinic visit, reviewing these patients’ medical records for possible eligibility, obtaining informed consent, performing full-body skin examination for keratinocyte carcinomas, obtaining comprehensive medical records in the prior 5 years).

Figure 2.
Number of Actinic Keratoses (AKs) on the Face or Ears
Number of Actinic Keratoses (AKs) on the Face or Ears

Error bars indicate SE.

Figure 3.
Number of Actinic Keratosis (AK) Treatments on the Face and Ears
Number of Actinic Keratosis (AK) Treatments on the Face and Ears

Error bars indicate SE.

Figure 4.
Cumulative Sum of Actinic Keratosis (AK) Treatments per Person
Cumulative Sum of Actinic Keratosis (AK) Treatments per Person
Table 1.  
Baseline Characteristics of Participantsa
Baseline Characteristics of Participantsa
Table 2.  
Number of Actinic Keratoses (AKs) on the Face or Ears and Percentage of Participants With No AKs on the Face or Ears
Number of Actinic Keratoses (AKs) on the Face or Ears and Percentage of Participants With No AKs on the Face or Ears
Table 3.  
Face and Ear Actinic Keratosis (AK) Treatments
Face and Ear Actinic Keratosis (AK) Treatments
1.
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.
PubMedArticle
2.
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.
PubMedArticle
3.
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.
PubMed
4.
Goldenberg  G, Perl  M.  Actinic keratosis: update on field therapy. J Clin Aesthet Dermatol. 2014;7(10):28-31.
PubMed
5.
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.
6.
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.
PubMed
7.
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.
PubMed
8.
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.
PubMed
9.
Nashan  D, Meiss  F, Müller  M.  Therapeutic strategies for actinic keratoses—a systematic review. Eur J Dermatol. 2013;23(1):14-32.
PubMed
10.
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.
PubMed
11.
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.
PubMed
12.
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.
PubMed
13.
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.
PubMed
14.
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.
PubMedArticle
15.
Lee  KC, Lew  R, Weinstock  MA.  Improvement in precision of counting actinic keratoses. Br J Dermatol. 2014;170(1):188-191.
PubMedArticle
16.
Gupta  AK, Paquet  M, Villanueva  E, Brintnell  W.  Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12:CD004415.
PubMed
17.
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.
PubMedArticle
18.
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.
PubMedArticle
Original Investigation
September 2015

Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic KeratosisA 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
Abstract

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

Introduction

The morbidity and cost associated with actinic keratoses (AKs) is notable in our aging population. Actinic keratoses are not malignant in themselves, but have malignant potential.1 The rate of AK transformation to squamous cell carcinoma has been observed to be 0.1% to 0.6% per lesion-year.1,2 In addition, AKs directly affect quality of life. The number of AKs on the face and ears has been shown to be a key correlate of a worse quality of life, independent of demographic factors or the number of prior keratinocyte carcinomas (KCs [basal cell and squamous cell carcinomas]).3

Actinic keratoses are treated to avoid morbidity and mortality associated with possible progression to KCs.4 Direct cost for AK treatment was reported to be $1.2 billion in the United States in the year of 2004 alone,5 and it has been projected to increase with time.6,7 Actinic keratoses are commonly treated by spot treatment such as liquid nitrogen or electrosurgery, but field treatment with topical medications (eg, fluorouracil, imiquimod, diclofenac, and ingenol mebutate) is used for multiple lesions in an area and/or evidence of the background photodamaged skin.6,8,9 Topical fluorouracil has been demonstrated to be effective in reducing the number of AKs and increasing the complete AK clearance rates compared with placebo. However, these randomized trials followed up the study participants no longer than 6 months after a course of topical fluorouracil application.1013 We studied the long-term efficacy of a single course of topical fluorouracil cream, 5%, in reducing the number of AKs and the need for spot treatment of AKs.

Methods
Study Population

Participants were recruited from 12 Veterans Affairs (VA) medical centers. All were at high-risk for KC, defined as at least 2 KCs in the 5 years prior to enrollment, at least 1 of which was on the face or ears. The KCs did not count toward the inclusion criteria if they occurred in the area of previous radiation therapy or on genital or perianal skin. Inclusion criteria included the following: (1) ability to comply with protocol requirements and to provide consent and (2) no skin cancer on full-body skin examination at randomization. Presence of an AK on the face or ears was not required for inclusion. Exclusion criteria were (1) current or prior field therapy for AKs on the face or ears in the past 3 years; (2) current or prior use of systemic fluorouracil or oral capecitabine within the past 3 years; (3) known allergy to sunscreen, triamcinolone, or fluorouracil; (4) solid organ transplant; (5) genetic disorders associated with high skin cancer risk (eg, basal cell nevus syndrome, erythrodysplasia verruciformis, xeroderma pigmentosum); (6) arsenic exposure; (7) psoralen plus UV-A treatment; (8) cutaneous T-cell lymphoma; (9) current or prior radiation therapy to the face or ears; (10) those with very high mortality risk at randomization (estimated <50% chance of surviving in 4 years); (11) women of childbearing potential not willing to use birth control; (12) dihydropyrimidine dehydrogenase enzyme deficiency; and (13) concurrent treatment with methotrexate.

This study was conducted in accordance with the Declaration of Helsinki Principles, and all participants gave written informed consent. The study was approved by the VA Central Institutional Review Board. The trial protocol is reproduced in Supplement 1.

Study Design and Treatment

The VA Keratinocyte Carcinoma Chemoprevention (VAKCC) trial (Cooperative Studies Program [CSP] 562) was a randomized, double-blind, parallel group, 2-arm trial comparing the efficacy of topical fluorouracil cream, 5%, vs vehicle control cream in a high-risk population for reducing KC risk. This article reports results of a secondary outcome of the CSP 562: long-term efficacy of a single course of fluorouracil in treating AKs.

Enrollment occurred from June 2009 through September 2011, and the follow-up was concluded in June 2013. Using a permuted block randomization stratified by study site, an electronic data system assigned participants in a 1:1 ratio to receive topical fluorouracil cream, 5%, or vehicle control cream. Figure 1 shows the randomization, stratification, and follow-up of study participants. The vehicle control cream was a vanishing cream base consisting of the same inactive ingredients as the fluorouracil cream: white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and parabens. Participants and study dermatologists responsible for counting AKs at follow-up study visits were blinded to the study cream assignment. Separate unblinded dermatologists and study nurses monitored adverse effects of the study medication during the active treatment period.

The participants were instructed to apply the study cream twice daily on the face and ears for a total of 56 doses (a 4-week course of treatment). They had telephone interviews or follow-up visits in alternating weeks to monitor for adverse effects during the active treatment period. The adverse effects monitored included erythema, pruritus, burning, soreness and/or tenderness, crusting and/or erosions, scaling and/or flaking, and swelling.14 Severity of the symptoms was graded weekly at telephone interviews and follow-up visits. If a participant could not tolerate the twice daily dosing because of adverse effects, the study medication was discontinued and triamcinolone cream, 0.1%, was applied twice daily for 5 days. If and only if the participant did not apply at least 28 doses, then the participant resumed the study medication once daily at 3 weeks after stopping the study medication to complete 56 doses. If the participant could not tolerate the study medication again, the study medication was discontinued and was not resumed. Additional field treatment on the face or ears with any topical medication or photodynamic therapy was not permitted during the follow-up period, but spot treatment (treatment of an individual AK without treating the surrounding area) was allowed at clinical discretion.

All participants received education about skin cancer, sun protection, and the use of sunscreen. Sunscreen (sun protection factor 30) was provided to all participants for the duration of the study. Participants were shown photographs of moderate to severe reactions to topical fluorouracil and counseled to contact the study nurse if they develop similar reactions.

Study Variables

Participants visited the blinded study dermatologist every 6 months for skin examination and AK counting after randomization. The dermatologist performed full-body skin examination including counting all AKs in predefined anatomical regions on the face and ears. They also recorded the number of hypertrophic and nonhypertrophic AKs. Once AKs on the face and ears were counted, individual lesions could be treated according to the study dermatologists’ clinical judgment. The number of AK treated at the study visit was recorded. If a participant had a treatment for an AK in between study visits, the number of the treatments, the area treated, and the method of spot treatment were documented from the medical record. Study dermatologists participated in annual meetings that included training and consensus development in AK counting.15

Statistical Analysis

The study sample size was powered to the primary outcome of KC development treated surgically. The baseline characteristics of the fluorouracil and the control groups were compared by a 2-tailed t test or χ2 test. We carried out a cross-sectional time-series regression with a generalized least squares estimator and first-order autoregressive covariance model to account for random effects and correlations within the repeated measures to compare the fluorouracil and the control groups for the overall study duration. The parameters compared in this model were the number of total AKs; the number of hypertrophic AKs; the percentage of participants without AKs; and the number of spot AK treatments at every 6-month interval, at the time of 6-month study visits, and in between study visits. Linear contrasts compared the number of AKs and AK treatments in the 2 groups at 6 months. We used the Kaplan-Meier method to compare the time to the first AK treatment in the fluorouracil group with the time in the control group. Statistical analyses were conducted with STATA SE version 8 (StataCorp).

Results

Of 932 participants, 468 were randomized to topical fluorouracil cream, 5%, and 464 to vehicle control cream (Figure 1). The mean follow-up durations were 2.62 and 2.61 years in the fluorouracil and the control groups, respectively. There was no significant difference in the baseline characteristics between the 2 groups, including the history of AK treatment and history of topical fluorouracil application on the face and/or ears (Table 1).

Skin Examination at Enrollment

The mean total AK count on the face and ears at enrollment was 11.1 in the fluorouracil group and 10.7 in the control group (Figure 2A and Table 2). The number of hypertrophic AKs was 0.7 per person (6% of all AKs) in the fluorouracil group and 0.8 per person (7% of all AKs) in the control group (Figure 2B and Table 2). Fifteen percent of the participants in the fluorouracil group and 12% in the control group had no AKs on the face and ears (Figure 2C and Table 2). At the time of enrollment, the fluorouracil and control groups were not different in the numbers of total and hypertrophic AKs and the proportion of the participants without AKs on the face and ears (P > .10 for all 3 comparisons).

AK Counts

Quiz Ref IDThe number of AKs on the face or ears in the fluorouracil group was reduced to 3.0 per participant (73% reduction) by 6 months after randomization (P < .001 in paired t test comparing the AK number at baseline with the number at 6 months in the fluorouracil group). The number of AKs in the control group was reduced to 8.1 per participant (24% reduction) for the same time interval (P < .001 in paired t test) (Figure 2A and Table 2). The fluorouracil group had fewer AKs on the face or ears compared with the control group at 6 months (P < .001 in linear contrast). The fluorouracil group also had fewer AKs compared with the control group over the 42-month period, when the AK numbers from baseline to 42 months were modeled by a generalized estimation model that accounted for random effects and correlations within repeated measures (P < .001) (Figure 2A).

In the same model, the number of hypertrophic AKs on the face or ears was not significantly different between the 2 groups in the entire follow-up period of 42 months (P = .60), but there were fewer hypertrophic AKs in the fluorouracil group than the control group at 6 months (P = .05) (Figure 2B, Table 2). The number of nonhypertrophic AKs in the fluorouracil and the control groups followed the similar pattern as those of the total AKs; significantly fewer nonhypertrophic AKs on the face or ears were counted in the fluorouracil group than in the control group at 6 months and for the entire 42-month follow-up period (P < .001 in linear contrast and P < .001 in generalized estimation model, respectively).

Complete Clearance of AKs

Quiz Ref IDThe proportion of the participants with no AKs on the face or ears in the fluorouracil group increased from 15% at enrollment to 38% at 6 months (P < .001). The proportion in the control group increased from 12% to 17% (P = .01) (Figure 2C and Table 2). At 6 months, the proportion of participants who were clear of AKs in the fluorouracil group was more than double the proportion in the control group (P < .001 in linear contrast). The generalized estimation model showed that the fluorouracil group overall had a significantly larger proportion of the participants without any AKs on the face and ears compared with the control group for the entire 42-month follow-up period (P < .001) (Figure 2C).

AK Treatment

The total number of each individual spot AK treatment for up to 42 months after randomization was 6491 in the fluorouracil group and 12 204 in the control group. Among these AK treatments, 5610 (86%) in the fluorouracil group and 10 589 (87%) in the control group occurred at the study visit every 6 months. The rest of the treatments were performed in between study visits. Ninety-eight percent of AK treatments during follow-up in this trial were cryotherapy.

Quiz Ref IDThe fluorouracil group had 2.0 (95% CI, 1.9-2.2) spot AK treatments per visit per participant, and the control group had 3.9 (95% CI, 3.7-4.2) treatments per visit per participant (P < .001).

The fluorouracil group received fewer spot treatments for AKs on the face or ears compared with the control group in the first 6 months after randomization (P < .001 in linear contrast) (Figure 3A and Table 3). The fluorouracil group also received fewer AK treatments compared with the control group for the entire study duration, when the total number of AK treatments at 6-month intervals in the 2 groups was compared in a generalized estimation model accounting for random effects (P < .001) (Figure 3A and Table 3). The number of spot treatments for AKs at the time of the 6-monthly study visits was fewer in the fluorouracil group compared with the control group (P < .001) (Figure 3B and Table 3). The fluorouracil group also had fewer spot AK treatments in between study visits compared with the control group (P = .008) (Figure 3C and Table 3).

A total of 382 participants in the fluorouracil group (82%), compared with 413 in the control group (89%), received at least 1 spot treatment for AKs on the face or ears after randomization. The fluorouracil group was less likely to receive any spot treatment for AKs compared with the control group (hazard ratio, 0.70; 95% CI, 0.60-0.80) (eFigure in the Supplement 2). Furthermore, the fluorouracil group experienced the first AK spot treatment after randomization later than the control group (median time to the first spot treatment, 6.2 months in fluorouracil group [95% CI, 6.0-6.3 months] and 6.0 months in control group [95% CI, 5.97-6.03 months]; P = .003 in median test).

The cumulative sum of the number of AK treatments on the face or ears at 6 months was 2.7 per person in the fluorouracil group and 6.8 per person in the control group (P < .001) (Figure 4). By 42 months, the fluorouracil group had 19.8 treatments per person, while the control group had 34.8 treatments per person (Figure 4).

Discussion

The VAKCC trial provides data on long-term efficacy of twice-daily application of topical fluorouracil cream, 5%, compared with vehicle control cream in treating AKs on the face and ears in a patient population at high risk for KCs. The participants who were treated with a course of fluorouracil cream had fewer total AKs and received fewer spot treatments for AKs for longer than 2 years.

Literature searches that aimed to identify all randomized clinical trials comparing topical fluorouracil cream with placebo in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/MEDLINE, and the US Food and Drug Administration (FDA) website found none comparing fluorouracil cream, 5%, with placebo. Two randomized clinical trials compared topical fluorouracil cream, 0.5%, in treating AKs with placebo, and 1 trial compared topical fluorouracil cream, 0.5%, cream and cryotherapy with vehicle cream and cryotherapy (eTable in the Supplement 2).1013 Jorizzo et al10 and Weiss et al11 randomized the participants to fluorouracil cream, 0.5%, or vehicle control cream for 1, 2, or 4 weeks for treatment of AKs on the face or frontal scalp. Both studies reported more reduction of AK counts in the fluorouracil group than in the control group at 4 weeks after completion of the assigned treatment. Jorizzo et al10 reported 22% reduction in AK counts in the control group, whereas fluorouracil given for 2 weeks resulted in 86% reduction in AK counts and for 4 weeks, 92% reduction. Similarly, in the study by Weiss et al,11 the control group had 34% reduction in AK counts, whereas the fluorouracil group had 84% reduction of AK counts at 2 weeks and 89% at 4 weeks.

A trial that randomized participants to either a 1-week course of fluorouracil cream, 0.5%, or 1-week course of vehicle cream compared AK counts in the 2 groups at 4 weeks after randomization (eTable in the Supplement 2).12,13 Cryotherapy was used in both groups at 4 weeks, and AKs were counted again at 6 months.12 Participants in this study underwent 2 additional cycles of study cream and cryotherapy.13 Even after cryotherapy was used to treat all the persistent AKs after topical treatment in both groups, the fluorouracil group had a significantly larger reduction of AKs compared with the vehicle cream group (21% mean difference in reduction rate) at 6 months after starting the first cycle. The fluorouracil group had the mean of 2 more lesions reduced from the baseline count compared with the control group at 6 months after starting the third cycle, but the difference was not statistically significant.13,16 Our study showed a 73% AK count reduction in the fluorouracil group and a 26% reduction in the vehicle control cream group at 6 months after randomization. A large part of the reduction in the control group was presumably due to spot treatments, which could be performed in both groups. Our results cannot be directly compared with the previous randomized trials because we used fluorouracil cream, 5%, not 0.5%, although a randomized trial of fluorouracil cream, 0.5%, vs fluorouracil cream, 5%, in treating AKs showed no difference in their efficacies.17 To our knowledge, our study is the only randomized clinical trial to date that showed superior efficacy of fluorouracil cream, 5%, compared with vehicle control cream in AK treatment.

Our results were notable for the larger decrease in total AKs and the larger increase in complete AK clearance rates in the fluorouracil group than in the control group at study visits, even when the fluorouracil group received fewer spot treatments. Quiz Ref IDThe consistently fewer AK counts and fewer spot AK treatments in the fluorouracil group indicate that field treatment with fluorouracil prevents occurrence and/or recurrence of AKs in the treated area. The preventive role of fluorouracil is also indicated by the delayed time to the first AK treatment after randomization; over 80% of the participants in both groups eventually received at least 1 spot treatment for a lesion during the follow-up period, but it took longer for the fluorouracil group to receive the first spot treatment than it did for the control group. In addition, we found that a single course of the topical fluorouracil cream, 5%, treatment may be effective in reducing the number of hypertrophic AKs in the first 6 months, but we could not demonstrate its effectiveness for the overall study duration. It should be noted that there were only a few hypertrophic AKs in the study, and the power to detect the differences in the number of hypertrophic AKs between the 2 groups was low.

A limitation of our trial is that AKs were diagnosed clinically without histological information. A previous study reported that the dermatologists in the CSP 562 trial had disagreement in AK diagnoses.18 They met annually to compare and review AK diagnoses among themselves, and the discrepancies decreased over time.15 Spot AK treatment was left to the study dermatologists’ clinical judgment with substantial potential variations. However, this study design may have an advantage of being more generalizable to the actual clinical practice, where AKs are treated according to clinical judgment rather than strict guidelines. Topical fluorouracil can cause severe cutaneous reactions and possibly reveal a participant’s treatment assignment, but our blinding method (see “Study Design and Treatment” in the Methods section) ensured that dermatologist counting AKs could remain blinded to each participant’s treatment assignment as much as possible because their first visit with the participant after randomization was at 6 months.

Conclusions

Quiz Ref IDOur findings highlight the long-term efficacy of topical fluorouracil cream in treating and preventing AKs. A single course of topical fluorouracil cream, 5%, treatment led to a sustained reduction of the number of AKs and subsequent AK treatments in the population at high risk for KC. These findings indicate that treating a patient with a single course of fluorouracil would reduce the subsequent number of spot treatments and benefit care of patients with multiple AKs for longer than 2 years.

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Article Information

Accepted for Publication: March 30, 2015.

Corresponding Author: Hyemin Pomerantz, MD, Center for Dermatoepidemiology, Providence VA Medical Center, 830 Chalkstone Ave, Providence, RI 02908 (hyemin.pomerantz@gmail.com).

Published Online: May 7, 2015. doi:10.1001/jamadermatol.2015.0502.

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

Study concept and design: Pomerantz, Swetter, Warshaw, Weinstock.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pomerantz, Weinstock.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Pomerantz, Lew, Weinstock.

Obtained funding: Weinstock.

Administrative, technical, or material support: Hogan, Eilers, Swetter, Warshaw, Stricklin, Dellavalle, Konnikov, Werth, Keri, Weinstock.

Study supervision: Eilers, Chen, Konnikov, Werth, Keri, Weinstock.

Conflict of Interest Disclosures: Dr Dellavalle receives royalties from UpToDate. Dr Werth serves as a consultant to Sanofi, Idera, Novartis, Biogen, Medimmune, Pfizer, Syntimmune, Roche, Genetech, GSK, UCB, Kirin, Celgen. Dr Werth received grants from Novartis, Biogen, and Celgene. Dr Werth owns stocks of UV Therapeutics. Dr Weinstock is employed by University 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, Celgene, Melafind, Merck, Palatin Technologies, and Personal Care Products Council.

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

Role of the Funder/Sponsor: The Office of Research and Development Cooperative Studies Program participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: Key personnel of the VAKCC trial include the following (superscript numbers refer to clinical centers listed at the end of this section): Study Chairman’s Office, Providence, Rhode Island: Martin A. Weinstock, MD, PhD (chair), Kimberly Marcolivio, MEd (national coordinator). Executive/Planning Committee: Martin A. Weinstock, MD, PhD; Suephy C. Chen, MD, MS4; Robert P. Dellavalle, MD, PhD, MSPH8; Erin M. Warshaw, MD, MS6; John J. DiGiovanna, MD; Ryan Ferguson, ScD, MPH; Robert Lew, PhD Robert Ringer, PharmD; Jean Yoon, PhD; Ciaran S. Phibbs, PhD; Ken Kraemer, MD (only in planning committee). Clinical Centers (Investigators): Daniel Hogan, MD1; David Eilers, MD2; Susan Swetter, MD3; Suephy C. Chen, MD, MD4; Sharon Jacob, MD5; Erin M. Warshaw, MD, MS6; George Stricklin, MD, PhD7; Robert P. Dellavalle, MD, PhD, MSPH8; Nellie Konnikov, MD9; Victoria P. Werth, MD10; Navjeet Sidhu-Malik, MD11; Jonette Keri, MD, PhD12. Clinical Centers (Co-investigators): James W. Swan, MD2; Kristin Nord, MD3; Brian Pollack, MD, PhD4; Stephen Kempiak, MD, PhD5; Whitney High, MD8; Nicole Fett, MD10; Russell P. Hall III, MD11; Javier Alonso-Llamazares, MD, PhD12; Georgette Rodriguez, MD, MS12. Clinical Centers (Study Coordinators): Lorine Sisler1; Mary O’Sullivan, MSN, RN, NP2; Sonya Wilson, RN3; Madhuri Agrawal, RN3; Debra Bartenfeld, RN4; Keith Nicalo, RN5; Deb Johnson, RN6; Patricia Parks6; Barbara Bidek, RN7; Nancy Boyd, RN8; Barbara Watson, RN8; Dianne Wolfe, RN8; Mark Zacheis, RN9; Joyce Okawa, RN10; Mary Ann Iannacchione, MSN11; Jalima Quintero, RN12. Clinical Centers (Unblinded Practitioners): Subbarayudu Cuddapah, MD1; Karen Muller, NP1; Vanessa Lichon, MD3; Todd Anhalt, MD3; Vista Khosravi, MD3; Zakia Rahman, MD3; Leslie Lawley, MD4; Roberta McCoy, NP5; Neal Foman, MD6; Andrea Bershow, MD6; John Zic, MD7; Jami Miller, MD7; H. Alan Arbuckle, MD8; Linnea Hemphill, RN, NP8; Mayumi Fujita, MD8; David Norris, MD8; Preethi Ramaswamy, MD9; Jennifer Nevas, CRNP10; Caroline H. Rao, MD11; Allen J. Gifford, PA-C11; Kelly A. Asher, PA-C11; Adela Rambi G. Cardones, MD11; Angela F. Richardson, MHS, PA-C11; Carmen Adams Patrick, PA12. Cooperative Studies Program Coordinating Center, MAVERIC, Boston, Massachusetts: Louis Fiore, MD, MPH; Ryan E. Ferguson, ScD, MPH; Soe Soe Thwin, PhD, MS; Robert Lew, PhD; Clara E. Kebabian, MPH; Jennifer Pavao. Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexica: Mike Sather PhD; Carol Fye, MS; Robert Ringer, PharmD, BCNP; David Hunt, MS. Dermatopathologists, Providence, Rhode Island: 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. Clinical Centers:1Bay Pines, Florida; 2Hines, Illinois; 3Palo Alto, California; 4Atlanta, Georgia; 5San Diego, California; 6Minneapolis, Minnesota; 7Nashville, Tennessee; 8Denver, Colorado; 9Boston, Massachusetts; 10Philadelphia, Pennsylvania; 11Durham, North Carolina; 12Miami, Florida.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs.

Previous Presentation: This article was presented at the Annual Meeting of the Society for Investigative Dermatology; May 7, 2015; Atlanta, Georgia.

References
1.
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.
PubMedArticle
2.
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.
PubMedArticle
3.
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.
PubMed
4.
Goldenberg  G, Perl  M.  Actinic keratosis: update on field therapy. J Clin Aesthet Dermatol. 2014;7(10):28-31.
PubMed
5.
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.
6.
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.
PubMed
7.
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.
PubMed
8.
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.
PubMed
9.
Nashan  D, Meiss  F, Müller  M.  Therapeutic strategies for actinic keratoses—a systematic review. Eur J Dermatol. 2013;23(1):14-32.
PubMed
10.
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.
PubMed
11.
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.
PubMed
12.
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.
PubMed
13.
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.
PubMed
14.
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.
PubMedArticle
15.
Lee  KC, Lew  R, Weinstock  MA.  Improvement in precision of counting actinic keratoses. Br J Dermatol. 2014;170(1):188-191.
PubMedArticle
16.
Gupta  AK, Paquet  M, Villanueva  E, Brintnell  W.  Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12:CD004415.
PubMed
17.
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.
PubMedArticle
18.
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.
PubMedArticle
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