Treatment of Precancers With a Single Course of 5FU May Remain Effective Over Time

Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial.
Pomerantz H, Hogan D, Eilers D, Swetter SM, Chen SC, Jacob SE, Warshaw EM, Stricklin G, Dellavalle RP, Sidhu-Malik N, Konnikov N, Werth VP, Keri J, Lew R, Weinstock MA; Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial Group.
JAMA Dermatol. 2015 Sep 1;151(9):952-60. doi: 10.1001/jamadermatol.2015.0502.

In summary, this study demonstrates the positive effect of topical 5-Fluorouracil (5FU) against Actinic Keratosis (AK). This was done by treating extensive surfaces in patients at risk for Keratinocyte Carcinoma (KC) (LINK) (Chemoprevention).

Introduction
-Actinic Keratosis (AK) are precancerous skin conditions where dysplasia is present in the epidermis. If untreated they can involute, stay the same or evolve into Squamous Cell Carcinoma (SCC) [in situ (Bowen’s) disease or invasive]. SCC has albeit infrequently the ability to metastasize.
-Also individual lesions are a marker of accumulated skin damage so not only it is important to treat the individual lesions, but also the background especially if photodamage is present. These area often contain microscopical areas of epidermal dysplasia and this is why they are also called Cancerization Fields.

AK treatment Guidelines
Treatment wise many guidelines have been elaborated, but generally speaking they can be summarized as follows:
–Individual AK lesions: cryotherapy as first line then followed by other methods such as 5-flurouracil (5FU), ingenol mebutate and imiquimod
–more than 5 lesions (with/without field cancerization): 5FU, ingenol mebutate, photodynamic therapy (PDT) are recommended as first line treatment.
-in immunosuppressed individuals there are no strong recommendations although lasers (CO2 and Erbium-YAG) are contraindicated

The guidelines (2015) can be accessed: HERE (PDF)

Study
-This study from the United States (Veterans Affairs medical centers) sought to evaluate chemoprevention by treating a high risk group for Keratinocyte Carcinoma (KC) (=having developed at least 2KCs in the 5 years prior to enrollment, at least 1 of which was on the face or ears.
-In this study 5FU 5% was compared with a control group (954 patients were randomly assigned to one of the 2 groups)
-The course consisted of applying the cream 2 times a day daily for 4 weeks (56 doses). The cream was applied on the face and ears (Chemoprevention = is is more extensive than Field Cancerization Treatment)
-The control group was treated with a cream containing the same vehicle base (inactive ingredients), but without 5FU.

AK on the face and ears were counted by study dermatologists at enrollment and at study visits every 6 months. The average follow-up period for each group was on average 2 and a half years

Results
-The number of AKs on the face and ears per participant was not different between
the 5FU and control groups at randomization (around 11 in both groups)
–After randomization, the fluorouracil group had fewer AKs compared with the control group at
6 months (3 vs 8).
-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
–The fluorouracil group took longer to require the first spot AK treatment (6.2 months) compared with the control group (6.0 months)

The study shows that a signal treatment course of 5FU remains effective in preventing AK recurrence for MORE THAN 2 YEARS:
-Even at 36 months, the difference remains big between the number of AK in the treated group vs control (3.7 vs 6.4)
-However 42 months after the treatment the difference dwindles between the lesion in the AK treated vs the treated group (4.3 +/-  0.8 vs 5.7 +/- 0.9)

Comments
-The clearance rate for the AK control group at 6 months is high (at 17%) which does suggest that other factors (natural evolution of AK) also play an important role
–The clearance rate starts going down after 12 months (=38%) in the treated group whereas it is somewhat stable in the control group:
-big differences are visible until 18 months (33% vs 19%), however the difference becomes small at 24 (35% vs 23%), 30 (31% vs 24%), 36 (29% vs 22% and 42 months (22% vs 20%) after treatment

Article selection: Prof Dr Jean-Hilaire Saurat – dermatologist. Geneva, Switzerland

Bibliography Actinic Keratosis treatments consensus. International League of Dermatological Societies (ILDS) in
cooperation with the European Dermatology Forum (EDF)
R.N. Werner, E. Stockfleth, S.M. Connolly, O. Correia, R. Erdmann, P. Foley, A.K., Gupta, A. Jacobs, H. Kerl, H.W. Lim, G. Martin, M. Paquet, D.M. Pariser, S., Rosumeck, H.-J. Röwert-Huber1, A. Sahota, O.P. Sangueza, S. Shumack, B., Sporbeck, N.A. Swanson, L. Torezan, A. Nast