Intervention: Fluorouracil
Trial phase: Phase 4
ATC code: L01BC02 | L01BC52
SMILES: O=c1[nH]cc(F)c(=O)[nH]1
Sex: All
Age groups: Child | Adult | Older Adult
Healthy volunteers: No
Participants at risk: 468
Group description: Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses

5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.
Eligibility criteria:
Inclusion Criteria:

Veteran who is at high risk for developing skin cancer defined as 2 keratinocyte carcinomas in the past 5 years, at least one of which was located on the face or ears

Exclusion Criteria:

Participants who are unable to speak English
Participants with KC at randomization
Participants currently using or having used field therapy for AKs on the face or ears in the past 3 years. The vast majority of these field treatments would have been with 5-FU cream. The investigators will allow recent use of therapies that are applied to individual AK lesions (e.g. cryotherapy), but not those that were used on an entire area (field) in the study treatment area Participants currently using or having used systemic 5-fluorouracil or oral capecitabine (Xeloda) within the past 3 years Participants with known allergy to sunscreen, triamcinolone and/or 5-fluorouracil.

Exclusions 6-l0: The investigators will exclude the small proportion who get their KCs for special reasons other than ultraviolet radiation exposure (see list below), since that etiologic difference, which is associated with a prognostic difference, could be associated with a biologic difference in response to chemoprevention efforts. These will include:

Solid organ transplant recipients, such as renal, hepatic, or cardiac transplant patients
Individuals with genetic disorders associated with very high cancer risk such as:
basal cell nevus syndrome
erythrodysplasia verruciformis
xeroderma pigmentosum
Arsenic exposure
PUVA (Psoralen plus UVA) treatment
Cutaneous T-cell lymphoma
Prior or current radiation therapy to the face and/or ears.

Additional exclusions (12-15) are:

Those who, in the opinion of the recruiting investigator, have very high mortality risk at randomization (less than 50% chance of surviving 4 years) due to co morbid illness such as metastatic cancer or COPD.
For women of childbearing potential an initial pregnancy test and ongoing birth control will be required for participation.
Patients with known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency by self report or noted in the medical record (they have increased toxicity from systemic 5-FU, although screening for this is not part of dermatologic practice and will not be part of this study).
Patients on methotrexate (these will constitute about 1% of potentially eligible individuals) because they may have more severe reactions to topical 5-FU.