CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin, both of which are
keratinocyte carcinomas (KCs), account for a half of all cancers in the United States, and
over 100,000 diagnoses per year in the VA. The standard treatment for these KCs is excision
of the lesion, and they cost the US health care system some $2.5 billion annually and about
$100 million annually in the VA. There is no proven means to prevent KCs (except perhaps for
a modest benefit of intensive daily sunscreen use). An effective prevention strategy would
dramatically change the way high-risk patients are managed and could substantially reduce the
costs of care. The investigators' preliminary analysis indicates that the savings will be
$116 per high-risk patient and will account for a total national savings of over $11 million.
These findings imply that the study would pay for itself by the end of 4 years. The
investigators hypothesize that topical 5-fluorouracil (5-FU) chemoprevention will prevent
skin cancer surgeries and will be cost-saving. To test this the investigators propose a
randomized controlled trial of 5-FU compared to a vehicle control to the face and ears in a
high-risk population.

In the study, 1000 Veterans at high-risk of skin cancer defined as at least 2 KCs in the
prior 5 years, at least one of which was on the face or ears, will be randomized to 5-FU or a
vehicle control cream, and followed for 2 to 4 years. The primary endpoint will be surgery
for any KC on the face and ears. The investigators will also assess the cost of care, quality
of life, the side effects associated with treatment, and the prevalence and number of actinic
keratoses, a skin cancer precursor and itself a cause of morbidity and cost. By targeting
patients at high-risk, the study focuses on high-cost patients for whom this treatment could
both improve outcomes (cancers and quality of life) and reduce costs.

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.