CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial

The main purpose of this study is to see if 5-fluorouracil (5-FU) skin cream can prevent the growth of new skin cancers on the face and ears. The cost of trying to prevent skin cancer will be compared to the usual cost of treating skin cancer. Participants are being asked to be a part of this study because the participants have been treated for two or more skin cancers within the past five (5) years. At least one of these cancers occurred on the face or ears. Having had two or more skins cancers in the past 5 years makes it likely that participants will develop additional skin cancers in the future. Exposure to ultraviolet radiation from the sun or artificial sources such as tanning beds is a major cause of basal cell and squamous cell carcinoma of the skin. Using lotions, creams, or gels that contain sunscreens can help protect the skin from premature aging and damage that may lead to skin cancer. The 5-FU skin cream used in this study is FDA-approved to treat some types of skin cancers and spots that might become skin cancer. However, 5-FU skin cream has never been studied to see if it can prevent skin cancer. This drug is not approved by the FDA for how it will be used in this study. In this study, one half of the patients will use the 5-FU cream and the other half will use a skin cream that looks identical to the 5-FU cream but does not have 5-FU or any other active drug in it. Approximately twelve VA medical centers will work together in this study. About one thousand (1000) patients will be in this study. The study is sponsored by the U.S. Department of Veterans Affairs Cooperative Studies Program.

Sex

All

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.

• BACKGROUNDLee KC, Lew R, Weinstock MA. Improvement in precision of counting actinic keratoses. Br J Dermatol. 2014 Jan;170(1):188-91. doi: 10.1111/bjd.12629. PMID 24102420
• BACKGROUNDKorgavkar K, Firoz EF, Xiong M, Lew R, Marcolivio K, Burnside N, Dyer R, Weinstock MA; VAKCC Trial Group. Measuring the severity of topical 5-fluorouracil toxicity. J Cutan Med Surg. 2014 Jul-Aug;18(4):229-35. doi: 10.2310/7750.2013.13143. PMID 25008439
• BACKGROUNDPomerantz 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. Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. JAMA Dermatol. 2015 Sep;151(9):952-60. doi: 10.1001/jamadermatol.2015.0502. PMID 25950503
• BACKGROUNDChen SC, Hill ND, Veledar E, Swetter SM, Weinstock MA. Reliability of quantification measures of actinic keratosis. Br J Dermatol. 2013 Dec;169(6):1219-22. doi: 10.1111/bjd.12591. PMID 24033340
• RESULTPomerantz H, Korgavkar K, Lee KC, Lew R, Weinstock MA; VAKCC Trial Group. Validation of Photograph-Based Toxicity Score for Topical 5-Fluorouracil Cream Application. J Cutan Med Surg. 2016 Sep;20(5):458-66. doi: 10.1177/1203475416643952. Epub 2016 Apr 18. PMID 27207349
• RESULTSiegel JA, Luber AJ, Weinstock MA; Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial and Department of Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial Groups. Predictors of actinic keratosis count in patients with multiple keratinocyte carcinomas: A cross-sectional study. J Am Acad Dermatol. 2017 Feb;76(2):346-349. doi: 10.1016/j.jaad.2016.09.020. No abstract available. PMID 28088997
• Walker JL, Siegel JA, Sachar M, Pomerantz H, Chen SC, Swetter SM, Dellavalle RP, Stricklin GP, Qureshi AA, DiGiovanna JJ, Weinstock MA. 5-Fluorouracil for Actinic Keratosis Treatment and Chemoprevention: A Randomized Controlled Trial. J Invest Dermatol. 2017 Jun;137(6):1367-1370. doi: 10.1016/j.jid.2016.12.029. No abstract available.