CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial

Conditions
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Carcinoma, Basal Cell, Carcinoma, Squamous Cell, Skin Neoplasms, Skin Diseases, Neoplasms, Basal Cell, Neoplasms, Squamous Cell, Carcinoma

Intervention / Treatment
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* Drug: 5-fluorouracil
* Drug: Placebo, vehicle control


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: 5-fluorouracil<br>Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses | Drug: 5-fluorouracil<br>* 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.<br>* Other names: Efudex, 5-FU;|
| Placebo Comparator: Arm 2: Placebo<br>Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses | Drug: Placebo, vehicle control<br>* Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, 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 vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream 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 vehicle control cream will be stopped.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Diagnosis of the First Keratinocyte Carcinoma (KC) on the Face or Ears for Which Surgery is Performed | Diagnosis of the first Primary Basil Cell Carcinoma (BCC) or primary Squamous Cell Carcinoma (SCC) on the face or ears that was removed surgically. | From randomization to last visit prior to end of study date (6/30/2013), assessed up to four years | 
| Hazard Ratio for Surgically Treated KC |  | date of randomization to last visit before end of study follow up (6/30/2013), assessed up to four years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, NMSC, nonmelanoma skin cancer, topical 5-FU 5% cream, Antineoplastic Agents, Therapeutic Uses, Dermatologic Agents, Neoplasms by Site, carcinoma, basal cell, carcinoma, squamous cell