5-Fluorouracil and Calcipotriene for Field Treatment of Actinic Keratoses

The primary objectives of this study is to determine whether chronic, systemic immunosuppression alters the short and long-term clinical 9 efficacy of 5FU/C, presumably through decreased CD4+ T cell-mediated immune response in the skin.

Our central hypothesis is that SOTRs (Solid Organ Transplant Recipients) exhibit attenuated immunologic activation in response to 5FU/C, resulting in reduced AK clearance and potentially requiring extended duration of treatment compared to their immunocompetent counterparts. To test our hypothesis, we propose the following aims:

Aim 1. To assess the clinical efficacy of 5FU/C to treat AKs.

Our primary endpoint is the percent change from baseline in total AKs at week 9. Secondary endpoints include complete (100%) and partial (75%) clearance of AKs at week 9. These endpoints mirror prior pivotal trials of 5FU/C and will directly evaluate whether immunosuppression reduces clinical efficacy of 5FU/C to treat AKs.1,2

Aim 2. To determine whether extending 5FU/C therapy from 4 days to 8 days improves AK clearance in immunosuppressed patients.

We wish to provide an evidence-based rationale for extended treatment courses among immunosuppressed patients. Prior studies suggest immunosuppressed patients experience reduced local inflammatory responses and lower clearance rates when using topical field treatments for AKs, and clinical practice often involves empirically extending therapy in these instances. No prospective trial, however, has evaluated whether extending treatment duration improves outcomes. Our study's internal comparison of an extended exposure to 5FU/C in SOTRs will optimize treatment parameters and will provide the first evidence-based guidance on treatment duration for field cancerization in SOTRs.

Aim 3. To determine whether systemic immunosuppression affects local immune function in the skin.

Topical chemotherapeutics and immunomodulating agents (e.g. 5FU/C) elicit local reactions including erythema, scaling, edema, erosions, and pain.1-4 These local cutaneous reactions often serve as markers of a patient's immune activation and predict expected treatment success following cessation of therapy. Given that 5FU/C relies on the host's immune system to mount a T cell-mediated immune response, we anticipate decreased immune activation (and, therefore, decreased local, cutaneous reactions) among immunosuppressed, compared to immunocompetent, patients following the standard 4-day treatment course. We aim to evaluate local cutaneous reactions among SOTRs following an extended 8-day treatment to determine whether immunosuppressed patients require longer duration of therapy to generate immune responses comparable to immunocompetent patients following the standard 4-day treatment.

Completion of this study will fill a major evidence gap by establishing how immunosuppression influences the efficacy of a widely used field of therapy in dermatology. The findings will directly inform clinical practice guidelines, optimize treatment duration for immunosuppressed patients, and reduce reliance on empiric decision-making. Given the expanding population of transplant recipients, nationally and at Cedars-Sinai, and their disproportionate NMSC burden, the proposed research addresses an urgent public health need and aligns directly with CS Cancer Center's focus on cancer prevention.