Field Treatment of Actinic Keratosis With Ingenol Mebutate

May 2016 | Volume 15 | Issue 5 | Original Article | 535 | Copyright © 2016

Brian Berman MD PhDa,b and Eggert Stockfleth MD PhDc

aCenter for Clinical and Cosmetic Research, Aventura, FL
bDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
cKlinik für Dermatologie, Venerlogie und Allergologie, St. Josef-Hospital, Ruhr-Universität Bochum, Germany

Abstract

There is a need for early, effective field treatments for actinic keratosis (AK) that target subclinical as well as clinically visible lesions to minimize the recurrence and emergence of new lesions. Ingenol mebutate gel is an effective and well-tolerated topical field therapy that has demonstrated sustained clearance and long-term reduction of AKs. This article reviews findings from the FIELD study program and highlights health-related quality of life (HRQoL) outcomes for patients receiving ingenol mebutate. Efficacy data from the FIELD study program are discussed and the tolerability profile of ingenol mebutate in the treatment of areas of up to 100 cm2 is considered. These findings are then placed in the context of HRQoL outcomes and their relevance for patients.

J Drugs Dermatol. 2016;15(5):535-542.

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INTRODUCTION

Actinic keratoses (AKs) are premalignant skin lesions considered part of a disease continuum with invasive squamous cell carcinoma (SCC),1-3 and a marker for an increased risk of non-melanoma skin cancer.4-6 Recent data indicate that the progression of a single AK to SCC ranges between 0–0.53% per year.7

AKs appear in skin areas that have been chronically exposed to UV radiation, a situation known as field cancerization8-11 (Figure 112). In theory, the field may include UV-damaged keratinocytes, subclinical AKs, early- and late-stage clinical AKs, and even invasive SCCs.13 Therefore, the greatest advantage of field-directed over lesion-directed treatment is clearance of multiple clinical and subclinical lesions.5,14,15

Ingenol mebutate gel (IngMeb) is a novel and effective topical field therapy for AK, used once daily for 2 or 3 days depending on body location. It provides sustained clinical clearance of AKs and is well tolerated on areas up to 100 cm2.16-18 Furthermore, when used following cryosurgery, IngMeb suppresses development of new AKs in the treated field.19

This article reviews the accumulating clinical evidence from the FIELD program studies, which support IngMeb as an effective field treatment for AK.

Evidence That IngMeb Is an Effective Field Therapy

Preclinical mouse studies showed that IngMeb treated the cancerized field, clearing mutant p53-expressing keratinocytes, subclinical AKs, and SCCs.20,21 Subclinical AK clearance has also been demonstrated in patients using reflectance confocal microscopy (RCM) and optical coherence tomography (OCT).22,23

A series of phase III clinical studies (the FIELD program) involving 1086 patients evaluated the use of IngMeb as field treatment for AK.

IngMeb Sequential to Cryosurgery

Cryosurgery is a common treatment for isolated AKs; however, it is associated with high recurrence rates and fails to address field cancerization. Recently, there has been interest in combining lesion-directed and field treatments. One study in the FIELD program therefore evaluated the efficacy and safety of field treatment of AKs on the face or scalp with IngMeb 0.015% gel following cryosurgery (NCT01541553).19,24 Complete clearance rates of AKs with IngMeb were higher versus vehicle (Figure 2A); similarly, the mean reduction in AKs was higher for IngMeb at 11 weeks (82.7% vs 75.6%) and 12 months (68.2% vs 54.1%; P=.002). The observed sustained clearance with IngMeb vs vehicle was attributed to reduced emergence of new AKs within the treatment field (demonstrated by tracking individual AKs to differentiate recurrent baseline AKs from new lesions arising from subclinical AKs) and a greater reduction in baseline AKs at 12 months (Figure 2B).

Repeat Use of IngMeb

Because AK is a chronic condition, patients regularly need follow-up treatment to reduce emergent AKs, and to minimize recurrence and risk of progression to SCC. Patients already diagnosed with AKs are prone to developing more in the following year;25 a systematic review reported recurrence rates of 15–53% for single AKs over 1 year.7 Another FIELD program study evaluated follow-up field treatment of the face and scalp with IngMeb 0.015% gel26 (NCT0160014). Complete clearance rates after initial and follow-up treatment are in Figure 3. Notably, follow-up IngMeb (in those who needed it) achieved higher

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