A Randomized Trial of Broad Area ALA–PDT for Field Cancerization Mitigation in High-Risk Patients

May 2020 | Volume 19 | Issue 5 | Original Article | 452 | Copyright © May 2020


Published online April 24, 2020

Daniel Piacquadio , Anna Houlihan , Mary Beth Ferdon , James E. Berg , Stuart L. Marcus

aTherapeutics, Inc., San Diego, CA bDUSA Pharmaceuticals, Inc., Wilmington, MA

Abstract
Background: The relationship between actinic keratoses (AKs) and nonmelanoma skin cancers (NMSCs) is well established. Patients with field cancerization are at high risk of developing new lesions. A treatment to interrupt new lesion formation or progression is required.
Objective: To evaluate occurrence of AKs in high-risk patients after field aminolevulinic acid–photodynamic therapy (ALA–PDT).
Methods: In this randomized, parallel-group, evaluator-blinded, 52-week study, patients with 4–15 facial AKs (N = 166) were random-ized (ALA 2x vs ALA 3x vs vehicle [VEH]-pooled [VEH 2x+VEH 3x], 1:1:1) to receive 2 or 3 PDT treatments (1-hour incubation) following cryotherapy at screening.
Results: More ALA-treated patients than VEH-treated patients had no AKs at week 52 (ALA 2x, 36.0%, P=0.0102; ALA 3x, 37.5%, P=0.0089; VEH, 18.9%). Week 52 lesion recurrence rates were 7.7% (P=0.0004) and 6.1% (P<0.0001) for ALA 2x and ALA 3x, respec-tively, versus 15.5% for VEH. Therapy was well tolerated; no patient requested early termination of light treatment. ALA 3x reduced NMSC development versus VEH (5 vs 12 lesions, P=0.0014).
Conclusion: 2 or 3 ALA–PDT treatments with 1-hour incubation can significantly reduce occurrence of AKs after 1 year in patients at high risk of NMSC versus VEH–PDT (NCT02239679).

J Drugs Dermatol. 2020;19(5):452-458. doi:10.36849/JDD.2020.4930

INTRODUCTION

Actinic keratoses (AKs) are precancerous, dysplastic epidermal lesions with potential for progression to squamous cell carcinoma (SCC). A study by Criscione et al1 revealed that in a high-risk population (≥2 keratinocyte carcinomas in previous 5 years), approximately 65% of all primary SCCs arose in lesions previously diagnosed as AKs. Furthermore, it demonstrated that the risk of malignant progression of AKs to primary SCC increases over time (0.6% at 1 year and 2.6% at 4 years).1 Cellular damage and atypia seen histologically in AKs are similar to those of surrounding nonlesional skin,2,3 suggesting that skin surrounding AKs may have an increased risk of skin cancer.

Photodynamic therapy (PDT) using a 20% topical solution of aminolevulinic acid HCl (ALA; Levulan® Kerastick®, DUSA Pharmaceuticals, Inc., Wilmington, MA) has been shown to be well tolerated and highly effective in treating minimally to moderately thick AKs of the face or scalp, when applied to lesions as indicated (10 J/cm2 of blue light [Blue Light Photodynamic Therapy Illuminator, BLU-U®; DUSA Pharmaceuticals, Inc.] delivered at 10 mW/cm2 after a 14- to 18-hour incubation period [drug–light interval]).4,5

ALA is absorbed into dysplastic lesions and metabolized to protoporphyrin IX (PpIX) over time,6 until activated by light in the presence of oxygen, resulting in a cytotoxic process. Cutaneous photosensitivity is transient (usually clearing within 24–48 hours), owing to metabolic conversion of the remaining PpIX to heme.7 ALA–PDT studies using short incubation times and/or broad-area application have also shown efficacy in AK treatment,8-10 with 1-hour incubation times providing significant clearance of AK lesions.11 PpIX concentrations in AKs are known to be significantly greater 1 and 2 hours post-ALA application than at baseline in 92% and 100% of lesions, respectively, and areas of normal-appearing skin also show elevated levels.6 Reducing incubation time may decrease the discomfort of broad-area PDT by decreasing the amount of PpIX produced, while maintaining a high AK clearance rate. This offers the potential to treat subclinical lesions that may exist alongside clinically typical AKs. In studies of ALA–PDT for AK treatment, in which patients were observed for >6 months, nonmelanoma skin cancers (NMSCs) arose during follow-up, as may be expected in a patient population with sun-damaged skin.5,12 In a Phase 2 study, incidence of NMSCs in areas treated with broad-area ALA–PDT was lower than for the control group.11 Studies of long-term ALA–PDT