Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis.

Stephen Chad Kanick,M Shane Chapman,Tayyaba Hasan,Edward V Maytin,Scott C Davis,Brian W Pogue,Yan Zhao

doi:10.1117/1.jbo.19.7.075002

Abstract

Dosimetry for aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy of actinic keratosis was examined with an optimized fluorescence dosimeter to measure PpIX during treatment. While insufficient PpIX generation may be an indicator of incomplete response, there exists no standardized method to quantitate PpIX production at depths in the skin during clinical treatments. In this study, a spectrometer-based point probe dosimeter system was used to sample PpIX fluorescence from superficial (blue wavelength excitation) and deeper (red wavelength excitation) tissue layers. Broadband white light spectroscopy (WLS) was used to monitor aspects of vascular physiology and inform a correction of fluorescence for the background optical properties. Measurements in tissue phantoms showed accurate recovery of blood volume fraction and reduced scattering coefficient from WLS, and a linear response of PpIX fluorescence versus concentration down to 1.95 and 250 nM for blue and red excitations, respectively. A pilot clinical study of 19 patients receiving 1-h ALA incubation before treatment showed high intrinsic variance in PpIX fluorescence with a standard deviation/mean ratio of > 0.9. PpIX fluorescence was significantly higher in patients reporting higher pain levels on a visual analog scale. These pilot data suggest that patient-specific PpIX quantitation may predict outcome response.

Highlights

Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) is an FDA-approved treatment for actinic keratosis (AK),[1] which starts as benign lesions from sun damage but can progress to squamous cell carcinoma if left untreated.[2]
The plot shows the fitted contributions of background tissue autofluorescence, protoporphyrin IX (PpIX), and the very small contributions from photoproducts to the total fluorescence. cbPlpuIeX versus [PpIX] data are shown on linear [Fig. 2(b)] and log [Fig. 2(c)] scales to illustrate the quality of the linear relationship over a wide range of [PpIX] values
This substantial difference in sensitivity is due to the fitting algorithm adequately decoupling fluorescence from PpIX and background fluorophores, while the integrated metric is confounded by these factors at low [PpIX] values

Summary

Introduction

Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) is an FDA-approved treatment for actinic keratosis (AK),[1] which starts as benign lesions from sun damage but can progress to squamous cell carcinoma if left untreated.[2]. Incomplete treatment responses are often associated with thicker lesions[8,9] and are generally attributed to a combination of poor ALA penetration, insufficient PpIX generation, or inadequate light dose. A recent trend in the clinic toward the use of shorter ALA incubation times, administering the light dose at 1 to 3 h after topical ALA,[10,11,12,13] exacerbates the potential problem of incomplete responses. The pharmacokinetics of PpIX generation at very short contact times is not well characterized, and considering that ALA-incubation in skin has been reported to generate peak PpIX values between 6 and 24 h after ALA administration,[14,15] times shorter than this may increase the likelihood of insufficient PpIX generation, especially at deeper levels within lesions. The hurdle to achieving such customized therapy, is the Journal of Biomedical Optics

Methods

Results

Conclusion