Review
Oncologic photodynamic therapy: Clinical strategies that modulate mechanisms of action

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Summary

Photodynamic therapy (PDT) is an elegant minimally invasive oncologic therapy. The clinical simplicity of photosensitizer (PS) drug application followed by appropriate illumination of target leading to the oxygen dependent tumor ablative Photodynamic Reaction (PDR) has gained this treatment worldwide acceptance. Yet the true potential of clinical PDT has not yet been achieved. This paper will review current mechanisms of action and treatment paradigms with critical commentary on means to potentially improve outcome using readily available clinical tools.

Introduction

The relative clinical simplicity of PDT has brought this oncologic intervention to a worldwide audience [1]. However, this straightforward elegance of drug/light reaction should not be misconstrued. Successful clinical PDT is a complex interplay of light and photosensitizers interacting in time and space to create the oxygen dependent, tumor ablative photodynamic reaction [2]. Yet in the clinic, PDT has evolved into a rote application of prescribed drug dose followed by a fixed light dose with both parameters set to maximize tumor ablation, even at the cost of potentially excessive normal tissue damage. In reality the clinician/scientist has multiple tools available to not only improve tumor response but also to minimize morbidity [3]. Furthermore, the clinician may also be able to modulate immune response through various manipulations of the actual photodynamic therapy [4]. This paper will challenge all involved with PDT to examine the potential to enhance therapy through a re-evaluation of both PDT components and mechanisms of action. Clinically relevant alterations of current treatment paradigms will also be examined on their ability to potentiate PDT.

Section snippets

Clinical and historical perspectives

Currently, clinical PDT involves application of a PS agent followed by illumination at an appropriate wavelength and intensity of light to activate the PS [5]. Ideally, this will result in an ablative photodynamic reaction that eliminates the lesion but spares normal tissue.

Historically, intravenous PS agents were developed and a therapeutic paradigm of a single illumination for ablation followed [6]. This may have been due to the difficulty of achieving adequate illumination, particularly for

Drugs, light, reaction

To better understand the mechanisms of action of PDT and appreciate how the currently available tools for PDT may be manipulated to improve the therapeutic ratio, we will examine PS, illumination and the PDR separately. This will ultimately allow us to speculate on the interplay of these potential variables for clinical enhancement.

Mechanisms

Once the PDR has occurred, well described but incompletely understood pathways are activated which impact tumor and normal tissue survival [59]. While the actual reaction is measured in nanoseconds and treatment time in minutes, response and outcome may take days, months or even years to occur. This section will describe the general response to PDT and then specific outcomes on tumor and normal tissue, vascular supply and immune response to PDT. Upon generation of the PDR both tumor and normal

Clinical tools

Currently, clinical PDT treatment protocol involves a standard dose of drug, a standard light dose and a standard drug-light interval. Yet clinical outcomes may vary tremendously. This is probably due to the individual patient's metabolism of the PS, lack of light homogeneously illuminating the target and a lack of dosemetric tools to help guide therapy. However, the clinician has a number of tools available to improve outcomes. An informed/experienced PDT clinician should consider not only the

Translation of the mechanisms of PDT to optimize results today

Upon consideration, it is clear that, while in the laboratory situation drug and light dose can be measured to achieve the optimal PDR results, in clinical PDT there are many variables that cannot yet be measured which affect outcomes. This is even more the case in cancer. Even for a specific cancer such as that of endobronchial, with all its sub types and variations in morphology and physical characteristics, it would be illogical to follow rigidly a “standard light/drug dose”. The standard is

Conflict of interest

None.

Acknowledgement

The authors would wish to acknowledge, with thanks, the contribution of Mrs Kate Dixon who read the manuscript and gave appropriate advice.

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