**1. Introduction**

Photodynamic therapy is a minimally invasive approach for the treatment of malignancy [1, 2]. It involves selective uptake of a photosensitizing agent, which is then activated by specific wavelengths of light [3, 4]. This results in oxidative damage to the cells by the production of reactive oxygen species [5, 6]. This results in targeted cellular destruction [5, 6]. Along with this direct cellular destruction, there are local inflammatory effects as well as vascular thromboemboli formation, which allow for a further delayed therapeutic effect [5, 6]. The thromboemboli effect blocks blood flow to the target and thereby results in ischemia [5–7]. Photodynamic therapy has been approved across the world for a number of different clinical indications [5, 6]. This chapter will review the mechanisms and clinical utility of photodynamic therapy.

A photosensitizer in this context is an agent, often a porphyrin which reacts to light in the 500–800 nanometer range depending upon the specific agent utilized [7]. The earliest described photodynamic effect was in 1900 by Raab, Von Tappeiner coined the term photodynamic therapy [3, 5]. Over time, hematoporphyrins were noted to result in tumor fluorescence [3]. This was gradually studied further and refined until the nature of the porphyrins was better understood. Light exposure following cellular uptake resulted in cellular damage and destruction [6]. Over time the fundamentals of this damage were better understood. Depending upon the exact photosensitizer, different mechanisms of damage have been proposed. The major mechanisms of damage are singlet oxygen and free radical formation inducing: apoptosis, autophagy, and necrosis [6, 8, 9]. Apoptosis is a form of

controlled cellular death which in this case is induced when photosensitizers cause damage to mitochondria or the proteins of bcl-2 [6]. These are major regulators of the cellular death pathway. Autophagy allows for the gradual destruction of cellular components in an ordered manner [8]. However, necrosis is a less orderly effect and can often result in unintended tissue damage due to the disorganized manner of tissue destruction [6, 8].

Over time, many different photosensitizers have been discovered, but of these, only a few have seen broad clinical approval and use [5, 6, 10]. Each photosensitizer is reactive at a specific wavelength of light. Hematoporphyrin (HPD) was the first photosensitizer approved by the FDA in 1995 for the indication of esophageal cancer. HPD was a hematoporphyrin mixture containing monomers and chains of varying lengths [3, 5, 6]. Photofrin (porfimer sodium) is a refined version of HPD with monomers removed, and it is one of the most common clinically used agents, see **Figure 1** [3, 5, 6]. Photosensitizers are primarily porphyrin-based and contain multiple ring structures [3, 5, 6, 11]. These can be applied locally or injected systemically, and over a period of time they will be selectively taken up by cells [3, 5, 6, 11]. Porfimer sodium is part of the first generation of photosensitizers developed in the 1970s and early 1980s [5, 10, 12]. Later generations were developed as the characteristics of the agents were chemically refined [5, 10, 12]. These later generation agents also tended to have decreased duration of systemic photosensitivity [3, 5, 6, 11]. The second generation has been refined to target longer wavelengths of light, thus allowing for deeper tissue penetration of the activating wavelength of light and, therefore greater effect [5, 6, 11]. In conjunction with the increased penetration of longer wavelengths of light, the light source can be embedded into the tissue to allow for an alternative way to increase the effect [6, 11].

Photodynamic therapy has approved indications for superficial or early-stage malignancies as well as late-stage malignancies [5, 6]. These indications intuitively make sense as light penetration is a vital component of this therapy. Given that later stages of malignancy typically spread systemically via blood or lymphatic spread, photodynamic therapy has limited utility in those cases unless it is for a local effect. For example, photodynamic therapy has been well described as an alternative therapy in addressing central airway obstructions in lung cancer [13]. Central airway obstructions are typically manifestations of late-stage cancer, but photodynamic

#### *Clinical Usage of Photodynamic Therapy DOI: http://dx.doi.org/10.5772/intechopen.95473*

therapy can be used to clear the tumor obstructing the airway even when it does not have the ability to affect the entirety of the metastatic tumor burden [1, 2, 13]. In many ways, this focused local effect is a significant advantage over alternative treatments which can have greater side effects [1, 2, 13]. These cases of central airway obstruction can be challenging and having an option to provide a delayed and gradual effect that specifically targets tumor cells can be a vital therapeutic intervention. Skin and endoluminal malignancy treatment are approved indications for photodynamic therapy, but this chapter will primarily focus on endoluminal malignancy and especially endobronchial malignancy. Of the photosensitizing agents commercially available, Protomir sodium is the most well studied and widely available, and the best understood.

Photodynamic therapy usage in lung cancer is used as the primary example for a few reasons. The primary being that in many ways. it is the most challenging application. The esophagus consists of a single cylindrical region where the therapy is applied, and blockage of it is not life threatening. Utilization of photodynamic therapy on the skin similarly has limited side effects. However, utilization of photodynamic therapy within the pulmonarysystem is limited to only some surfaces, and damage to this tissue has the potential for life threatening complications. Therefore, understanding the practical applications of photodynamic therapy within the context of lung cancer can be extrapolated to other vital organs.
