**4. Fundamentals of photodynamic therapy for lung cancer**

In the United States, the FDA has approved the usage of photodynamic therapy (porfimer sodium) for endobronchial malignancy [17]. Within the airway, this treatment is applied to non-small cell lung cancer that is not otherwise treatable by surgery or radiation therapy [17]. Beyond this, the limitation to therapy is solely the ability to illuminate the desired areas of disease with the correct wavelength of light [3, 6, 11, 22]. This, therefore limits therapy to lesions that are primarily visible on bronchoscopy. Standard bronchoscopy is able to visualize airways out to the fourth or fifth generation of airways [23]. The airways of the human go out past twenty generations which can limit utility to only the larger central airways [24]. There have been preliminary studies utilizing electromagnetic navigational bronchoscopic approaches to treat more distal malignancies, but these are still early studies [25]. There are also tools now available, including robotic bronchoscopic platforms that allow for navigation, direct visualization, and intervention down to the ninth generation of airways [26]. Although not directly studied with photodynamic therapy, these recent developments could greatly expand the role of photodynamic therapy in lung cancer.

Currently, the major roles for photodynamic therapy in lung cancer are utilizing it early-stage carcinoma in situ or in central airway lesions [1, 2, 13, 20, 27]. There have been multiple off-label uses and case series reporting success in other disease processes, such as in tracheal papillomatosis [28]. This is a relatively benign but recurrent papillomatosis disease of the trachea causing partial obstruction overtime with significant risk for malignant transformation of the underlying papillomas [28]. Although not directly approved for this indication, as will be discussed, endoluminal obstruction in an early or premalignant disease process is not too far from the currently approved indications [28].

Photodynamic therapy can also target the vasculature that feeds areas of malignancy [5]. This can require illumination with the appropriate wavelength of light up to 30 minutes after exposure/injection to the photosensitizer [5, 7]. This ensures the photosensitizers are still circulating and in the vasculature near the target malignant cells [5, 7]. This approach is more often used in ocular conditions such as macular degeneration to target neovascularization as well as cutaneous lesions of the skin [5]. Photodynamic therapy targeting vasculature has demonstrated efficacy in animal models of solid tumors [7]. However, additional studies need to be performed.

There has been increasing interest in the local injection of photosensitizers directly into tumors [5, 12]. Although only early studies have been done, this has demonstrated efficacy in tumors as small as 8 mm in diameter [12]. However, again these are results from early studies. In general, there are many areas of research both clinical and in basic science for photodynamic therapy. However, clinical utilization often has stringent criteria [17]. Therefore, the focus on the currently approved indications will be to better understand where growth in clinical utilization of this technique will need to occur. Given the requirements for safely delivering therapy to patients, understanding these limitations can help guide the future direction of clinical and translational research. Lung cancer will be utilized as a primary model given the unique characteristics of its prevalence and complexity, and esophageal cancer use will be contrasted to it.
