Lung cancer is the most common cause of cancer death among both men and women. It is estimated that in 2001, there will be 169,500 new cases of lung cancer and 157,400 deaths. 1a It is well-known that lung cancer can be cured when diagnosed and resected at its earliest stage; however, many lung cancer patients cannot undergo curative resection because of either poor pulmonary reserve or advanced disease. Obstruction of the large central airways is not an uncommon complication in these patients, and hence strategies to preserve functional lung tissue and to palliate symptoms of dyspnea are of importance. A wide range of nonsurgical interventional therapeutic modalities are now available to treat central airway obstruction. These include Nd:YAG laser, cryotherapy, electrocautery, and endobronchial stenting. Because of its selectivity, photodynamic therapy (PDT) has received notable attention in recent years as an important adjunctive modality in the management of lung cancer. The Food and Drug Administration has approved photofrin for treating early-stage, microinvasive, endobronchial nonsmall cell lung cancer in patients for whom surgery and radiotherapy are not indicated and for palliation of advanced lung cancer with airway obstruction. EFFICACY AND SAFETY The efficacy of PDT in primary pulmonary as well as metastatic nonpulmonary endobronchial tumors has been demonstrated in multiple studies. 1b–3 It has also been shown to be effective in curing early-stage lung cancer. 2 PDT has been found to be most effective for small lesions with a longitudinal length of less than 1.0 cm. 2,5 In patients with advanced disease (stage III or IV), PDT has been effective in relieving obstruction, improving symptoms of dyspnea, and improving spirometric measures of lung function. 4 Even patients dependent on mechanical ventilation can be liberated from the ventilator with effective PDT. 6 PDT is a safe method for treating early-stage as well as advance-stage lung cancer. Furuse et al. 5 assessed toxicity of PDT in patients treated for centrally located early-stage lung cancer. Toxicity assessment was quantified according to World Health Organization criteria. World Health Organization grade 2 toxicities included transient elevation of ALT (1.9%), allergic reaction (7.7%), and sunburn (1.9%). World Health Organization grade 2 pulmonary toxicity was seen in 7.7% of patients and included exertional dyspnea, fever, and obstructive pneumonitis. No World Health Organization grade 3 or 4 toxicities were seen. In all the studies of PDT in early-stage disease, the side effect profile has been very favorable, including in patients with low Karnofsky scores (<40 points). 7 MECHANISM OF ACTION The photodynamic effect is essentially a photochemical oxidative process that uses a photosensitive agent to destroy tumor. Laser light of a specific wavelength activates the drug and, in the presence of oxygen, generates highly reactive singlet oxygen species that lead to a cytotoxic reaction. Currently the most commonly used agent is Porfimer sodium (PhotofrinII; Sanofi Pharmaceuticals, New York, NY, USA) which is a dihematoporphyrin ether consisting of a complex mixture of porphyrinoids including hematoporphyrin, hydroxyethylvinyldeuteroporphyrin, and a hydrophobic fraction responsible for tumor localization and photosensitization. 8 A standard dose of 2 mg/kg is injected slowly intravenously over 5 minutes. The half-life is usually 20 to 30 hours and it is cleared from most organ systems within 72 hours. However, it is retained for a longer period of time in tumors, liver, spleen, and skin (as long as 6 weeks). The mechanisms involved in the tissue selectivity of dihematoporphyrin ether is unknown, but possible explanations include variations in the route of delivery, binding to lipoproteins, pH changes within tumor stroma and cells, tumor angiogenesis factors, and poor tumor lymphatic drainage. 9 After the selective retention of the drug in the tumor cells, the ground state photosensitizer is excited by the absorption of light energy and interacts with ground state oxygen to produce singlet oxygen. This singlet oxygen then undergoes additional reactions with electron-rich substrates to produce oxidized products, leading to cell death. More detailed review is available elsewhere. 7,13 The indications, advantages, and disadvantages are given in Table 11b,4,10,11 and contraindications are presented in Table 2.TABLE 1: Indications, advantages, and disadvantages of PDTTABLE 2: Contraindications of PDT therapyPROCEDURE Properties and Infusion of the Photosensitizer Drug The spectrum of dihematoporphyrin ether reveals absorption of light at a wavelength of 630 nm and allows tissue penetration and cytotoxicity for 5 to 10 mm, with amelioration of the light absorbance by the naturally present chromophores such as hemoglobin. After a set time interval, usually 48 to 72 hours after infusion of the drug, the tumor is exposed to light energy of a specific wavelength, which triggers the cytotoxic reaction. Hence, after the infusion, the patient becomes photosensitive and remains so for about a month. It is of utmost importance that careful instruction is given to the patient to avoid direct sunlight (Table 3).TABLE 3: Typical written instructions provided to the patient before the PDT procedureLight Source and Dosimetry Laser light is used to activate the photosensitizer and initiate the photodynamic reaction. The most commonly used light sources are argon or potassium–titanyl–phosphate pump dye lasers that emit nonthermal laser light at a wavelength of 630 nm. However, in theory, any laser with the proper wavelength could be used. We use the 600 series Dye module with a potassium–titanyl–phosphate pump dye laser (Laserscope, San Jose, CA, USA) with an OPTIGUIDE fiberoptic delivery system (fibersdirect.com, Kirkland, WA). The two important components of light dosimetry include the rate of energy delivery (power) and the total energy delivered. Light exposure is usually scheduled 48 hours after the drug infusion. The laser energy is transmitted via a flexible quartz fiber, which can be used through either a flexible or rigid bronchoscope. The laser fibers can be tailored to fit the clinical situation, with cleaved probes for forward light projection, bulbous tips for isotropic spherical distributions, or cylindrical coatings for light perpendicular to the axis of the fiber. The fiber tip can be placed in close approximation to the tumor mass, or it can be embedded in the tumor. When using a cylindrical light diffusing fiber, a power of 400 mW/cm is typically used, with a total energy delivery of 200 to 300 J/cm. Typically 200 J/cm is used for carcinoma in situ, whereas 300 J/cm is used for more advanced disease. In urgent cases, treatment on the same day with a slightly higher energy (as high as 400 J/cm) can be used. Of the cylindrical fibers currently available for use with the bronchoscope, the 1-and 2.5-cm fibers are the most useful and are commercially available. Two parameters need to be calculated, the total power delivered to the fiber (in Watts) and the treatment time (in seconds). Note that in all cases, the desired power output per linear centimeter of the fiber is always 0.4 W/cm. What varies is the total power delivered to the fiber (Watts), because this is expressed as power, not power per centimeter. The following power and light dosimetry equations are used to calculate power and treatment time:EQUATION Example 1: If a tumor of 1 cm in length is to be treated with a tissue dose of 200 J/cm using a cylindrical diffuser with a length of 1.0 cm and a power of 0.4 W/cm, then EQUATION Example 2: A tumor of 5 cm in length is to be treated with a tissue dose of 300 J/cm using a cylindrical diffuser with a length of 2.5 cm and a power of 0.4 W/cm. The tumor will have to be treated in two sections of 2.5 cm each. Each treatment will require EQUATION Residual disease or recurrence of the tumor after PDT is more frequent in tumors located distal to a segmental bronchus or in bronchial stumps. 12 Insufficient light illumination resulting from extreme bending of the fiber or inability of the light to penetrate the full length of the bronchial stump may contribute to treatment failure. 12 In these special circumstances, a microlens fiber can be used to treat the tumor. Scheduling the Procedure The general steps in PDT therapy include 1.) infusion of the photosensitizer; 2.) a waiting period of 48 to 72 hours to allow systemic porphyrins to be cleared from normal tissues; 3.) bronchoscopy with application of light; 4.) cleanup bronchoscopy after a waiting period of 24 to 48 hours and reapplication of laser light, if required; and 5.) subsequent cleanup bronchoscopy. To optimize the availability of staff in the event of emergencies, we recommend infusing the drug late on Friday so that light activation and subsequent cleanup bronchoscopy can be completed during the subsequent week. PDT can be performed either as an inpatient or an outpatient. Patients with borderline pulmonary reserve should be considered for inpatient treatment. Conditions necessary for outpatient PDT therapy are listed in Table 4.TABLE 4: Suitable candidates for outpatient PDTPersonnel Requirement A dedicated nurse is usually preferred for PDT programs but is not absolutely required. We have three registered nurses with 4 to 5 years of experience in assisting in bronchoscopy who have received extra inservice lectures in using the dye laser machines and the OPTIGUIDE fiberoptic delivery system. All personnel should be aware of the exact procedure to be followed, including drug administration, making sure the patient has light protective clothing and ensuring that the patient does not have any additional questions before the procedure. A dedicated area for the infusion of the drug is preferred but is not required. The procedure room itself or the bronchoscopy recovery room can be used for the infusion for outpatients. For inpatients, infusions are administered on the medical ward. Technique In general, PDT can be performed safely with a flexible bronchoscope and the patient under conscious sedation. Supplemental oxygen is given routinely, and oxygen saturation is monitored continuously. A suitable fiber of appropriate tip length is selected, depending on the length of the lesion. After adequate sedation, the bronchoscope is introduced either nasally or orally. We prefer the nasal route because it is easier to hold the bronchoscope stationary during light application. Good local anesthesia is absolutely essential to eliminate coughing. When the tumor is visualized, the preselected fiber is introduced through the working channel of the bronchoscope and its tip is either embedded into the tumor or held tangentially in contact with the tumor. After the tip of the fiber is placed, light of appropriate wavelength (630 nm) is applied for the specified time period. Standard OSHA guidelines for laser safety should be used. When laser treatment is initiated, the whole field of vision turns red. This can cause video bronchoscopes to lose their picture. To avoid this, we use older direct fiberoptic bronchoscopes. Use of red laser safety glasses allows clear vision with this system. An alternative is to use a red filter in the video bronchoscope, but this can be cumbersome. Alternatively, fiber position can be checked periodically by turning off the laser. Every effort should be made to keep the fiber under constant vision during treatment. Excessive movement of the fiber during delivery of the laser light should also be avoided. If the lesion is long enough such that it requires multiple treatment fields, we usually treat the distal segment first. This is because distance measurements are more reproducible when pulling the fiber in toward the bronchoscope than when pushing it forward. The bronchoscope is positioned with the tip just proximal to the proximal edge of the treatment field. The catheter is advanced out so that the distal tip of the fiber is at the proximal edge of the treatment field. The fiber is then marked at the site where it enters the instrument port. A second mark is placed at a distance above the first mark on the fiber equal to the length of the treatment field. The fiber is then advanced while holding the bronchoscope stationary until the second mark is at the instrument entry site. The first field is treated. The fiber is then pulled back the distance of the laser tip, using the second mark as a guide. Usually the first mark then appears at the instrument port. In this way, overlapping fields can be minimized. When every area is treated properly and after suctioning out all the secretions, the bronchoscope is removed. Depending on the size of the tumor treated and the ability of the patient to cough, necrotic debris will obstruct the airway, and hence a repeat cleanup bronchoscopy is needed 24 to 48 hours later. If residual tumor is present after removal of necrotic debris, repeat laser treatment can be done during the same sitting. If an additional laser treatment is given, repeat bronchoscopy is mandatory 24 to 48 hours later. Aggressive debridement of all necrotic debris is critical because it will absorb light and limit the efficacy of any further laser treatment, in addition to leading to atelectasis and respiratory compromise. The post-PDT-treated tumor will have the consistency of very thick mucus and will be somewhat gelatinous in nature. Hence, the subsequent cleanup bronchoscopy may be time-consuming, requiring approximately 1 to 2 hours. We prefer to have cryotherapy available during these procedures because the cryoprobe can be used to extract these large mucus plugs, and this may greatly decrease the procedure time. The steps involved to initiate PDT treatment are shown in Fig. 1.FIG. 1: Typical sequential steps involved in photodynamic therapy treatment.COMBINING PDT WITH OTHER THERAPEUTIC MODALITIES PDT can be combined with other local or systemic treatment protocols along with other modalities like the Nd:YAG laser, brachytherapy, external beam radiation, and chemotherapy. Recently, one investigator demonstrated rapid local tumor necrosis with improvement in airway patency when PDT was combined with hyperbaric oxygen therapy. 14 External beam radiation therapy and PDT can be combined sequentially. However, we prefer completion of PDT treatment before initiation of external beam radiation therapy because the amount of time to restore a patent airway is reduced. This not only reduces the risk of postobstructive pneumonia, it also improves pulmonary reserve, thereby enhancing the ability of the patient to tolerate future complications, such as pneumonia or radiation pneumonitis. If possible, we prefer to wait 2 weeks after completing PDT to initiate radiation therapy. Similarly, we prefer PDT before initiation of chemotherapy to avoid having a situation in which the patient develops postobstructive pneumonia while being pancytopenic secondary to chemotherapy. Nd:YAG laser therapy is used when rapid reopening of the airway is needed. Hence, it is usually applied before PDT therapy. Most complications resulting from laser therapy occur either during or within a few days after completion of therapy. Mucosal edema is a common occurrence after Nd:YAG laser therapy, which may last for several days. Delayed hemorrhage or perforation may occur over a period of a few days with either PDT or Nd:YAG laser therapy. Because PDT can worsen edema further and lead to tissue necrosis, delayed hemorrhage and perforation could occur theoretically if both therapies were applied within a short period of time. We therefore recommend a minimum duration of 2 weeks between these therapies if extensive Nd:YAG laser therapy is undertaken. The optimal sequencing of various therapeutic modalities is currently not clear, however, and requires further study. CONCLUSIONS PDT is a safe therapeutic modality for the treatment of early-stage lung cancer and for palliation of advanced disease with endoluminal tumor. However, careful patient selection is critical because life-threatening complications can occur. It can be used in a multimodality approach to complement other therapeutic techniques such as radiotherapy, brachytherapy, and Nd:YAG laser therapy. Future areas of investigation should focus on the need to develop new photosensitizers to improve tissue selectivity and to reduce skin photosensitivity.