Lung cancer is the now the leading cause of cancer death in both men and women in the United States and is the most common cancer in the Western world. Although surgery remains the treatment of choice, the majority of patients will be unresectable. For patients with tracheobronchial involvement, the aim of endoscopic interventions is to restore airway patency in a palliative fashion. Tracheobronchial interventions have included the neodymium yttrium aluminum garnet (ND-YAG) laser, cryotherapy, radiofrequency ablation, electrocautery and brachytherapy. Of these, the Nd-YAG laser has been widely employed and its usefulness has been widely accepted. The development of photodynamic therapy (PDT) with its selective targeting of tumor tissue for use with carcinoma in situ (CIS) has encouraged the study of its application to more advanced endobronchial tumors. PDT has been studied by a number of investigators in patients with both early stage primary lung cancer and in those with advanced disease with endobronchial obstruction. 1–5 These studies have demonstrated excellent safety and efficacy for both early stage disease and for patients with advanced disease. In the majority of the cases with advanced disease, PDT has been performed under general anesthesia with a rigid bronchoscope. 1,2 As this has not been formally assessed, the aim of this study was to evaluate the safety and efficacy of PDT performed exclusively with the flexible bronchoscope for patients with advanced and early stage, unresectable lung tumors, both primary and metastatic.
During a period of 19 months, 37 consecutive patients with advanced and inoperable endobronchial tumors were treated with PDT. Data was collected prospectively for all patients including clinical demographics, tumor type, tumor location, and indication for treatment (Table 1). All cases had a tissue diagnosis and had previously been rejected for surgical resection. All patients had a full history and physical examination, focusing on the recording of symptoms of airway obstruction, cough, dyspnea and hemoptysis. Routine laboratories, radiography, and CT results were recorded. The primary indication for PDT was recorded for all patients. Bronchoscopic assessment was carried out in all cases prior to PDT to assess location and degree of stenosis, and extent of disease. The percentage of airway stenosis was assessed using the flexible bronchoscope. Only patients with endobronchial obstruction were eligible for PDT (as compared with extrinsic compression or submucosal spread). Patients with significant concurrent extrinsic compression were eligible for airway stenting at the discretion of the attending physician.
Informed consent was obtained from all patients prior to PDT. Treatment used intravenous infusion of 2 mg/kg of porfimer sodium (Photofrin®, Sanofi Pharmaceuticals) as the photosensitizing agent. After an interval of 48–72 hours after injection flexible bronchoscopy was performed in a standard fashion, using the transnasal or transoral approach. Topical anesthesia was accomplished with lidocaine solution and all patients received conscious sedation using midazolam, fentanyl or meperidine. A KTP 532 pump laser (Laserscope Inc.,San Jose, CA) with dye module was used as the laser system. Bronchoscopic illumination of the tumor was carried out with a cylindrical diffusing fiberoptic cable (Optiguide®, QLT Phototherapeutics Inc. Seattle, WA) passed through the instrument port of the bronchoscope. Red light at a wavelength of 630 nm with a power of 400 mW/cm was delivered for 500–750 seconds for a total energy delivery of 200–300 J/cm for each section treated. Total application times per patient ranged from 500 to 2,000 seconds (8–32 minutes). Immediately after illumination any necrotic debris was removed. Prophylactic antibiotics were given at the discretion of the attending physician beginning after the first laser illumination and were continued until the final pulmonary hygiene bronchoscopy. No standard antibiotic regimen was used. Antibiotics used included trovofloxacin, amoxicillin-clavulinate, and cefuroxime-axetil. Follow-up flexible bronchoscopy was done at 48 hours after the initial illumination to remove additional debris and to assess airway patency. Debris was removed with the help of forceps, brushes and the use of suction. A second laser illumination was undertaken at this time based on the degree of residual tumor in the airway. Subsequent pulmonary hygiene bronchoscopy was then repeated in another 48 hours if additional laser illumination had been given. A third and final laser illumination was given in some cases if residual tumor was seen. Pulmonary hygiene bronchoscopy was repeated at 48 hours after each laser illumination and as needed thereafter. All patients were eligible for subsequent treatment with chemotherapy and/or radiation therapy.
The primary outcome measures were airway stenosis and complication rates. Airway stenosis at the end of treatment was assessed by flexible bronchoscopy. Complete response was defined as absence of visible tumor within the airway combined with negative biopsy. Partial response was macroscopic absence with a positive biopsy or less than a 50% residual stenosis. No response was defined as greater than 50% stenosis at the end of treatment. No rigid bronchoscopy and no general anesthesia were used. Follow-up bronchoscopy was performed only if symptoms or signs or airway obstruction recurred. All complications, including bleeding, pneumonia, atelectasis, and respiratory distress were recorded. Intraoperative complications were recorded, as were all events within the first week of treatment. Complications within this time period, such as pneumonia or atelectasis, were considered related to the procedure.
37 patients underwent PDT, including 24 males and 13 females for a total of 65 applications. The demographics and details of the individual patients are shown in Table 1. Indications included early stage non-small cell cancer in three, advanced lung cancer with airway obstruction in 27, and metastatic non-pulmonary cancer with airway involvement in seven patients. The average light energy applied was 268 J/cm (range 200–300 J/cm).
PDT resulted in a complete or partial response in 33 of the 37 patients. Of the three patients who were treatment failures, two (cases 16, 28) demonstrated extensive tumor distal to the obstruction and one (case 19) failed to respond rapidly and subsequent to starting PDT was found to have brain metastases. A fourth patient (case 21) had a very unusual primary glomus tumor of the trachea. The patient had failed previous rigid bronchoscopy with Nd-YAG laser at an outside institution and was referred for PDT. The PDT was tolerated without difficulty but had minimal effect on the tumor. The patient was subsequently successfully treated with cryotherapy.
No treatment related mortality was noted. Intraoperative and postoperative complications included atelectasis in four, fever in five patients, and one episode of respiratory failure requiring intubation 24 hours after the procedure secondary to airway compromise of the trachea. One patient developed pneumonia within one week of PDT. No patients experienced significant bleeding and there were no significant skin photosensitivity reactions. After completion of treatment, all patients with either a complete or partial response demonstrated a subjective decrease in dyspnea. All patients tolerated the flexible bronchoscopies well and in no case had the procedure been converted to accommodate rigid bronchoscopy or anesthesia.
PDT was developed first as a treatment of CIS and early stage lung cancer. There has been much less evaluation of PDT as a treatment of patients with advanced lung cancer with endobronchial obstruction. Since there is currently no method in wide clinical use for early detection or cancer localization, this population represents a far larger group of patients than the CIS group. The standard of therapy for advanced endobronchial disease currently is Nd-YAG laser resection. Other alternatives include radiation therapy, brachytherapy, cryotherapy, and electrocautery.
Most of the data with PDT are derived from case series. Reports on the efficacy of PDT in this arena are therefore difficult to compare with results with other modalities. In a large prospective series by Moghissi et al of 100 patients with endobronchial obstruction from advanced inoperable stage IIIA-IV bronchogenic cancer, PDT resulted in significant improvement in terms of endobronchial obstruction, pulmonary function testing, and palliation of symptoms. 1 Mean percentage of endoluminal obstruction fell from 85.8% to 17.5% with an improvement in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) of 430 mL and 280 mL respectively. All patients in this study had PDT performed with the rigid bronchoscope. In another series by McCaughan in patients with advanced primary lung cancer, the mean endobronchial obstruction fell from 84% prior to PDT to 18% four weeks later. 6 Thus, there is evidence that PDT can perform well for palliation of advanced endobronchial obstruction and that compared with previous studies, our results with the flexible bronchoscope are comparable to the good results obtained previously with the rigid bronchoscope.
Advantages of PDT over other tumor destructive techniques include the technical ease of the procedure, greater margin for error, especially in smaller bronchi, less risk of bronchial perforation, decreased risk of intraoperative hemorrhage, and perhaps longer duration of response. 2,6 It may be that this longer duration of response is secondary to destruction of invisible submucosal tumor that is missed with the Nd-YAG laser. The side effect profile is at least as good as Nd-YAG in terms of immediate intraoperative risk. In our case series the incidence of skin photosensitivity, essentially the only additional risk associated with PDT, was small and was lower than in previous series. 1,2,6 This is probably due to meticulous pre-bronchoscopy patient education. All patients receive written and verbal instructions before ever having the Photofrin infusion. They have repeated educational sessions with every bronchoscopy, with instructions being given to family as well as patients. With these added steps, the incidence and severity of skin photosensitivity is minimal.
PDT does have important limitations in terms of treatment of advanced endobronchial disease. Among these limitations are high cost, the need for repeat pulmonary toilet bronchoscopies, and photosensitivity of the skin.
In summary, this case series confirms the findings of previous investigators regarding the efficacy of PDT for patients with endobronchial obstruction from advanced tumors. It also confirms the previously observed excellent safety profile of PDT. Finally, it adds to the experience with PDT for advanced disease by demonstrating that PDT can be performed with the flexible bronchoscope alone without resorting to rigid bronchoscopy or general anesthesia to achieve these excellent results. This has important implications if PDT is to be used widely, since most pulmonologists in the United States do not perform rigid bronchoscopy. It also allows PDT to be performed in a less costly fashion, outside of the operating room with only conscious sedation.
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