Ann Thorac Surg 2003;76:370-375
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Photodynamic therapy for endobronchial metastases from nonbronchogenic primaries
Virginia R. Litle, MDa,
Neil A. Christie, MDa,
Hiran C. Fernando, MDa,
Percival O. Buenaventura, MDa,
Peter F. Ferson, MDa,
James D. Luketich, MDa*
a Division of Thoracic and Foregut Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
Accepted for publication February 13, 2003.
* Address reprint requests to Dr Luketich, Division of Thoracic and Foregut Surgery, University of Pittsburgh Medical Center, C-800 PUH, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
e-mail: luketichjd{at}msx.upmc.edu
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Abstract
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BACKGROUND: Endobronchial metastases (EBM) occur in 2% of nonbronchogenic malignancies and frequently present with hemoptysis or dyspnea. This report summarizes our recent experience with photodynamic therapy (PDT) for EBM.
METHODS: All patients who have undergone PDT for the treatment of symptomatic EBM from nonbronchogenic primaries were identified in the Division of Thoracic Surgery database to determine number of treatments, frequency of symptom relief, and patient survival.
RESULTS: Endobronchial PDT was administered to 27 patients from April 1997 through December 2000. The predominant primary tumor was renal cell (44%). Endobronchial metastases presented metachronously in 74% of patients. Patients underwent a median of two PDT treatments. Local anesthesia with sedation was used in 76% of treatments. Four patients (15%) developed immediate postoperative respiratory distress. Follow-up bronchoscopy 24 to 48 hours after initial treatment demonstrated tumor necrosis in all cases. Acute relief of hemoptysis and dyspnea was achieved in 85% of patients. Seven patients died within 6 weeks of treatment. Median survival time after PDT was 4 months (range 0.2 to 30 months).
CONCLUSIONS: Patients with EBM treated with PDT had a median survival of 4 months and patients with limited metastatic disease survived up to 30 months. Photodynamic therapy was effective in palliating hemoptysis or dyspnea from EBM with an acceptable morbidity, although the 30-day mortality was 22%.
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Introduction
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Endobronchial metastases (EBM) represent 2% of disseminated nonbronchogenic solid tumors in autopsy series [1]. Breast, colorectal, and renal cell carcinomas comprise the most frequent primary sites responsible for these uncommon metastases [2]. Patients most often present with hemoptysis, but stridor, dyspnea, or pneumonia secondary to obstruction also may occur. Overall survival averages 1 to 2 years after diagnosis of the EBM, although recent reports have been published describing individual cases of 3- to 5-year survival after treatment of EBM with external beam radiation or bronchoscopic extraction [3, 4].
Treatment options include endobronchial approaches with airway stents, rigid bronchoscopic extraction, thermal laser ablation, brachytherapy, and photodynamic therapy (PDT) or nonoperative therapy with external beam radiation and chemotherapy. Laser treatment with the thermal neodymium:yttrium-aluminum-garnet (Nd:YAG) laser or with the nonthermal laser of PDT can be used in combination with other endobronchial methods. After coring out an endobronchial tumor with the rigid bronchoscope, hemostasis can be achieved with the laser. In addition, patency of an endobronchial lumen can be optimized with stent placement after laser treatment of an obstruction. Brachytherapy relieves endobronchial disease but requires weekly bronchoscopies over 3 to 5 weeks [5, 6]. Of the laser treatments the Nd:YAG laser effectively vaporizes the endobronchial tumor; however, the procedure is potentially complicated by pulmonary hemorrhage [7], fire, and smoke plume, which can obscure accurate identification of the true bronchial wall.
Photodynamic therapy, a two-stage process requiring administration of both drug and light, relieves bleeding and obstruction secondary to endobronchial malignancies [4, 7–9], and in nonrandomized studies PDT is more effective than Nd:YAG laser at preventing bronchial reobstruction [7]. We have used PDT for symptomatic endobronchial metastatic tumors for 4 years and in this report we summarize our experience with EBM in 27 patients with 10 different primary tumor sites.
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Patients and methods
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The Division of Thoracic and Foregut Surgery, University of Pittsburgh Medical Center began treating patients with EBM from nonbronchogenic primary tumors with PDT in 1997. All such patients treated through December 2000 were identified in the Thoracic Division database, and the period of review extended through November 2002. Endobronchial metastases were defined as any nonpulmonary metastases involving the central airways. Patient histories, presenting symptoms, radiographs, and operative reports were reviewed from medical records after obtaining Institutional Review Board approval for the review (Institutional Review Board date of approval August 8, 2001). Patients complaining of hemoptysis or shortness of breath or who had suspicious endobronchial lesions on radiographs underwent bronchoscopy for potential intervention. Patients with massive hemoptysis, defined as more than 600 mL in 24 hours or bleeding requiring urgent intubation, were not included in this review, as they were generally treated with urgent rigid bronchoscopy and bronchial artery embolization. Bleeding or obstructive endobronchial lesions with potentially patent distal airways were indications for PDT.
Patients received an intravenous injection of the photosensitizing agent porfimer sodium (Photofrin; 1.5 to 2.0 mg/kg) (Sanofi Winthrop, New York, NY) 24 to 48 hours before PDT. A cylindrical diffuser fiber (1.0 or 2.5 cm) (Laserscope, San Jose, CA) was used to treat tumors with a 630-nm (nm) wavelength (red) light, which was delivered by flexible bronchoscopy. The fiber was either placed alongside or impaled into the tumor. A range of 200 to 400 J/cm was administered. A "clean-up" flexible bronchoscopy was performed on postoperative day one or two. Patients were advised to avoid sunlight for 4 to 6 weeks after administration of Photofrin. Relief of symptoms, complications, and survival outcome was determined from chart review and phone calls to patients and referring physicians.
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Results
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From April 1997 through December 2000, 27 patients (17 men and 10 women) underwent treatment with PDT for EBM. The median age at time of initial PDT was 61 years (range 29 to 80 years). The most frequent chief complaint was hemoptysis in 19 patients (70%), but 5 patients (19%) presented with dyspnea, 2 (7%) with cough, and 1 (4%) with pneumonia. The EBM was diagnosed synchronously in 19% of patients and metachronously (more than 12 months after treatment of primary tumor) in 74%. The median interval between primary treatment and EBM diagnosis was 48 months (range 0 to 204 months) and was longest (median 72 months) for the subset of patients with renal cell carcinoma (Table 1).
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Table 1. Time Interval Between Primary Tumor Treatment and Initial Photodynamic Therapy (PDT) for Endobronchial Metastasis and Follow-Up Time After PDT
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An endobronchial abnormality was suggested on plain chest radiographs in 4 (15%) patients and on chest computed tomography (CT) scans in 10% of patients (Fig 1).
Mediastinal lymphadenopathy was present on CT in 58%. Of the 26 patients who had preoperative radiographs, normal chest radiographs and chest CT scans were obtained in 35% and 32% of patients before PDT (Table 2).
Nineteen patients had metastatic disease at other sites, and 74% of these patients had radiographic or known pulmonary parenchymal metastases. The 8 patients without distant metastases had multiple or mainstem EBM not amenable to surgical resection. Other sites of extrabronchial metastases included 3 patients with brain lesions (renal cell, breast, and laryngeal carcinoma) and 2 with bone involvement (renal cell and esophageal squamous cell carcinoma).
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Fig 1. Preoperative (A) plain chest radiograph and (B) chest computed tomography scan of an ovarian endobronchial metastasis (arrow) in the right mainstem bronchus treated subsequently with photodynamic therapy.
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Table 2. Chest Roentgenogram and Chest Computed Tomography Scan Findings for Patients With Endobronchial Metastases
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Sixty-nine (76%) of 90 total PDT treatments in our series of 27 patients were performed with local anesthetic and intravenous sedation. Indications for general anesthesia included concomitant video-assisted thoracoscopic surgery or patient preference. Four patients had concurrent PDT and Nd:YAG thermal ablation, and 1 patient had an endobronchial stent placed after the PDT. Table 3
summarizes the distribution of EBM tracheobronchial sites and the presenting signs or symptoms. One patient with lobar endobronchial disease presented with an obstructive pneumonia; however, the remaining 10 patients with lobar or segmental disease complained of hemoptysis.
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Table 3. Number of Patients Presenting With Hemoptysis or Obstructive Symptoms and Distribution of Predominant Endobronchial Metastasis Sites
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Postoperative respiratory distress developed in 4 patients, resulting in urgent bronchoscopy for mucus plugging in 2 patients, endotracheal intubation on post-PDT day one in 1 patient, and an inability to extubate postoperatively in another. One of these 4 patients recovered after therapeutic bronchoscopy but died of respiratory failure at home 6 weeks later. The 30-day perioperative mortality was 22% (6/27), and 83% (5/6) of the deaths were secondary to respiratory failure (Table 4):
2 patients died at home, 2 patients died after withdrawal of ventilatory support by family, and additional details of deaths were unknown for 2 remaining patients. All 6 patients had extensive pulmonary metastases, mediastinal lymphadenopathy, or multiple EBM.
Tumor necrosis was demonstrated in all patients at follow-up bronchoscopy, although the only case of melanoma EBM showed minimal response to PDT. The result of PDT on a breast EBM in the bronchus intermedius is depicted in Figure 2.
Acute (within 30 days) relief of hemoptysis or airway obstruction was achieved in 85% (23/27) of patients. No cases of photosensitivity were documented.
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Fig 2. Breast endobronchial metastasis in the bronchus intermedius (A) before photodynamic therapy (PDT) and (B) after debridement of necrosis the first day after PDT.
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Patients underwent a median of two PDT treatments (range 1 to 10). One PDT treatment was defined as a single visit to the operating room for light therapy. Six patients had more than one Photofrin injection at 1.5- to 16-month intervals. Indications for initial and repeat PDT sessions are summarized in Table 5. Five patients underwent repeat PDT for recurrent hemoptysis, whereas 1 patient had persistent airway obstruction. One patient with metastatic breast cancer underwent PDT six times in a 1-year period with good palliation of hemoptysis and obstruction without treatment-related morbidity. She subsequently died of brain metastases. One patient with metastatic sarcoma and a history of hemoptysis was alive at 23 months follow-up.
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Table 5. Indications for Initial and Subsequent Photodynamic Therapy in 6 Patients With Various Endobronchial Metastases Who Underwent Multiple Photofrin Injections
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Twenty-four (88%) patients were known to have died at time of follow-up. Median survival time was 4 months (range 0.2 to 30 months) from time of first PDT treatment. Causes of death were known for 13 patients and included respiratory failure secondary to extensive pulmonary metastases (9 patients), massive hemoptysis (1), advanced esophageal carcinoma (1), and brain metastases (1). One patient who lived 30 months after PDT had metastatic colon cancer and eventually died of malignant biliary obstruction. Fifteen patients who underwent only one PDT treatment survived longer than 30 days. The median survival time for such patients was 3.5 months, and the overall survival curve is depicted in Figure 3.
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Fig 3. The probability of overall survival after one photodynamic therapy treatment for endobronchial metastases of nonbronchogenic origin, as calculated by the Kaplan–Meier method for 15 patients surviving longer than 30 days.
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Comment
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Photodynamic therapy has been used to treat multiple tumor sites. It effectively ablates tumor cells by several mechanisms. After intravenous injection of Photofrin, the photosensitizer enters tumor cells and vascular endothelium by selective endocytosis. Tumor neovascularity with increased permeability, poor lymphatic drainage, and acidic pH results in increased binding of the porphyrin in malignant cells. When the tumor is exposed to light at 630 nm, the reaction produces singlet oxygen and free radicals, which results in cell membrane damage, tumor vessel thrombosis, and cell death.
Photodynamic therapy has been used to treat primary tumors and palliate metastases. Our goals were to determine the characteristics of patients presenting with symptomatic EBM, the efficacy of PDT for palliation of symptoms, and the survival outcome of our cohort. Eighty-one percent of the patients in our group were symptomatic on presentation, primarily with hemoptysis but also with dyspnea, cough, or pneumonia. In other series 22% to 52% of patients were asymptomatic on presentation but had evidence of EBM or lobar collapse on chest roentgenograms [10, 11]. In our series as many as 35% of patients had no evidence of active disease on chest radiographs; thus, any unexplained dyspnea or mild hemoptysis warrants bronchoscopic evaluation, in particular in patients with a history of malignancy.
As in other studies we found a predominance of renal cell EBM. Although many women with metastatic breast cancer are treated at our institution, interestingly we treated only one case (4%) of symptomatic breast EBM with PDT. Thus the incidence of EBM in our referral pattern was much lower than that reported in the literature [2].
The morbidity of PDT for EBM in our series was hypoxemia with 15% of our patients requiring intubation or bronchoscopy within 24 hours after PDT, and 7 patients dying primarily of respiratory failure within 6 weeks. The incidence of respiratory failure after PDT or Nd:YAG for endobronchial primary and metastatic tumors in other large series occurred in 5% to 6% of cases [4]. The initial respiratory failure appears to be related to a swelling of the endobronchial lesion as a result of PDT-induced damage. Routine follow-up bronchoscopy with debridement of necrotic tumor minimizes airway obstruction. In our early experience with PDT for near-obstructing airway lesions, this response was observed to be dramatic with total endobronchial or tracheal obstruction. Most patients with tracheal tumors or near-obstructing main bronchus tumors are now approached with initial rigid bronchoscopy and core-out to avoid this acute airway compromise. Patients with extensive mediastinal lymphadenopathy or pulmonary metastases are at higher risk for postprocedural respiratory failure.
Using an aggressive patient and family education approach with all our PDT patients, we have minimized the complications of increased skin photosensitivity associated with Photofrin, although the overall incidence of this complication has decreased when compared with earlier reports of PDT for malignancies [12, 13].
Airway PDT is effective at palliating respiratory symptoms. Six patients in our cohort required repeat PDT for recurrent hemoptysis or persistent airway obstruction. Hemoptysis was the most common initial indication for PDT, and although this symptom was palliated in most patients, 28% subsequently required repeat PDT for recurrent symptoms.
The presence of EBM typically suggests widespread disseminated disease. Nineteen patients (70%) in our series had known extrabronchial metastatic sites and 88% of all the patients died within the follow-up period. Several investigations have suggested a better outcome with a longer disease-free interval before diagnosis of metastases [3, 14]; however, in our series the median interval from primary to EBM diagnosis for the patients alive at follow-up was actually shorter than the median interval for the subset of patients who died (3 vs 4 years).
Once EBM is diagnosed in a patient, survival is generally limited; however, 1 patient in our series lived 30 months after PDT for metastatic colon cancer. Fifty percent of the 10 patients in our series who lived longer than 3 months had metastatic renal cell cancer. We cannot conclude from our series that PDT will cure cancer in patients with EBM; however, in select patients with a single site of metastasis or with indolent metastatic disease, PDT may provide long-term survival.
Other treatments for EBM have included surgical resection [2, 15], bronchoscopic extraction [3], airway stents [16, 17], external beam radiation therapy [2, 10, 14, 18], brachytherapy [3, 14, 18, 19], thermal laser ablation, and chemotherapy [10]. Long-term survival rates of 30% after lobectomy or pneumonectomy for selected patients with EBM have been reported [15, 20]. One study does describe a patient with metastatic renal cancer living 5.5 years with repeated bronchoscopic extractions of an upper lobe bronchial metastasis [3].
Patients who probably would not benefit from PDT for palliation of EBM include those with poor performance status who may not tolerate repeat bronchoscopy for debridement after PDT, and patients who do not want their quality of life hindered by increased skin photosensitivity. Photodynamic therapy is good for controlling hemoptysis and is a good option for palliation among patients with limited life expectancy. The only endobronchial tumor, which had minimal response to PDT, was melanoma. No conclusion may be made from this single observation, although 5-year survival after pulmonary metastasectomy for melanoma is known to be poor, at less than 10% [20].
Photodynamic therapy is an additional modality for palliation of EBM. Because many patients with advanced endobronchial cancers die of bleeding complications or sepsis from bronchial obstruction, PDT represents a good palliative option. Several advantages of this therapeutic option, when compared with other approaches, include relative simplicity of treatment, use of conscious sedation, limited treatment time, and minimal associated pain. Disadvantages of this treatment include prolonged skin photosensitivity, expensive equipment, and the high cost of the photosensitizing agent. We conclude that PDT is effective at palliating patients with symptomatic EBM disease, although the cost-effectiveness as compared with other treatment modalities needs to be determined.
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Acknowledgments
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Financial support for the project was provided by Axcan Scandipharm, Inc (grant No. 5701576).
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Abstract
Introduction
