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* From the New York University School of Medicine, North Shore University Hospital, Manhasset, NY.
Correspondence to: David Ost, MD, FCCP, New York University School of Medicine, North Shore University Hospital, 300 Community Dr, Manhasset, NY 11030; e-mail: dost{at}nshs.edu
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Abstract |
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 TOP Abstract IntroductionCasesDiscussionSummaryReferences |
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Key Words: bronchoscopy • endobronchial disease • laser therapy • lung cancer • photodynamic therapy • respiratory failure
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Introduction |
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Three patients with endobronchial tumors of the mainstem bronchi developed respiratory failure requiring mechanical ventilation. All three underwent treatment with PDT. A hematoporphyrin derivative (Photofrin; Sanofi-Synthelabo; New York, NY) was used as the photosensitizing agent in all patients. This was infused once, only prior to the initial PDT treatment, at a dose of 2 mg/kg. After 48 to 72 h, a cylindrical light diffusing fiber (Laserscope; Holden, MA) was used to deliver 300 J/cm at a power output of 400 mW/cm to the tumor. The length of the fiber chosen was based on knowledge of normal bronchial anatomy and an estimate of the length of tumor involvement. Each patient received two subsequent PDT treatments at 48-h intervals. All three PDT treatments were completed within 1 week of the hematoporphyrin infusion. Prior to each PDT treatment, bronchoscopic toilet and debridement was performed. Subsequent bronchoscopic toilet and debridement was done on a case-by-case basis. All three patients had a minimum of four bronchoscopies: the original bronchoscopy to evaluate the airway plus the three PDT treatments.
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Cases |
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Patient 3
The third patient was a 65-year-old woman with small cell lung
cancer. The patient was intubated for respiratory distress. The patient
had a 90% occlusion of the left mainstem bronchus secondary to
extrinsic compression, and a 99% obstruction of the right bronchus
intermedius due to an endobronchial lesion. The left mainstem bronchus
was successfully opened with an expandable metal stent (Ultraflex;
Boston Scientific Microvasive) with a residual narrowing of 10%.
Despite this, the patient continued to require mechanical ventilation.
PDT treatments were applied to the right bronchus intermedius lesion,
along with debridement and bronchoscopic toilet. Debridement was
successful to the level of the right lower lobe bronchus, but
additional tumor remained with a 100% endobronchial obstruction in the
distal airways. This required a total of five bronchoscopies. The
extent of this additional tumor had not been fully appreciated on the
preoperative CT scan due to the surrounding atelectasis. Multiple
attempts at weaning were unsuccessful. Mechanical ventilation was then
withdrawn, and the patient died.
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Discussion |
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PDT involves the administration of a photosensitizing agent that is preferentially retained in tumor cells, followed by local activation of the agent by light of a specific wavelength.1 2 PDT has been used for almost 2 decades to treat cancers within the tracheobronchial tree. PDT has been used in the treatment of both large endobronchial tumors and carcinoma in situ.3 4 5 PDT is effective for both primary lung cancer and metastatic tumors to the lung. PDT has been successful in the treatment of centrally located early stage lung cancer.6 7 PDT has also shown success in partially obstructive lung cancer and has recently received approval by the US Food and Drug Administration for this indication.1
Hematoporphyrin derivative is selectively retained in tumors as compared with normal tissue. The mechanisms involved in the preferential distribution of sensitizers in tumors are not fully understood but may be associated with a decreased pH or elevated low-density protein receptors.1 8 PDT leads to necrosis of the normal soft tissue of the tracheobronchial tree, but there is complete healing, with less risk of perforation (due to collagen preservation), and no effect on cartilage.2 PDT depends on the light energy delivered for effective drug activation. This dosimetry is based on the power output and the time of delivery. The effectiveness of PDT is dependent on the depth of mucosa that the light can penetrate. Light at a wavelength of 630 nm penetrates mucosa to a depth of approximately 5 mm. This has both advantages and disadvantages. The advantage is that drug activation is localized to the 5-mm depth of light penetration, sparing the deeper surrounding tissue. The disadvantage is that larger tumors will require two or three light treatments as well as debridement of necrotic tissue.
This fluence of light has been chosen to allow adequate depth without initiating photobleaching of the photosensitizer. Photobleaching is when there is a reduction of photosensitizer levels due to illumination of the tissue thus decreasing the efficacy of PDT. This occurs when the fluence rates are high. Fluence rates that are too low would prevent adequate tissue penetration of the light energy.1
The light is emitted laterally from the cylindrical fiber, not directly forward. Thus, the fiber needs to pass alongside or into the lesion for best results. If the lesion totally obstructs the airway, a different type of lens must be used to project the light directly forward. This may result in poor dosimetry and an increased rate of treatment failures.9 The other major disadvantages of PDT are photosensitivity and high cost. Photosensitivity only lasts 4 weeks and is prevented by having the patient avoid sunlight. Closing blinds and wearing protective clothing easily accomplishes this. The cost of one dose of the hematoporphyrin derivative (Photofrin; Sanofi-Synthelabo) is approximately $5,000.
The preoperative assessment of the tumor is essential. In our third patient, the CT scan detected the proximal tumor margin but did not accurately assess the distal margin of the tumor and underestimated the amount of parenchymal tumor involvement. The difficulty with accurate preoperative assessment is demonstrated by this case. The ideal patient would have a short, central, endobronchial lesion that is not completely occlusive. This would allow passage of the light fiber alongside the lesion. Patients with a large amount of postobstructive atelectasis with viable and reexpandable lung distal to the lesion will benefit from PDT, as opposed to those without viable lung distal to the obstruction. Unfortunately, CT scan, sonography, and MRI cannot always differentiate atelectatic but viable lung due to endobronchial obstruction from lung with tumor involvement and endobronchial obstruction. All of these factors should be considered prior to undertaking PDT in the patient receiving mechanical ventilation.
What will be the role of PDT, and where does it fit in with respect to other therapeutic modalities for endobronchial disease? Currently available options include stents, Nd-YAG laser, cryotherapy, RT, and brachytherapy.
Expandable metal stents have been shown to facilitate weaning from mechanical ventilation.10 Indications for airway stents include malignant tracheobronchial obstruction with extrinsic compression of the large airways, tracheal stenosis, or bronchial stenosis.11 Expandable metal stents are not indicated for endobronchial malignant lesions. PDT is effective for endobronchial lesions. Stents may be complimentary to PDT in such cases after PDT reopens the airway.
The Nd-YAG laser has been used to treat malignant endobronchial obstructions.12 13 Moghissi et al14 concluded that endoscopic PDT in patients with lung cancer and major airway obstruction is more effective than Nd-YAG laser treatment with respect to percent of luminal patency and pulmonary functions at 1 month. The Nd-YAG laser has some disadvantages compared to PDT. The Nd-YAG laser has a risk of causing endobronchial ignition. There is also the risk of the endotracheal tube or the laser fiber catching fire. This risk is increased in patients requiring an fraction of inspired oxygen (FIO2) > 40%.15 16 Perforation of a major vessel is always a concern. This is more likely when the anatomy is distorted as can occur due to a tumor. Nd-YAG laser is relatively contraindicated in those patients in whom the bronchial lumen cannot be adequately visualized due to tumor.17 18 19 In contrast, PDT does not have any limits on the FIO2 content and can be used safely in patients receiving mechanical ventilation with a high FIO2 requirement. The inability to visualize the bronchial lumen is not a contraindication for PDT because it is only necessary to be able to pass the fiber alongside the lesion. This allows treatment of some lesions that may have more risk with the Nd-YAG laser. Our patients underwent PDT because the bronchial lumens could not adequately be visualized.
The advantage of Nd-YAG is speed. PDT typically takes two to three sessions, whereas the Nd-YAG has an immediate effect. PDT also results in significant mucus plugging after the PDT is completed, secondary to tumor necrosis. Since this usually occurs after bronchoscopy is completed, PDT frequently results in atelectasis. This is usually well tolerated in those patients who already have significant atelectasis secondary to endobronchial obstruction, since there is little gas exchange in the areas distal to the obstruction prior to PDT. Mucus plugging in these cases is readily treatable using therapeutic bronchoscopy. This mucus plugging becomes a problem when dealing with tracheal lesions, however. For this reason, the ND-YAG is probably superior for large endotracheal lesions.
Cryotherapy has been used for the treatment of tracheobronchial obstruction. Originally, it required rigid bronchoscopy to allow passage of the probe. Recently, development of a new flexible cryoprobe has permitted cryotherapy to be performed via the flexible fiberoptic bronchoscope. The risks of cryotherapy include excessively rapid thawing, premature detachment of the probe that may result in bleeding or tissue fracture, and damage to normal tissue by inappropriate placement of the cryoprobe.20 The major disadvantage of cryotherapy vs PDT is the time required for a response in the tumor size. In a study by Mathur et al,21 18 of 20 patients had all visible endobronchial tumor cleared by cryotherapy. In a study by Marasso et al,22 there was a mean improvement of 22% 2 weeks after a single cryotherapy treatment and only an additional 20% improvement 4 weeks after a second treatment. Cryotherapy requires 2 to 4 weeks to be maximally effective. The main drawback of cryotherapy in the patient receiving mechanical ventilation is the amount of time required for a clinically significant response. This amount of time is longer than PDT and much longer than Nd-YAG laser.
RT is another alternative for locally advanced lung cancer. External beam RT is the most frequently used radiation technique for lung cancer.23 High-dose external beam RT requires many weeks of daily treatment. Side effects include damage to surrounding organs, which can lead to significant morbidity from esophagitis and pneumonitis.24 PDT has a distinct advantage over external beam RT in the setting of mechanical ventilation because PDT is quicker. Decreased time away from the ICU also decreases the risk and difficulty associated with transport of these critically ill patients. Radiation can be used after PDT after successful reopening of the airway and does not seem to adversely interact with PDT. Also, in a study by Lam et al,25 PDT combined with RT resulted in complete airway opening in 70% of patients vs 10% in the RT alone group. Thus, radiation may play an important role in the multimodality approach to endobronchial disease.
Brachytherapy is another modality to treat locally invasive tumors in the airways. Brachytherapy involves the placement of radioactive sources into the desired target. The goal is to safely deliver high radiation doses to tumors with relative sparing of the surrounding tissues. Originally, brachytherapy for endobronchial tumors involved low-dose-rate treatment. This was a lengthy procedure, and there was a risk to personnel of radiation exposure. Recently, there has been a resurgence in brachytherapy for endobronchial disease. In the early 1990s, Speiser and Spratling26 showed that high-dose-rate remote afterloading brachytherapy had similar success for treatment of endoluminal disease as lower dose rates. The time required for this procedure is markedly lower and also reduces the risk to personnel. In the study be Collins et al24 of 406 patients, only 83 patients had a repeat bronchoscopy. Of these patients, complete tumor resolution occurred in 65% at the 3-month point. The risks of brachytherapy are made evident by this study, in which 38 of the 83 patients (46%) developed varying degrees of radiation reaction ranging from bronchitis to fibrosis, and 32 of the 406 patients (8%) had fatal hemoptysis.27 For the intubated patient with large obstructing lesions, brachytherapy appears to be a less feasible option than PDT. Besides the above-stated risk of fatal hemoptysis, there are technical problems. With high-dose-rate remote afterloading, the patient would have to be isolated for the duration of the treatment for a minimum of 10 to 15 min. In these critically ill patients, the isolation time and high risk of fatal hemoptysis make brachytherapy a less favorable option than PDT.
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Summary |
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TOPAbstractIntroductionCasesDiscussionSummaryReferences |
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Footnotes |
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Received for publication January 26, 1999. Accepted for publication April 18, 2000.
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References |
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This article has been cited by other articles:
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  M. M. Wahidi and A. Ernst Role of the Interventional Pulmonologist in the Intensive Care Unit J Intensive Care Med, May 1, 2005; 20(3): 141 - 146. [Abstract] [PDF]
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 A. Ernst, D. Feller-Kopman, H. D. Becker, and A. C. Mehta Central Airway Obstruction Am. J. Respir. Crit. Care Med., June 15, 2004; 169(12): 1278 - 1297. [Abstract] [Full Text] [PDF]
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 D. G. Pfister, D. H. Johnson, C. G. Azzoli, W. Sause, T. J. Smith, S. Baker Jr, J. Olak, D. Stover, J. R. Strawn, A. T. Turrisi, et al. American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: Update 2003 J. Clin. Oncol., January 15, 2004; 22(2): 330 - 353. [Full Text] [PDF]
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