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The Pulmonologist’s Diagnostic and Therapeutic Interventions in Lung Cancer
T h e P u l m o n o l o g i s t ’s Diagnostic and Therapeutic Interventions in Lung Cancer Jonathan Puchalski, MD, MEda,*, David Feller-Kopman, MDb KEYWORDS Bronchoscopy Endobronchial ultrasound Electromagnetic navigation Airway stents
DIAGNOSTIC BRONCHOSCOPY Early Detection of Endobronchial Lung Cancer Lung cancer is the leading cause of cancer death worldwide and accounted for approximately 157,300 deaths in the United States in 2010.1 Although the potential benefits of lung cancer screening are eagerly anticipated,2 unfortunately lung cancer is often detected in an advanced stage either incidentally or in patients with symptoms of late disease.
Lung cancer that is limited to the mucosa in the central airways is usually not detected with available imaging techniques. Imaging modalities such as autofluorescence, narrow band imaging, optical coherence tomography, confocal endomicroscopy, high magnification bronchoscopy, and multimodality fluorescein imaging are being investigated for the detection of early-stage lung cancer or carcinoma in situ.3,4 Although many of these modalities have been found to have significantly higher sensitivity than white-light bronchoscopy for detecting high-grade dysplasia and carcinoma in situ, the primary limitation remains the poor specificity.5 Miniaturized radial EBUS probes fitted with a catheter that carries a water-inflatable balloon at its tip (different from the peripheral and convex EBUS probes described later) improve bronchial wall contact to allow detailed images of the bronchial wall structure. EBUS images correlate extremely well with histologic specimens and are better than CT scans for determining airway invasion versus compression.6 However, no gold standard currently exists for the bronchoscopic diagnosis of early-stage central-airway-limited lung cancer, and the efficacy of these techniques is less understood than EBUS, electromagnetic
This work was not supported by any grant. The authors have nothing to disclose. a Division of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Boardman Building 205, 330 Cedar Street, New Haven, CT 06510, USA b Bronchoscopy and Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 East Monument Street, Fifth Floor Baltimore, MD 21205, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 32 (2011) 763–771 doi:10.1016/j.ccm.2011.08.010 0272-5231/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
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Diagnostic and therapeutic strategies for lung cancer have improved with advancing technology and the acquisition of the necessary skills by bronchoscopists to fully use these advanced techniques. The diagnostic yield for lung cancer has significantly increased with the advent of technologies such as endobronchial ultrasound (EBUS), navigational systems, and improved imaging modalities. Similarly, the therapeutic benefit of bronchoscopy in advanced lung cancer has begun to be understood for its impact on quality and quantity of life. This article highlights the pulmonologists’ diagnostic advances and therapeutic options, with an emphasis on outcomes.
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Puchalski & Feller-Kopman navigation (EMN), and the techniques described in the following paragraphs for diagnosing mediastinal and hilar adenopathy and solitary pulmonary nodules and masses.
Endosonography for Adenopathy and Central Lesions Esophageal ultrasound (EUS) and EBUS are highly accurate techniques for diagnosing and staging lung cancer. EUS was initially developed for gastrointestinal disease in the 1970s and is used during biopsy of lymph nodes for suspected lung cancer in stations 1L, 2L, 4L, 7, 8, and 9. It may also be the preferred technique for assessing metastases to the left adrenal gland. A recent meta-analysis described the ability of EUS to stage lung cancer, with a pooled sensitivity of 88% and specificity of 97% for patients with enlarged mediastinal lymph nodes. The sensitivity was 58% in the absence of mediastinal adenopathy.7 The efficacy of EBUS advanced in the 1990s with miniaturization of the curvilinear ultrasound transducer. The convex probe EBUS bronchoscope allows real-time visualization of needle aspiration in stations 1, 2R, 2L, 4R, 4L, 7, 10R, 10L, 11R, and 11L. A meta-analysis of EBUS for these lesions reported a 93% sensitivity, with a 9% false-negative rate.8 EUS and EBUS are complementary techniques that, when used together, further increase the diagnostic yield. Although the two different scopes with different practitioners may be used, the EBUS scope may be passed into the esophagus, enabling both procedures to be accomplished by one operator in the same setting. This approach has been shown to increase the diagnostic accuracy and the number of lymph node stations that can be biopsied.9,10 Although mediastinoscopy has long been considered the gold standard for mediastinal lymph node staging, the technique is used in fewer than 30% of patients undergoing lung resection, and when performed, lymph node tissue is obtained in fewer than 50%.11 Additionally, EBUS has been shown to have a higher diagnostic yield compared with mediastinoscopy, especially at station 7.12 The yield of endoscopic evaluation (EUS/EBUS) plus mediastinoscopy is higher than either modality alone.13 Therefore, the need for mediastinoscopy has decreased in most institutions that routinely use EUS and EBUS.
10% quoted for bronchoscopic biopsies.15 Although the historical yield for bronchoscopy in diagnosing peripheral lesions has been low, new techniques have significantly improved bronchoscopists’ ability to obtain the correct diagnosis. Peripheral EBUS (pEBUS) uses a 20-MHz radialtype probe and may be used with or without a guide sheath. The typical “snowstorm” seen in the parenchyma will convert to a more homogenous image when the lesion in question is approached. A recent meta-analysis reviewed 16 studies that included 1420 patients and found a point sensitivity of 0.73 for the detection of lung cancer, with a positive likelihood ratio of 26.84 and a negative likelihood ratio of 0.28. The sensitivity for diagnosing malignant lesions smaller than 2 cm is increased with the use of peripheral EBUS.16 The addition of transbronchial needle aspiration to conventional techniques such as biopsy forceps, cytology brushing, and bronchoalveolar lavage increased the yield when using pEBUS.17 Prototype bronchoscopes that are smaller and can navigate further into the periphery are currently under investigation. Electromagnetic navigation (EMN) combines real-time three-dimensional CT images with virtual bronchoscopy and uses a locatable guide that has active steering capability to guide more readily and accurately to peripheral lung lesions. The steps of the process have been well summarized and include planning, mapping, navigation, and then the biopsies.18 Its use has increased since 2003 and the overall diagnostic yield has ranged from 59% to 77%. The efficacy of the technique is not necessarily impacted by the size of the lesion, with several studies showing a similar diagnostic accuracy for lesions smaller or larger than 2 cm.13 Lesions in which a bronchus leads to the abnormality in question (“bronchus sign”) have a significantly higher yield than those without a visible airway to the lesion.19 Combining EMN with pEBUS in a randomized controlled trial improved the diagnostic yield to 88% compared with pEBUS (69%) and EMN (59%) alone.20 New technologies using both virtual bronchoscopic navigation and combined virtual bronchoscopic and electromagnetic navigation are being developed and actively investigated. Images from these advanced endoscopic techniques are shown in Fig. 1 and diagnostic procedures are summarized in Table 1.
The Assessment of Peripheral Lesions
Therapeutics
Nonmalignant lesions are found in up to 55% of patients undergoing resection for suspicious pulmonary opacities.14 CT-guided biopsy has a high diagnostic yield but is associated with a pneumothorax rate of 20% to 25%, higher than the 5% to
Interventional procedures for lung cancer are often palliative in nature, although early-stage lung cancers may also be treated definitively. This section focuses on topical endobronchial modalities, airway stenting, and palliative pleural
Diagnostic-Therapeutic Lung Cancer Interventions
Fig. 1. Advanced diagnostic tools include the convex probe EBUS (A), peripheral EBUS (B), and EMN (C). The lesion is biopsied in real-time (A), and identified with advanced techniques before biopsy (B, C).
procedures aimed at improving dyspnea. It highlights not only the technical success of the procedures but also what is known regarding the outcomes related to dyspnea and quality of life stemming from these procedures.
Topical Therapies Various forms of topical therapy may be applied to the tracheobronchial tree through a bronchoscope. These techniques include mechanical debulking and the use of thermal and nonthermal modalities,
Table 1 The pulmonologist’s advanced tools for diagnosing malignancya Convex EBUS Peripheral EBUS EMN Ultrasound-guided thoracentesis Pleuroscopy a
Meta-analysis: sensitivity 0.88–0.93 for mediastinal staging in patients with lung cancer43,44 Meta-analysis: Sensitivity 0.73 for detection of lung cancer16 May increase diagnostic accuracy when added to peripheral EBUS20 Ultrasound improves safety of thoracentesis45; the yield of thoracentesis for malignant effusions is 62%–90% and increases with multiple fluid collections46 Diagnostic sensitivity for malignant effusions is 93%–95%41
Newer technologies have improved the diagnostic yield for common bronchoscopic and pleural procedures.
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Puchalski & Feller-Kopman such as laser, electrocautery, argon plasma coagulation (APC), cryotherapy, brachytherapy, and photodynamic therapy (PDT). Mechanical debulking is often accomplished with the rigid bronchoscope itself. Tumors may be easily cored out, achieving airway patency within a matter of minutes. The microdebrider is a tool with a rotary blade and continuous suction capability. It is used with the rigid bronchoscope to rapidly recanalize the airway.21 Both of these techniques are faster and more efficacious than flexible bronchoscopy with biopsy forceps. Various forms of thermal energy can be used endobronchially. Cryotherapy uses a probe through the working channel of a flexible bronchoscope to freeze exophytic airway lesions down to the lobar or segmental level. After directly applying the probe to the tumor, the probe and bronchoscope are withdrawn with the frozen pieces of tumor in a rapid and safe procedure. Heat may also be used in the airways to destroy tumor. The electrocautery probe is technically similar to cryotherapy but applies an electrical current to generate heat. The operator controls the depth of penetration, although the visual extent of destruction is less than what is seen pathologically. Cautery may also be delivered through a snare or knife. APC uses ionized argon gas charged with an electric current to achieve thermal tissue destruction. It does not require direct contact because the energized argon gas finds the nearest grounded tissue to create necrosis to a depth of 3 to 4 mm. A unique risk of APC is systemic gas embolization.21 The most common laser used in the tracheobronchial tree is the neodymium:yttrium-aluminum-garnet (Nd:YAG), although carbon dioxide may also used in the airway. Tissue vaporization is immediate and the depth of penetration can be up to 10 mm with the Nd:YAG. With all therapies that use heat, the patient’s fraction of inspired oxygen requirements must be 40% or less to prevent airway fires. The immediate response rate ranges from 69% to 100%.22 Most of these techniques are used together as a combined approach to endobronchial therapy. PDT uses systemic injection of light-activated chemical compounds that cause cell death. It is used for centrally located early-stage or inoperable cancers, although its use in the periphery has also been described. Light of a specific wavelength (nonthermal laser) is used to activate the drug, and tumor destruction results from the generation of cytotoxic singlet oxygen species. The effects of PDT are delayed and thus it is indicated predominantly for patients who are nonoperable and not candidates for external-beam radiation therapy, or as palliative treatment in the absence of acute
dyspnea.22 In a recent retrospective analysis of 529 cases in 133 patients, the distal airway was opened in 81% of patients, the Modified Medical Research Council (MMRC) dyspnea scale improved in 74% of patients, morbidity was 15%, and the median 5-year survival was 43%. The authors commented on equal efficacy between PDT and laser therapy but preferred PDT for patients with bloody tumors, such as metastatic renal cell carcinoma and melanoma.23 One disadvantage is that patients remain photosensitized for 4 to 6 weeks after the procedure and thus must avoid sunlight; another is the cost of the Photofrin, which is currently approximately $13,000. Brachytherapy involves the direct placement of radioactive seeds into or in proximity to an airway tumor. Iridium-92 is a common radioactive source and is used to alter DNA and induce apoptosis. Improvement and palliation of symptoms has been reported in 65% to 95% of cases.22 The median survival in a retrospective analysis of 226 patients who received high-dose rate brachytherapy was 28.6 months, with 2- and 5-year survival rates of 57% and 29%. Complete endobronchial response was seen in 93.6% of patients at 3 months, although complications were seen in up to 30%.24 High-dose rate brachytherapy followed by PDT has been described in a small patient population.25
Airway Stenting Approximately 30% of patients with lung cancer present with central airway obstruction.26 Airway stenting is often useful in addition to the ablative techniques described earlier and is the only endoscopic modality that can treat airway obstruction caused by external compression. Stents are made of metal, silicone, or a hybrid combination of the two, and are available from different manufacturers. They are available in tubular, Y, L, or T configurations. Silicone stents require rigid bronchoscopy for insertion, whereas metal stents may be placed via flexible bronchoscopy. Silicone stents, however, can be much easier to remove, because tumor ingrowth and epithelization occur less frequently than with metal stents. Other complications include migration, mucus plugging, granuloma formation, and infection.26 Examples of therapeutic bronchoscopic procedures are shown in Fig. 2 and a summary of these procedures is shown in Table 2.
Therapeutic Outcomes for Airway Disease The aforementioned airway interventions require specialized training and have their associated risks. A recent prospective analysis of 554 therapeutic procedures performed in four hospitals showed
Diagnostic-Therapeutic Lung Cancer Interventions
Fig. 2. Therapeutic bronchoscopy. Rigid bronchoscopy can debulk large central tumors (A, B). Heat modalities, including APC (C), electrocautery (D), and laser (E) may be used to topically ablate endobronchial tumor. Prolonged therapy may result from stent placement (F).
that complications were common (19.8%) and that the 30-day mortality was 7.8%. Patients with malignant indications who had the highest rate of complications included current smokers and patients with hypertension, diabetes, and endobronchial disease. Of the deaths at 30 days, only one was
procedure-related, whereas the others were related to the progression of underlying disease. Patients with an American Society of Anesthesiologists score of greater than two and higher Zubrod scores were at the greatest risk for complications.27
Table 2 The pulmonologist’s therapeutic tools for treating malignancya Laser resection Electrocautery Argon plasma coagulation Brachytherapy Photodynamic therapy Airway stenting Rigid bronchoscopy
Tunneled pleural catheter Pleurodesis a
Success rate for symptoms, radiographic or endoscopic findings approaches 93%47 Success rate is similar to laser, although the cost is less47 Success rate is similar to laser, although the cost is less47 Low-dose and high-dose brachytherapy response rates may approach 89%–94%47 Efficacy similar to laser23 Relief of symptoms in up to 90% of patients48 Combined with flexible bronchoscopy to core-out central airway obstruction; all of these techniques are often used in conjunction as multimodality therapy Symptomatic improvement in 96% of patients37 Talc poudrage via pleuroscopy is successful in up to 90% of patients41
Common techniques used by pulmonologists for symptomatic relief in patients with lung cancer.
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Puchalski & Feller-Kopman Many studies show the immediate value of reopening a large central airway that has been obstructed by tumor. The techniques are usually combinations of debulking, heat or cold destruction, and stenting. The greatest benefit is seen when the obstruction is in the trachea, right or left mainstem, or bronchus intermedius (eg, the central airways). Lobar obstruction may be relieved when disease is proximal and the resultant atelectasis has been present for less than 1 month, although the benefits may not be as pronounced as when the central airways are reestablished. The technical success of achieving patency is high. More recent studies have begun to define the benefits of therapeutic airway procedures beyond the immediate postprocedural period. In 2008, Amjadi, and colleagues28 performed one of the first studies evaluating quality of life in patients receiving interventional airway procedures. They used the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and included 20 patients over 6 months. These patients were nonoperable and did not undergo chemotherapy or radiation therapy during the first 30 days of the study. Therapeutic procedures included mechanical debulking and dilation, Nd:YAG laser, cryotherapy, or stents. More than 80% of the airway caliber was restored in 80% of patients, and 85% of patients showed improved dyspnea scores within 24 hours that extended to 30 days, and most went from a severe category to slight. Significant variability was seen in overall quality of life changes after the procedure. Patients with the best and worst preprocedure quality of life scores seemed to benefit the least, whereas those with an intermediate quality of life benefited the most. The investigators hypothesized that improved dyspnea led to improvements in quality of life but that other factors were also important in overall quality of life assessments. A recent prospective cohort study of 37 patients with high-grade symptomatic central airway obstruction were evaluated for exercise capacity, lung function, and quality of life. Most (91.9%) had restoration of airway patency (>50% of airway lumen restored). Statistically significant improvements in the 6-minute walk test were noted at days 30, 90, and 180 compared with baseline. The dyspnea scores, resting Borg, forced expiratory volume in 1 second, and forced vital capacity were also improved at day 30. An improvement in overall quality of life was seen in 43% of patients. The median survival was 166 days (23.7 weeks) and the 6-month survival was 46%.29 Some emerging reports show potential survival benefits related to interventional pulmonary
procedures. A retrospective study of 50 patients who underwent stenting for central airway obstruction suggested that symptoms were effectively palliated as measured by the Medical Research Council (MRC) dyspnea score and Eastern Cooperative Oncology Group performance status. Compared with historical controls, patients in the intermediate performance status group experienced a significant survival advantage. This finding was not seen in patients with a poor performance status. The median survival was 117 days and the 6-month survival was 40%. A median survival of approximately 8 months was seen in patients who underwent airway stenting, compared with 3 months in patients with a high MRC score or poor performance status and 1 to 2 months in historical untreated patients with central airway obstruction.30 In contrast, a retrospective study of 65 patients showed no survival benefit with airway stenting. Although 98% of patients experienced immediate relief of the airway obstruction, the 1year survival was 25.2% and the median survival was 6.2 months. A 4-month increase in median survival was seen in patients who received stenting plus adjuvant chemotherapy, but overall survival was not changed.31 Despite terminal central airway obstruction, other studies have shown the overall benefit of providing palliative care for these patients. In a study of 14 patients with imminent airway obstruction who could choose euthanasia, all patients undergoing stent placement experienced immediate improvement in symptoms.32 In another study consisting of patients requiring intensive care, 62.5% of the 32 patients could be transferred to a lower level of care immediately after emergency intervention. Benefits also included withdrawal from mechanical ventilation, relief of symptoms, and extended survival.33 Compared with patients without central airway obstruction receiving therapy for advanced non–small cell lung cancer, those who were treated for central airway obstruction did not have a worsened overall survival.34 Additional studies report the value of therapeutic bronchoscopy as a combined approach before surgery for curative intent, noting that this may permit parenchyma-sparing surgery in patients with lung cancer.35
Diagnostic and Therapeutic Approaches for Malignant Pleural Disease Of the 150,000 patients per year who develop malignant pleural effusions, lung cancer and breast cancer account for up to 75%.36 The median survival for patients with a malignant pleural effusion is 4 months.37 Dyspnea results from loss of functional lung tissue caused by
Diagnostic-Therapeutic Lung Cancer Interventions atelectasis, mediastinal shift, and, most importantly, reduced compliance of the chest wall. The diagnosis may be established through routine thoracentesis in up to 80% of cases, although more than one thoracentesis is often necessary. Pleural biopsy may be required for cytologically negative effusions. Once diagnosed, the options for management include treatment of the underlying malignancy, repeated thoracentesis, chest tube placement with pleurodesis, thoracoscopy with pleurodesis, or placement of pleural catheters. Pleurectomy and pleuroperitoneal shunts are rarely performed.38 Given that the life expectancy is poor, early and aggressive pleural palliation may be the best option for some patients. Thoracentesis may be performed and several liters of fluid can be removed. For recurrent effusions, however, repeated thoracentesis subjects patients to the risks of the procedure in addition to the uncertainty that revolves around how quickly the effusion will reaccumulate and contribute to respiratory distress. Therefore, most patients should undergo a more definitive therapy. Chest tube placement with instillation of a sclerosing agent requires inpatient hospitalization to enable ongoing drainage of the effusion and adhesion of the pleural surfaces. Smaller chest tubes (10–14 French) work as well as larger chest tubes.
Doxycycline has a reported pleurodesis rate of 76% compared with talc (95%).38 Controversy exists as to whether talc slurry is as efficacious as aerosolized talc (via thoracoscopy).36 The two techniques are likely equally effective, although talc poudrage may be preferred in patients with malignant effusions from lung or breast cancer.39 In a recent phase III prospective study of 482 patients, no overall difference in pleurodesis was seen between talc slurry and insufflation, although the rate was higher with insufflation in patients with lung cancer.40 The concern with using talc is the risk for lung injury and acute respiratory distress syndrome (ARDS), possibly related to particle size. None of the patients in a recent prospective study of 558 patients developed ARDS with the use of large talc particles.36 Thoracoscopic pleurodesis can be achieved either through video-assisted thoracoscopic surgery or medical pleuroscopy. The latter may be performed with a rigid scope or a flexi-rigid scope. Medical pleuroscopy can be performed outside of the operating room without general anesthesia or single lung ventilation. Talc poudrage performed thoracoscopically has a pleurodesis rate of at least 90%.41 Discharge from the hospital may be accomplished sooner through placing a tunneled
Fig. 3. Diagnostic and therapeutic pleural procedures are important considerations in malignant disease. Onetime (thoracentesis) and recurrent drainage of effusions (tunneled catheters) may improve dyspnea (A, B, C). Pleuroscopy may be used to biopsy pleural lesions (D) and then pleurodese with agents such as talc (E, F).
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Puchalski & Feller-Kopman pleural catheter at the same time as thoracoscopic pleurodesis.42 The tunneled pleural catheter system (PleurX, CareFusion, Waukwgan, IL USA) is a 15.5-French catheter that may be placed in an outpatient setting. Drainage is typically performed daily or every other day by the patient, family members, or visiting health care professionals. Spontaneous pleurodesis occurs in 46% of patients at 29 to 56 days postplacement of the catheter, although rates from 21% to 58% have been reported. Symptomatic improvement occurs in 81% to 100% of patients,38 with a recent review of 1370 patients showing a 95.6% improvement in symptoms.37 Quality of life measurements are infrequently reported, but 46 of 46 patients showed improvement.37 Additional systems exist but have not been well-studied. Complications are generally considered to be low, but range from 5% to 27%38 and are absent in 87.5% of cases.37 The major complications include empyemas (2.8%), other infection (2%), and pneumothorax (5.9%).37 Survival after placement of tunneled pleural catheter is a mean of 87 days and median of 59.5 to 144 days.37 Because these catheters may be placed on an outpatient basis without general anesthesia, costs seem to be less than for tube thoracostomy and thoracoscopy.36 A more recent study suggested that talc pleurodesis may be less expensive than tunneled pleural catheter placement. The cost of the drainage bottles significantly contributes to the price, and thus patients surviving longer may incur this larger expense.37 Combining pleurodesis with placement of a tunneled catheter may provide a minimal hospital stay (1.7 days) and short catheter duration (7 days).42 Fig. 3 shows examples of these procedures.
SUMMARY The diagnostic bronchoscopic approach to lung cancer has changed significantly with the advent of new technology and appropriate training. Therapeutic strategies have also developed that provide an improvement in symptoms and quality of life for patients with advanced lung cancer. Aggressive palliation of pleural disease provides similar benefits. These improvements are likely foreshadowing of future advances as technology continues to expand.
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32. Vonk-Noordegraaf A, Postmus PE, Sutedja TG. Tracheobronchial stenting in the terminal care of cancer patients with central airways obstruction. Chest 2001;120(6):1811–4. 33. Colt HG, Harrell JH. Therapeutic rigid bronchoscopy allows level of care changes in patients with acute respiratory failure from central airways obstruction. Chest 1997;112(1):202–6. 34. Chhajed PN, Baty F, Pless M, et al. Outcome of treated advanced non-small cell lung cancer with and without central airway obstruction. Chest 2006; 130(6):1803–7. 35. Chhajed PN, Eberhardt R, Dienemann H, et al. Therapeutic bronchoscopy interventions before surgical resection of lung cancer. Ann Thorac Surg 2006; 81(5):1839–43. 36. Musani AI. Treatment options for malignant pleural effusion. Curr Opin Pulm Med 2009;15(4):380–7. 37. Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med 2011;26(1):70–6. 38. Spector M, Pollak JS. Management of malignant pleural effusions. Semin Respir Crit Care Med 2008;29(4):405–13. 39. Dresler CM, Olak J, Herndon JE II, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 2005; 127(3):909–15. 40. Chen H, Brahmer J. Management of malignant pleural effusion. Curr Oncol Rep 2008;10(4):287–93. 41. Michaud G, Berkowitz DM, Ernst A. Pleuroscopy for diagnosis and therapy for pleural effusions. Chest 2010;138(5):1242–6. 42. Reddy C, Ernst A, Lamb C, et al. Rapid pleurodesis for malignant pleural effusions: a pilot study. Chest 2011;139(6):1419–23. 43. Adams K, Shah PL, Edmonds L, et al. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis. Thorax 2009;64(9):757–62. 44. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer 2009;45(8):1389–96. 45. Gordon CE, Feller-Kopman D, Balk EM, et al. Pneumothorax following thoracentesis: a systematic review and meta-analysis. Arch Intern Med 2010;170(4):332–9. 46. Heffner JE. Diagnosis and management of malignant pleural effusions. Respirology 2008;13(1):5–20. 47. Lee P, Tamm M, Chhajed PN. Advances in bronchoscopy–therapeutic bronchoscopy. J Assoc Physicians India 2004;52:905–14. 48. Theodore PR. Emergent management of malignancyrelated acute airway obstruction. Emerg Med Clin North Am 2009;27(2):231–41.
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DIAGNOSTIC BRONCHOSCOPY Early Detection of Endobronchial Lung Cancer Lung cancer is the leading cause of cancer death worldwide and accounted for approximately 157,300 deaths in the United States in 2010.1 Although the potential benefits of lung cancer screening are eagerly anticipated,2 unfortunately lung cancer is often detected in an advanced stage either incidentally or in patients with symptoms of late disease.
Lung cancer that is limited to the mucosa in the central airways is usually not detected with available imaging techniques. Imaging modalities such as autofluorescence, narrow band imaging, optical coherence tomography, confocal endomicroscopy, high magnification bronchoscopy, and multimodality fluorescein imaging are being investigated for the detection of early-stage lung cancer or carcinoma in situ.3,4 Although many of these modalities have been found to have significantly higher sensitivity than white-light bronchoscopy for detecting high-grade dysplasia and carcinoma in situ, the primary limitation remains the poor specificity.5 Miniaturized radial EBUS probes fitted with a catheter that carries a water-inflatable balloon at its tip (different from the peripheral and convex EBUS probes described later) improve bronchial wall contact to allow detailed images of the bronchial wall structure. EBUS images correlate extremely well with histologic specimens and are better than CT scans for determining airway invasion versus compression.6 However, no gold standard currently exists for the bronchoscopic diagnosis of early-stage central-airway-limited lung cancer, and the efficacy of these techniques is less understood than EBUS, electromagnetic
This work was not supported by any grant. The authors have nothing to disclose. a Division of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Boardman Building 205, 330 Cedar Street, New Haven, CT 06510, USA b Bronchoscopy and Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 East Monument Street, Fifth Floor Baltimore, MD 21205, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 32 (2011) 763–771 doi:10.1016/j.ccm.2011.08.010 0272-5231/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
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Diagnostic and therapeutic strategies for lung cancer have improved with advancing technology and the acquisition of the necessary skills by bronchoscopists to fully use these advanced techniques. The diagnostic yield for lung cancer has significantly increased with the advent of technologies such as endobronchial ultrasound (EBUS), navigational systems, and improved imaging modalities. Similarly, the therapeutic benefit of bronchoscopy in advanced lung cancer has begun to be understood for its impact on quality and quantity of life. This article highlights the pulmonologists’ diagnostic advances and therapeutic options, with an emphasis on outcomes.
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Puchalski & Feller-Kopman navigation (EMN), and the techniques described in the following paragraphs for diagnosing mediastinal and hilar adenopathy and solitary pulmonary nodules and masses.
Endosonography for Adenopathy and Central Lesions Esophageal ultrasound (EUS) and EBUS are highly accurate techniques for diagnosing and staging lung cancer. EUS was initially developed for gastrointestinal disease in the 1970s and is used during biopsy of lymph nodes for suspected lung cancer in stations 1L, 2L, 4L, 7, 8, and 9. It may also be the preferred technique for assessing metastases to the left adrenal gland. A recent meta-analysis described the ability of EUS to stage lung cancer, with a pooled sensitivity of 88% and specificity of 97% for patients with enlarged mediastinal lymph nodes. The sensitivity was 58% in the absence of mediastinal adenopathy.7 The efficacy of EBUS advanced in the 1990s with miniaturization of the curvilinear ultrasound transducer. The convex probe EBUS bronchoscope allows real-time visualization of needle aspiration in stations 1, 2R, 2L, 4R, 4L, 7, 10R, 10L, 11R, and 11L. A meta-analysis of EBUS for these lesions reported a 93% sensitivity, with a 9% false-negative rate.8 EUS and EBUS are complementary techniques that, when used together, further increase the diagnostic yield. Although the two different scopes with different practitioners may be used, the EBUS scope may be passed into the esophagus, enabling both procedures to be accomplished by one operator in the same setting. This approach has been shown to increase the diagnostic accuracy and the number of lymph node stations that can be biopsied.9,10 Although mediastinoscopy has long been considered the gold standard for mediastinal lymph node staging, the technique is used in fewer than 30% of patients undergoing lung resection, and when performed, lymph node tissue is obtained in fewer than 50%.11 Additionally, EBUS has been shown to have a higher diagnostic yield compared with mediastinoscopy, especially at station 7.12 The yield of endoscopic evaluation (EUS/EBUS) plus mediastinoscopy is higher than either modality alone.13 Therefore, the need for mediastinoscopy has decreased in most institutions that routinely use EUS and EBUS.
10% quoted for bronchoscopic biopsies.15 Although the historical yield for bronchoscopy in diagnosing peripheral lesions has been low, new techniques have significantly improved bronchoscopists’ ability to obtain the correct diagnosis. Peripheral EBUS (pEBUS) uses a 20-MHz radialtype probe and may be used with or without a guide sheath. The typical “snowstorm” seen in the parenchyma will convert to a more homogenous image when the lesion in question is approached. A recent meta-analysis reviewed 16 studies that included 1420 patients and found a point sensitivity of 0.73 for the detection of lung cancer, with a positive likelihood ratio of 26.84 and a negative likelihood ratio of 0.28. The sensitivity for diagnosing malignant lesions smaller than 2 cm is increased with the use of peripheral EBUS.16 The addition of transbronchial needle aspiration to conventional techniques such as biopsy forceps, cytology brushing, and bronchoalveolar lavage increased the yield when using pEBUS.17 Prototype bronchoscopes that are smaller and can navigate further into the periphery are currently under investigation. Electromagnetic navigation (EMN) combines real-time three-dimensional CT images with virtual bronchoscopy and uses a locatable guide that has active steering capability to guide more readily and accurately to peripheral lung lesions. The steps of the process have been well summarized and include planning, mapping, navigation, and then the biopsies.18 Its use has increased since 2003 and the overall diagnostic yield has ranged from 59% to 77%. The efficacy of the technique is not necessarily impacted by the size of the lesion, with several studies showing a similar diagnostic accuracy for lesions smaller or larger than 2 cm.13 Lesions in which a bronchus leads to the abnormality in question (“bronchus sign”) have a significantly higher yield than those without a visible airway to the lesion.19 Combining EMN with pEBUS in a randomized controlled trial improved the diagnostic yield to 88% compared with pEBUS (69%) and EMN (59%) alone.20 New technologies using both virtual bronchoscopic navigation and combined virtual bronchoscopic and electromagnetic navigation are being developed and actively investigated. Images from these advanced endoscopic techniques are shown in Fig. 1 and diagnostic procedures are summarized in Table 1.
The Assessment of Peripheral Lesions
Therapeutics
Nonmalignant lesions are found in up to 55% of patients undergoing resection for suspicious pulmonary opacities.14 CT-guided biopsy has a high diagnostic yield but is associated with a pneumothorax rate of 20% to 25%, higher than the 5% to
Interventional procedures for lung cancer are often palliative in nature, although early-stage lung cancers may also be treated definitively. This section focuses on topical endobronchial modalities, airway stenting, and palliative pleural
Diagnostic-Therapeutic Lung Cancer Interventions
Fig. 1. Advanced diagnostic tools include the convex probe EBUS (A), peripheral EBUS (B), and EMN (C). The lesion is biopsied in real-time (A), and identified with advanced techniques before biopsy (B, C).
procedures aimed at improving dyspnea. It highlights not only the technical success of the procedures but also what is known regarding the outcomes related to dyspnea and quality of life stemming from these procedures.
Topical Therapies Various forms of topical therapy may be applied to the tracheobronchial tree through a bronchoscope. These techniques include mechanical debulking and the use of thermal and nonthermal modalities,
Table 1 The pulmonologist’s advanced tools for diagnosing malignancya Convex EBUS Peripheral EBUS EMN Ultrasound-guided thoracentesis Pleuroscopy a
Meta-analysis: sensitivity 0.88–0.93 for mediastinal staging in patients with lung cancer43,44 Meta-analysis: Sensitivity 0.73 for detection of lung cancer16 May increase diagnostic accuracy when added to peripheral EBUS20 Ultrasound improves safety of thoracentesis45; the yield of thoracentesis for malignant effusions is 62%–90% and increases with multiple fluid collections46 Diagnostic sensitivity for malignant effusions is 93%–95%41
Newer technologies have improved the diagnostic yield for common bronchoscopic and pleural procedures.
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Puchalski & Feller-Kopman such as laser, electrocautery, argon plasma coagulation (APC), cryotherapy, brachytherapy, and photodynamic therapy (PDT). Mechanical debulking is often accomplished with the rigid bronchoscope itself. Tumors may be easily cored out, achieving airway patency within a matter of minutes. The microdebrider is a tool with a rotary blade and continuous suction capability. It is used with the rigid bronchoscope to rapidly recanalize the airway.21 Both of these techniques are faster and more efficacious than flexible bronchoscopy with biopsy forceps. Various forms of thermal energy can be used endobronchially. Cryotherapy uses a probe through the working channel of a flexible bronchoscope to freeze exophytic airway lesions down to the lobar or segmental level. After directly applying the probe to the tumor, the probe and bronchoscope are withdrawn with the frozen pieces of tumor in a rapid and safe procedure. Heat may also be used in the airways to destroy tumor. The electrocautery probe is technically similar to cryotherapy but applies an electrical current to generate heat. The operator controls the depth of penetration, although the visual extent of destruction is less than what is seen pathologically. Cautery may also be delivered through a snare or knife. APC uses ionized argon gas charged with an electric current to achieve thermal tissue destruction. It does not require direct contact because the energized argon gas finds the nearest grounded tissue to create necrosis to a depth of 3 to 4 mm. A unique risk of APC is systemic gas embolization.21 The most common laser used in the tracheobronchial tree is the neodymium:yttrium-aluminum-garnet (Nd:YAG), although carbon dioxide may also used in the airway. Tissue vaporization is immediate and the depth of penetration can be up to 10 mm with the Nd:YAG. With all therapies that use heat, the patient’s fraction of inspired oxygen requirements must be 40% or less to prevent airway fires. The immediate response rate ranges from 69% to 100%.22 Most of these techniques are used together as a combined approach to endobronchial therapy. PDT uses systemic injection of light-activated chemical compounds that cause cell death. It is used for centrally located early-stage or inoperable cancers, although its use in the periphery has also been described. Light of a specific wavelength (nonthermal laser) is used to activate the drug, and tumor destruction results from the generation of cytotoxic singlet oxygen species. The effects of PDT are delayed and thus it is indicated predominantly for patients who are nonoperable and not candidates for external-beam radiation therapy, or as palliative treatment in the absence of acute
dyspnea.22 In a recent retrospective analysis of 529 cases in 133 patients, the distal airway was opened in 81% of patients, the Modified Medical Research Council (MMRC) dyspnea scale improved in 74% of patients, morbidity was 15%, and the median 5-year survival was 43%. The authors commented on equal efficacy between PDT and laser therapy but preferred PDT for patients with bloody tumors, such as metastatic renal cell carcinoma and melanoma.23 One disadvantage is that patients remain photosensitized for 4 to 6 weeks after the procedure and thus must avoid sunlight; another is the cost of the Photofrin, which is currently approximately $13,000. Brachytherapy involves the direct placement of radioactive seeds into or in proximity to an airway tumor. Iridium-92 is a common radioactive source and is used to alter DNA and induce apoptosis. Improvement and palliation of symptoms has been reported in 65% to 95% of cases.22 The median survival in a retrospective analysis of 226 patients who received high-dose rate brachytherapy was 28.6 months, with 2- and 5-year survival rates of 57% and 29%. Complete endobronchial response was seen in 93.6% of patients at 3 months, although complications were seen in up to 30%.24 High-dose rate brachytherapy followed by PDT has been described in a small patient population.25
Airway Stenting Approximately 30% of patients with lung cancer present with central airway obstruction.26 Airway stenting is often useful in addition to the ablative techniques described earlier and is the only endoscopic modality that can treat airway obstruction caused by external compression. Stents are made of metal, silicone, or a hybrid combination of the two, and are available from different manufacturers. They are available in tubular, Y, L, or T configurations. Silicone stents require rigid bronchoscopy for insertion, whereas metal stents may be placed via flexible bronchoscopy. Silicone stents, however, can be much easier to remove, because tumor ingrowth and epithelization occur less frequently than with metal stents. Other complications include migration, mucus plugging, granuloma formation, and infection.26 Examples of therapeutic bronchoscopic procedures are shown in Fig. 2 and a summary of these procedures is shown in Table 2.
Therapeutic Outcomes for Airway Disease The aforementioned airway interventions require specialized training and have their associated risks. A recent prospective analysis of 554 therapeutic procedures performed in four hospitals showed
Diagnostic-Therapeutic Lung Cancer Interventions
Fig. 2. Therapeutic bronchoscopy. Rigid bronchoscopy can debulk large central tumors (A, B). Heat modalities, including APC (C), electrocautery (D), and laser (E) may be used to topically ablate endobronchial tumor. Prolonged therapy may result from stent placement (F).
that complications were common (19.8%) and that the 30-day mortality was 7.8%. Patients with malignant indications who had the highest rate of complications included current smokers and patients with hypertension, diabetes, and endobronchial disease. Of the deaths at 30 days, only one was
procedure-related, whereas the others were related to the progression of underlying disease. Patients with an American Society of Anesthesiologists score of greater than two and higher Zubrod scores were at the greatest risk for complications.27
Table 2 The pulmonologist’s therapeutic tools for treating malignancya Laser resection Electrocautery Argon plasma coagulation Brachytherapy Photodynamic therapy Airway stenting Rigid bronchoscopy
Tunneled pleural catheter Pleurodesis a
Success rate for symptoms, radiographic or endoscopic findings approaches 93%47 Success rate is similar to laser, although the cost is less47 Success rate is similar to laser, although the cost is less47 Low-dose and high-dose brachytherapy response rates may approach 89%–94%47 Efficacy similar to laser23 Relief of symptoms in up to 90% of patients48 Combined with flexible bronchoscopy to core-out central airway obstruction; all of these techniques are often used in conjunction as multimodality therapy Symptomatic improvement in 96% of patients37 Talc poudrage via pleuroscopy is successful in up to 90% of patients41
Common techniques used by pulmonologists for symptomatic relief in patients with lung cancer.
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Puchalski & Feller-Kopman Many studies show the immediate value of reopening a large central airway that has been obstructed by tumor. The techniques are usually combinations of debulking, heat or cold destruction, and stenting. The greatest benefit is seen when the obstruction is in the trachea, right or left mainstem, or bronchus intermedius (eg, the central airways). Lobar obstruction may be relieved when disease is proximal and the resultant atelectasis has been present for less than 1 month, although the benefits may not be as pronounced as when the central airways are reestablished. The technical success of achieving patency is high. More recent studies have begun to define the benefits of therapeutic airway procedures beyond the immediate postprocedural period. In 2008, Amjadi, and colleagues28 performed one of the first studies evaluating quality of life in patients receiving interventional airway procedures. They used the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and included 20 patients over 6 months. These patients were nonoperable and did not undergo chemotherapy or radiation therapy during the first 30 days of the study. Therapeutic procedures included mechanical debulking and dilation, Nd:YAG laser, cryotherapy, or stents. More than 80% of the airway caliber was restored in 80% of patients, and 85% of patients showed improved dyspnea scores within 24 hours that extended to 30 days, and most went from a severe category to slight. Significant variability was seen in overall quality of life changes after the procedure. Patients with the best and worst preprocedure quality of life scores seemed to benefit the least, whereas those with an intermediate quality of life benefited the most. The investigators hypothesized that improved dyspnea led to improvements in quality of life but that other factors were also important in overall quality of life assessments. A recent prospective cohort study of 37 patients with high-grade symptomatic central airway obstruction were evaluated for exercise capacity, lung function, and quality of life. Most (91.9%) had restoration of airway patency (>50% of airway lumen restored). Statistically significant improvements in the 6-minute walk test were noted at days 30, 90, and 180 compared with baseline. The dyspnea scores, resting Borg, forced expiratory volume in 1 second, and forced vital capacity were also improved at day 30. An improvement in overall quality of life was seen in 43% of patients. The median survival was 166 days (23.7 weeks) and the 6-month survival was 46%.29 Some emerging reports show potential survival benefits related to interventional pulmonary
procedures. A retrospective study of 50 patients who underwent stenting for central airway obstruction suggested that symptoms were effectively palliated as measured by the Medical Research Council (MRC) dyspnea score and Eastern Cooperative Oncology Group performance status. Compared with historical controls, patients in the intermediate performance status group experienced a significant survival advantage. This finding was not seen in patients with a poor performance status. The median survival was 117 days and the 6-month survival was 40%. A median survival of approximately 8 months was seen in patients who underwent airway stenting, compared with 3 months in patients with a high MRC score or poor performance status and 1 to 2 months in historical untreated patients with central airway obstruction.30 In contrast, a retrospective study of 65 patients showed no survival benefit with airway stenting. Although 98% of patients experienced immediate relief of the airway obstruction, the 1year survival was 25.2% and the median survival was 6.2 months. A 4-month increase in median survival was seen in patients who received stenting plus adjuvant chemotherapy, but overall survival was not changed.31 Despite terminal central airway obstruction, other studies have shown the overall benefit of providing palliative care for these patients. In a study of 14 patients with imminent airway obstruction who could choose euthanasia, all patients undergoing stent placement experienced immediate improvement in symptoms.32 In another study consisting of patients requiring intensive care, 62.5% of the 32 patients could be transferred to a lower level of care immediately after emergency intervention. Benefits also included withdrawal from mechanical ventilation, relief of symptoms, and extended survival.33 Compared with patients without central airway obstruction receiving therapy for advanced non–small cell lung cancer, those who were treated for central airway obstruction did not have a worsened overall survival.34 Additional studies report the value of therapeutic bronchoscopy as a combined approach before surgery for curative intent, noting that this may permit parenchyma-sparing surgery in patients with lung cancer.35
Diagnostic and Therapeutic Approaches for Malignant Pleural Disease Of the 150,000 patients per year who develop malignant pleural effusions, lung cancer and breast cancer account for up to 75%.36 The median survival for patients with a malignant pleural effusion is 4 months.37 Dyspnea results from loss of functional lung tissue caused by
Diagnostic-Therapeutic Lung Cancer Interventions atelectasis, mediastinal shift, and, most importantly, reduced compliance of the chest wall. The diagnosis may be established through routine thoracentesis in up to 80% of cases, although more than one thoracentesis is often necessary. Pleural biopsy may be required for cytologically negative effusions. Once diagnosed, the options for management include treatment of the underlying malignancy, repeated thoracentesis, chest tube placement with pleurodesis, thoracoscopy with pleurodesis, or placement of pleural catheters. Pleurectomy and pleuroperitoneal shunts are rarely performed.38 Given that the life expectancy is poor, early and aggressive pleural palliation may be the best option for some patients. Thoracentesis may be performed and several liters of fluid can be removed. For recurrent effusions, however, repeated thoracentesis subjects patients to the risks of the procedure in addition to the uncertainty that revolves around how quickly the effusion will reaccumulate and contribute to respiratory distress. Therefore, most patients should undergo a more definitive therapy. Chest tube placement with instillation of a sclerosing agent requires inpatient hospitalization to enable ongoing drainage of the effusion and adhesion of the pleural surfaces. Smaller chest tubes (10–14 French) work as well as larger chest tubes.
Doxycycline has a reported pleurodesis rate of 76% compared with talc (95%).38 Controversy exists as to whether talc slurry is as efficacious as aerosolized talc (via thoracoscopy).36 The two techniques are likely equally effective, although talc poudrage may be preferred in patients with malignant effusions from lung or breast cancer.39 In a recent phase III prospective study of 482 patients, no overall difference in pleurodesis was seen between talc slurry and insufflation, although the rate was higher with insufflation in patients with lung cancer.40 The concern with using talc is the risk for lung injury and acute respiratory distress syndrome (ARDS), possibly related to particle size. None of the patients in a recent prospective study of 558 patients developed ARDS with the use of large talc particles.36 Thoracoscopic pleurodesis can be achieved either through video-assisted thoracoscopic surgery or medical pleuroscopy. The latter may be performed with a rigid scope or a flexi-rigid scope. Medical pleuroscopy can be performed outside of the operating room without general anesthesia or single lung ventilation. Talc poudrage performed thoracoscopically has a pleurodesis rate of at least 90%.41 Discharge from the hospital may be accomplished sooner through placing a tunneled
Fig. 3. Diagnostic and therapeutic pleural procedures are important considerations in malignant disease. Onetime (thoracentesis) and recurrent drainage of effusions (tunneled catheters) may improve dyspnea (A, B, C). Pleuroscopy may be used to biopsy pleural lesions (D) and then pleurodese with agents such as talc (E, F).
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Puchalski & Feller-Kopman pleural catheter at the same time as thoracoscopic pleurodesis.42 The tunneled pleural catheter system (PleurX, CareFusion, Waukwgan, IL USA) is a 15.5-French catheter that may be placed in an outpatient setting. Drainage is typically performed daily or every other day by the patient, family members, or visiting health care professionals. Spontaneous pleurodesis occurs in 46% of patients at 29 to 56 days postplacement of the catheter, although rates from 21% to 58% have been reported. Symptomatic improvement occurs in 81% to 100% of patients,38 with a recent review of 1370 patients showing a 95.6% improvement in symptoms.37 Quality of life measurements are infrequently reported, but 46 of 46 patients showed improvement.37 Additional systems exist but have not been well-studied. Complications are generally considered to be low, but range from 5% to 27%38 and are absent in 87.5% of cases.37 The major complications include empyemas (2.8%), other infection (2%), and pneumothorax (5.9%).37 Survival after placement of tunneled pleural catheter is a mean of 87 days and median of 59.5 to 144 days.37 Because these catheters may be placed on an outpatient basis without general anesthesia, costs seem to be less than for tube thoracostomy and thoracoscopy.36 A more recent study suggested that talc pleurodesis may be less expensive than tunneled pleural catheter placement. The cost of the drainage bottles significantly contributes to the price, and thus patients surviving longer may incur this larger expense.37 Combining pleurodesis with placement of a tunneled catheter may provide a minimal hospital stay (1.7 days) and short catheter duration (7 days).42 Fig. 3 shows examples of these procedures.
SUMMARY The diagnostic bronchoscopic approach to lung cancer has changed significantly with the advent of new technology and appropriate training. Therapeutic strategies have also developed that provide an improvement in symptoms and quality of life for patients with advanced lung cancer. Aggressive palliation of pleural disease provides similar benefits. These improvements are likely foreshadowing of future advances as technology continues to expand.
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