Stenting at the Flow-limiting Segment in Tracheobronchial Stenosis due to Lung Cancer

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1 Stenting at the Flow-limiting Segment in Tracheobronchial Stenosis due to Lung Cancer Teruomi Miyazawa, Yuka Miyazu, Yasuo Iwamoto, Atsuko Ishida, Koji Kanoh, Hidetaka Sumiyoshi, Masao Doi, and Noriaki Kurimoto Department of Pulmonary Medicine, Hiroshima City Hospital; Department of Internal Medicine, Fukushima Co-op Hospital; Department of Pulmonary Medicine, Hiroshima Prefectural Hospital; and Department of Surgery, Hiroshima National Hospital, Hiroshima City, Hiroshima, Japan Airway stenting at the wave-speed flow-limiting segment (the choke point) is assessed. We determined prospectively the precise location of the choke point using the flow volume curve, endobronchial ultrasonography, ultrathin bronchoscopy, and three-dimensional computed tomography scan before and after stenting in 64 patients with extrincic compression due to lung cancer. We noted distinct flow volume curve patterns specific to the type of stenosis. The tracheal stenosis group indicated fixed narrowing patterns with an expiratory plateau, bronchial stenosis group dynamic collapse patterns with an expiratory flow deterioration (choking), carinal stenosis group combined fixed and dynamic patterns, and extensive stenosis group complex patterns containing elements of all the former. After stenting, almost full-function patterns with significant improvement in PEF were observed in all groups (p 0.01, p 0.05, p 0.001, p 0.01, respectively). In patients with extensive stenosis, implantation of additional stents was required when the choke points were observed to have migrated to the areas of malacia with cartilage destruction by the tumor. Secondary stenting at migrated choke points resulted in a significant improvement in PEF over the initial stenting (p 0.01). Stenting at the choke point improved expiratory flow limitation by increasing the cross-sectional area, supporting the weakened airway wall and relieving dyspnea. Keywords: choke point; expiratory flow limitation; dynamic airway collapse; flow volume curve More than 50% of patients with advanced stage lung cancer have stenoses of the central airways (1). In patients with symptoms, interventional pulmonology (2) is considered as a method of maintaining airway patency. Intraluminal tumors can be resected endoscopically by means such as laser photoresection or argon plasma coagulation (3). However, if airway stenoses are predominantly due to extrinsic compression by the tumor or metastatic lymph nodes, airway stenting should be considered (4 9). In our previous studies (7 9), stenting proved an effective procedure. However, some patients received no relief from dyspnea after stenting. We observed in these patients that the placement of the stent caused the area of greatest compression to shift to a weaker segment of the airway. Therefore we postulated that stenting might change the location of the flow-limiting segment (the choke point). Flow limitation during forced expiration is affected by the relationship between transmural pressure (Ptm) and cross-sectional area (A) of the airway. The wave (Received in original form November 24, 2003; accepted in final form February 9, 2004) Supported in part by a Grant-in-Aid for Cancer Research (12-01) from the Ministry of Health, Labor, and Welfare. Correspondence and requests for reprints should be addressed to Teruomi Miyazawa, M.D., Ph.D., Department of Pulmonary Medicine, Hiroshima City Hospital, 7-33 Naka-Ku, Moto-machi, Hiroshima, Japan miyazawt@carrot. ocn.ne.jp Am J Respir Crit Care Med Vol 169. pp , 2004 Originally Published in Press as DOI: /rccm OC on February 12, 2004 Internet address: speed is dependent on the stiffness of the airway wall, i.e., dptm/ da and on the cross-sectional airway itself (10, 11). The flow volume curve manifested specific configuration details related to the location of the choke point. Analysis of the flow volume curve could be used in defining the nature of the stenosis (12 15). Whereas the digestive tract (16) and airway are similar tubular organs, only the airway has cartilage that strongly supports the lumen. According to the wave-speed theory (10, 11), we considered that the location of the choke point might have a close relationship to the presence of the cartilage. In our previous studies (17 19), endobronchial ultrasonography images revealed the layered structure of the cartilage of the tracheobronchial wall. Imaging using new technologies such as endobronchial ultrasonography, ultrathin bronchoscopy, and three-dimensional computed tomography (CT) scan might show collapsible segments and choke points in the airway. The aim of our study was to determine optimal positioning of the stent and its impact on pulmonary function. This study was designed to characterize the choke point, its location and migrations by flow volume curve (12 15), endobronchial ultrasonography (17 20), ultrathin bronchoscopy (21), and three-dimensional CT scan (22 26), which can aid in the planning of bronchoscopic intervention. METHODS Selection of Patients Between October 1998 and October 2003, we performed a prospective study, which was approved by the Ethics Committee. Written informed consent was obtained from all patients. To study the pure functional effect of stenting, we excluded patients with endoluminal tumors. We selected 64 patients who met all the following criteria: patients with World Health Organization dyspnea Grade III IV, stage IIIB/IV inoperable lung cancer without further treatment options, central airway stenosis due to extrinsic compression, and residual stenosis of more than 50% after balloon dilatation. A randomized study of stenting using a no treatment arm or an unsuccessful treatment arm as a control group could not be selected due to the terminal nature of the patient s disease. Thus, a before and after study was done to obtain accurate information on tumor sites by dividing patients into four groups: tracheal stenosis, carinal stenosis, bronchial, and extensive stenosis from the trachea, carina, extending to the bronchi due to tumor and/or mediastinal lymphadenopathy. Flow Volume Curve, Endobronchial Ultrasonography, Ultrathin Bronchoscopy, and Three-dimensional CT Scan before and after Stenting Spirometry and flow volume curves were measured according to the guidelines of the American Thoracic Society (27) using a spirometer (CHESTAC-33; Chest Corp., Tokyo, Japan) before and after stenting. Endobronchial ultrasonography (EU-M 20; Olympus, Tokyo, Japan) was used to assess the layered structure of the tracheobronchial wall, cartilage damage, and the extent of the tumor. We measured the diameter and length of the affected tracheobronchial tree using a 20-MHz frequency radial ultrasonic probe with a water-filled balloon sheath (UM- BS20-26R, MAJ-643R; Olympus). A flexible bronchoscope (BF 240; Olympus) was used to locate choke points. An ultrathin bronchoscope

2 Miyazawa, Miyazu, Iwamoto, et al.: Stenting at the Choke Point in Lung Cancer 1097 (BF-XP 40; Olympus) was used to observe the collapsing segment at its narrowest point, e.g., the choke point. Helical CT scanning was performed with a Hispeed Advantage SG CT system (GE Yokogawa Medical Systems, Tokyo, Japan) at end-expiration during forced expiration. Scanning parameters included 3-mm radiograph beam collimation, 3 mm/second table speed, and 1 mm reconstruction intervals. Helical CT image data were used to create three-dimensional CT images at a computer workstation with Voxtool software (Advantage Windows RP; GE Yokogawa Medical Systems). After induction of general anesthesia, patients were intubated with a rigid bronchoscope (EFER, La Ciotat, France). After dilatation using a balloon catheter, a Dumon stent (Novatech, Aubagne, France) and an uncovered Ultraflex stent (Boston Scientific, Natick, MA) were placed according to the technique recommended by their originators (4, 5). All patients were examined monthly by bronchoscopy after stent placement to check its position and airway patency. Statistical Analysis All analyses were performed using SAS software (Release 8.02; SAS Institute, Cary, NC). Continuous variables before and after stenting in tracheal stenosis, carinal stenosis, and bronchial stenosis were tested by paired t test and the Wilcoxon signed rank test. Stepwise changes in extensive stenosis were tested by paired t test and the Wilcoxon signed rank test using the Bonferroni correction. The survival after stenting among groups was examined by Kaplan Meier analysis with the use of the log-rank test. Characteristics of the patients were compared by paired t test and the 2 test. All results were presented as the mean SD. All tests of significance were two-sided, and p values of less than 0.05 were considered to indicate statistically significant differences. RESULTS Characteristics of the Patients In these 64 patients with inoperable lung cancer, histopathologically, there were 38 patients with adenocarcinoma, 18 with squamous cell carcinoma, and 8 with recurrence of small cell carcinoma after chemotherapy and/or radiotherapy. Groups were matched for sex, age, type of lung cancer, and previous treatment (Table 1). A total of 64 Dumon stents including 36 Y stents and 28 uncovered Ultraflex stents were placed. Dumon stents including Y stents were used alone in just one session in patients with tracheal, carinal, and bronchial stenosis. Dumon Y stents and uncovered Ultraflex stents were used in combination in a second session in patients with extensive stenosis. Analysis of the Flow-Volume Curve Configurations before and after Stenting All groups showed distinct flow volume curve patterns particular to their type of stenosis. This study demonstrated tracheal stenosis indicated fixed narrowing patterns with an expiratory plateau, bronchial stenosis dynamic collapse patterns with an expiratory choking (an initial transient peak flow followed by acute flow deterioration and consecutive low flow), carinal stenosis combined fixed and dynamic patterns (descending expiratory limb with a plateau and choking), and extensive stenosis complex patterns containing elements of all the former. After stenting, each group exhibited a return to a near normal flow volume curve configuration. In patients with extensive stenosis, the patterns of the flow volume curve showed a stepwise improvement over the initial stenting after secondary stenting (Figure 1). Physiologic Parameters of Spirometry and Flow Volume Curve before and after Stenting We show measured values obtained by spirometry and flow volume curve in all groups in Table 2. Significant improvement of FVC after stenting was observed in tracheal and bronchial stenosis groups (p 0.05, p 0.01, respectively). Significant improvement of FEV 1 after stenting was observed in tracheal, carinal, bronchial, and extensive stenosis groups (p 0.001, p 0.001, p 0.01, p 0.01, respectively). Significant improvement of PEF after stenting was seen in all groups (p 0.01, p 0.001, p 0.05, p 0.01, respectively). In the extensive stenosis group, a stepwise procedure was required after the initial intervention. Significant improvement in FEV 1, PEF, and V max 50% (maximal flow at 50% FEV) was seen after secondary stenting compared with the results of the initial stenting (p 0.01, p 0.01, p 0.01, respectively). Endobronchial Ultrasonography, Ultrathin Bronchoscopy, and Three-dimensional CT Scan before and after Stenting The precise length and size of the stents were chosen according to the assessment by endobronchial ultrasonography to sufficiently cover the area affected by the tumor (e.g., tumor compression and invasion). Endobronchial ultrasonography revealed specific details of the submucosal thickening and cartilage destruction by the tumor. Endobronchial ultrasonography showed the cause of the dynamic collapse and choke point migration to be a result of malacia due to destruction of the cartilage or other factors TABLE 1. CHARACTERISTICS OF THE PATIENTS WITH TRACHEOBRONCHIAL STENOSIS DUE TO LUNG CANCER Tracheal Stenosis Carinal Stenosis Bronchial Stenosis Extensive Stenosis Characteristics (n 20) (n 16) (n 18) (n 10) p Value Age, yr 0.14 Mean SD Range Sex 0.41 Male Female Type of lung cancer 0.68 Adenocarcinoma Squamous cell Small cell Previous treatment 0.48 Chemotherapy Radiotherapy The functional effect on tumor site was studied by dividing into four groups: tracheal, carinal, bronchial, and extensive stenoses. Groups were matched for sex, age, type of lung cancer, and previous treatment.

3 1098 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Typical patterns of three-dimensional computed tomography (CT) and flow volume curve before and after stenting. Arrows indicate the area of stenosis. The serial flow volume curve represented by the dotted line shows the result prestenting and the bold line the result poststenting. If stepwise changes are induced after the initial intervention, more curves are shown. In patients with tracheal stenosis, the flow volume curve shows marked reduction of the expiratory flow with a plateau. After stenting, the plateau is no longer apparent, and the flow increased. In patients with carinal stenosis, the flow volume curve shows a descending expiratory limb with a plateau and choking and was improved by placement of a Dumon Y stent. In patients with bronchial stenosis, the flow volume curve shows decreased flow with choking. Stenting resulted in a marked rightward, nearly parallel shift of the descending expiratory limb. In patients with extensive stenosis from the trachea, carina, extending to the bronchi due to tumor and/or mediastinal lymphadenopathy, the flow volume curve shows severe reduction of the expiratory flow. After placement of the Dumon Y stent, the flow volume curve reveals increased flow without a plateau. There was still choking present in the flow volume curve. After the implantation of additional Ultraflex stents at the migrated choke points, the flow volume curve returned to an almost normal pattern. impacting the airway wall. Bronchoscopy performed under local anesthesia during forced expiration confirmed the extent of the collapsed segment, and we then passed an ultrathin bronchoscope beyond the choke point. The choke point was located just below the area of dynamic collapse and the airway gradually dilated distal to it. A three-dimensional CT scan revealed the choke point located in the trachea and/or bronchi, but the distal bronchi remained dilated at end-expiration during forced expiration (Figure 2). Dyspnea Grades before and after Stenting We observed a shift in dyspnea to Grade 0 or I in all patients after stenting. The dyspnea grades (World Health Organization Index) improved significantly in tracheal, carinal, bronchial, and extensive stenosis groups (p 0.001, p 0.001, p 0.001, and p 0.01, respectively). In the extensive stenosis group, we observed a stepwise improvement after secondary stenting. A comparison of secondary stenting with initial stenting showed significant difference (p 0.01) (Table 3). Survival after Stenting and Causes of Death The tracheal stenosis, carinal stenosis, and bronchial stenosis groups were similar, but the extensive stenosis group showed significantly shorter survival times after stenting (p 0.01) (Figure 3). Median survival times after stenting in the groups were as follows: tracheal stenosis group, ; carinal stenosis group, ; bronchial stenosis group, ; and extensive stenosis group, months. The causes of death were as follows: 39 patients died of cachexia, 15 patients died of respiratory infections, 6 patients died of respiratory failure, 3 patients died of cardiac failure, and 1 patient died of massive hemoptysis. None of the patients died of suffocation. Death could not be directly attributed to stent-related complications such as retained secretions (31%), tumor growth (28%), granulation tissue formation (22%), and stent migration (8%). Within the four groups there were no significant differences in stentrelated complications. The complications we observed were all easily managed, and the patient s quality of life was not impaired in any major way. DISCUSSION This study indicates that correct positioning of the stent at the exact location of the choke point provides the greatest functional benefit to patients with extrincic compression due to lung cancer. The choke point occurs originally where the cross-sectional area of the airway is the narrowest. After stenting, migration of the choke point to a nonstented segment of the weakened airway results in its subsequent collapse. Secondary stenting at the site of migrated choke points, after initial stenting, results in significant functional improvement in patients with extensive stenosis from the trachea to the bronchi. On the basis of wave-speed concepts of maximal expiratory flow limitation, stenting at the choke point improved expiratory flow limitation by increasing the cross-sectional area, supporting the weakened airway wall and relieving dyspnea. We succeeded in localizing the site of the choke point and defining the nature of the stenosis, i.e., whether due to fixed narrowing by tumor compression or to dynamic collapse by weakened cartilages. We noted distinct flow volume patterns specific to the type of stenosis. A marked reduction of the expiratory flow with a plateau typically seen in a fixed narrowing indicated that the choke point disappears at higher lung volume

4 Miyazawa, Miyazu, Iwamoto, et al.: Stenting at the Choke Point in Lung Cancer 1099 TABLE 2. PHYSIOLOGIC PARAMETERS OF SPIROMETRY AND FLOW VOLUME CURVE BEFORE AND AFTER STENTING IN THE FOUR GROUPS After Stenting Before Stenting First Stenting Second Stenting Tracheal stenosis (n 20) FVC, L * FEV 1, L PEF, L/s V max 50%, L/s * V max 25%, L/s Carinal stenosis (n 16) FVC, L FEV 1, L PEF, L/s V max 50%, L/s * V max 25%, L/s Bronchial stenosis (n 18) FVC, L FEV 1, L PEF, L/s * V max 50%, L/s V max 25%, L/s Extensive stenosis (n 10) FVC, L FEV 1, L * PEF, L/s * V max 50%, L/s V max 25%, L/s Mean values ( SD) are given for FVC, FEV 1, PEF, V max 50%, and V max 25%. *p 0.05 after first stenting vs. before stenting. p after first stenting vs. before stenting. p 0.01 after first stenting vs. before stenting. p 0.01 after second stenting vs. after first stenting. p 0.01 after second stenting vs. before stenting. levels. Constant flow represented by a plateau was seen on the expiratory curve in the effort-dependent portion near total lung capacity. It was caused by an increased airway resistance at the site of compression due to tumor, so that V max could not reach the peak during forced expiration. A descending expiratory limb with a peak and plateau in the flow volume curve indicated that the choke point was located in the trachea. An expiratory flow deterioration (choking), typically seen in a dynamic collapse, indicated that the choke point had moved to the bronchi. Poststenting, almost full-function patterns were observed in all groups. Theoretical and experimental studies in both mechanical models and animals have been conducted and have predicted possible clinical uses of the choke point (11 14). Pedersen and Ingram (12) demonstrated the various effects of central airway changes produced in a two-compartment mechanical model of the lungs simulating both the trachea and bronchi. They observed the phenomenon of flow limitation as follows: when the trachea is partially obstructed at the site of the central choke point, the flow volume curve shows a decrease in maximum flow volume over a plateau. When both bronchi are partially obstructed, choking occurs in airways showing decreasing V max. Moreover, they reported that when a collapsing trachea is supported by a rigid tube, no choke point appears in the trachea but migrates to the bronchus. Postinterventional analysis of the flow volume curve demonstrated that a plateau indicated that the choke point was being located in the trachea, but when the choke point migrates to the peripheral bronchi after the procedure, there is a disappearance of the plateau. In this study, we also found that the choke point migrated during the procedure of stenting. In some patients, even though the stent was accurately placed at the choke point, there was still choking present in flow volume curve and implantation of additional stents was required when the choke points were observed to have migrated to the areas of malacia with cartilage destruction by the tumor. Whereas several patients in previous studies (7, 8) had suffered from continuing dyspnea after the procedure, which was evaluated by changes in the dyspnea grade, the postprocedure of the present study revealed that no patient suffered from persisting dyspnea greater than or equal to World Health Organization dyspnea Grade II. We demonstrated stepwise functional improvements after secondary stenting and relief of dyspnea in patients with extensive stenosis. However, the extensive stenosis group showed a significantly shorter survival time after stenting than other groups. Although stents provide only palliative treatment for relief of dyspnea, they can restore much of a patient s quality of life (28). The limitations of this study were due in part to underlying chronic obstructive pulmonary disease. The location of the choke point in patients with chronic obstructive pulmonary disease may be more peripheral than in other subjects. In patients with chronic obstructive pulmonary disease, MEF showed marked reduction in flow volume curve, and superimposed lesions may be physiologically camouflaged (29). Whereas the flow volume curve is actually useful in localizing the site of the choke point in the airway, new technologies such as endobronchial ultrasonography, ultrathin bronchoscopy, and three-dimensional CT scan demonstrate the choke point during forced expiration. Endobronchial ultrasonography revealed specific details of the cartilage destruction, enabling a diagnosis of malacia to be made in real time. An ultrathin bronchoscope was

5 1100 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 2. Three-dimensional CT scan, bronchoscopy (standard and ultrathin types), and endobronchial ultrasonography images in extensive tracheobronchial stenosis. The images from top left clockwise are: choke points observed by an ultrathin bronchoscope passed through the collapsed segment of the left and right mainstem bronchus; top right, rigid bronchoscopic and endobronchial ultrasonography findings of dynamic collapse of the trachea; bottom right and left, flexible bronchoscopic and endobronchial ultrasonography findings of the collapsing segment. The stenoses were caused by compression of an extraluminal tumor and dynamic collapse due to lack of supporting cartilage destroyed by tumor invasion. Endobronchial ultrasonography revealed the collapsible segment, and the arrows indicate the remains of the cartilage and absence of supporting cartilage. able to pass the collapsing segment and allowed assessment of the choke point directly. Three-dimensional CT images were obtained at end-expiration and provided an accurate, noninvasive method of assessing airway stenosis. In this study scanning was performed using single-detector helical CT; however, recent advances in CT imaging such as multidetector scanners should improve the overview of the airway, eliminating errors due to artifacts caused by motion, etc. The fast speed of CT scanning now permits dynamic assessment of the central airways (24 26). We are convinced that our procedure is a change in interventional practice as the combined use of endobronchial ultrasonography, ultrathin bronchoscope providing real-time imagery, with the adjunct of flow volume analysis, plus threedimensional CT imagery provide a new method of correctly TABLE 3. DYSPNEA GRADE BEFORE AND AFTER STENTING Tracheal Stenosis (n 20) Carinal Stenosis (n 16) Bronchial Stenosis (n 18) Extensive Stenosis (n 10) After Stenting After Stenting After Stenting After Stenting Dyspnea Before First Second Before First Second Before First Second Before First Second Grade Stenting Stenting* Stenting Stenting Stenting* Stenting Stenting Stenting* Stenting Stenting Stenting Stenting I II III IV The Dyspnea Grade (World Health Organization Index) was used before and immediately after stenting. Grade 0 asymptomatic while climbing stairs; Grade I symptomatic climbing stairs; Grade II symptomatic after walking 100 m on flat ground; Grade III symptomatic with the least effort (talking, getting dressed); Grade IV symptomatic in bed, at rest. *p after first stenting vs. before stenting. p 0.01 after first stenting vs. before stenting. p 0.01 after second stenting vs. after first stenting. p 0.01 after second stenting vs. before stenting.

6 Miyazawa, Miyazu, Iwamoto, et al.: Stenting at the Choke Point in Lung Cancer 1101 Figure 3. Kaplan Meier analysis of survival after stenting. The tracheal stenosis, carinal stenosis, and bronchial stenosis groups were similar, but the extensive stenosis group showed significantly shorter survival times after stenting (p 0.01). Median survival times after stenting in the groups were as follows: tracheal stenosis group: ; carinal stenosis group: ; bronchial stenosis group: ; extensive stenosis group: months. positioning stents and effecting positive results in patients. These procedures are now standard at our institution due to the relative ease and short time required, resulting in maximum quality of life to patients with malignant airway stenosis. Many recent studies (30 35) have shown improved expiratory flow limitation after placement of metallic stents or silicone stents in benign or malignant stenosis. In this study, we used mainly the Dumon stent, which is made of silicone. The Dumon Y stent appears to be particularly good for stenosis involving the carina. We selected uncovered Ultraflex nitinol stents as the additional stents used because of their resistance to dynamic compression. Furthermore, this stent can be implanted without occluding the side bronchus. To our knowledge, this is the first clinical study to investigate the management of airway stenosis focusing on the choke point as the primary site for the accurate placement of stents in humans. We believe that the results of our study of choke point in humans closely follows the physiologic models predicted by the wave-speed theory of expiratory flow limitation. This clinical study might provide useful information on the significance of the choke point for the planning of interventional pulmonology. We consider this study has provided insight, eliminating or simplifying many procedures used in the bronchoscopic treatment of emergency conditions. 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