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Original Research Pulmonary Procedures
]
Endosonographic Mediastinal Lymph Node Staging of Lung Cancer Moishe Liberman, MD, PhD; John Sampalis, PhD; André Duranceau, MD; Vicky Thiffault, RN; Rachid Hadjeres, MD; and Pasquale Ferraro, MD
It is unclear whether endoscopic mediastinal lymph node (LN) staging techniques are equivalent to surgical mediastinal staging (SMS) techniques in patients with potentially operable non-small cell lung cancer (NSCLC).
BACKGROUND:
METHODS: A total of 166 patients with confirmed or suspected NSCLC who required SMS based on current guidelines were enrolled in this prospective controlled trial comparing endosonographic mediastinal LN staging with SMS. Each patient served as his or her own control. All patients underwent endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and SMS during a single procedure. Results of EBUS, EUS, and combined EBUS/EUS were compared with SMS (gold standard) and in patients with negative LN staging results, with LN sampling at pulmonary resection.
EBUS, EUS, combined EBUS/EUS, and SMS sampled a mean of 2.2, 1.7, 3.9, and 3.1 LN stations, respectively. The prevalence of mediastinal nodal disease (N2/N3) was 32% (53 of 166 patients). The sensitivity, negative predictive value, and diagnostic accuracy of the endoscopic staging modalities, respectively, were EBUS, 72% (95% CI, 0.58-0.83), 88% (0.81-0.93), and 91% (0.85-0.95); EUS, 62% (0.48-0.75), 85% (0.78-0.91), and 88% (0.82-0.92); and combined EBUS/EUS, 91% (0.79-0.97), 96% (0.90-0.99), and 97% (0.93-0.99). Endosonography was diagnostic for N2/N3/M1 disease in 24 patients in whom SMS findings were negative, preventing futile thoracotomy in an additional 14% of patients.
RESULTS:
The combined EBUS/EUS procedure can replace surgical mediastinal staging in patients with potentially resectable NSCLC. Additionally, endosonography leads to improved staging compared with SMS because it allows the biopsy of LNs and metastases unattainable with SMS techniques.
CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT01011595; URL: www.clinicaltrials.gov CHEST 2014; 146(2):389-397
Manuscript received October 2, 2013; revision accepted February 5, 2014; originally published Online First March 6, 2014. ABBREVIATIONS: AM 5 anterior mediastinotomy; CM 5 cervical mediastinoscopy; EBUS 5 endobronchial ultrasound; EUS 5 endoscopic ultrasound; LN 5 lymph node; NSCLC 5 non-small cell lung cancer; SMS 5 surgical mediastinal staging AFFILIATIONS: From the CHUM Endoscopic Tracheobronchial and Oesophageal Center (CETOC), Division of Thoracic Surgery (Drs Liberman, Duranceau, and Ferraro and Ms Thiffault), and Department of Pathology (Dr Hadjeres), University of Montréal; Centre Hospitalier de l’Université de Montréal (Drs Liberman, Duranceau, Hadjeres, and Ferraro and Ms Thiffault); and Department of Epidemiology (Dr Sampalis), McGill University, Montréal, QC, Canada. Part of this article has been presented in abstract form at the American Thoracic Society International Conference, May 17-22, 2013, Philadelphia, PA.
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This study was funded by the Canadian Foundation for Innovation, the Society of University Surgeons, and the Fonds de Recherche en Santé du Québec. CORRESPONDENCE TO: Moishe Liberman, MD, PhD, CHUM Endoscopic Tracheobronchial and Oesophageal Center (CETOC), Division of Thoracic Surgery, Centre Hospitalier de l’Université de Montréal, 1560 rue Sherbrooke Est, 8e CD-Pavillon Lachapelle, Bureau D-8051, Montréal, QC H2L 4M1, Canada; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2349 FUNDING/SUPPORT:
389
The gold standard techniques to stage mediastinal lymph nodes (LNs) in patients with potentially resectable non-small cell lung cancer (NSCLC) consist of cervical mediastinoscopy (CM) and anterior mediastinotomy (AM) or video-assisted thoracoscopic surgery.1 Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) are endosonographic techniques used to stage the mediastinum without surgery; however, current comparative data have been limited primarily to individual comparisons of endosonographic techniques (EBUS vs CM). These studies have demonstrated acceptable diagnostic accuracies, but the combined modality approach (EBUS and EUS) may
offer additional accuracy that improves on even traditional surgical staging. Current NSCLC staging guidelines recommend mediastinal LN staging by a needle technique (EBUS, EUS, or combined EBUS/EUS) as a first test; however, if the findings are negative and clinical suspicion is high, the recommendation is to follow the needle techniques with a confirmatory surgical biopsy using either CM or video-assisted thoracoscopic surgery (surgical mediastinal staging [SMS]).1 The objective of the present trial was to compare endoscopic mediastinal staging techniques (EBUS and EUS) to gold standard SMS techniques in patients with potentially resectable NSCLC.
Materials and Methods
with lymphadenopathy (short-axis LN diameter on CT scan . 10 mm) or PET-CT scan positivity in station 5 or 6. In these cases, frozen section analysis was first performed on all LN biopsy specimens obtained during CM. AM was then performed only if it would change the overall stage and clinical management of the patient.
Study Design This single-center prospective study was conducted in patients with potentially resectable NSCLC. All subjects underwent EBUS, EUS, and SMS as well as a CT scan of the chest and upper abdomen and PETCT scan prior to enrollment. The study was approved by the Institutional Review Board at the Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM IRB: 09.107). Study Participants Patients with a new or suspected diagnosis of lung cancer at the Centre Hospitalier de l’Université de Montréal who met criteria for invasive mediastinal staging2 and were deemed by a general thoracic surgeon to have potentially resectable lesions were prospectively enrolled. Inclusion and exclusion criteria are listed in Table 1. Study Interventions All procedures took place in the operating room under general anesthesia. Through a laryngeal mask airway, flexible videobronchoscopy was used to survey the airway. EBUS was then performed with a linear puncture echoendobronchoscope (BF-UC180F; Olympus America, Inc). All accessible LN stations were examined, and standard SMS LN stations were biopsied by fine-needle aspiration with a 22-gauge needle (NA-201SX-4022; Olympus America, Inc) under real-time EBUS guidance. Other suspicious LN stations based on CT scan, PET-CT scan, or EBUS were also biopsied. LN stations were defined using the Mountain Classification for mediastinal LNs.3,4 The laryngeal mask airway was removed, and patients underwent orotracheal intubation with a single-lumen endotracheal tube. EUS was then performed with the same technique used for EBUS (EUS linear scope GF-UC140P-AL5 [Olympus America, Inc] and EUS 22-gauge needle ECHO-1-22 [Cook Medical Ireland Ltd]). In addition to mediastinal LN stations, the celiac axis LNs, liver, and bilateral adrenal glands were evaluated and biopsied if found to be abnormal. A minimum of two needle passes was performed into each LN station. The decision to perform a minimum of two passes per LN was based on institutional review of optimal yields obtained by EBUS and EUS during the preceding 1,000 EBUS/EUS procedures. Rapid-on-site cytologic examination of EBUS/EUS specimens was not performed. EBUS and EUS were immediately followed by CM. An attempt to biopsy stations 4R, 4L, and 7 was made in all patients. Stations 1, 2R, and 2L were biopsied selectively based on clinical suspicion (CT scan, PET-CT scan, and surgical evaluation). Patients with isolated mediastinal adenopathy in the level 5 or 6 position underwent CM followed by left-sided AM (Chamberlain procedure).4 AM was only used in patients
390 Original Research
Multiple thoracic surgeons and trainees performed the study procedures. All procedures were supervised by the principal author (M. L.). The order of LN biopsy for EBUS, EUS, and mediastinoscopy was from the highest-level station to the lowest-level station to avoid crosscontamination of lower-level stations and avoid upstaging. All medically acceptable patients with negative mediastinal staging results following endosonographic and traditional staging underwent anatomic pulmonary resection. Pulmonary resection was performed during a separate operation. Systematic mediastinal LN sampling or dissection was performed at the time of pulmonary resection. All patients were followed-up at 30 days either at time of pulmonary resection, in the postoperative clinic, or by telephone call to assess for complications related to the staging procedure. Sample Size Sample size calculation was based on the available literature for mediastinoscopy, EUS, and EBUS for lung cancer and mediastinal lymphadenopathy.5-14 Traditional SMS techniques (CM, AM) were considered to be the gold standard in mediastinal staging and diagnosis and, therefore, were considered as having 100% accuracy and sensitivity. Published sample size calculation tables from studies of design accuracy in diagnostic tests with binary outcomes were used.15 The expected sensitivity for the combination of EBUS/EUS was taken to be 0.9314 with a lower 95% confidence limit . 0.85; the sample size derived from the exact method15 was 166 patients. Statistical Analysis Traditional staging techniques (CM, AM) were considered the gold standard tests for mediastinal diagnosis and staging to which other modalities and combinations of modalities were compared. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Results of EBUS, EUS, and the combination of EBUS/EUS were compared with SMS. Ninety-five percent CIs were calculated using the Clopper-Pearson exact method. Interprocedural agreement was assessed using the Cohen k coefficient. Secondary analyses were performed to evaluate the true accuracy of all mediastinal diagnostic strategies. These analyses included the results from mediastinal LN sampling and dissections performed at the time of pulmonary resection in patients with pulmonary pathology and negative results of all mediastinal LN biopsy specimens.
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TABLE 1
] Inclusion and Exclusion Criteria
Criteria Inclusion criteria Lung lesion (, 1 cm) with mediastinal lymphadenopathya and/or positive PET-CT scan in the mediastinum Lung lesion (ⱖ 1 cm) without mediastinal lymphadenopathya or positive PET-CT scan in the mediastinum Exclusion criteria Age , 18 y CT scan and/or PET-CT scan positivity in an extrathoracic site (adrenal gland, liver, brain, bone) Indeterminate pulmonary nodule , 1 cm in diameter without mediastinal lymphadenopathya on CT scan and a negative PET-CT scan History of previous mediastinoscopy Biopsy specimen-proven positive mediastinal LNs Inability to consent for the study Cervical or thoracic anatomy precluding mediastinoscopy Inability to tolerate general anesthesia Preoperative plan for carinal resection or carinal pneumonectomy (CM contraindicated prior to operative procedure due to additional difficulty secondary to scarring at time of resection) Active pulmonary infection (bronchitis, pneumonia) Active cutaneous infection overlying proposed surgical sites CM 5 cervical mediastinoscopy; LN 5 lymph node. aLymphadenopathy was defined as short-axis lymph node diameter of . 10 mm on CT scan.
Results Patients
Over a 30-month period, 501 patients were screened, of whom 251 were eligible and 169 agreed to participate. Three patients withdrew consent or were excluded prior to the procedure due to progression of disease. A total of 166 patients underwent both surgical and endosonographic mediastinal staging (Fig 1). AM was performed in five patients. Baseline characteristics of the study patients are described in Table 2. Mean (range) procedural times for the mediastinal LN staging procedures were 16.9 (8-42) min for CM, 22.9 (12-30) min for AM, 16.2 (4-30) min for EBUS, and 10.2 (1-27) min for EUS. Primary Outcome
EBUS, EUS, combined EBUS/EUS, and SMS sampled a mean of 2.2, 1.7, 3.9, and 3.1 LN stations, respectively (Table 3). The prevalence of N2/N3 disease was 32% (53 of 166 patients). The sensitivity, negative predictive value, and diagnostic accuracy, respectively, of the endoscopic staging modalities compared with SMS were EBUS, 72% (95% CI, 0.58-0.83), 88% (0.81-0.93), and 91% (0.85-0.95); EUS, 62% (0.48-0.75), 85% (0.780.91), and 88% (0.82-0.92); and combined EBUS/EUS, 91% (0.79-0.97), 96% (0.90-0.99), and 97% (0.93-0.99)
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(Tables 4, 5). There were five patients in whom the SMS procedure yielded positive results for N2 disease and the endosonographic mediastinal staging procedure findings were negative. Secondary Outcomes
A total of 114 patients had negative mediastinal LN staging results and underwent pulmonary resection. The negative predictive value and diagnostic accuracy, respectively, of the LN staging procedures compared with mediastinal LN sampling at thoracotomy were EBUS, 90% (95% CI, 0.83-0.95) and 90% (0.83-0.95); EUS, 90% (0.83-0.95) and 89% (0.82-0.94); combined EBUS/EUS, 92% (0.85-0.96) and 91% (0.84-0.96); and SMS, 89% (0.82-0.94) and 89% (0.82-0.94). Interprocedural agreement between mediastinal LN staging strategies and mediastinal LN sampling at the time of surgery were EBUS, 0.24 (95% CI, 20.18 to 0.67); EUS, 0.22 (20.20 to 0.64); combined EBUS/EUS, 0.41 (0.05-0.76); and SMS, 0.13 (20.34 to 0.59). Endosonography led to a diagnosis of N2/N3/M1 disease in 24 patients in whom SMS findings were negative, preventing futile thoracotomy in an additional 14% of patients. Mean ⫾ SD long- and short-axis LN size for EBUS LN biopsy specimens were 1.24 ⫾ 0.45 cm and 0.90 ⫾ 0.46 cm, respectively. Mean long- and short-axis LN 391
Major adverse events occurring during EBUS were leftsided mainstem bronchus laceration requiring surgical repair (n 5 1) and massive hemoptysis controlled with endoscopic interventions (n 5 1). There were no major adverse events during EUS. No minor adverse events occurred during endosonography. Minor intraprocedural adverse events occurring during SMS were minor bleeding (n 5 7), bradycardia (n 5 1), and arrhythmia (n 5 1). Postprocedural adverse events (30 days) were pneumothorax (n 5 1), cervical bleeding (n 5 1), minor hemoptysis (n 5 3), cervical wound seroma (n 5 2), and cervical hematoma (n 5 1).
Discussion In this single-center prospective trial comparing the results of SMS with endosonography, the endosonography results based on a combined EBUS/EUS procedure were similar to those of SMS. The negative predictive value for endosonography using the combined EBUS/EUS technique was 96%, with a very strong interprocedural agreement (k 5 93%). Additionally, endosonography was superior to SMS because it allows for the biopsy of LNs and metastases unattainable with SMS techniques, which led to the prevention of futile thoracotomy in an additional 14% of patients who would have been operated on based on SMS findings alone. These results suggest that endosonography using a combined EBUS/EUS procedure in the preoperative staging of NSCLC is superior to SMS and should be considered the new gold standard in mediastinal staging.
Figure 1 – Flow of study participant selection. *Lymphadenopathy was defined as short-axis lymph node diameter of 0.10 mm on CT scan. LN 5 lymph node.
size for EUS LN biopsy specimens were 1.43 ⫾ 0.63 cm and 0.83 ⫾ 0.40 cm, respectively. Adverse Events
Six major and nine minor intraprocedural adverse events occurred. There was no mortality related to mediastinal staging. Major adverse events occurring during SMS were tracheal injury requiring muscle flap coverage (n 5 1), external jugular vein injury requiring vessel ligation (n 5 1), left-sided recurrent nerve injury resulting in vocal cord paralysis (n 5 1), and left-sided vocal cord paresis that recovered after 4 months (n 5 1). 392 Original Research
The use of combined EBUS/EUS as a staging procedure compared with SMS, EBUS alone, and EUS alone allowed more LN stations to be sampled, leading to a diagnosis of mediastinal and extrathoracic metastases otherwise unattainable through traditional SMS. The combined EBUS/EUS procedure, therefore, allowed thoracic surgeons to be highly selective regarding which patients to operate on and prevented futile pulmonary resection in patients who had N2/N3/M1 disease, which would have not been diagnosed through traditional SMS. SMS is the gold standard technique to stage the mediastinum in patients with lung cancer. CT scan and PETCT scan have improved the radiologic staging of the mediastinum; however, these techniques are unable to provide for a definitive tissue diagnosis and are associated with low sensitivities and specificities.2,16-23 EBUS and EUS endosonographic technologies are proving to be extremely useful in mediastinal staging.24-29 These minimally invasive, transluminal techniques do not require general anesthesia and can be performed safely,
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TABLE 2
] Baseline Characteristics of the Study Patients
Characteristic
Range
] (continued)
Characteristic Value
Age, y Mean
TABLE 2
64 ⫾ 9.4 42-85
Sex
CT scan
11 (6.6)
PET-CT scan
13 (7.8)
Unknown CT scan
Female
84 (50.6)
Male
82 (49.4)
Right side
92 (55.4)
Left side
74 (44.6)
Right upper lobe
68 (41.0)
Right middle lobe
3 (1.8)
Right lower lobe
21 (12.7)
Left upper lobe
49 (29.5)
Left lower lobe
25 (15.1)
Histology in patients undergoing pulmonary resection (n 5 114) Adenocarcinoma
56 (49.1)
Squamous cell carcinoma
31 (27.2) 2 (1.7)
Large cell carcinoma
6 (5.3)
Other NSCLC
7 (6.1)
Carcinoid
4 (3.5)
Small cell carcinoma
1 (0.9)
Benign
7 (6.1)
Clinical stage IA CT scan
33 (20.0)
PET-CT scan
21 (12.7)
IB CT scan PET-CT scan
18 (10.8) 11 (6.6)
IIA CT scan PET-CT scan
16 (9.6) 29 (17.5)
IIB CT scan
23 (13.9)
PET-CT scan
20 (12.1)
IIIA CT scan
58 (34.9)
PET-CT scan
59 (35.5)
IIIB CT scan PET-CT scan
7 (4.2) 10 (6.0) (Continued)
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PET-CT scan
0 3 (1.8)
Data are presented as No. (%) unless otherwise indicate. NSCLC 5 nonsmall cell lung cancer.
Location of primary tumor
Adenosquamous carcinoma
Value
IV
rapidly, and accurately at a low cost.26,30,31 They complement each other5,32-34 and may complement surgical,7 bronchoscopic,35 and radiologic36 staging. Endosonographic techniques have quickly become the accepted and recommended first test for mediastinal staging in patients with a high likelihood of mediastinal LN positivity based on CT scan or PET scan.1,37 When the cytologic analysis is positive, the results are very reliable. However, when the cytology result is negative, the question remains about whether the patient should be subjected to invasive mediastinal staging. Furthermore, the accuracy of endosonography in mediastinal staging for patients with a radiologically normal mediastinum has not been established. Because of the cost, inconvenience, and risk associated with traditional SMS, many physicians are foregoing tissue diagnosis of the mediastinum, which results in incomplete preoperative staging for patients. Among 11,668 patients treated surgically for NSCLC in a multicenter survey of US hospitals, only 27% underwent CM.38 More importantly, of those patients undergoing CM, only 47% had LNs biopsied. This is likely related to the lack of appropriate surgical training and has been used as an important teaching point for surgeon training programs. Several retrospective and prospective studies have examined the safety and efficacy of these new techniques, but to date, no head-to-head prospective comparative studies have evaluated combined transluminal (EBUS/EUS) and traditional gold standard techniques on the same group of patients. Annema et al7 used a combination of EUS and CM to preoperatively stage patients with potentially resectable NSCLC. EUS added to CM in this study improved the sensitivity of CM in the diagnosis of both tumor invasion and LN metastases (CM and EUS 5 86% sensitivity compared with 61% with CM alone and 71% with EUS alone). Annema et al39 also performed a multicenter randomized
393
TABLE 3
] EBUS and EUS Sampling Data No. Passes
LN Station
No. Times Biopsied
Mean per Station
EBUS
EUS
EBUS
5
5 1
2R
SD
Sample Adequacy, %
EUS
EBUS
EUS
2.2
2.4
0.45
0.89
a
2.0
a
...
EBUS
EUS
Proportion Positive, % EBUS
80
100
a
100
1.02
86
100
21.5
40.0
1.04
81
100
16.7
15.8
2.1
a
0.69
a
2.5
a
1.22
a
2L
a
4R
102
15
2.8
2.3
1.11
4L
78
19
2.5
2.7
0.92
5
a
88
a
6
a
4
a
7
40.0
EUS
a
20.0 100
87.5
a
18.0
75
a
25.0
152
82
2.7
2.4
0.91
0.73
84
8R
a
23
a
2.2
a
0.67
a
100 91
12.5 a
13.0
17.0
8L
a
23
a
2.1
a
0.66
a
100
a
21.7
9R
a
2
a
2.5
a
0.71
a
100
a
50.0
9L
a
3
a
0
a
100
a
33.3
2.0
a
10R
13
a
2.3
a
1.17
a
77
a
23.0
a
10L
7
a
2.3
a
1.11
a
71
a
14.0
a
11R
4
a
2.5
a
1.73
a
100
a
11L
7
a
2.6
a
0.89
a
71
a
12R
1
a
3.0
a
...
a
100
a
100
a
12L
1
a
2.0
a
...
a
100
a
0
a
0 28.6
a a
Adrenal
a
7
a
2.1
a
0.69
a
100
a
14.0
Liver
a
1
a
2.0
a
...
a
100
a
100
EBUS 5 endobronchial ultrasound; EUS 5 endoscopic ultrasound. See Table 1 legend for expansion of other abbreviation. LN station not assessed using the specified technique.
a
controlled trial comparing surgical staging with a combined EBUS/EUS procedure. They showed that combining endosonography with surgical staging resulted in improved sensitivity (94%) compared with endosonography alone (85%). This mediastinal LN staging strategy was also more cost-effective compared with surgical staging alone.40 Wallace et al14 showed that the combination of EBUS/EUS allowed for near-complete minimally invasive mediastinal staging in a prospective cohort of patients with suspected lung cancer. All patients underwent EBUS, EUS, and conventional transbronchial needle aspiration TABLE 4
LN biopsy. The combination of EBUS/EUS was associated with the highest sensitivity (93%) and negative predictive value (97%) compared with either method alone. However, there was no surgical control group in this study. Yasufuku et al41 compared EBUS with CM for the staging of lung cancer in a head-to-head study in patients with potentially resectable lung cancer and did not find any differences in mediastinal staging between EBUS and CM. Both Adams et al42 and Gu et al43 performed meta-analyses of published studies looking at mediastinal LN staging using EBUS. Their meta-analyses included 10 and
] Diagnostic Accuracy and Interprocedural Agreement Between Endosonographic Diagnostic Modalities and Surgical Mediastinal Staging Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
EBUS
0.72 (0.58-0.83)
1.0 (0.97-1.0)
1.0 (0.91-1.0)
0.88 (0.81-0.93) 0.91 (0.85-0.95) 0.77 (0.66-0.88)
EUS
0.62 (0.48-0.75)
1.0 (0.97-1.0)
1.0 (0.89-1.0)
0.85 (0.78-0.91) 0.88 (0.82-0.92) 0.69 (0.56-0.82)
Combined EBUS/EUS
0.91 (0.79-0.97)
1.0 (0.97-1.0)
1.0 (0.93-1.0)
0.96 (0.90-0.99) 0.97 (0.93-0.99) 0.93 (0.87-0.99)
Modality
Accuracy (95% CI)
NPV (95% CI)
Cohen k Coefficient (95% CI)
NPV 5 negative predictive value; PPV 5 positive predictive value. See Table 3 legend for expansion of other abbreviations.
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TABLE 5
] Biopsy Results by Staging Modality CM
LN Station 1
Total No. LNs Biopsied
AM
Malignant LNs
Total No. LNs Biopsied
EBUS
EUS
Malignant LNs
Total No. LNs Biopsied
Malignant LNs
Total No. LNs Biopsied
Malignant LNs
…
…
…
…
2
5
1
15
0
…
…
9
2
…
…
2L
…
…
…
…
…
…
1
1
4R
165
23
…
…
102
22
15
6
4L
161
12
…
…
78
13
19
3
5
…
…
2
1
…
…
88
16
2R
5
6
…
…
4
4
…
…
4
1
7
164
18
…
…
152
19
82
14
8R
…
…
…
…
…
…
23
3
8L
…
…
…
…
…
…
23
5
9R
…
…
…
…
…
…
2
1
9L
…
…
…
…
…
…
3
1
10, 11, 12R
0
…
…
33
7
…
…
…
…
…
…
…
…
…
…
Left adrenal
…
…
…
…
…
…
6
1
Right adrenal
…
…
…
…
…
…
1
0
Liver
…
…
…
…
…
…
1
1
10, 11, 12L
1
AM 5 anterior mediastinotomy. See Table 1 and 3 legends for expansion of other abbreviations.
11 studies, respectively. Pooled sensitivities for EBUS LN staging were 88% and 93%, respectively. Endoscopic techniques are quickly replacing traditional techniques in some centers; however, when replacing a gold standard test with a new modality, one must first prove equivalence in safety and efficacy. Furthermore, because of the lack of large prospective clinical trials demonstrating equivalence in patients that are potentially operable, many physicians do not subscribe to the minimally invasive mediastinal staging strategies and, therefore, are still relying on surgical staging of the mediastinum or completely foregoing mediastinal staging.38 When endosonographic LN biopsy results are positive, it is easy for the treating physician to establish the nodal status (N stage) of patients with NSCLC. However, when the LN result is negative, the question remains about whether confirmatory SMS LN biopsy is required.1 The results of the present trial suggest that patients with negative LN biopsy results on combined endosonographic (EBUS/EUS) mediastinal LN staging do not require confirmatory invasive mediastinal LN staging. Interprocedural agreement between mediastinal LN staging strategies and surgical mediastinal LN sampling was higher for EBUS than for EUS but was strongest for journal.publications.chestnet.org
the combined EBUS/EUS procedure. Preoperative LN staging strategies (EBUS, EUS, combined EBUS/ EUS, SMS) did not perform well compared with LN staging at the time of thoracotomy or thoracoscopy primarily because of the low number of positive LN findings in patients who underwent lung resection. Patients with N2 or N3 tumors by mediastinal staging prior to surgery were excluded, and, therefore, the incidence of positive LN findings in patients undergoing surgical lung resection was low, contributing to the lower sensitivity. Major adverse events related to endosonography are rare. In this study, we report on two major procedurerelated morbidities following EBUS. A major airway laceration occurred during EBUS biopsy of a subcarinal LN (station 7). This complication has been reported previously.44 The patient who had massive hemoptysis from an EBUS puncture site had endoscopic control of bleeding with bronchoscopic pressure and topical tranexamic acid. This EBUS complication has been previously reported by another group and has even resulted in death.45 The strengths of this study include the strict inclusion criteria, which mirror current LN staging guidelines for 395
patients with NSCLC and gold standard SMS control in all patients. A randomized design for a study such as this would make it impossible to assign sensitivity and negative predictive values to the diagnostic staging modalities because of the heterogeneity in LN station positivity and the inability to verify the accuracy of LN staging results in patients randomized to one technique or the other. An important weakness of the study is that all procedures were performed in a single center, which somewhat limits the external validity but was minimized by having the procedures performed by multiple endoscopists at all levels of training and experience. The lack of rapid-on-site cytologic LN examination reflects real-world practice and may underestimate
Acknowledgments Author contributions: M. L. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M. L., J. S., A. D., and P. F. contributed to obtaining of funding; M. L. and J. S. contributed to study concept and design; M. L. and P. F. contributed to study supervision; V. T. and R. H. contributed to the data acquisition and critical revision of the manuscript for important intellectual content; M. L., A. D., and P. F. contributed to data acquisition, analysis, and interpretation; J. S. contributed to data analysis and interpretation; M. L. and J. S. contributed to statistical analysis; and M. L., J. S., A. D., and P. F. contributed to the drafting of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors contributed to the salary of the research assistants, study equipment and materials, computer hardware and software, biostatistic fees, and projectrelated travel fees. Other contributions: The authors thank Sandra Larivée, PhD, biostatistician, Research Center, Centre Hospitalier de l’Université de Montréal for conducting portions of the data analysis of this trial. She was financially compensated for statistical analysis.
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ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3_suppl):202S-220S. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111(6):1710-1717. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest. 1997;111(6):1718-1723. Rintoul RC, Skwarski KM, Murchison JT, Wallace WA, Walker WS, Penman ID. Endobronchial and endoscopic ultrasound-guided real-time fine-needle aspiration for mediastinal staging. Eur Respir J. 2005;25(3):416-421. Annema JT, Versteegh MI, Veseliç M, Voigt P, Rabe KF. Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol. 2005;23(33): 8357-8361. Annema JT, Versteegh MI, Veseliç M, et al. Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer. JAMA. 2005;294(8):931-936. LeBlanc JK, Devereaux BM, Imperiale TF, et al. Endoscopic ultrasound in non-small cell lung cancer and negative mediastinum on computed tomography. Am J Respir Crit Care Med. 2005; 171(2):177-182. Wallace MB, Ravenel J, Block MI, et al. Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography. Ann Thorac Surg. 2004;77(5):1763-1768. Ernst A, Anantham D, Eberhardt R, Krasnik M, Herth FJ. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol. 2008;3(6):577-582. Herth FJ, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61(9):795-798.
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31. Aabakken L, Silvestri GA, Hawes R, Reed CE, Marsi V, Hoffman B. Cost-efficacy of endoscopic ultrasonography with fineneedle aspiration vs. mediastinotomy in patients with lung cancer and suspected mediastinal adenopathy. Endoscopy. 1999;31(9):707-711. 32. Herth FJF, Lunn W, Eberhardt R, Becker HD, Ernest A. Transbronchial vs. transesophageal ultrasound-guided aspiration of enlarged mediastinal lymph nodes. Am J Respir Crit Care Med. 2005;171(10):1164-1167. 33. Cerfolio RJ, Bryant AS, Eloubeidi MA. Routine mediastinoscopy and esophageal ultrasound fine-needle aspiration in patients with non-small cell lung cancer who are clinically N2 negative: a prospective study. Chest. 2006;130(6):1791-1795. 34. Vilmann P, Krasnik M, Larsen SS, Jacobsen GK, Clementsen P. Transesophageal endoscopic ultrasoundguided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUSTBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy. 2005;37(9):833-839. 35. Khoo KL, Ho KY, Nilsson B, Lim TK. EUS-guided FNA immediately after unrevealing transbronchial needle aspiration in the evaluation of mediastinal lymphadenopathy: a prospective study. Gastrointest Endosc. 2006;63(2): 215-220. 36. Okamoto H, Watanabe K, Nagatomo A, et al. Endobronchial ultrasonography for mediastinal and hilar lymph node metastases of lung cancer. Chest. 2002;121(5):1498-1506. 37. Ost DE, Yeung SC, Tanoue LT, Gould MK. Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest. 2013;143(5_suppl):e121S-e141S.
38. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg. 2005;80(6):2051-2056. 39. Annema JTMJ, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010;304(20):2245-2252. 40. Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess. 2012;16(18):1-75. 41. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011;142(6):1393-1400. 42. Adams KSP, Shah PL, Edmonds L, Lim E. 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):757-762. 43. Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasoundguided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45(8):1389-1396. 44. Liberman M, Duranceau A, Martin J, Thiffault V, Ferraro P. Major airway laceration secondary to endobronchial ultrasound transbronchial lymph node biopsy. J Bronchology Interv Pulmonol. 2010;17(3):264-265. 45. Aguilar-Lopez CA, Weir I, Winter S. Fatal hemoptysis after endobronchial ultrasound guided mediastinal biopsies. Am J Respir Crit Care Med. 2013;187:A5809.
397
Original Research Pulmonary Procedures
]
Endosonographic Mediastinal Lymph Node Staging of Lung Cancer Moishe Liberman, MD, PhD; John Sampalis, PhD; André Duranceau, MD; Vicky Thiffault, RN; Rachid Hadjeres, MD; and Pasquale Ferraro, MD
It is unclear whether endoscopic mediastinal lymph node (LN) staging techniques are equivalent to surgical mediastinal staging (SMS) techniques in patients with potentially operable non-small cell lung cancer (NSCLC).
BACKGROUND:
METHODS: A total of 166 patients with confirmed or suspected NSCLC who required SMS based on current guidelines were enrolled in this prospective controlled trial comparing endosonographic mediastinal LN staging with SMS. Each patient served as his or her own control. All patients underwent endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and SMS during a single procedure. Results of EBUS, EUS, and combined EBUS/EUS were compared with SMS (gold standard) and in patients with negative LN staging results, with LN sampling at pulmonary resection.
EBUS, EUS, combined EBUS/EUS, and SMS sampled a mean of 2.2, 1.7, 3.9, and 3.1 LN stations, respectively. The prevalence of mediastinal nodal disease (N2/N3) was 32% (53 of 166 patients). The sensitivity, negative predictive value, and diagnostic accuracy of the endoscopic staging modalities, respectively, were EBUS, 72% (95% CI, 0.58-0.83), 88% (0.81-0.93), and 91% (0.85-0.95); EUS, 62% (0.48-0.75), 85% (0.78-0.91), and 88% (0.82-0.92); and combined EBUS/EUS, 91% (0.79-0.97), 96% (0.90-0.99), and 97% (0.93-0.99). Endosonography was diagnostic for N2/N3/M1 disease in 24 patients in whom SMS findings were negative, preventing futile thoracotomy in an additional 14% of patients.
RESULTS:
The combined EBUS/EUS procedure can replace surgical mediastinal staging in patients with potentially resectable NSCLC. Additionally, endosonography leads to improved staging compared with SMS because it allows the biopsy of LNs and metastases unattainable with SMS techniques.
CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT01011595; URL: www.clinicaltrials.gov CHEST 2014; 146(2):389-397
Manuscript received October 2, 2013; revision accepted February 5, 2014; originally published Online First March 6, 2014. ABBREVIATIONS: AM 5 anterior mediastinotomy; CM 5 cervical mediastinoscopy; EBUS 5 endobronchial ultrasound; EUS 5 endoscopic ultrasound; LN 5 lymph node; NSCLC 5 non-small cell lung cancer; SMS 5 surgical mediastinal staging AFFILIATIONS: From the CHUM Endoscopic Tracheobronchial and Oesophageal Center (CETOC), Division of Thoracic Surgery (Drs Liberman, Duranceau, and Ferraro and Ms Thiffault), and Department of Pathology (Dr Hadjeres), University of Montréal; Centre Hospitalier de l’Université de Montréal (Drs Liberman, Duranceau, Hadjeres, and Ferraro and Ms Thiffault); and Department of Epidemiology (Dr Sampalis), McGill University, Montréal, QC, Canada. Part of this article has been presented in abstract form at the American Thoracic Society International Conference, May 17-22, 2013, Philadelphia, PA.
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This study was funded by the Canadian Foundation for Innovation, the Society of University Surgeons, and the Fonds de Recherche en Santé du Québec. CORRESPONDENCE TO: Moishe Liberman, MD, PhD, CHUM Endoscopic Tracheobronchial and Oesophageal Center (CETOC), Division of Thoracic Surgery, Centre Hospitalier de l’Université de Montréal, 1560 rue Sherbrooke Est, 8e CD-Pavillon Lachapelle, Bureau D-8051, Montréal, QC H2L 4M1, Canada; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2349 FUNDING/SUPPORT:
389
The gold standard techniques to stage mediastinal lymph nodes (LNs) in patients with potentially resectable non-small cell lung cancer (NSCLC) consist of cervical mediastinoscopy (CM) and anterior mediastinotomy (AM) or video-assisted thoracoscopic surgery.1 Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) are endosonographic techniques used to stage the mediastinum without surgery; however, current comparative data have been limited primarily to individual comparisons of endosonographic techniques (EBUS vs CM). These studies have demonstrated acceptable diagnostic accuracies, but the combined modality approach (EBUS and EUS) may
offer additional accuracy that improves on even traditional surgical staging. Current NSCLC staging guidelines recommend mediastinal LN staging by a needle technique (EBUS, EUS, or combined EBUS/EUS) as a first test; however, if the findings are negative and clinical suspicion is high, the recommendation is to follow the needle techniques with a confirmatory surgical biopsy using either CM or video-assisted thoracoscopic surgery (surgical mediastinal staging [SMS]).1 The objective of the present trial was to compare endoscopic mediastinal staging techniques (EBUS and EUS) to gold standard SMS techniques in patients with potentially resectable NSCLC.
Materials and Methods
with lymphadenopathy (short-axis LN diameter on CT scan . 10 mm) or PET-CT scan positivity in station 5 or 6. In these cases, frozen section analysis was first performed on all LN biopsy specimens obtained during CM. AM was then performed only if it would change the overall stage and clinical management of the patient.
Study Design This single-center prospective study was conducted in patients with potentially resectable NSCLC. All subjects underwent EBUS, EUS, and SMS as well as a CT scan of the chest and upper abdomen and PETCT scan prior to enrollment. The study was approved by the Institutional Review Board at the Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM IRB: 09.107). Study Participants Patients with a new or suspected diagnosis of lung cancer at the Centre Hospitalier de l’Université de Montréal who met criteria for invasive mediastinal staging2 and were deemed by a general thoracic surgeon to have potentially resectable lesions were prospectively enrolled. Inclusion and exclusion criteria are listed in Table 1. Study Interventions All procedures took place in the operating room under general anesthesia. Through a laryngeal mask airway, flexible videobronchoscopy was used to survey the airway. EBUS was then performed with a linear puncture echoendobronchoscope (BF-UC180F; Olympus America, Inc). All accessible LN stations were examined, and standard SMS LN stations were biopsied by fine-needle aspiration with a 22-gauge needle (NA-201SX-4022; Olympus America, Inc) under real-time EBUS guidance. Other suspicious LN stations based on CT scan, PET-CT scan, or EBUS were also biopsied. LN stations were defined using the Mountain Classification for mediastinal LNs.3,4 The laryngeal mask airway was removed, and patients underwent orotracheal intubation with a single-lumen endotracheal tube. EUS was then performed with the same technique used for EBUS (EUS linear scope GF-UC140P-AL5 [Olympus America, Inc] and EUS 22-gauge needle ECHO-1-22 [Cook Medical Ireland Ltd]). In addition to mediastinal LN stations, the celiac axis LNs, liver, and bilateral adrenal glands were evaluated and biopsied if found to be abnormal. A minimum of two needle passes was performed into each LN station. The decision to perform a minimum of two passes per LN was based on institutional review of optimal yields obtained by EBUS and EUS during the preceding 1,000 EBUS/EUS procedures. Rapid-on-site cytologic examination of EBUS/EUS specimens was not performed. EBUS and EUS were immediately followed by CM. An attempt to biopsy stations 4R, 4L, and 7 was made in all patients. Stations 1, 2R, and 2L were biopsied selectively based on clinical suspicion (CT scan, PET-CT scan, and surgical evaluation). Patients with isolated mediastinal adenopathy in the level 5 or 6 position underwent CM followed by left-sided AM (Chamberlain procedure).4 AM was only used in patients
390 Original Research
Multiple thoracic surgeons and trainees performed the study procedures. All procedures were supervised by the principal author (M. L.). The order of LN biopsy for EBUS, EUS, and mediastinoscopy was from the highest-level station to the lowest-level station to avoid crosscontamination of lower-level stations and avoid upstaging. All medically acceptable patients with negative mediastinal staging results following endosonographic and traditional staging underwent anatomic pulmonary resection. Pulmonary resection was performed during a separate operation. Systematic mediastinal LN sampling or dissection was performed at the time of pulmonary resection. All patients were followed-up at 30 days either at time of pulmonary resection, in the postoperative clinic, or by telephone call to assess for complications related to the staging procedure. Sample Size Sample size calculation was based on the available literature for mediastinoscopy, EUS, and EBUS for lung cancer and mediastinal lymphadenopathy.5-14 Traditional SMS techniques (CM, AM) were considered to be the gold standard in mediastinal staging and diagnosis and, therefore, were considered as having 100% accuracy and sensitivity. Published sample size calculation tables from studies of design accuracy in diagnostic tests with binary outcomes were used.15 The expected sensitivity for the combination of EBUS/EUS was taken to be 0.9314 with a lower 95% confidence limit . 0.85; the sample size derived from the exact method15 was 166 patients. Statistical Analysis Traditional staging techniques (CM, AM) were considered the gold standard tests for mediastinal diagnosis and staging to which other modalities and combinations of modalities were compared. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Results of EBUS, EUS, and the combination of EBUS/EUS were compared with SMS. Ninety-five percent CIs were calculated using the Clopper-Pearson exact method. Interprocedural agreement was assessed using the Cohen k coefficient. Secondary analyses were performed to evaluate the true accuracy of all mediastinal diagnostic strategies. These analyses included the results from mediastinal LN sampling and dissections performed at the time of pulmonary resection in patients with pulmonary pathology and negative results of all mediastinal LN biopsy specimens.
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TABLE 1
] Inclusion and Exclusion Criteria
Criteria Inclusion criteria Lung lesion (, 1 cm) with mediastinal lymphadenopathya and/or positive PET-CT scan in the mediastinum Lung lesion (ⱖ 1 cm) without mediastinal lymphadenopathya or positive PET-CT scan in the mediastinum Exclusion criteria Age , 18 y CT scan and/or PET-CT scan positivity in an extrathoracic site (adrenal gland, liver, brain, bone) Indeterminate pulmonary nodule , 1 cm in diameter without mediastinal lymphadenopathya on CT scan and a negative PET-CT scan History of previous mediastinoscopy Biopsy specimen-proven positive mediastinal LNs Inability to consent for the study Cervical or thoracic anatomy precluding mediastinoscopy Inability to tolerate general anesthesia Preoperative plan for carinal resection or carinal pneumonectomy (CM contraindicated prior to operative procedure due to additional difficulty secondary to scarring at time of resection) Active pulmonary infection (bronchitis, pneumonia) Active cutaneous infection overlying proposed surgical sites CM 5 cervical mediastinoscopy; LN 5 lymph node. aLymphadenopathy was defined as short-axis lymph node diameter of . 10 mm on CT scan.
Results Patients
Over a 30-month period, 501 patients were screened, of whom 251 were eligible and 169 agreed to participate. Three patients withdrew consent or were excluded prior to the procedure due to progression of disease. A total of 166 patients underwent both surgical and endosonographic mediastinal staging (Fig 1). AM was performed in five patients. Baseline characteristics of the study patients are described in Table 2. Mean (range) procedural times for the mediastinal LN staging procedures were 16.9 (8-42) min for CM, 22.9 (12-30) min for AM, 16.2 (4-30) min for EBUS, and 10.2 (1-27) min for EUS. Primary Outcome
EBUS, EUS, combined EBUS/EUS, and SMS sampled a mean of 2.2, 1.7, 3.9, and 3.1 LN stations, respectively (Table 3). The prevalence of N2/N3 disease was 32% (53 of 166 patients). The sensitivity, negative predictive value, and diagnostic accuracy, respectively, of the endoscopic staging modalities compared with SMS were EBUS, 72% (95% CI, 0.58-0.83), 88% (0.81-0.93), and 91% (0.85-0.95); EUS, 62% (0.48-0.75), 85% (0.780.91), and 88% (0.82-0.92); and combined EBUS/EUS, 91% (0.79-0.97), 96% (0.90-0.99), and 97% (0.93-0.99)
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(Tables 4, 5). There were five patients in whom the SMS procedure yielded positive results for N2 disease and the endosonographic mediastinal staging procedure findings were negative. Secondary Outcomes
A total of 114 patients had negative mediastinal LN staging results and underwent pulmonary resection. The negative predictive value and diagnostic accuracy, respectively, of the LN staging procedures compared with mediastinal LN sampling at thoracotomy were EBUS, 90% (95% CI, 0.83-0.95) and 90% (0.83-0.95); EUS, 90% (0.83-0.95) and 89% (0.82-0.94); combined EBUS/EUS, 92% (0.85-0.96) and 91% (0.84-0.96); and SMS, 89% (0.82-0.94) and 89% (0.82-0.94). Interprocedural agreement between mediastinal LN staging strategies and mediastinal LN sampling at the time of surgery were EBUS, 0.24 (95% CI, 20.18 to 0.67); EUS, 0.22 (20.20 to 0.64); combined EBUS/EUS, 0.41 (0.05-0.76); and SMS, 0.13 (20.34 to 0.59). Endosonography led to a diagnosis of N2/N3/M1 disease in 24 patients in whom SMS findings were negative, preventing futile thoracotomy in an additional 14% of patients. Mean ⫾ SD long- and short-axis LN size for EBUS LN biopsy specimens were 1.24 ⫾ 0.45 cm and 0.90 ⫾ 0.46 cm, respectively. Mean long- and short-axis LN 391
Major adverse events occurring during EBUS were leftsided mainstem bronchus laceration requiring surgical repair (n 5 1) and massive hemoptysis controlled with endoscopic interventions (n 5 1). There were no major adverse events during EUS. No minor adverse events occurred during endosonography. Minor intraprocedural adverse events occurring during SMS were minor bleeding (n 5 7), bradycardia (n 5 1), and arrhythmia (n 5 1). Postprocedural adverse events (30 days) were pneumothorax (n 5 1), cervical bleeding (n 5 1), minor hemoptysis (n 5 3), cervical wound seroma (n 5 2), and cervical hematoma (n 5 1).
Discussion In this single-center prospective trial comparing the results of SMS with endosonography, the endosonography results based on a combined EBUS/EUS procedure were similar to those of SMS. The negative predictive value for endosonography using the combined EBUS/EUS technique was 96%, with a very strong interprocedural agreement (k 5 93%). Additionally, endosonography was superior to SMS because it allows for the biopsy of LNs and metastases unattainable with SMS techniques, which led to the prevention of futile thoracotomy in an additional 14% of patients who would have been operated on based on SMS findings alone. These results suggest that endosonography using a combined EBUS/EUS procedure in the preoperative staging of NSCLC is superior to SMS and should be considered the new gold standard in mediastinal staging.
Figure 1 – Flow of study participant selection. *Lymphadenopathy was defined as short-axis lymph node diameter of 0.10 mm on CT scan. LN 5 lymph node.
size for EUS LN biopsy specimens were 1.43 ⫾ 0.63 cm and 0.83 ⫾ 0.40 cm, respectively. Adverse Events
Six major and nine minor intraprocedural adverse events occurred. There was no mortality related to mediastinal staging. Major adverse events occurring during SMS were tracheal injury requiring muscle flap coverage (n 5 1), external jugular vein injury requiring vessel ligation (n 5 1), left-sided recurrent nerve injury resulting in vocal cord paralysis (n 5 1), and left-sided vocal cord paresis that recovered after 4 months (n 5 1). 392 Original Research
The use of combined EBUS/EUS as a staging procedure compared with SMS, EBUS alone, and EUS alone allowed more LN stations to be sampled, leading to a diagnosis of mediastinal and extrathoracic metastases otherwise unattainable through traditional SMS. The combined EBUS/EUS procedure, therefore, allowed thoracic surgeons to be highly selective regarding which patients to operate on and prevented futile pulmonary resection in patients who had N2/N3/M1 disease, which would have not been diagnosed through traditional SMS. SMS is the gold standard technique to stage the mediastinum in patients with lung cancer. CT scan and PETCT scan have improved the radiologic staging of the mediastinum; however, these techniques are unable to provide for a definitive tissue diagnosis and are associated with low sensitivities and specificities.2,16-23 EBUS and EUS endosonographic technologies are proving to be extremely useful in mediastinal staging.24-29 These minimally invasive, transluminal techniques do not require general anesthesia and can be performed safely,
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TABLE 2
] Baseline Characteristics of the Study Patients
Characteristic
Range
] (continued)
Characteristic Value
Age, y Mean
TABLE 2
64 ⫾ 9.4 42-85
Sex
CT scan
11 (6.6)
PET-CT scan
13 (7.8)
Unknown CT scan
Female
84 (50.6)
Male
82 (49.4)
Right side
92 (55.4)
Left side
74 (44.6)
Right upper lobe
68 (41.0)
Right middle lobe
3 (1.8)
Right lower lobe
21 (12.7)
Left upper lobe
49 (29.5)
Left lower lobe
25 (15.1)
Histology in patients undergoing pulmonary resection (n 5 114) Adenocarcinoma
56 (49.1)
Squamous cell carcinoma
31 (27.2) 2 (1.7)
Large cell carcinoma
6 (5.3)
Other NSCLC
7 (6.1)
Carcinoid
4 (3.5)
Small cell carcinoma
1 (0.9)
Benign
7 (6.1)
Clinical stage IA CT scan
33 (20.0)
PET-CT scan
21 (12.7)
IB CT scan PET-CT scan
18 (10.8) 11 (6.6)
IIA CT scan PET-CT scan
16 (9.6) 29 (17.5)
IIB CT scan
23 (13.9)
PET-CT scan
20 (12.1)
IIIA CT scan
58 (34.9)
PET-CT scan
59 (35.5)
IIIB CT scan PET-CT scan
7 (4.2) 10 (6.0) (Continued)
journal.publications.chestnet.org
PET-CT scan
0 3 (1.8)
Data are presented as No. (%) unless otherwise indicate. NSCLC 5 nonsmall cell lung cancer.
Location of primary tumor
Adenosquamous carcinoma
Value
IV
rapidly, and accurately at a low cost.26,30,31 They complement each other5,32-34 and may complement surgical,7 bronchoscopic,35 and radiologic36 staging. Endosonographic techniques have quickly become the accepted and recommended first test for mediastinal staging in patients with a high likelihood of mediastinal LN positivity based on CT scan or PET scan.1,37 When the cytologic analysis is positive, the results are very reliable. However, when the cytology result is negative, the question remains about whether the patient should be subjected to invasive mediastinal staging. Furthermore, the accuracy of endosonography in mediastinal staging for patients with a radiologically normal mediastinum has not been established. Because of the cost, inconvenience, and risk associated with traditional SMS, many physicians are foregoing tissue diagnosis of the mediastinum, which results in incomplete preoperative staging for patients. Among 11,668 patients treated surgically for NSCLC in a multicenter survey of US hospitals, only 27% underwent CM.38 More importantly, of those patients undergoing CM, only 47% had LNs biopsied. This is likely related to the lack of appropriate surgical training and has been used as an important teaching point for surgeon training programs. Several retrospective and prospective studies have examined the safety and efficacy of these new techniques, but to date, no head-to-head prospective comparative studies have evaluated combined transluminal (EBUS/EUS) and traditional gold standard techniques on the same group of patients. Annema et al7 used a combination of EUS and CM to preoperatively stage patients with potentially resectable NSCLC. EUS added to CM in this study improved the sensitivity of CM in the diagnosis of both tumor invasion and LN metastases (CM and EUS 5 86% sensitivity compared with 61% with CM alone and 71% with EUS alone). Annema et al39 also performed a multicenter randomized
393
TABLE 3
] EBUS and EUS Sampling Data No. Passes
LN Station
No. Times Biopsied
Mean per Station
EBUS
EUS
EBUS
5
5 1
2R
SD
Sample Adequacy, %
EUS
EBUS
EUS
2.2
2.4
0.45
0.89
a
2.0
a
...
EBUS
EUS
Proportion Positive, % EBUS
80
100
a
100
1.02
86
100
21.5
40.0
1.04
81
100
16.7
15.8
2.1
a
0.69
a
2.5
a
1.22
a
2L
a
4R
102
15
2.8
2.3
1.11
4L
78
19
2.5
2.7
0.92
5
a
88
a
6
a
4
a
7
40.0
EUS
a
20.0 100
87.5
a
18.0
75
a
25.0
152
82
2.7
2.4
0.91
0.73
84
8R
a
23
a
2.2
a
0.67
a
100 91
12.5 a
13.0
17.0
8L
a
23
a
2.1
a
0.66
a
100
a
21.7
9R
a
2
a
2.5
a
0.71
a
100
a
50.0
9L
a
3
a
0
a
100
a
33.3
2.0
a
10R
13
a
2.3
a
1.17
a
77
a
23.0
a
10L
7
a
2.3
a
1.11
a
71
a
14.0
a
11R
4
a
2.5
a
1.73
a
100
a
11L
7
a
2.6
a
0.89
a
71
a
12R
1
a
3.0
a
...
a
100
a
100
a
12L
1
a
2.0
a
...
a
100
a
0
a
0 28.6
a a
Adrenal
a
7
a
2.1
a
0.69
a
100
a
14.0
Liver
a
1
a
2.0
a
...
a
100
a
100
EBUS 5 endobronchial ultrasound; EUS 5 endoscopic ultrasound. See Table 1 legend for expansion of other abbreviation. LN station not assessed using the specified technique.
a
controlled trial comparing surgical staging with a combined EBUS/EUS procedure. They showed that combining endosonography with surgical staging resulted in improved sensitivity (94%) compared with endosonography alone (85%). This mediastinal LN staging strategy was also more cost-effective compared with surgical staging alone.40 Wallace et al14 showed that the combination of EBUS/EUS allowed for near-complete minimally invasive mediastinal staging in a prospective cohort of patients with suspected lung cancer. All patients underwent EBUS, EUS, and conventional transbronchial needle aspiration TABLE 4
LN biopsy. The combination of EBUS/EUS was associated with the highest sensitivity (93%) and negative predictive value (97%) compared with either method alone. However, there was no surgical control group in this study. Yasufuku et al41 compared EBUS with CM for the staging of lung cancer in a head-to-head study in patients with potentially resectable lung cancer and did not find any differences in mediastinal staging between EBUS and CM. Both Adams et al42 and Gu et al43 performed meta-analyses of published studies looking at mediastinal LN staging using EBUS. Their meta-analyses included 10 and
] Diagnostic Accuracy and Interprocedural Agreement Between Endosonographic Diagnostic Modalities and Surgical Mediastinal Staging Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
EBUS
0.72 (0.58-0.83)
1.0 (0.97-1.0)
1.0 (0.91-1.0)
0.88 (0.81-0.93) 0.91 (0.85-0.95) 0.77 (0.66-0.88)
EUS
0.62 (0.48-0.75)
1.0 (0.97-1.0)
1.0 (0.89-1.0)
0.85 (0.78-0.91) 0.88 (0.82-0.92) 0.69 (0.56-0.82)
Combined EBUS/EUS
0.91 (0.79-0.97)
1.0 (0.97-1.0)
1.0 (0.93-1.0)
0.96 (0.90-0.99) 0.97 (0.93-0.99) 0.93 (0.87-0.99)
Modality
Accuracy (95% CI)
NPV (95% CI)
Cohen k Coefficient (95% CI)
NPV 5 negative predictive value; PPV 5 positive predictive value. See Table 3 legend for expansion of other abbreviations.
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TABLE 5
] Biopsy Results by Staging Modality CM
LN Station 1
Total No. LNs Biopsied
AM
Malignant LNs
Total No. LNs Biopsied
EBUS
EUS
Malignant LNs
Total No. LNs Biopsied
Malignant LNs
Total No. LNs Biopsied
Malignant LNs
…
…
…
…
2
5
1
15
0
…
…
9
2
…
…
2L
…
…
…
…
…
…
1
1
4R
165
23
…
…
102
22
15
6
4L
161
12
…
…
78
13
19
3
5
…
…
2
1
…
…
88
16
2R
5
6
…
…
4
4
…
…
4
1
7
164
18
…
…
152
19
82
14
8R
…
…
…
…
…
…
23
3
8L
…
…
…
…
…
…
23
5
9R
…
…
…
…
…
…
2
1
9L
…
…
…
…
…
…
3
1
10, 11, 12R
0
…
…
33
7
…
…
…
…
…
…
…
…
…
…
Left adrenal
…
…
…
…
…
…
6
1
Right adrenal
…
…
…
…
…
…
1
0
Liver
…
…
…
…
…
…
1
1
10, 11, 12L
1
AM 5 anterior mediastinotomy. See Table 1 and 3 legends for expansion of other abbreviations.
11 studies, respectively. Pooled sensitivities for EBUS LN staging were 88% and 93%, respectively. Endoscopic techniques are quickly replacing traditional techniques in some centers; however, when replacing a gold standard test with a new modality, one must first prove equivalence in safety and efficacy. Furthermore, because of the lack of large prospective clinical trials demonstrating equivalence in patients that are potentially operable, many physicians do not subscribe to the minimally invasive mediastinal staging strategies and, therefore, are still relying on surgical staging of the mediastinum or completely foregoing mediastinal staging.38 When endosonographic LN biopsy results are positive, it is easy for the treating physician to establish the nodal status (N stage) of patients with NSCLC. However, when the LN result is negative, the question remains about whether confirmatory SMS LN biopsy is required.1 The results of the present trial suggest that patients with negative LN biopsy results on combined endosonographic (EBUS/EUS) mediastinal LN staging do not require confirmatory invasive mediastinal LN staging. Interprocedural agreement between mediastinal LN staging strategies and surgical mediastinal LN sampling was higher for EBUS than for EUS but was strongest for journal.publications.chestnet.org
the combined EBUS/EUS procedure. Preoperative LN staging strategies (EBUS, EUS, combined EBUS/ EUS, SMS) did not perform well compared with LN staging at the time of thoracotomy or thoracoscopy primarily because of the low number of positive LN findings in patients who underwent lung resection. Patients with N2 or N3 tumors by mediastinal staging prior to surgery were excluded, and, therefore, the incidence of positive LN findings in patients undergoing surgical lung resection was low, contributing to the lower sensitivity. Major adverse events related to endosonography are rare. In this study, we report on two major procedurerelated morbidities following EBUS. A major airway laceration occurred during EBUS biopsy of a subcarinal LN (station 7). This complication has been reported previously.44 The patient who had massive hemoptysis from an EBUS puncture site had endoscopic control of bleeding with bronchoscopic pressure and topical tranexamic acid. This EBUS complication has been previously reported by another group and has even resulted in death.45 The strengths of this study include the strict inclusion criteria, which mirror current LN staging guidelines for 395
patients with NSCLC and gold standard SMS control in all patients. A randomized design for a study such as this would make it impossible to assign sensitivity and negative predictive values to the diagnostic staging modalities because of the heterogeneity in LN station positivity and the inability to verify the accuracy of LN staging results in patients randomized to one technique or the other. An important weakness of the study is that all procedures were performed in a single center, which somewhat limits the external validity but was minimized by having the procedures performed by multiple endoscopists at all levels of training and experience. The lack of rapid-on-site cytologic LN examination reflects real-world practice and may underestimate
Acknowledgments Author contributions: M. L. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M. L., J. S., A. D., and P. F. contributed to obtaining of funding; M. L. and J. S. contributed to study concept and design; M. L. and P. F. contributed to study supervision; V. T. and R. H. contributed to the data acquisition and critical revision of the manuscript for important intellectual content; M. L., A. D., and P. F. contributed to data acquisition, analysis, and interpretation; J. S. contributed to data analysis and interpretation; M. L. and J. S. contributed to statistical analysis; and M. L., J. S., A. D., and P. F. contributed to the drafting of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors contributed to the salary of the research assistants, study equipment and materials, computer hardware and software, biostatistic fees, and projectrelated travel fees. Other contributions: The authors thank Sandra Larivée, PhD, biostatistician, Research Center, Centre Hospitalier de l’Université de Montréal for conducting portions of the data analysis of this trial. She was financially compensated for statistical analysis.
3.
4.
5.
6.
7.
8.
9.
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