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Page 1: Web viewWord count text : 2634. Word count abstract : 225. E. ndosonography . for mediastinal nodal staging of . clinical N1 non-small cell lung cancer: a prospective

Word count text : 2634.

Word count abstract : 225.

Endosonography for mediastinal nodal staging of clinical N1 non-small

cell lung cancer : a prospective multicenter study.

Christophe Dooms, PhD1*; Kurt G. Tournoy, PhD2*; Olga Schuurbiers, PhD3; Herbert Decaluwe,

MD4; Frédéric De Ryck, MD5; Ad Verhagen, MD6; Roel Beelen, MD7; Erik van der Heijden, PhD3;

Paul De Leyn, PhD4.

1 Respiratory Division, University Hospitals Leuven, Belgium.2 Department of Pneumology, University Hospital Ghent and OLV Ziekenhuis Aalst, Belgium.3 Department of Pulmonary Disease, Radboud University Medical Center Nijmegen, The

Netherlands.4 Department of Thoracic Surgery, University Hospitals Leuven, Belgium.5 Department of Thoracic Surgery, University Hospital Ghent, Belgium.6 Department of Cardiothoracic Surgery, Radboud University Medical Center Nijmegen, The

Netherlands.7 Department of Cardiothoracic Surgery, OLV Ziekenhuis Aalst, Belgium.

* These authors equally contributed to this manuscript.

Summary conflict of interest statement : none for all authors.

Funding source : none.

Corresponding author:

Christophe Dooms, MD, PhD,

Respiratory Division,

University Hospitals Leuven,

Herestraat 49, B-3000 Leuven, Belgium

e-mail : [email protected]

1

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Abstract.

Background:  Patients with clinical N1 (cN1) lung cancer based on imaging are at risk

for malignant mediastinal nodal involvement (N2-disease). Endosonography with a

needle technique is suggested over surgical staging as a best first test for preoperative

invasive mediastinal staging. The addition of a confirmatory mediastinoscopy seems

questionable in patients with a normal mediastinum on imaging. This prospective

multicenter trial investigated the sensitivity of preoperative linear endosonography and

mediastinoscopy for mediastinal nodal staging of cN1 lung cancer.

Methods:  Consecutive patients with operable and resectable cN1 non-small cell lung

cancer underwent a lobe-specific mediastinal nodal staging by endosonography. The

primary study outcome was sensitivity to detect N2-disease. The secondary endpoints

were the prevalence of N2-disease, the negative predictive value (NPV) of both

endosonography and endosonography with confirmatory mediastinoscopy, and the

number of patients needed to detect one additional N2-disease with mediastinoscopy.

Results:  Of the 100 patients with cN1 on imaging, 24 patients were diagnosed with N2-

disease. Invasive mediastinal nodal staging with endosonography alone has a sensitivity

of 38%, which can be increased to 73% by adding a mediastinoscopy. Its NPV was 81%

and 91%, respectively. Ten mediastinoscopies are needed to detect one additional N2-

disease missed by endosonography.

Conclusions: Endosonography alone has an unsatisfactory sensitivity to detect

mediastinal nodal metastasis in cN1 lung cancer, and the addition of a confirmatory

mediastinoscopy is of added value. [clinicaltrials.gov NCT01456429]

2

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Introduction.

Patients with non-small cell lung cancer (NSCLC) presenting with enlarged or FDG-avid

hilar lymph nodes (cN1) have a considerable risk to have malignant mediastinal nodal

disease (N2-disease). N2-disease has been documented in 19-30% of cN1 lung cancer,

despite a normal appearance of mediastinal lymph nodes on CT alone or integrated

PET/CT.1-4 Therefore, invasive mediastinal nodal staging before resection is strongly

recommended over staging by imaging alone in patients with cN1 on integrated

PET/CT.5-6

The recently updated recommendations on the staging of lung cancer have redefined

the role of invasive mediastinal staging tools. A minimally invasive endosonography

(endobronchial ultrasonography or combined endobronchial-esophageal

ultrasonography) is suggested over surgical staging as a best first test for all lung cancer

patients with any suspicion for mediastinal nodal disease.5-7 The recommendation to

perform a confirmatory mediastinoscopy after a negative endosonography is solid for

patients with suspect mediastinal nodes on imaging (i.e. discrete enlarged and/or 18F-

fluorodeoxyglucose positron emission tomography (FDG-PET) positive mediastinal

nodes), but its clinical benefit for patients with a normal mediastinum on imaging is a

matter of debate.8-10 It has been suggested that proceeding directly to surgical resection

might be justified in case the preoperative endosonography is negative.10 However,

patients with cN1 only represent a minority (<10%) in the controlled studies on which

this suggestion is based.11-12 We therefore investigated the sensitivity of linear

endosonography and mediastinoscopy to detect N2-disease in a large prospective

multicenter trial dedicated to the patient with cN1 (without distant metastases) NSCLC

by integrated PET/CT.

Patient and methods.

Patients with operable and resectable (suspected) NSCLC were eligible for the study if

they had cN1 disease after an integrated whole-body PET/CT. The cN1 was based on

either an enlarged hilar N1 lymph node on CT scan or visual FDG-uptake on PET in a

hilar N1 lymph node. The FDG-uptake within the lymph node was compared to the

3

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background FDG accumulation in the mediastinal vessel pool and reported positive

whenever a FDG uptake higher than the background uptake in the mediastinal vessel

pool was present. Patients with irresectable disease or with distant metastases were not

eligible for this study. Only resectable clinical T stages T1, T2, and selected T3 (i.e.

intraparenchymal tumor >7cm, T3 chest wall, or T3 additional nodule in the same lobe)

were allowed. Exclusion criteria were CT enlarged or FDG-PET positive mediastinal

lymph nodes, technical contraindication to endosonography or cervical

mediastinoscopy, any centrally located primary tumor staged T3 or T4 by CT scan, or

inability to consent.

This investigator-initiated study was approved by the institutional review boards at the

3 participating hospitals (University Hospital Ghent, IRB 2010/014; University Hospitals

Leuven, IRB S51974; Radboud University Medical Center Nijmegen, IRB 2010/387), and

registered as ASTER 2. The trial was registered (clinicaltrials.gov NCT01456429). All

patients provided written informed consent.

Endosonography.

Endosonography of the mediastinum was performed using a dedicated convex probe

ultrasound bronchoscope or combined convex probe ultrasound bronchoscope and

esophageal endoscope. Transbronchial and esophageal procedures were performed

during a single session by the same bronchoscopist in each center. The minimal

requirement was to perform a lobe-specific mediastinal nodal examination using EBUS

or combined EBUS-EUS. Therefore the requirement was to explore stations 2L-4L-7 in

case of a left-sided upper lobe primary tumor, stations 4L-7-8-9 in case of a left-sided

lower lobe primary tumor, or stations 2R-4R-7 in case of a right-sided primary tumor.

Nodes larger than 5mm in short axis were sampled three times (in case no ROSE was

available) or at least two times (in case ROSE was available) under real-time ultrasound

guidance with a 22-gauge needle, labeled according to the IASLC lymph node map and

sent for pathological examination.

Cervical mediastinoscopy and surgical resection.

Surgical staging was performed by cervical videomediastinoscopy according to current

guidelines.13 A systematic assessment of left and right high and lower paratracheal and

4

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subcarinal nodes was performed. Thoracotomy or VATS resection with systematic nodal

dissection were performed according to current guidelines and considered the reference

standard.14

Study design.

A non-randomized prospective multicenter trial performing EBUS-TBNA or combined

endosonography (EBUS-EUS) for mediastinal nodal staging of consecutive patients with

operable and resectable NSCLC staged cT1-3N1M0 based on integrated PET/CT.

End points.

The primary endpoint was sensitivity to detect mediastinal nodal involvement (N2

disease) by linear endosonography (either EBUS or combined EBUS-EUS). Sensitivity

was defined as the proportion of patients with N2 disease in whom the linear

endosonography did show mediastinal nodal disease. Thoracotomy or VATS resection

with nodal dissection was considered the reference standard for cases without N2

disease after preoperative mediastinal nodal staging.

Secondary endpoints were: (1) the negative predictive value (NPV) and negative

posttest probability for linear endosonography; (2) sensitivity, NPV and negative

posttest probability for mediastinal nodal disease after both a negative endosonography

and negative cervical mediastinoscopy; (3) comparison of sensitivity and NPV between

the three participating centers; (4) the number needed to treat (NNT) as the number of

patients needed to undergo a cervical mediastinoscopy to identify one case of

mediastinal nodal disease missed by endosonography.

Statistical analysis.

Based on an incremental 25% sensitivity for endosonography compared to a sensitivity

of 65% for surgical staging to detect N2 disease, we calculated a minimum sample size of

80 patients for a one proportion study group consisting of resectable cN1 lung cancer,

having a prevalence for N2 disease of 20% (two-sided type I error of 5% and a power of

80%). A sample size of 100 patients was judged to be adequate to prove that a well-

performed linear endosonography enables the clinician to discard a confirmatory

cervical mediastinoscopy.

5

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For the primary analysis, sensitivity, NPV and negative posttest probability regarding

mediastinal nodal status were calculated on an intention-to-treat basis for all included

patients. For patients with missing reference standard, a multiple imputation analysis

was performed. Imputation for missing values on mediastinoscopy or surgical resection

was performed using a logistic regression model including primary tumor location,

clinical T stage, clinical N1 station, clinical N1 short axis size, and center as predictor

variables.

In a secondary analysis, sensitivity, NPV and negative posttest probability were

calculated on those patients for whom complete information on mediastinal nodal status

was available. Differences between the three centers with respect to sensitivity and NPV

are based on the multiple imputation data and tested using a logistic regression model.

The probability of a positive mediastinoscopy after a negative endosonography for any

given patient is calculated as the product of the probability of a positive surgery after a

negative endosonography and the probability of a positive mediastinoscopy in case of a

positive surgery. The NNT is the smallest integer that gives a value 1 when multiplied

with the probability of a positive mediastinoscopy after a negative endosonography.

All analyses were performed using SAS software, version 9.3 of the SAS system for

Windows (SAS Inc, Cary, NC, USA). All tests performed are two-sided and a 5%

significance level is assumed for all tests. Two-sided 95% Wilson score confidence limits

were given for sensitivity, NPV and negative posttest probability in cases of complete

case analysis. Confidence limits and statistical tests based on multiple imputation data

are based on the method of Rubin.

Results.

Between December 2009 and September 2013, 100 consecutive patients with operable

and resectable (suspected) clinical N1 NSCLC were included (Figure 1). The clinical

patient characteristics are shown in Table 1.

Endosonography procedure and the detection of nodal metastasis.

The characteristics of the endosonography procedure are depicted in Table 2. At

endosonography, a mean of 2.1 mediastinal nodal stations were biopsied.

Endosonography was performed in all patients and detected mediastinal nodal 6

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metastases in 10 patients (10%). Eighty-five patients without evidence of mediastinal

nodal disease underwent surgical staging followed by resection or immediate resection,

showing missed mediastinal nodal metastasis in 14 additional patients (Figure 1).

These missed mediastinal metastases were single station N2 disease in 12 patients and

multi-station N2 disease in 2 patients (Table 3). The missed mediastinal metastases

were located in station 7 (n=5), station 4R (n=4), station 2R (n=1), station 4L (n=2),

station 8 (n=1), and station 5 (n=3). No association was found, either between false

negative endosonography and T stage, or between overall mediastinal nodal

involvement and T stage, location of primary tumor or histology.

Surgical procedures.

Upon surgical resection, additional mediastinal nodal metastases were found in an

additional 6 patients after a negative mediastinoscopy: station 7 (n=1), station 4R (n=1),

station 4L (n=1), and station 5 (n=3). The characteristics of the surgical procedures are

depicted in Table 2. A mean of 3.4 mediastinal lymph node stations were biopsied

during mediastinoscopy. At surgical resection (thoracotomy or VATS), a mean of 4

mediastinal lymph node stations were dissected. For 6 patients, there was no surgical

verification of node negative findings at preoperative staging (Figure 1).

Study endpoints.

The prevalence of mediastinal nodal metastases was 24% overall. According to an

intention-to-treat analysis (n=100; Table 4) for detecting mediastinal nodal metastases,

sensitivity for endosonography alone was 0.38 (95% CI 0.18-0.57) and sensitivity for

endosonography plus cervical mediastinoscopy was 0.73 (95% CI 0.55-0.91). The NPV

for endosonography alone was 0.81 (95% CI 0.71-0.91) and for endosonography plus

cervical mediastinoscopy 0.91 (95% CI 0.83-0.98). The posttest probability for

endosonography alone was 0.19 (95% CI 0.13-0.27), and for endosonography plus

cervical mediastinoscopy 0.09 (95% CI 0.04-0.17). As such, a patient with a negative

endosonography has a probability of 19% of a positive surgical result with respect to

mediastinal lymph nodes.

According to a complete cases analysis (n=94) for detecting mediastinal nodal

metastases, the sensitivity for endosonography alone was 0.42 (95% CI 0.25-0.61) and

7

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the sensitivity for endosonography plus cervical mediastinoscopy was 0.74 (95% CI

0.54-0.88). The NPV for endosonography alone was 0.83 (95% CI 0.74-0.90) and for

endosonography plus cervical mediastinoscopy 0.91 (95% CI 0.82-0.96). The posttest

probability for endosonography alone was 0.17 (95% CI 0.11-0.25), and for

endosonography plus cervical mediastinoscopy 0.08 (95% CI 0.03-0.17).

There was no statistical significant difference between the three participating centers

based on the multiple imputation data, neither for sensitivity (p=0.35) or NPV (p=0.37)

of endosonography alone, nor for sensitivity (p=0.41) or NPV (p=0.61) of

endosonography plus mediastinoscopy. Two patients had occult mediastinal nodal

disease restricted to station 5 (Table 3). According to a complete cases analysis (n=92)

for detecting mediastinal nodal disease within superior and inferior mediastinal nodal

stations, the sensitivity and NPV for endosonography alone were 0.45 (95% CI 0.25-

0.67) and 0.85 (95%CI 0.75-0.92), respectively.

The estimated NNT based on multiple imputation data was a cervical mediastinoscopy

in 10 patients with cN1 NSCLC to identify one case of mediastinal nodal disease after a

negative endosonography.

Discussion.

The most important findings of this study are that one in four patients with cN1 lung

cancer on imaging ends up with N2-disease, and that invasive staging with

endosonography alone has a sensitivity of 38% to detect N2-disease which can be

increased to 73% by adding a mediastinoscopy.

The recommendation to use endosonography as the preoperative mediastinal staging

tool of choice for all lung cancer patients with a suspicion for mediastinal nodal

involvement is based on data from several (non-)randomized clinical trials. These trials

included unselected clinical stage I-III lung cancer patients, mainly with suspect

mediastinal nodes after imaging (clinical N2). Only a minority of the patients had a

centrally located tumor or cN1 with a normal mediastinum on imaging.11,12,15 The current

prospective multicenter study is therefore unique in its kind, since we implemented the

recommendation by exposing a large cohort of consecutive well-defined patients with

cN1 lung cancer to endosonography and tested the assumption made on the role of a

8

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confirmatory mediastinoscopy in case no nodal metastasis were found after

endosonography.

First, we confirm prospectively what was suggested by others concerning the

prevalence of N2-disease in cN1 lung cancer despite a normal mediastinum on both CT

and PET scan. Twenty-four percent of patients ending up with N2-disease underscores

there is no doubt on the indication for preoperative invasive mediastinal nodal staging

of cN1 lung cancer.

Second, test characteristics of endosonography are disappointingly low for the cN1

lung cancer patient. We found that the sensitivity and NPV of endosonography was 38%

and 81%, respectively. A possible explanation is that the majority of the patients (75%)

underwent a single EBUS procedure, while only twenty-five patients (25%) had a

combined endobronchial and esophageal procedure. The decision to add an esophageal

procedure (either with dedicated EUS scope or with the EBUS scope) was left at the

discretion of the operator. This decision to add a EUS procedure was based on the need

to sample lymph nodes that were inaccessible to the EBUS. This differs from a strategy

to perform a systematic nodal mapping of all nodes accessible by both EBUS and EUS.

Indeed, the performance of a systematic combined EBUS-EUS procedure could have

been of relevance also for the cN1 lung cancer patient. One the one hand, we observed

that EBUS did adequately biopsy 9/11 (82%) of the technically reachable false negative

stations (Table 3). In 3 patients the mediastinal nodal N2 disease was out of reach for

the EBUS technique (stations 5 and 8). On the other hand, we calculated that a maximum

of 7 patients could have been picked up with N2-disease provided an EUS procedure

was added systematically to the EBUS procedure. With this reasoning, a systematic

combined approach might have resulted in a sensitivity of 70% and NPV of 92%, which

is in agreement with published results of ASTER 1.10 We see this as an argument that an

EBUS procedure alone might be inadequate and that a systematic combined EBUS and

EUS procedure could be favorable especially in cN1 patients.

Another point is that we did a lobe-specific mediastinal nodal staging during

endosonography in the current trial. It has been observed that N2-disease follows a

predictable lobe-specific pattern in patients with clinically negative mediastinal nodes

by PET-CT scan and that N3 skip metastases are unlikely.16 Overall 23 of 24 patients

(96%) had mediastinal nodal N2 disease, while only one patient had non-skip N3

9

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disease proven by endosonography. Our strategy translated in a median of 2 mediastinal

nodal stations biopsied by endosonography in the current trial, which is less than the 3

mediastinal nodal stations sampled per patient in the ASTER 1 trial.

Finally, our data shed a clear light on the role of a confirmatory mediastinoscopy after

a negative endosonography. The posttest probability of 0.19 indicates that one should

not proceed directly to surgical resection after a negative endosonography. Since

endosonography missed (14/24) 58% of N2-disease amongst cN1 patients and since

mediastinoscopy picked up at least half of these, we argue that a confirmatory

mediastinoscopy should be done. This however implies a considerable cost and

investment: we estimated that ten cN1 patients should undergo a mediastinoscopy to

detect one patient with N2-disease missed by endosonography. As a consequence, one

could question whether endosonography (especially a single EBUS procedure) is really

the best choice to start with in resectable cN1 lung cancer patients.

Our study has some limitations that deserve attention. First, the endosonography

procedure did not require a systematic combined EBUS-EUS assessment of the lobe-

specific mediastinal nodal stations in all patients. This could have been of importance,

since the biopsy of normal sized (<10mm) mediastinal lymph nodes is more challenging

by endosonography as compared to enlarged nodes. Second, there were few patients in

whom no surgical verification of the nodal status took place. However, with 95% of the

patients ending up with a pathological verification of the mediastinal nodal status and

only 5% without, we believe the data set is solid. Both intention to treat and complete

data set analysis showed comparable results.

In conclusion, we analyzed the performance of endosonography in a well-defined

cohort of patients presenting with resectable cN1 lung cancer. We found that one in four

has N2-disease. We found that endosonography alone has an unsatisfactory sensitivity

to detect mediastinal nodal metastasis, and that the addition of a confirmatory

mediastinoscopy is of added value.

Acknowledgements for each author :

Planning of the work : CD, KT, PDL.

Conduct of the work : all authors.

Reporting of the work : all authors.

Responsible for the overall content : CD. 10

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References.

1. Watanabe S, Asamura H, Suzuki K, Tsuchiya R. Problems in diagnosis and surgical

management of clinical N1 non-small cell lung cancer. Ann Thorac Surg.

2005;79(5):1682–1685.

2. Hishida T, Yoshida J, Nishimura M, Nishiwaki Y, Nagai K. Problems in the current

diagnostic standards of clinical N1 non-small cell lung cancer. Thorax.

2008;63(6):526–531.

3. Cerfolio R, Bryant A, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical

staging of patients with NSCLC: a prospective trial. Ann Thorac Surg. 2005;80:1207-

13;discussion 1213-4.

4. Kim D, Choi YS, Kim HK, Kim K, Kim J, Shim YM. Heterogeneity of Clinical N1 Non-

Small Cell Lung Cancer. Thorac Cardiovasc Surg. 2013. doi:10.1055/s-0032-

1333067.

5. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive

Summary: Diagnosis and management of lung cancer, 3rd ed: American College of

Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5

Suppl):7S–37S.

6. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative

mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac

Surg. 2014 Feb 26. [Epub ahead of print]

7. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung

cancer: Diagnosis and management of lung cancer, 3rd ed: American College of

Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5

Suppl):e211S-50S.

8. Szlubowski A, Zieliński M, Soja J, et al. A combined approach of endobronchial and

endoscopic ultrasound-guided needle aspiration in the radiologically normal

mediastinum in non-small-cell lung cancer staging--a prospective trial. Eur J

Cardiothorac Surg. 2010 May;37(5):1175-9.

11

Page 12: Web viewWord count text : 2634. Word count abstract : 225. E. ndosonography . for mediastinal nodal staging of . clinical N1 non-small cell lung cancer: a prospective

9. Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided

transbronchial needle aspiration of lymph nodes in the radiologically and positron

emission tomography-normal mediastinum in patients with lung cancer. Chest. 2008

Apr;133(4):887-91.

10. Tournoy KG, Keller SM, Annema JT. Mediastinal staging of lung cancer: novel

concepts. Lancet Oncol. 2012 May;13(5):e221-9.

11. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM,

DeLeyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F,

Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs

endosonography for mediastinal nodal staging of lung cancer: a randomized trial.

JAMA. 2010 Nov 24;304(20):2245-52.

12. 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 Dec;142(6):1393-400.

13. De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative lymph

node staging for non-small cell lung cancer. Eur J Cardiothorac Surg. 2007

Jul;32(1):1-8.

14. Lardinois D, De Leyn P, Van Schil P, et al. ESTS guidelines for intraoperative lymph

node staging in non-small cell lung cancer. Eur J Cardiothorac Surg. 2006;30(5):787–

792.

15. Kang HJ, Hwangbo B, Lee GK, et al. EBUS-centred versus EUS-centred mediastinal

staging in lung cancer: a randomised controlled trial. Thorax. 2014 Mar;69(3):261-8.

16. Shapiro M, Kadakia S, Lim J, et al. Lobe-specific mediastinal nodal dissection is

sufficient during lobectomy by video-assisted thoracic surgery or thoracotomy for

early-stage lung cancer. Chest. 2013;144(5):1615–1621.

12

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Tables.

Table 1. Clinical patient characteristics.

Number of patients 100

Age, years, mean (SD) 65 (9.8)

Indication, known NSCLC : suspected NSCLC, n 48:52

Primary tumor, localization, n

LUL : LLL 22 : 16

RUL : RML : RLL 35 : 2 : 25

T stage, n

T1a : T1b 18 : 17

T2a : T2b 31 : 20

T3 14

Nodal N1 stage, n

by PET (visual FDG avidity) 94

by CT (short axis 10mm) 68

Hilar nodal N1 station, n

10 : 11 : 12 13 : 73 : 14

Hilar nodal station, short axis largest node, mm

mean (SD) 12 (5)

Final pathological diagnosis

NSCLC, n

adenocarcinoma 51

squamous cell carcinoma 36

NSCLC NOS 4

large cell carcinoma 3

other : LCNEC; carcinoid; mucoepidermoid Ca 4

Benign, n

tuberculosis 1

normal lung parenchyma 1

Table 2. Endosonography and surgical procedure findings.

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Endosonography findings (n=100)

Type of endosonography performed

EBUS-TBNA only , % 75

EBUS-TBNA + EUS-FNA , % 15

EBUS-TBNA + EUS-B FNA , % 10

Type of sedation, %

Moderate sedation : General anesthesia 94:6

Short axis of largest mediastinal lymph node, mm

mean (SD) 6.9 (2.2)

Number of mediastinal nodal stations observed

mean (SD) 3.2 (0.7)

Number of mediastinal nodal stations biopsied

mean (SD) 2.1 (1.1)

Number of mediastinal lymph nodes biopsied

mean (SD) 2.3 (1.2)

Surgical findings

CERVICAL MEDIASTINOSCOPY (n=75)

Number of mediastinal nodal stations biopsied

mean (SD) 3.4 (1.0)

SURGICAL RESECTION (n=77)

Number of mediastinal nodal stations dissected

mean (SD) 4 (1.7)

Type of surgery

(bi)lobectomy 67

pneumectomy 7

segmentectomy or wedge resection 3

14

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Table 3. Characteristics of patients with false negative endosonography findings.

N Local T-stage Final PA Endosonography+ mediastinoscopy Node metastasisEBUS adequately

done ? EUS of potential added value ?

1 RML T3 Large cell Ca true positive station 7 at mediastinoscopy Yes No, has been done

2 LLL T1a Large cell Ca false negative stations 5 and 8 at resection Out of reach Yes, was not done

3 RUL T2a Adenocarcinoma true positivestations 2R and 4R at

mediastinoscopy No, inadequate sample No, out of reach

4 RLL T2a Adenocarcinoma false negative station 4R at resection Yes No, out of reach

5 RLL T2a Squamous cell Ca true positive station 7 at mediastinoscopy Yes Yes, was not done

6 RLL T2a Adenocarcinoma true positive station 4R at mediastinoscopy Yes No, out of reach

7 LLL T1b Adenocarcinoma true positive station 4L at mediastinoscopy No, inadequate sample Yes, was not done

8 LUL T2b Adenocarcinoma false negative station 5 at resection Out of reach No, out of reach

9 RLL T2b Adenocarcinoma false negative station 7 at resection Yes Yes, was not done

10 LLL T2a adenocarcinoma false negative station 4L at resection Yes Yes, was not done

11 LUL T2a Adenocarcinoma false negative station 5 at resection Out of reach No, out of reach

12 RUL T1b LCNEC true positive station 7 at mediastinoscopy Yes Yes, was not done

13 RLL T3 Carcinoid na station 7 at resection Yes Yes, was not done

14 RUL T2a Adenocarcinoma true positive station 4R at mediastinoscopy Yes No, out of reach

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Table 4. Diagnostic performance based on multiple imputation analysis.

Endosonography alone

Endosonography + cervical mediastinoscopy

Sensitivity 0.38 (0.18-0.57) 0.73 (0.55-0.91)

Negative Predictive Value 0.81 (0.71-0.91) 0.91 (0.83-0.98)

Posttest Probability 0.19 (0.13-0.27) 0.09 (0.04-0.17)

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Figure 1. Flow chart of patients undergoing mediastinal nodal staging for clinical N1

(suspected) non-small cell lung cancer.

N, number of patients.

* patient refusal or physicians’ choice not to perform a mediastinoscopy after a negative

endosonography

** physician decided to give induction chemotherapy, based on N1 proven by EBUS

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