Word count text : 2634.
Word count abstract : 225.
Endosonography for mediastinal nodal staging of clinical N1 nonsmall 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 : christophe.dooms@uzleuven.be
1
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 N2disease. 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 N2disease 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
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
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
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 wellperformed linear endosonography enables the clinician to discard a confirmatory
cervical mediastinoscopy.
5
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
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
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 0.250.67) 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 welldefined patients with cN1 lung cancer to endosonography and tested the assumption
8
made on the role of a 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
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 lobespecific 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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12
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
RUL : RML : RLL
22 : 16
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
13
Table 2. Endosonography and surgical procedure findings.
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
Table 3. Characteristics of patients with false negative endosonography findings.
N
Local
T-stage
Final PA
Endosonography+ mediastinoscopy
Node metastasis
EBUS 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 positive
stations 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
15
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)
16
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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