EBUS-TBNA in the nodal staging of Stereotactic ablative body radiotherapy patients

Abstract

Background

Patients with non-small cell lung cancer (NSCLC) being evaluated for Stereotactic Ablative Body Radiation (SABR) are typically staged non-invasively with positron emission tomography/computed tomography (PET/CT). Incorporating endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) into the staging workup of these patients has not been evaluated. Our primary objective was to compare the performance of PET/CT with EBUS-TBNA for intra-thoracic nodal assessment among SABR-eligible patients.

Methods

This was a retrospective study consisting of two parts. First, we assessed the concordance for nodal metastasis of PET/CT and EBUS-TBNA. Secondly, we evaluated clinical outcomes among patients who underwent SABR with and without a prior EBUS-TBNA.

Results

We identified 246 eligible patients. Compared with PET/CT, EBUS-TBNA led to a stage shift in 48 of 246 patients (19%). Out of 174 N0 patients by PET/CT, 6 (3.4%) had nodal metastasis on EBUS-TBNA. Among 72 clinical N1 patients, 36 (50%) were downstaged to N0 after EBUS-TBNA, therefore becoming SABR-eligible. Concordance between PET/CT and EBUS-TBNA for nodal metastasis was 83% (kappa 0.53). Clinical outcomes of patients who underwent SABR with or without a prior EBUS-TBNA did not differ significantly.

Conclusions

Concordance of PET/CT and EBUS-TBNA for nodal disease was only moderate. Incorporating EBUS-TBNA into the staging workup was beneficial in both identifying occult nodal metastasis that would otherwise be left untreated with SABR, and in expanding the pool of potentially SABR-eligible patients.

Stereotactic ablative radiation therapy (SABR) is emerging as an effective therapeutic alternative for early stage Non-Small Cell Lung Cancer (NSCLC), with response rates exceeding 90%^1,2. Given that reported response rates are higher than those obtained with conventional radiotherapy and comparable to surgery³, SABR is no longer being limited to those at high surgical risk. Furthermore, as the median age of patients with lung cancer increases⁴, there is an associated increase in the number of patients in whom a less invasive option may be preferred.

Despite the excellent initial tumor response rates, locoregional recurrence at 2 years is approximately 15% and rates appear to be higher than those reported for surgical resection^5,6. This may be partly explained by the presence of occult lymph node metastasis at the time of initial treatment, since SABR only targets the primary tumor. Eligibility criteria for SABR includes the absence of known nodal metastasis but the lack of routine nodal sampling in SABR patients limits the pretreatment evaluation of nodal involvement and undiagnosed nodal disease might therefore remain undetected and untreated.

Patients with NSCLC being evaluated for SABR are typically staged non-invasively with positron emission tomography/computed tomography (PET/CT). Prior reports have shown that nodal metastasis can be found in up to 22.3% of patients who have no evidence of mediastinal disease on PET/CT⁷. PET/CT can also demonstrate false positive results in intrathoracic lymph nodes particularly among patients from regions with endemic granulomatous diseases, potentially preventing these patients from being considered for SABR⁸

In order to improve the diagnostic accuracy of intrathoracic nodal staging some centers have incorporated minimally invasive sampling with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as part of the standard workup prior to SABR. EBUS-TBNA is a safe procedure⁹ with superior diagnostic accuracy compared to imaging modalities alone for assessing nodal stage in patients with radiographic evidence of nodal metastases¹⁰, however the added benefit of EBUS-TBNA over non-invasive staging methods has not been evaluated in SABR-eligible patients with no radiographic evidence of nodal disease, since prior studies did not have a primary tumor size limitation.

The primary objective of this study was to assess the performance of PET/CT as compared with EBUS-TBNA in nodal staging among potentially SABR-eligible patients by evaluating the concordance between the two tests. We also postulated that optimizing patient selection for SABR by improving pretreatment staging accuracy would improve outcomes, hence, we also examined the rates of progression-free survival and overall survival among patients who underwent SABR following EBUS-TBNA compared to patients that received SABR without a prior EBUS-TBNA.

Patients and Methods

Study design

This was a retrospective study of patients with early stage NSCLC who were evaluated at our institution from January 2007 to January 2013. The study consisted of two parts involving two distinct cohorts. The first part assessed the concordance of PET/CT with EBUS-TBNA for intra-thoracic nodal assessment among potentially SABR-eligible patients. The second part evaluated clinical outcomes among patients who underwent SABR following an EBUS-TBNA compared with those who underwent SABR without a prior EBUS-TBNA. The institutional review board at MDACC approved the study (IRB protocol PA14-0591) along with a waiver of consent.

Study population

For the first part of the study, we included all potentially SABR-eligible patients aged 18 or older with a biopsy proven diagnosis of NSCLC that underwent PET/CT and EBUS-TBNA for mediastinal staging. Criteria for potential SABR-eligibility was defined as a primary tumor <5 cm in size, without clinical radiographic evidence of mediastinal nodal disease or distant metastasis. Patients in this group were included if they were potential candidates for SABR, independent of the final treatment.

The second part of the study consisted of two distinct cohorts:

1. Patients with early stage NSCLC treated with SABR for curative intent whose stage was established by clinical and radiographic criteria (PET/CT), without a prior EBUS-TBNA.

2. Patients with early stage NSCLC treated with SABR for curative intent whose stage was established by a combination of PET/CT and EBUS-TBNA.

For both parts of the study we excluded patients with synchronous malignancies, prior mediastinal radiation or chemotherapy due to an intrathoracic malignancy, those who did not have an available PET/CT and those who were planning to receive definitive treatment outside of our institution.

Definitions and procedures

Study subjects were identified using billing codes for EBUS-TBNA and the Radiation Oncology database. The medical records were screened to identify patients meeting inclusion criteria. Study data was abstracted using a standardized form by two study investigators. A lesion was classified as positive on PET/CT if the standardized uptake value (SUV) was ≥2.5. Lymph nodes were considered enlarged on CT if they measured ≥ 10 mm in short axis. Central tumor was defined as located within the inner third of the hemithorax, and peripheral if within the outer two thirds.

Patients were considered to have a recurrence if imaging showed evidence of progressive soft-tissue abnormalities over time that corresponded to FDG avid (SUV >5) areas on PET/CT at least 6 months after SABR. Biopsy confirmation was not necessary for the purposes of this study. Time to recurrence was defined as time from end of treatment to the time at which the follow up imaging first showed the abnormalities.

EBUS-TBNA was performed under general anesthesia in the standard fashion as follows: We perform a systematic examination of the accessible intra-thoracic lymph nodes using a linear array ultrasound bronchoscope and identify those that meet any of the following criteria for sampling. These ultrasound criteria include short axis diameter > 0.5 cm and/or a combination of features that are associated with malignancy (sharp margins, heterogeneity, central necrosis sign, absence of a central hilar structure and rounded shape). The size of the LN on ultrasound imaging is measured on static images. Nodal sampling begins at the contralateral hilum to avoid the possibility of specimen cross-contamination and potential staging inaccuracies. For each node a minimum of 3 passes are performed by passing a 22 gauge needle through the working channel of the bronchoscope. Rapid on-site cytologic evaluation (ROSE) was available for all procedures. The lymph node stations were described according to the International Association for the Study of Lung Cancer classification.

SABR technique has been described previously¹¹. Treatment is delivered in 4 fractions over consecutive days if the total dose was 50 Gy or in 10 fractions if the total dose was 70 Gy. Standard follow up of patients after SABR at our institution includes a physical exam and chest CT every 3 months for the first 2 years and then every 6 months in the third year. After 3 years, routine follow up continues on a yearly basis. If needed, further studies are obtained according to the judgment of the treating physician.

For follow up information we obtained data from the medical records and from the Tumor Registry at our institution. This registry records the vital status of each patient on a yearly basis. If there are no scheduled appointments within 6 months, patients are contacted via mail or phone calls.

Outcomes

Primary outcome was concordance of PET/CT imaging and EBUS-TBNA for nodal disease in patients with early stage NSCLC. Secondary outcomes were overall survival, progression free survival and locoregional recurrence rate in those who underwent SABR with and without a prior EBUS-TBNA.

Statistics

Summary statistics, including the mean, standard deviation, median, and range for continuous variables, as well as frequency count and percentage for categorical variables were calculated. Wilcoxon rank sum tests were used to compare continuous variables between the two groups. Chi-squared tests were used to compare categorical variables. Agreement between two tests was measured using Kappa statistics. Kaplan-Meier curves were plotted for overall survival and progression-free survival and log-rank tests were used to compare these endpoints between patient groups. Gray tests, which accounted for death as the competing risk, were used to compare time to progression outcomes between patient groups. The comparison in every time-to-event outcomes were also adjusted for age, ECOG, FEV1, tumor size, tumor location (central or peripheral), and histologic type (adenocarcinoma or others). Two-tailed p-value of <0.05 was considered statistically significant. All analyses were performed using SAS software (version 9.3; SAS Institute, Cary, NC).

Results

Study Part 1

For the first part of the study, we reviewed a total of 4,198 patients who underwent an EBUS-TBNA during the specified period and identified 246 potential SABR candidates. The demographics and tumor characteristics of this group are shown in Table 1. By radiographic criteria, 72 (29%) of the 246 patients had clinical N1 disease and 174 (71%) had clinical N0 disease.

Table 1.

Demographic and tumor characteristics of potential SABR candidates that underwent EBUS-TBNA n=246

Mean age, y (range)	69 (44–89)
Male sex, no. (%)	127 (51.6)
Ethnicity, no. (%)
White	212 (86.2)
Non-white	34 (13.8)
Smoking history
Yes, no (%)	224 (91.0)
No, no (%)	22 (8.9)
ECOG performance status, no. (%)
0	111 (45.12)
1	113 (45.9)
≥2	22 (8.95)
Pulmonary function tests
FEV1% mean (SD)*	75 (22.7)
DLCO (SD)**	69.5 (24.5)
Mean tumor size on CT (range), cm	2.7 (0.7–5)
Tumor location
Central	55 (22.4)
Peripheral	191 (77.6)
Histology, no. (%)
Adenocarcinoma	127 (51.6)
Squamous cell carcinoma	91 (37)
NSCLC NOS	21 (8.5)
Others	7 (2.85)
FDG avidity
SUV ≥2.5	227 (92.3)
SUV <2.5	19 (7.7)

^*data was missing on 11 patients.

^**data was missing on 22 patients

On EBUS-TBNA, a total of 644 lymph node stations were biopsied in 246 patients, with a median of 3 lymph nodes per patient (range, 0–6). The average size of these lymph nodes was 0.77 cm (min 0.32 and max. 2.89) with adequate samples, meaning pathologic evidence of lymph node sampling obtained in ninety-five percent. There were no immediate complications from EBUS-TBNA.

Compared with clinical radiographic staging, EBUS-TBNA led to a stage shift in 48 (19%) of the 246 patients (Figure 1). Among clinical N0 patients, nodal metastases was identified in 6 (3.4%, 95%CI: 0.013–0.074) of 174 by EBUS-TBNA. Two were upstaged to N2 and 4 to N1 (Table 2). Among the 72 clinical N1 patients, 6 were upstaged to N2 (8%), 36 (50%) were downstaged to N0 and in 30 patients (42%) the nodal stage remained unchanged after EBUS-TBNA.

Fig 1.

Flow diagram of all patients undergoing EBUS-TBNA. uN0= ultrasound N0, uN1=ultrasound N1, uN2=ultrasound N2.

Table 2.

Characteristics of cN0 patients with nodal metastasis identified on EBUS-TBNA

Patient	Age	Tumor lobe	Tumor centrality	Histology	Size in cm
1	49	RUL	peripheral	Adenocarcinoma	2.5
2	69	RLL	peripheral	Adenocarcinoma	3.2
3	73	RLL	peripheral	Squamous cell	2.3
4	62	RLL	peripheral	Adenocarcinoma	3.2
5	55	RML	central	Adenocarcinoma	2.3
6	86	RLL	peripheral	Adenocarcinoma	3.3

RLL=Right Lower Lobe, RUL= Right Upper Lobe, RML=Right Middle Lobe

Concordance of EBUS-TBNA and PET/CT for nodal metastasis was 83% with a kappa coefficient of 0.53 (95%CI 0.41–0.65) (Table 3).

Table 3.

Concordance of EBUS-TBNA and PET/CT for nodal metastasis

Nodal metastasis on PET/CT	Nodal metastasis on EBUS/TBNA		Total number of patients
	Present	Absent
Present	36	36	72
Absent	6	168	174
Total	42	204	246

Study Part 2

For the second part of the study, we identified a cohort of 81 patients who underwent SABR following staging with EBUS-TBNA. The majority of these patients were clinical N0, but 8 (10%) of these patients were initially clinical N1 and subsequently downstaged by EBUS-TBNA to N0, and as such received SABR. We compared this EBUS staged cohort (n=81) to a separate cohort of 88 clinical N0 patients who underwent SABR treatment after clinical radiographic staging alone.

The majority of patients in both cohorts had a dose of 50Gy delivered in 5 fractions, with a few patients receiving 70 Gy in 10 fractions. Treatment was well tolerated in the majority of patients (78%), with only minor complications reported on follow up visits consisting mainly of dermatitis, fatigue, cough and chest pain. Two patients from the EBUS cohort had radiation pneumonitis that required steroid treatment. We did not observe any significant differences in terms of overall survival, progression free survival, or locoregional recurrence between the groups, even after adjusting for age, ECOG status, FEV1, tumor size, tumor location, and histologic type (Fig 2).

Fig 2.

Overall survival (A); progression free survival (B) and locoregional recurrence (C) comparing patients with uN0 versus cN0 disease.

Comment

Patients with NSCLC undergoing SABR have traditionally been staged by imaging. PET/CT, while highly sensitive for metastatic disease in patients with enlarged lymph nodes, is a conditional test and in settings with low prevalence of nodal disease, the sensitivity is estimated at 62%.¹² This is the first study to assess concordance of PET/CT and EBUS-TBNA in assessing nodal metastasis among patients potentially SABR-eligible patients and to describe the incremental value of performing an EBUS-TBNA. We found an 83% concordance rate with only a moderate agreement (kappa 0.53) between the PET/CT and EBUS-TBNA findings. As such, incorporating EBUS-TBNA as part of the staging work-up changed the N descriptor in a substantial fraction (19%) of patients. These findings are consistent with the previously reported performance of PET/CT in surgical patients with “negative mediastinum”^7,8.

Among patients staged as N0 by PET/CT, 3.4% had nodal metastasis on EBUS-TBNA. This is relatively low compared to recent studies reporting nodal disease in up to 22% of patients with clinical N0 disease⁷. Although our findings may be partly explained by differences in the study population, with smaller tumor sizes in our patients, it may also be due to the inherent limitations of EBUS-TBNA in this particular population with reported sensitivities of 35–37%^7,13. In a more comparable population of SABR-eligible patients who underwent surgery and lymphadenectomy, the prevalence of occult nodal metastasis was found to be lower (9%)¹⁴, nonetheless higher than in this study. This suggests that the reliability of current minimally invasive staging modalities including EBUS-TBNA is still an open question in this population.

While EBUS-TBNA can clearly identify some additional patients with occult nodal disease compared with PET/CT, the comparative effectiveness of incorporating EBUS-TBNA in the staging work up prior to SABR is unclear, and risk stratification studies are likely needed to improve patient selection. Additionally, strategies to enhance the incremental value of EBUS-TBNA in this setting may include a revision of lymph node size thresholds for sampling or incorporation of biomarker assays to increase the sensitivity for detecting occult nodal metastasis.¹³

A very intriguing finding in this study was that the use of EBUS-TBNA in the clinical N1 population downstaged a significant number of patients. This is consistent with a recent study where 47 of 69 patients with N1 disease by CT or PET/CT were downstaged by EBUS.⁸ Among patients with clinical N1 or greater disease, whether EBUS downstaging to N0 disease is sufficiently robust to permit treatment with SABR is an important question that deserves additional investigation. Given the lower sensitivity of EBUS in this setting, it is unlikely that a negative EBUS in the setting of PET/CT positive nodal disease will provide enough evidence to confidently proceed with SABR therapy, but it is more plausible that patients who are clinical N1 by CT criteria but not by PET criteria and are subsequently found to be node negative by EBUS may be considered for SABR. Such a strategy could potentially increase the pool of SABR eligible patients.

Failure to identify nodal disease prior to SABR might result in poorer outcomes, but whether outcomes would improve by incorporating EBUS-TBNA as part of the routine staging strategy remains unclear. We did not detect any differences in either overall survival, progression free survival or loco regional recurrence between those staged with EBUS compared with PET/CT staging alone. Our study was however underpowered to address this question fully, and additional studies are warranted.

A limitation of our study is that patients that had an EBUS prior to SABR might have been intrinsically different from those that did not. As with most retrospective studies, we do not have enough information as to what determined the physician’s choice for an EBUS-TBNA and, therefore cannot correct for these variables.

Also our findings were obtained from a single cancer referral center where all procedures are performed by highly experienced interventional pulmonologists with rapid onsite cytology (ROSE). Results might differ significantly in other settings, limiting the generalizability of our findings.

In summary, we found that EBUS-TBNA was beneficial in both identifying occult nodal disease that would have been untreated with SABR and in downstaging some clinical N1 patients, thereby potentially expanding the pool of patients eligible for SABR. Whether routinely incorporating EBUS-TBNA as part of the staging strategy prior to SABR could improve outcomes remains unclear and should be the subject of prospective studies.