Background

Lung Cancer

Individuals who are suspected of having lung cancer may present with widely differing signs and symptoms related to the type of cancer (e.g., non-small-cell lung cancer [NSCLC] vs small-cell lung cancer), its location within the lung, and the stage of disease (i.e., localized, locoregionally advanced, metastatic). All three of the major parameters of type, location, and the stage will dictate subsequent management of cancer, determining whether it is primarily surgical or requires systemic chemotherapy. Early diagnosis of lung cancer is essential because of the uniformly poor prognosis when cancer is diagnosed later in the disease course.

Approximately 75% to 80% of newly diagnosed lung cancers are NSCLC. The clinical presentation and findings on computed tomography (CT) or a fluorine 18 fluorodeoxyglucose positron emission tomography (PET) scan of the chest will typically permit a presumptive diagnosis of lung cancer and differentiation between NSCLC and small-cell lung cancer. If small-cell lung cancer is suspected based on radiographic characteristics and other clinical findings, a diagnosis is made by whatever means is the least invasive (e.g., sputum cytology, thoracentesis if an accessible pleural effusion is present, fine-needle aspiration of a supraclavicular node).^1, The diagnostic technique to evaluate suspected NSCLC is usually dictated by the apparent stage of the disease. NSCLC can present with extensive infiltration of the mediastinum, defined as a mass with no visible lymph nodes, or it may present as a solitary pulmonary nodule that may be bronchogenic or peripheral. In any patient with suspected NSCLC, the diagnosis should be established by the method that has the most favorable risk-benefit ratio.^1,

Diagnosis of Peripheral Pulmonary Nodules

Solitary pulmonary lesions are typically identified on plain chest radiographs or chest CT scans, often incidentally. Although most of these nodules will be benign, some will be cancerous. Peripheral lung lesions and solitary pulmonary nodules (most often defined as asymptomatic nodules less than 8 mm) are more difficult to evaluate than larger, centrally located lesions. There are several options for diagnosis; however, none of the methods is ideal for safely and accurately diagnosing malignant disease in all patients.^2, Sputum cytology is the least invasive approach.^1, Reported sensitivity rates are relatively low and vary widely across studies, and sensitivity is even lower for peripheral lesions. Sputum cytology, however, has a high specificity, and a positive test may obviate the need for more invasive testing.

Flexible bronchoscopy, a minimally invasive procedure, is the most common approach to evaluating pulmonary nodules. The sensitivity of flexible bronchoscopy for diagnosing bronchogenic carcinoma has been estimated at 88% for central lesions and 78% for peripheral lesions.^2, For small peripheral lesions less than 1.5 cm in diameter, the sensitivity may be as low as 10%, due to the inability to reach into smaller bronchioles.

Transthoracic (percutaneous) needle aspiration, using CT guidance, can be performed for peripheral nodules that are beyond the reach of traditional bronchoscopy. The diagnostic accuracy of transthoracic needle aspiration tends to be as high or higher than that of flexible bronchoscopy for peripheral lesions; the sensitivity and specificity are both greater than 90%.^2, A disadvantage of transthoracic needle aspiration is that a pneumothorax could occur in as many as 15% of patients (range, 1%-15%). Between 1% and 7% will require chest tube insertion. PET scans are also highly sensitive for evaluating pulmonary nodules, yet may miss small lesions less than 1 cm in size. Surgical lung biopsy is the criterion standard for diagnosing pulmonary nodules but is an invasive procedure not indicated for all patients.

Staging of Lung Cancer and Assessment of Mediastinal Involvement

The stage of lung cancer (its extent through the body) at diagnosis will directly impact the management approach for each patient.^3,4, The first step in staging is to identify whether the patient has the distant metastatic disease (M stage) or if the tumor is confined to the chest; this will determine whether treatment should be aimed at palliation or at a potential cure, respectively. If the primary tumor is confined (T stage), determining whether the mediastinal lymph nodes (N stage) are involved is a crucial factor in guiding therapy.

As with diagnostic procedures, there are a number of options for mediastinal staging. The choice of a noninvasive or invasive staging method is dictated by the patient's condition and whether he or she can tolerate or will elect surgery. Thus, staging procedures may be based on noninvasive imaging methods (i.e., CT or PET, or combined PET-CT), or may be fully invasive, such as a mediastinoscopy-a surgical procedure that is performed under general anesthesia and is regarded as the reference standard for staging lung cancer.^3,

Recent advances in technology have led to enhancements that may increase the yield of established needle-based diagnostic methods that represent a third approach, between noninvasive and surgical procedures.^1, CT scanning equipment can be used to guide flexible bronchoscopy and bronchoscopic transbronchial needle biopsy but has the disadvantage of exposing the patient and staff to radiation.

Endobronchial Ultrasound With Transthoracic Needle Aspiration

Among its potential applications, endobronchial ultrasound (EBUS) using ultrasound probes can locate and guide the sampling of pulmonary lesions and mediastinal lymphadenopathy.

EBUS uses two distinct types of transducers that have specific uses: radial probe and convex probe.

A radial probe EBUS comprises a 20- or 30-MHz rotating transducer to provide high-resolution 360° radial images. The probe is inserted into the airways via a standard therapeutic bronchoscope. With the use of an ultrathin bronchoscope combined with radial probe EBUS through a guide sheath, an endoscopist can reach and visualize the sixth- to eighth-generation bronchi, whereas a traditional bronchoscope can only reach the fourth-generation bronchi. The use of radial probe EBUS imaging allows the physician to verify visually that a lesion has been reached and to maintain a position in the periphery to allow a needle biopsy to be performed for diagnosis.^5, These probes do not allow real-time imaging during the biopsy. For biopsy or tissue sampling, the target area is located by radial probe EBUS; the radial probe is subsequently retracted and is replaced with a biopsy or sampling device.

Convex probe EBUS transducers are adjustable within a frequency range of 5 to 12 MHz. Such transducers are incorporated into the structure of a dedicated bronchoscope and provide real-time pie-slice sector views of 50° to 60° parallel to the axis of the bronchoscope. Convex probe EBUS with transbronchial needle aspiration (EBUS-TBNA) also can be used for staging the mediastinal nodes.^6, The curved linear probe technology allows real-time visualization and needle aspiration of a lesion. Because EBUS-TBNA of the mediastinal nodes may be performed under conscious sedation, it may be used in patients who are not surgical candidates but for whom accurate staging is needed to guide choice among systemic treatments, particularly targeted systemic agents such as tyrosine kinase inhibitors.^7,

Regulatory Status

A number of instruments are commercially available to perform EBUS-TBNA for diagnosis and staging of lung cancer. All have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process and are shown in Table 1.

Table 1. FDA-Cleared Instruments Used to Perform EBUS-TBNA

Device Name	Manufacturer	Date Cleared	510(k)	Indications
EVIS EXERA Bronchofibervideoscope, Olympus BF type UC160F-OL8 bronchoscope and its diagnostic ultrasound transducer	Olympus Medical Systems	Aug 2004	K042140	To provide real-time endoscopic US imaging and US-guided FNA, including the upper airways and tracheobronchial tree
EU-M60 EUS EXERA Endoscopic Ultrasound Center	Olympus Medical Systems	Dec 2004	K04327	To acquire and to display high-resolution and high-penetration, real-time endoscopic US B-mode 2D and 3D images, including the upper airways and tracheobronchial tree
XBF-UC180F-DT8 Ultrasonic Bronchofibervideoscope and the ALOKA SSD-Alpha 5/10 Ultrasound System	Olympus Medical Systems	Jul 2007	K070983	To provide real-time endoscopic US imaging and US-guided FNA including the upper airways and tracheobronchial tree
SonoTip® II EBUS-TBNA Needle System	Medi-Globe	May 2009	K091257	For US-guided FNA of submucosal and extraluminal lesions of the tracheobronchial tree
EchoTip® Ultra High Definition Endobronchial Ultrasound Needle	Cook Medical	Jan 2010	K093195	For use in conjunction with an EBUS endoscope to gain access to and sample submucosal and extramural lesions within or adjacent to the tracheobronchial tree through the accessory channel of an EBUS for FNA
PENTAX Ultrasound Video Bronchoscope EB-1970UK + HI VISION Preirus endoscopic ultrasound	PENTAX Medical	Apr 2014	K131946	To provide optical visualization of, ultrasonic visualization of, and therapeutic access to, the pulmonary tract including but not restricted to the nasal passages, pharynx, larynx, trachea, bronchial tree (including access beyond the stem), and underlying areas
SonoTip® Pro and Pro Flex EBUS-TBNA Needle System	Medi-Globe	May 2014	K133763	Intended for US-guided FNA of submucosal and extraluminal lesions of the tracheobronchial tree and gastrointestinal tract (e.g., lymph nodes, abnormal tissue in the mediastinum)
Expect™ Pulmonary Endobronchial Ultrasound Transbronchial Aspiration Needle	Boston Scientific	Nov 2015	K151315	For use with EBUS endoscopes for US-guided FNA of the submucosal and extramural lesions of the tracheobronchial tree

EBUS: endobronchial ultrasound; EUS: endoscopic ultrasound; FDA: Food and Drug Administration; FNA: fine-needle aspiration; TBNA: transbronchial needle aspiration; US: ultrasound.

Related Policies

• Electromagnetic Navigation Bronchoscopy (Policy #117 in the Surgery Section)

• Tissue biopsy of the peripheral pulmonary lesion is required for diagnosis (see Policy Guidelines section)
• The peripheral pulmonary lesion is not accessible using standard bronchoscopic techniques.

• The member is suitable and willing to undergo specific treatment for lung cancer, with either curative or palliative intent (see Policy Guidelines section)
• Tissue biopsy of abnormal mediastinal lymph nodes seen on imaging is required for staging and specific treatment planning (see Policy Guidelines section)
• Abnormal lymph nodes seen on imaging are accessible by EBUS-TBNA.

Diagnosis and Staging Guidelines
The American College of Chest Physicians published comprehensive, evidence-based clinical practice guidelines on the diagnosis and management of lung cancer in 2013 (Rivera et al, 2013). Key elements of those guidelines relevant to this policy are outlined next.

The general approach to patients who are suspected of having lung cancer begins with a comprehensive history and physical examination. Imaging studies will include a computed tomography (CT) scan of the chest and a whole body positron emission tomography (PET) or PET-CT study to seek extrathoracic lesions. A patient’s suitability and desire for curative treatment of a proven lung cancer are among the chief considerations in choosing among subsequent management options. These factors, in turn, will guide the approach to establishing a diagnosis and staging the disease, as follows:

1. Some individuals may prefer no treatment, particularly those with life-limiting comorbid conditions. In such individuals, neither surgical biopsy nor staging is justified. Aggressive surveillance using serial CT may be used to monitor symptoms for palliation.

2. Two categories of patients, who could potentially benefit from curative surgical resection based on the presence of a solitary, locally confined pulmonary lesion and documented absence of extrathoracic metastatic disease, will not proceed to surgery for completely different reasons.


a. One group would be considered ineligible for surgery due to sufficiently impaired cardiopulmonary function or other comorbidity that precludes general anesthesia.
b. A second group of individuals would otherwise be eligible for curative surgery but for personal reasons refuse surgical resection.

For either category of patients listed above, surgical diagnostic and staging procedures are contraindicated. Their options include functional imaging (PET, PET-CT, magnetic resonance imaging), CT scan surveillance, and needle-based nonsurgical biopsy, including guided bronchoscopic procedures such as endobronchial ultrasound (EBUS).


3. Patients who are candidates for curative surgical resection by virtue of documented (PET, PET-CT) absence of distant metastatic lesions, locally confined single tumors, and otherwise sound physical condition are eligible for any type of diagnostic and staging procedure.

4. In patients suspected of having lung cancer based on radiographic imaging (CT), functional imaging (PET, PET-CT), and clinical findings (signs and symptoms of lung cancer), a presumptive diagnosis must be confirmed, preferably by the least invasive method, as dictated by the patient’s presentation and desire for definitive treatment.

5. For patients with extensive mediastinal infiltration of tumor and no distant metastases, it is suggested that radiographic (CT) assessment of the mediastinal stage is usually sufficient without invasive confirmation.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Diagnosis of Lung Cancer

Clinical Context and Test Purpose

The purpose of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients who have pulmonary lesions and suspected lung cancer is to isolate and biopsy the lesions in order to diagnose and stage detected cancers.

The question addressed in this policy is whether there is sufficient evidence that EBUS-TBNA used to diagnose lung cancer improves the net health outcome compared with standard bronchoscopic techniques. The primary question of interest to the review is as follows: Is EBUS-TBNA as or more accurate than standard techniques and does it offer fewer harms? Whether any improvement in accuracy leads to improved survival outcomes is also of interest, but due to the lack of published data, that question is not a focus of the review.

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with peripheral pulmonary lesions (PPLs) and suspected lung cancer.

Interventions

The intervention of interest is EBUS-TBNA.

Comparators

Because EBUS is intended as an adjunct to standard bronchoscopic techniques, the primary comparator is flexible bronchoscopy with TBNA. EBUS-TBNA can also be compared with other methods for determining whether PPLs are cancerous: transthoracic (percutaneous) needle aspiration using computed tomography (CT) guidance for lesions outside the reach of traditional bronchoscopy, mediastinoscopy, or surgical lung biopsy.

Outcomes

Outcomes of interest for diagnostic accuracy include test accuracy, test validity (e.g., sensitivity, specificity) and potential harms of testing (e.g., pneumothorax and chest tube insertion rates). The primary outcomes of interest for clinical utility are overall mortality and lung cancer-specific mortality.

EBUS-TBNA would be performed after PPLs were identified or when a prior less invasive test was inconclusive.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

A substantial body of literature exists on the use of radial probe EBUS to diagnose lung cancer in individuals with solitary pulmonary nodules or lesions. Several systematic reviews of the literature have been published. Appendix Table 1 provides a crosswalk of studies included in select reviews.

Han et al (2018) published a systematic review and meta-analysis comparing radial EBUS and CT-guided transthoracic needle biopsy for the diagnosis of pulmonary lesions 3 cm or smaller.^8, Twenty-four studies were identified, 9 for EBUS (813 procedures) and 15 for CT (3463 procedures). The pooled diagnostic yield was 75% for EBUS and 93% for CT. For pulmonary lesions 2 cm or smaller, the pooled diagnostic yield was 66% and 92% for EBUS and CT, respectively. Complications were less common for EBUS than for CT; only 10 cases of pneumothorax were reported for EBUS while 660 were reported for CT. The review was limited by the following: (1) all EBUS studies were conducted in the same country, (2) study quality was not uniform, (3) different imaging tools were used in the CT group, and (4) possible study selection bias.

Ali et al (2017) published a systematic review and meta-analysis of studies on the accuracy of radial probe EBUS for diagnosing PPLs.^9, Fifty-seven studies reporting on 7872 lesions met the eligibility criteria. The pooled data on diagnostic yield, using 54 studies, was 70.6%. In a subgroup analysis of 25 prospective studies (n=2920 lesions), the pooled diagnostic yield was 72.3% (95% confidence interval [CI], 67.5% to 76.8%). In the 28 studies that reported diagnostic yield separately by lesion size, pooled diagnostic yield was 60.5% for lesions 2 cm or smaller and 75% (95% CI, 72.1% to 79.2%) for lesions greater than 2 cm. The overall complication rate was 2.8%. There was a total of 160 reported complications, 82 pneumothoraxes, 61 bleeds, and 17 cases of pneumonia.

The performance of radial probe EBUS in the Ali et al (2017) meta-analysis appears to be at least as high as flexible bronchoscopy for peripheral nodules as reported in an earlier meta-analysis by the American College of Chest Physicians (ACCP; diagnostic sensitivity, 33% for lesions less than 2 cm, 62% for lesions greater than 2 cm, 57% for all peripheral lesions), which is discussed below.^1,

A systematic review and meta-analysis by Ye et al (2017) focused on fluoroscopy guidance.^10, Reviewers identified 4 studies (totaln=461 patients). In a pooled analysis, the overall diagnostic accuracy was significantly higher in the EBUS transbronchial biopsy (TBB) group than in the conventional TBB group (odds ratio, 2.21; 95% CI, 1.42 to 3.44; p less than 0.001).

The ACCP has published two reviews.^1,2, The ACCP reviews indicated that, in general, most of the evidence comes from small retrospective or prospective studies, plus two randomized controlled trials (RCTs).

Tables 2 and 3 summarize the characteristics and results of systematic reviews assessing the clinical validity studies using EBUS to diagnose lung cancer.

Table 2. Characteristics of Systematic Reviews Assessing the Clinical Validity of R-EBUS for Diagnosing Lung Cancer

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Han et al (2018)8,	2000-2016	24	Patients with small PLs ≤3 cm	4249 (24-795)	Prospective, retrospective	NR
Ali et al (2017)9,	2002-2016	57	Patients receiving R-EBUS for diagnosing PPLs	7872 lesions (20-815 lesions)	Prospective, retrospective	NR
Ye et al (2017)10,	2004-2014	4	Patients with PPLs referred for diagnostic bronchoscopy or R-EBUS-guided bronchoscopy	461 (92-145)	Prospective, retrospective	NR

NR: not reported; PL: pulmonary lesion; PPL: peripheral pulmonary lesion; R-EBUS: radial endobronchial ultrasound.

Table 3. Results of Systematic Reviews Assessing of Radial EBUS for Diagnosing Lung Cancer

Study	Diagnostic Yield, %	Diagnostic Yield PLs ≤2 cm, %	Overall Complication Rate, %	Pneumothorax, n/N (%)
Han et al (2018)8,
EBUS	75	66		10/815 (1.23)
95% CI	69 to 80	55 to 76
Computed tomography	93	92		660/3434 (19.23)
95% CI	90 to 96	88 to 95
Ali et al (2017)9,
	70.6	60.5	2.8
95% CI	68 to 73.1	56.6 to 64.4
Ye et al (2017)10,
Odds ratio	2.183	5.045
95% CI	1.368 to 3.485	2.063 to 12.337
p	0.001	less than 0.001

CI: confidence interval; EBUS: endobronchial ultrasound; PL: pulmonary lesion.

Randomized Controlled Trials

Two small randomized trials were identified that evaluated EBUS: one compared its use with TBB and the other, with conventional fluoroscopy-guided flexible bronchoscopy. An RCT by Fielding et al (2012) aimed to determine the diagnostic, complication, and patient tolerability rates of EBUS with a guide sheath EBUS and CT-guided percutaneous core biopsy for peripheral lung lesions among patients with visible lesions suspicious of malignancy.^11, Patients with lesions greater than 1 cm diameter on CT were randomized to guide sheath EBUS biopsy or CT-guided biopsy. Diagnostic sensitivity was 67% (22/33 cases) for guide sheath EBUS biopsy and 78% (19/24 cases) for CT-guided biopsy (p greater than 0.1). In those with negative results, nine patients in the EBUS group had a CT-guided biopsy as a crossover, seven of which were diagnostic. In the CT group, four had crossover EBUS biopsy, three of which were diagnostic. When both initial and crossover procedures were evaluated, sensitivity for malignancy was 17 (74%) of 23 for EBUS biopsy and 23 (88%) of 26 for CT-guided biopsy (p greater than 0.1). For lesions less than 2 cm, a CT-guided biopsy had a significantly better diagnostic yield (80% vs 50%, p=0.05). In EBUS biopsy cases, for lesions with an air bronchogram, sensitivity was 89%. Pneumothorax and intercostal catheter insertion were performed in three and two cases, respectively, for EBUS, and ten and three cases for CT-guided biopsy (p=0.02 for pneumothorax). Nine unexpected admissions occurred after CT-guided biopsy compared with three after guide sheath EBUS biopsy.

In the RCT by Paone et al (2005), patients with identified peripheral lung lesions suspicious as malignancy who could undergo a complete clinical diagnostic follow-up (n=293) were enrolled in the trial and randomized to EBUS-TBB or TBB.^12, Lung cancer was diagnosed in 61 patients in the EBUS-TBB group and in 83 patients in the TBB group. The sensitivity of EBUS (78.7%) was significantly higher than TBB (55.4%; p=0.004). The specificity was 100% in both groups. Overall, the accuracy was 85% in the EBUS group and 69% in the TBB group (p=0.007). The analysis of a subset of patients with lesions greater than 3 cm showed no significant difference in diagnostic ability between the two procedures. A considerable decline in TBB sensitivity (31%) and accuracy (50%; p less than 0.000) was observed in lesions less than 3 cm, while EBUS-TBB sensitivity (75%) and diagnostic yield (83%; p=0.001) were maintained. A similar difference was observed when the sensitivity of the 2 procedures was compared in lesions less than 2 cm (23% vs 71%, p less than 0.001).

Tables 4 and 5 summarize the characteristics and results of RCTs assessing the clinical validity studies using EBUS to diagnose lung cancer.

Table 4. Characteristics of RCTs Assessing the Clinical Validity of EBUS for Diagnosing Lung Cancer

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Fielding et al (2012)11,	Australia	1	2007-2011	Patients with PPLs greater than 1 cm	EBUS-GS (n=33)	CT-guided biopsy (n=31)
Paone et al (2005)12,	Italy	1	2001-2003	Patients with PPLs	EBUS-TBB (n=87)	TBB (n=119)

CT: computed tomography; EBUS-GS: EBUS-guide sheath; EBUS-TBB: endobronchial ultrasound-driven transbronchial biopsy; PPL: peripheral pulmonary lesion; RCT: randomized controlled trial; TBB: transbronchial biopsy.

Table 5. Results of RCTs Assessing the Clinical Validity of EBUS for Diagnosing Lung Cancer

Study	Sens, %	Spec, %	Acc, %	Sensitivity for PPLs less than 2 cm, %	Sensitivity for PLLs less than 3 cm, %	Diagnostic Yield for PPLs less than 2 cm, %	Pneumothorax, n (%)
Fielding et al (2012)11,
EBUS-GS	74					50	3 (8.1)
CT-guided biopsy	88					80	10 (30.3)
p	NR					0.05	0.02
Paone et al (2005)12,
EBUS-TBB	78.7	100	85	71	75
TBB	55.4	100	69	23.3	30.7
p	0.004	NR	0.007	less than 0.001	0.001

Acc: accuracy; CI: confidence interval; CT: computed tomography; EBUS-GS: guide sheath endobronchial ultrasound; EBUS-TBB: endobronchial ultrasound-driven transbronchial biopsy; PPL: peripheral pulmonary lesion; RCT: randomized controlled trial; Sens: sensitivity; Spec: specificity.

The purpose of the limitations tables (see Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 6. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Fielding et al (2012)11,					1. Follow-up duration not clear; perhaps 1-3 d
Paone et al (2005)12,				5. Complications (e.g., pneumothorax, chest tube insertions) not reported	1. Follow-up duration not reported

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.

^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.

^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).

^e Follow-Up key: 1. Follow-up duration not sufficient with respect tonatural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Allocationa	Blindingb	Selective  Reportingc	Data  Completenessd	Powere	Statisticalf
Fielding et al (2012)11,	1. Unclear if allocation was concealed from patients	1. No blinding was performed		2. 7/64 (10.9%) did not complete the study
Paone et al (2005)12,	1. Unclear if allocation was concealed from patients	1. Physicians performing procedures could not be blinded		2. 15/221 (6.8%) patients lost to follow-up and others unavailable, making treatment groups uneven (87 vs 119)

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (i.e., convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs or other controlled studies reporting on longer-term health outcomes (i.e., mortality) were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence for the clinical utility of EBUS-TBNA as an adjunct to standard bronchoscopy for the diagnosis of lung cancer is based on an examination of the data on diagnostic accuracy and an examination of harms associated with various diagnostic methods.

The available evidence supports a conclusion that EBUS-TBNA has diagnostic performance characteristics for solitary pulmonary lesions similar to those of traditional flexible bronchoscopic techniques with a transthoracic needle biopsy. The evidence also indicates the safety profile of EBUS-TBNA may be less risky than other techniques, as reflected by pneumothorax and chest tube insertion rates. For example, as found by Fielding et al (2012; discussed above), although CT-guided biopsy had higher yields in lesions less than 2 cm, EBUS-GS had better tolerability and fewer complications.^11, The evidence does not establish that one technique is better than the others. Thus, the chain of evidence suggests that EBUS-TBNA can improve the net health outcome (i.e., has a similar benefit to alternative techniques with less harm).

Section Summary: Diagnosis of Lung Cancer

Evidence from three meta-analyses and twoRCTs supports a conclusion that EBUS-TBNA has diagnostic performance characteristics for solitary pulmonary lesions similar to those of traditional flexible bronchoscopic techniques with a transthoracic needle biopsy. The available evidence also indicates the safety profile of EBUS-TBNA may be better than other techniques (e.g., CT-guided biopsy). This evidence does not establish that any technique is better than the others. The choice of technique for biopsy depends on a number of factors, including the size and location of the lesion(s) and the risks of the planned procedure.

Staging of Lung Cancer

Clinical Context and Test Purpose

The purpose of EBUS-TBNA in patients who have lung cancer is to biopsy the lesions in order to stage the disease.

The question addressed in this policy is whether there is sufficient evidence that EBUS-TBNA used for lung cancer staging improves the net health outcome compared with standard bronchoscopic techniques. Specifically, is EBUS-TBNA as or more accurate than standard techniques and does it have fewer harms?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with lung cancer and mediastinal lymph nodes seen on imaging.

Interventions

The intervention of interest is EBUS-TBNA.

Comparators

Because EBUS is intended as an enhancement to standard bronchoscopic techniques, the primary comparator is flexible bronchoscopy with TBNA. EBUS-TBNA can also be compared with other methods for staging lung cancer, which includes positron emission tomography, transthoracic needle aspiration using CT guidance, and mediastinoscopy.

Outcomes

Outcomes of interest for diagnostic accuracy include test accuracy, test validity (e.g., sensitivity, specificity) and potential harms of testing (e.g.,pneumothorax and chest tube insertion rates). The primary outcomes of interest for clinical utility are overall mortality and lung cancer-specific mortality.

EBUS-TBNA would be performed after lung cancer is diagnosed.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Appendix Table 2 provides a crosswalk of studies included in select reviews.

El-Osta et al (2018) published a meta-analysis evaluating EBUS-TBNA for nodal staging of non-small-cell lung cancer with radiologically normal mediastinum.^13, Thirteen studies were included, with a total of 1905 patients (range, 57-258 patients). Sensitivity was 49.5%, negative predictive value was 93.0%, and the diagnostic odds ratio was 5.069. The meta-analysis was limited by (1) major heterogeneity across included studies, (2) publication bias, (3) a lack of essential data in some studies, and (4) size, location, and histology of tumor were not considered due to inconsistent reporting.

A systematic review, published by Ge et al (2015), compared EBUS-TBNA with mediastinoscopy for the mediastinal staging of lung cancer.^14, Due to the extremely low rate of false-positive results, reviewers assumed that all positive results were true-positives. Thus, they only pooled analyses of sensitivity (with no false-positives, the specificity would be 100%). For the EBUS-TBNA studies, the pooled sensitivity was 83%; for mediastinoscopy, it was 86%. The difference in sensitivity was not statistically significant (p=0.632). Seventeen complications, including two pneumothoraces, two cases of perioperative bleeding, one esophagus injury, and one wound infection, occurred in the mediastinoscopy group and only four minor injuries occurred in the EBUS-TBNA group. A limitation of the literature selected for the systematic review is that studies were not head-to-head comparisons of staging techniques.

Tables 8 and 9 summarize the characteristics and results of systematic reviews assessing the clinical validity studies using EBUS to stage lung cancer.

Table 8. Characteristics of Systematic Reviews Assessing the Clinical Validity of EBUS-TBNA for Staging Lung Cancer

Study	Dates	Trials	Participants	N (Range)	Design	Duration
El-Osta et al (2018)13,	2006-2017	13	Patients receiving EBUS-TBNA to detect NSCLC with no radiologic mediastinal involvement	1905 (57-258)	Prospective, retrospective	NR
Ge et al (2015)14,	2003-2014	16	Patients with suspected or confirmed lung cancer	1914 (18-216)	Prospective, retrospective	NR

EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle aspiration; NR: not reported; NSCLC: non-small-cell lung cancer.

Table 9. Results of Systematic Reviews Assessing the Clinical Validity of EBUS-TBNA for Staging Lung Cancer

Study	Sensitivity, %	Complications, n/N (%)	NPV, %	Diagnostic Odds Ratio
El-Osta et al (2018)13,
EBUS-TBNA	49.5		93.0	5.069
95% CI	36.4 to 62.6		90.3 to 95.0	4.212 to 5.925
Ge et al (2015)14,
EBUS-TBNA	0.83	4/999 (0.4)
95% CI	0.79 to 0.87	NR
Mediastinoscopy	0.86	17/915 (1.9)
95% CI	0.82 to 0.90	NR

CI: confidence interval; EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle aspiration; NPV: negative predictive value; NR: not reported.

The ACCP published a systematic review, conducted by Silvestri et al (2013), with pooled analyses that provided a comprehensive resource for noninvasive and invasive methods to stage the mediastinum, including EBUS-based techniques.^3, Table 10 summarizes the pooled test performance characteristics for a number of staging procedures drawn from the ACCP policy.

Table 10. Pooled Performance Characteristics of Techniques Used to Stage the Mediastinum in Patients With Lung Cancer^a

Technique	N	Cancer Prevalence, %	Sens, %	Spec, %	PPV, %	NPV, %
CT with contrast enhancement	7368	30	55	81	58	83
PET alone	4105	28	80	88	75	91
PET-CT	2014	22	62	90	63	90
Traditional mediastinoscopy	9267	33	78	(100)a	(100)a	91
Video-assisted mediastinoscopy	995	31	89	(100)a	(100)a	92
Mediastinal lymphadenectomy	386	34	81	(100)a	(100)a	91
Video-assisted thoracic surgery	246	63	99	(100)a	(100)a	96
Transthoracic needle aspiration (percutaneous)	215	84	94	(100)a	(100)a	NRb
TBNA	2408	81	78	(100)a	(100)a	77
Esophageal EUS-guided needle aspiration	2443	58	89	(100)a	(100)a	86
Real-time EBUS-TBNA	2756	58	89	(100)a	(100)a	91

Adapted from Silvestri et al (2013).^3,
CT: computed tomography; EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle aspiration; EUS: endoscopic ultrasound; NPV: negative predictive value; NR: not reported; PET: positron emission tomography; PPV: positive predictive value; Sens: sensitivity; Spec: specificity; TBNA: transbronchial needle aspiration.

^a Technically, the specificity, and positive predictive value cannot be assessed in the studies reporting 100% values because a positive result was not followed by an additional criterion standard test.
^b All patients had a mediastinal disease.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs or other controlled studies were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence of the clinical utility of EBUS-TBNA for the staging of lung cancer is based on an examination of the EBUS-TBNA data on diagnostic accuracy and harms associated with various staging techniques. The evidence underlying the pooled accuracy for mediastinal staging is less than optimal. The literature review for staging did not identify any RCT evidence to compare EBUS guidance with any other needle-based technique. There are differences among the patient populations and the use of reference standard confirmation of node positivity. The evidence summarized herein supports a conclusion that EBUS-TBNA exhibits test performance characteristics similar to other needle-based methods used to stage the mediastinum in patients diagnosed with lung cancer. Although EBUS-TBNA could be used in patients who are surgical candidates and plan to undergo surgery, it also may be suitable for those who are not eligible for curative resection-or for those who refuse to undertake major surgery but still require staging for planning systemic or radiotherapy. A major advantage of EBUS-based methods is that they can be performed on an outpatient basis under limited sedation if necessary, and thus would be less invasive and less risky than traditional mediastinoscopy. Thus, the chain of evidence suggests that EBUS-TBNA may be more beneficial in certain situations

Section Summary: Staging of Lung Cancer

The literature review on the use of EBUS-TBNA for staging did not identify any RCT evidence that compared EBUS guidance with any other needle-based technique. The evidence summarized herein from systematic reviews supports a conclusion that EBUS-TBNA exhibits test performance characteristics similar to other needle-based methods used to stage the mediastinum in patients diagnosed with lung cancer. Although it could be used in patients who are surgical candidates and plan to undergo surgery, it also may be suitable for those who are not eligible for curative resection or refuse to undertake major surgery but still require staging for planning systemic or radiotherapy. A major advantage of EBUS-based methods is that they are less invasive and less risky than traditional mediastinoscopy.

Summary of Evidence

For individuals who have peripheral pulmonary lesions and suspected lung cancer who receive EBUS-TBNA for diagnosis, the evidence includes recent systematic reviews, meta-analyses, and two small randomized trials. The relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and morbid events. Evidence supports a conclusion that EBUS-TBNA has diagnostic performance characteristics for solitary pulmonary lesions similar to those of traditional flexible bronchoscopy with transthoracic needle aspiration. The evidence also indicates that the safety profile of EBUS-TBNA may be better than the profile of other techniques, as reflected by pneumothorax and chest tube insertion rates. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have lung cancer and mediastinal lymph nodes that are seen on imaging who receive EBUS-TBNA for staging, the evidence includes systematic reviews and meta-analyses. The relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and morbid events. Evidence from systematic reviews supports a conclusion that EBUS-TBNA exhibits test performance characteristics similar to other needle-based methods used to stage the mediastinum in patients diagnosed with lung cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

National Comprehensive Cancer Network guidelines on non-small-cell lung cancer (v.5.2019) ^15, state:

"The least invasive biopsy with the highest yield is preferred as the first diagnostic study…. Patients with peripheral (outer one-third) nodules may benefit from navigational bronchoscopy, radial EBUS [endobronchial ultrasound], or transthoracic needle aspiration (TTNA)…. Patients with suspected nodal disease should be biopsied by EBUS, EUS [endoscopic ultrasound], navigational bronchoscopy or mediastinoscopy."

American College of Chest Physicians

The American College of Chest Physicians has offered a number of evidence-based guidelines on the use of EBUS-guided needle aspiration of pulmonary lesions for diagnosis of lung cancer^1, and mediastinal staging of patients diagnosed with lung cancer (see Table 11).^3, A separate guideline and expert panel report (2016) has addressed the technical aspects of EBUS-guided transbronchial needle aspiration and its use outside the setting of lung cancer.^16,

Table 11. Guidelines on Use of Endobronchial Ultrasound to Diagnose and Stage Lung Cancer

Recommendation	Grade
Diagnosis of peripheral pulmonary nodules
"2.3.2. In patients suspected of having lung cancer, who have extensive infiltration of the mediastinum based on radiographic studies and no evidence of extrathoracic metastatic disease (negative PET scan), it is recommended that the diagnosis of lung cancer be established by the least invasive and safest method (bronchoscopy with TBNA, endobronchial ultrasound-guided needle aspiration [EBUS-NA], endoscopic ultrasound-guided needle aspiration [EUS-NA], transthoracic needle aspiration [TTNA], or mediastinoscopy)."	1C
"3.3.2.1. In patients suspected of having lung cancer, who have a peripheral lung nodule, and a tissue diagnosis is required due to uncertainty of diagnosis or poor surgical candidacy, radial EBUS is recommended as an adjunct imaging modality."	1C
Staging of the mediastinum in patients diagnosed with lung cancer
"4.4.4.3. In patients with high suspicion of N2,3 involvement, either by discrete mediastinal lymph node enlargement or PET uptake (and no distant metastases), a needle technique (endobronchial ultrasound [EBUS]-needle aspiration [NA], EUS-NA or combined EBUS/EUS-NA) is recommended over surgical staging as a best first test…. Remark: In cases where the clinical suspicion of mediastinal node involvement remains high after a negative result using a needle technique, surgical staging (e.g., mediastinoscopy, video-assisted thoracic surgery [VATS], etc) should be performed."	1B

PET: positron emission tomography.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for endobronchial ultrasound have been identified.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 12.

Table 12. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02719847	Additive Value of EBUS TBNA for Staging Non-Small Cell Lung Cancer in Patients Evaluated for Stereotactic Body Radiation Therapy	150	Mar 2021
Unpublished
NCT00559611	Prospective Comparison of Endobronchial Ultrasound Needle Biopsy Versus Mediastinoscopy for Staging of Mediastinal Nodes in Patients With Clinical Stage IIIA Non-Small Cell Lung Cancer (NSCLC)	53	Mar 2018 (completed)

NCT: national clinical trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Endobronchial Ultrasound for Diagnosis and Staging of Lung Cancer
EBUS
EBUS TBNA

References:
1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. May 2013;143(5 Suppl):e142S-165S. PMID 23649436

2. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. May 2013;143(5 Suppl):e93S-120S. PMID 23649456

3. 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. May 2013;143(5 Suppl):e211S-250S. PMID 23649440

4. Almeida FA, Uzbeck M, Ost D. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med. Jul 2010;16(4):307-314. PMID 20453649

5. Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest. Aug 2012;142(2):385-393. PMID 21980059

6. Colt HG, Davoudi M, Murgu S. Scientific evidence and principles for the use of endobronchial ultrasound and transbronchial needle aspiration. Expert Rev Med Devices. Jul 2011;8(4):493-513. PMID 21728734

7. Anantham D, Koh MS, Ernst A. Endobronchial ultrasound. Respir Med. Oct 2009;103(10):1406-1414. PMID 19447014

8. Han Y, Kim HJ, Kong KA, et al. Diagnosis of small pulmonary lesions by transbronchial lung biopsy with radial endobronchial ultrasound and virtual bronchoscopic navigation versus CT-guided transthoracic needle biopsy: A systematic review and meta-analysis. PLoS One. Jan 2018;13(1):e0191590. PMID 29357388

9. Ali MS, Trick W, Mba BI, et al. Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis. Respirology. Apr 2017;22(3):443-453. PMID 28177181

10. Ye J, Zhang R, Ma S, et al. Endobronchial ultrasound plus fluoroscopy-guided biopsy compared to fluoroscopy-guided transbronchial biopsy for obtaining samples of peripheral pulmonary lesions: A systematic review and meta-analysis. Ann Thorac Med. Apr-Jun 2017;12(2):114-120. PMID 28469722

11. Fielding DI, Chia C, Nguyen P, et al. Prospective randomised trial of endobronchial ultrasound-guided sheath versus computed tomography-guided percutaneous core biopsies for peripheral lung lesions. Intern Med J. Aug 2012;42(8):894-900. PMID 22212110

12. Paone G, Nicastri E, Lucantoni G, et al. Endobronchial ultrasound-driven biopsy in the diagnosis of peripheral lung lesions. Chest. Nov 2005;128(5):3551-3557. PMID 16304312

13. El-Osta H, Jani P, Mansour A, et al. Endobronchial ultrasound for nodal staging of patients with non-small-cell lung cancer with radiologically normal mediastinum. a meta-analysis. Ann Am Thorac Soc. Jul 2018;15(7):864-874. PMID 29684288

14. Ge X, Guan W, Han F, et al. Comparison of endobronchial ultrasound-guided fine-needle aspiration and video-assisted mediastinoscopy for mediastinal staging of lung cancer. Lung. Oct 2015;193(5):757-766. PMID 26186887

15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 5.2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 22, 2019.

16. Wahidi MM, Herth F, Yasufuku K, et al. Technical aspects of endobronchial ultrasound-guided transbronchial needle aspiration: CHEST Guideline and Expert Panel Report. Chest. Mar 2016;149(3):816-835. PMID 26402427

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

31652
31653
31654