Review questions

RQ 1.1: What is the clinical and cost effectiveness of using non-ultrasound-guided TBNA, EBUS-TBNA or EUS-FNA as the first invasive test for people with a probability of mediastinal malignancy?

RQ 1.2: What is the clinical and cost-effectiveness of EBUS-TBNA alone, EUS-FNA alone or EBUS-TBNA and EUS-FNA in combination compared with surgical staging to diagnose and/or stage lung cancer?

Economic evidence

Standard health economic filters were applied to the clinical search for this question, and a total of 1,788 citations was returned. Details of the literature search are provided in Appendix C. Following review of titles and abstracts, 24 full-text studies were retrieved for detailed consideration. One relevant cost–utility analysis, 1 health economics paper with a survival model and one health economics paper with an influence diagram were identified. Therefore 3 studies were included in this review.

EBUS-FNA plus EBUS-TBNA vs surgical staging

Sharples et al. (2012) conducted a cost-utility analysis alongside a 6-month RCT (ASTER) in the UK, Belgium and the Netherlands (n=247). Patients were eligible for the trial if they had known/suspected non-small cell lung cancer (NSCLC), with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and had no evidence of metastatic disease. Patients were excluded from the trial if they had previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; or were not suitable for surgical staging. One hundred and twenty three patients were randomised to endosonography followed by surgical staging if no nodal metastases were found at endosonography, whilst 118 patients were randomised to surgical staging alone. The primary research objective of the study was to determine whether endosonography is better than standard surgical staging techniques in terms of sensitivity, diagnostic accuracy and negative predictive value for diagnosing and staging the mediastinum in lung cancer. A secondary research objective was to conduct a comparative cost analysis of the diagnostic strategies of the two trial arms.

Endosonography in this study was EBUS-TBNA combined with EUS-FNA. Surgical staging was performed by (video) mediastinoscopy, left anterior mediastinoscopy or video-assisted thoracoscopy or combination.

The authors’ base case adopted a UK NHS perspective. Resource use was collected in terms of numbers of procedures done, (surgical, radiotherapy, chemotherapy) treatments administered, hospital and hospice stays. Costs were taken from the Department of Health (DoH) NHS reference costs 2008–2009. Cost estimates for endosonography were estimated by Papworth Hospital finance department. The price year was 2008–2009.

Utility was measured using the EQ-5D at baseline, end of staging, 2 months and 6 months, using a UK tariff.

Bayesian parametric modelling was used to estimate final expected costs and quality-adjusted life-years (QALYs) while simultaneously estimating missing data based on randomisation group, centre and stage.

Base-case results for patients for whom complete information on trial costs and QALYs were available (endosonography n=58, surgical staging n=56) are shown in Table 3.

Table 3

Costs and effects from Sharples et al. (2012).

Endosonography followed by surgical staging compared to surgical staging alone was £972 cheaper and produced 0.00652 more QALYs, rending endosonography followed by surgical staging as a dominant strategy. (Strategies that are dominant cost less and are more effective than their comparator.)

Because of the very small QALY difference, the authors concluded that an ICER could not be reliably estimated but in the probabilistic sensitivity analysis, 63% of bootstrapped samples showed endosonography dominated (which means it was less expensive and produced more benefit compared to) surgical staging and endosonography was cost-effective at a threshold of £30,000/QALY in 99.9% of samples.

EBUS-TBNA vs conventional approaches

Navani et al. (2015) conducted a cost-effectiveness analysis alongside LUNG-BOOST, an open-label, multicentre, pragmatic, randomised controlled trial. Patients were recruited from 6 centres in the UK, who were suspected to have stage I to IIIA lung cancer on the basis of CT scans of the neck, thorax, and upper abdomen were eligible for trial entry. For inclusion into the trial, patients had to be aged at least 18 years and fit enough to undergo thoracotomy and lung resection. Exclusion criteria were significant concurrent malignant disease or any condition or concurrent medicine that contraindicated EBUS-TBNA or mediastinoscopy. Patients with known extrathoracic malignant disease, supraclavicular lymphadenopathy, or pleural effusion were also excluded. Of the 133 RCT participants, 66 participants were randomised to endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), whilst 67 patients were randomised to conventional diagnosis and staging (CDS).

The primary endpoint was the time from first outpatient appointment with the respiratory specialist to treatment decision by the multidisciplinary team, after completion of the diagnosis and staging procedures. Analysis took a UK NHS perspective.

Effectiveness in this study was measured using mean time to treatment decision from the first outpatient appointment with the respiratory specialist, using hazard ratios. This is in contrast to the NICE reference case, where effects are measured in QALYs. Unit costs were obtained from NHS reference costs, NICE 2011 lung cancer guideline, and a published study; these were multiplied by the resource use and summed across all resource items. The price year was 2010–2011.

Lung cancer was diagnosed in 57 (86%) patients in the CDS group and 50 (76%) in the EBUS group (p=0·196), and clinical staging did not differ significantly between the groups in patients with non-small-cell lung cancer.

The median time-to-treatment decision was longer after CDS (29 days [95% CI 23–35]), than after EBUS (14 days [14–15]; HR 1·98, 95% CI 1·39–2·82, p<0·0001) in the intention-to-diagnose population. Therefore, patients in the EBUS group of the trial were likely to receive a treatment decision twice as fast as patients in the CDS group. A greater proportion of patients had diagnosis and staging completed by 14 days in the EBUS group than in the CDS group (35 [53%] vs 8 [12%], p<0·0001). In the subset of patients with non-small-cell lung cancer, initial EBUS-TBNA resulted in a shorter time-to-treatment decision of 15 days (95% CI 14–16), compared with 30 days (95% CI 23–34) in the CDS group (HR 2·09, 95% CI 1·38–3·15, p=0·0002).

In a post-hoc analysis, the median survival of patients with non-small-cell lung cancer in the EBUS group of 503 days (95% CI 312–715) was longer than the median survival in the CDS group of 312 days (95% CI 231–488; HR 0·60, 0·37–0·98, p=0·0382;). An exploratory analysis of lung cancer patients who underwent surgery suggested that postoperative survival was better in the EBUS group than in the CDS group.

For diagnosis and staging, EBUS-TBNA was found to cost £2,407 (SD £180.50) whilst CDS was found to cost £2,348 (SD £192.20). This represents an incremental cost for EBUS-TBNA of £59 (95% CI −£463 to £581). Mean initial treatment costs per patient in those diagnosed with lung cancer were £4452 (£180·00) and £4261 (£257·90), respectively (difference £191, 95% CI −447 to 829).

The results from the trial suggest that routine use of EBUS-TBNA as an initial investigation after a staging CT for suspected lung cancer scan results in a faster treatment decision, with fewer investigations at no significant difference in cost, and, in post-hoc analysis, seems to improve survival, compared with conventional diagnosis and staging methods.

Influence Diagram model to determine optimal sequence of tests for mediastinal staging of lung cancer

Luque et al. (2016) created an influence diagram (ID) model for a Spanish public healthcare system to determine the optimal sequence of tests for the mediastinal staging of non-small cell lung cancer (NSCLC) by considering sensitivity, specificity, and the economic cost of each test. This was stated to be important, as correct staging of the disease as early as possible helps to determine which patients may benefit from surgery and, in turn, to avoid dangerous, painful, and unnecessary surgery when metastasis has already occurred.

The model assumed that all patients first had a computed tomography (CT) scan, and then could have a transbronchial needle aspiration (TBNA), positron emission tomography (PET), endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), or a mediastinoscopy (MED) in various sequences.

IDs are a new modelling method that makes use of advanced statistical and computer science techniques to handle problems where the numbers of sequential decisions and probabilities are too large to be easily evaluated by a conventional decision tree. An auxiliary Bayesian network was built that could handle every possible sequence of tests as well as patients’ decisions and outcomes.

The ID model was evaluated twice, first without considering economic costs, and then considering cost effectiveness using a willingness-to-pay of €30,000 per QALY, the shadow threshold estimated for the Spanish health system. The authors performed several types of sensitivity analysis to study the effect of the uncertainty in the numerical parameters of the model.

The authors reported the optimal strategies using the two different criteria. When considering only effectiveness, a positive computed tomography (CT) scan should be followed by a transbronchial needle aspiration (TBNA) and an endobronchial ultrasound (EBUS). Endoscopic ultrasound (EUS) and mediastinoscopy are then used to either confirm negative findings or when the results of two tests are contradictory. When the CT scan is negative, a positron emission tomography (PET) and EBUS are performed. EUS and mediastinoscopy are used in the case of negative or contradictory results.

Economic model conducted for the 2011 NICE lung cancer guideline

The economic model built for the 2011 NICE lung cancer guideline included a range of diagnosis and staging strategies for people with an intermediate probability of mediastinal malignancy.

The model was a decision tree comprising 27 possible strategies which included one or several of neck ultrasound, PET-CT, conventional TBNA, EBUS TBNA and mediastinoscopy in various orders. Patients at each final end point entered a two state Markov model comprising survival and death states.

Disease prevalence, distribution of treatment options and survival estimates were drawn from registry data and expert opinion. Costs were drawn from standard NHS sources and resource use was drawn from expert opinion. The test accuracy data was drawn from expert opinion. Utility data were drawn from published literature and expert opinion.

The model concluded that PET-CT followed by conventional TBNA was the optimal strategy. This was due to the combination of high sensitivity and low cost parameters used within the model for these tests. The model was reasonably robust with regards to deterministic sensitivity analysis but no probabilistic sensitivity analysis was conducted. The guideline committee concluded that while the model had a number of limitations, the results provided them with useful information when developing a diagnostic testing algorithm.

Review protocol for the clinical and cost effectiveness of using non-ultrasound-guided TBNA, EBUS-TBNA or EUS-FNA as the first invasive test for people with a probability of mediastinal malignancy

Review protocol for the clinical and cost-effectiveness of EBUS-TBNA alone, EUS-FNA alone or EBUS-TBNA and EUS-FNA in combination compared with surgical staging to diagnose and/or stage lung cancer

What is the clinical and cost-effectiveness of EBUS-TBNA alone, EUS-FNA alone or EBUS-TBNA and EUS-FNA in combination compared with surgical staging to diagnose and/or stage lung cancer?

Priority screening

The reviews undertaken for this guideline all made use of the priority screening functionality with the EPPI-reviewer systematic reviewing software. This uses a machine learning algorithm (specifically, an SGD classifier) to take information on features (1, 2 and 3 word blocks) in the titles and abstract of papers marked as being ‘includes’ or ‘excludes’ during the title and abstract screening process, and re-orders the remaining records from most likely to least likely to be an include, based on that algorithm. This re-ordering of the remaining records occurs every time 25 additional records have been screened.

• Research is currently ongoing as to what are the appropriate thresholds where reviewing of abstract can be stopped, assuming a defined threshold for the proportion of relevant papers it is acceptable to miss on primary screening. As a conservative approach until that research has been completed, the following rules were adopted during the production of this guideline:

  • In every review, at least 50% of the identified abstract (or 1,000 records, if that is a greater number) were always screened.
  • After this point, screening was only terminated when the threshold was reached for a number of abstracts being screened without a single new include being identified. This threshold was set according to the expected proportion of includes in the review (with reviews with a lower proportion of includes needing a higher number of papers without an identified study to justify termination), and was always a minimum of 250.
  • A random 10% sample of the studies remaining in the database when the threshold were additionally screened, to check if a substantial number of relevant studies were not being correctly classified by the algorithm, with the full database being screened if concerns were identified.
• As an additional check to ensure this approach did not miss relevant studies, the included studies lists of included systematic reviews were searched to identify any papers not identified through the primary search.

Evidence synthesis and meta-analyses

Where possible, meta-analyses were conducted to combine the results of studies for each outcome. For mean differences, where change from baseline data were reported in the studies and were accompanied by a measure of spread (for example standard deviation), these were extracted and used in the meta-analysis. Where measures of spread for change from baseline values were not reported, the corresponding values at study end were used and were combined with change from baseline values to produce summary estimates of effect. All studies were assessed to ensure that baseline values were balanced across the treatment/comparison groups; if there were significant differences in important confounding variables at baseline these studies were not included in any meta-analysis and were reported separately.

When averages were given as medians, no meta-analysis of the data were performed.

Evidence of effectiveness of interventions

Diagnostic test accuracy evidence

In this guideline, diagnostic test accuracy (DTA) data are classified as any data in which a test result or the output of an algorithm – is observed in some people who have the condition of interest at the time of the test and some people who do not. Such data either explicitly provide, or can be manipulated to generate, a 2x2 classification of true positives and false negatives (in people who, according to the reference standard, truly have the condition) and false positives and true negatives (in people who, according to the reference standard, do not).

The ‘raw’ 2×2 data can be summarised in a variety of ways. Those that were used for decision making in this guideline are as follows:

• Sensitivity is the probability that the feature will be positive in a person with the condition.
  • sensitivity = TP/(TP+FN)
• Negative predictive value is the probability that people for whom the feature is negative truly do not have the condition.
  • negative predictive value = TN/(TN+FN)

Negative predictive value was used rather than specificity. This is because all studies assumed that the pathologist made no false positives. Therefore, sensitivity and negative predictive value (with prevalence information) are more meaningful measurements of performance because they do not involve false positives.

Scoping search strategies

Scoping searches Scoping searches were undertaken on the following websites and databases (listed in alphabetical order) in April 2017 to provide information for scope development and project planning. Browsing or simple search strategies were employed.

Clinical search literature search strategy

Search strategy

Study Design Filters

Health Economics literature search strategy

Sources searched to identify economic evaluations

• NHS Economic Evaluation Database – NHS EED (Wiley) last updated Apr 2015
• Health Technology Assessment Database – HTA (Wiley) last updated Oct 2016
• Embase (Ovid)
• MEDLINE (Ovid)
• MEDLINE In-Process (Ovid)

Search filters to retrieve economic evaluations and quality of life papers were appended to the review question search strategies. For some health economics strategies additional terms were added to the original review question search strategies (see sections 4.2, 4.3 and 4.4) The searches were conducted between October 2017 and April 2018 for 9 review questions (RQ).

Searches were re-run in May 2018.

Searches were limited to those in the English language. Animal studies were removed from results.

Clinical evidence study selection

Economic evidence study selection

RQ 1.1: Mediastinoscopy + EUS-FNA vs mediastinoscopy + EUS-FNA only if CT shows invasion adjacent to the oesophagus: intervention evidence

RQ 1.1: EUS-FNA vs straight to surgical staging: intervention evidence

RQ 1.1: EUS-FNA vs straight to surgical staging: diagnostic accuracy evidence. Reference standards: For benign results, surgical confirmation. For malignant results, pathology

RQ 1.1 and RQ 1.2: Bronchoscopy, EBUS-TBNA then EUS (B)-FNA if necessary on mediastinal nodes inaccessible or difficult to access by EBUS-TBNA vs bronchoscopy, EUS-FNA then EBUS-TBNA if necessary on mediastinal nodes inaccessible or difficult to access by EUS-FNA: intervention evidence

RQ 1.1 and RQ 1.2: Bronchoscopy, EBUS-TBNA then EUS (B)-FNA if necessary vs bronchoscopy, EUS-FNA then EBUS-TBNA if necessary: diagnostic accuracy evidence. Reference standards: For benign results, surgical confirmation. For malignant results, pathology

RQ 1.1 and RQ 1.2: EBUS-TBNA (or EUS-FNA) vs conventional (bronchoscopy or CT-guided biopsy etc): intervention evidence

RQ 1.1 and RQ 1.2: EBUS-TBNA (or EUS-FNA) vs conventional (bronchoscopy or CT-guided biopsy etc): diagnostic accuracy evidence. Reference standards: For benign results, surgical confirmation. For malignant results, pathology

RQ 1.2: EUS-FNA followed by EBUS-TBNA vs straight to surgical staging: intervention evidence

RQ 1.2: EUS-FNA followed by EBUS-TBNA vs straight to surgical staging: diagnostic accuracy evidence. Reference standards: For benign results, surgical confirmation. For malignant results, pathology

Excluded clinical studies

Excluded economic studies

Clinical Studies - Included

• Annema J T, van Meerbeeck, J P, Rintoul R C, Dooms C, Deschepper E, Dekkers O M, De Leyn, P, Braun J, Carroll N R, Praet M, de Ryck, F, Vansteenkiste J, Vermassen F, Versteegh M I, Veselic M, Nicholson A G, Rabe K F, and Tournoy K G (2010) Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 304(20), 2245–52 [PubMed: 21098770]
• Kang H J, Hwangbo B, Lee G K, Nam B H, Lee H S, Kim M S, Lee J M, Zo J I, Lee H S, and Han J Y (2014) EBUS-centred versus EUS-centred mediastinal staging in lung cancer: a randomised controlled trial. Thorax 69(3), 261–8 [PubMed: 24172712]
• Larsen S S, Vilmann P, Krasnik M, Dirksen A, Clementsen P, Maltbaek N, Lassen U, Skov B G, and Jacobsen G K (2005) Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: preliminary results from a randomised clinical trial. Lung Cancer 49(3), 377–85 [PubMed: 16102606]
• Navani N, Nankivell M, Lawrence D R, Lock S, Makker H, Baldwin D R, Stephens R J, Parmar M K, Spiro S G, Morris S, Janes S M, and Lung Boost trial investigators (2015) Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. The Lancet Respiratory Medicine 3(4), 282–9 [PMC free article: PMC4648022] [PubMed: 25660225]
• Sharples L D, Jackson C, Wheaton E, Griffith G, Annema J T, Dooms C, Tournoy K G, Deschepper E, Hughes V, Magee L, Buxton M, Rintoul R C (2012) Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technology Assessment 16(18), 1–100 [PubMed: 22472180]
• Tournoy K G, De Ryck, F, Vanwalleghem L R, Vermassen F, Praet M, Aerts J G, Van Maele, G, van Meerbeeck, and J P (2008) Endoscopic ultrasound reduces surgical mediastinal staging in lung cancer: a randomized trial. American Journal of Respiratory & Critical Care Medicine 177(5), 531–5 [PubMed: 17962631]

Clinical studies – Excluded

• Adams K, Shah P L, Edmonds L, and Lim E (2009) Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis. Thorax 64(9), 757–62 [PubMed: 19454408]
• Akulian J A, Belanger A R, and Yarmus L (2014) Molecular profiling of adenocarcinoma of the lung. Minerva Pneumologica 53(1), 1–8
• Almeida F A (2012) Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer. Cleveland Clinic Journal of Medicine 79 Electronic Suppl 1, eS11–6 [PubMed: 22614959]
• Anantham D, and Koh M S (2010) Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis and staging of lung cancer. Thoracic Cancer 1(1), 9–16 [PubMed: 27755787]
• Boonsarngsuk V, Kanoksil W, and Laungdamerongchai S (2015) Comparison of diagnostic performances among bronchoscopic sampling techniques in the diagnosis of peripheral pulmonary lesions. Journal of Thoracic Disease 7(4), 697–703 [PMC free article: PMC4419296] [PubMed: 25973236]
• Casal R F, Staerkel G A, Ost D, Almeida F A, Uzbeck M H, Eapen G A, Jimenez C A, Nogueras-Gonzalez G M, Sarkiss M, and Morice R C (2012) Randomized clinical trial of endobronchial ultrasound needle biopsy with and without aspiration. Chest 142(3), 568–573 [PMC free article: PMC3610596] [PubMed: 22156610]
• Chao T Y, Chien M T, Lie C H, Chung Y H, Wang J L, and Lin M C (2009) Endobronchial ultrasonography-guided transbronchial needle aspiration increases the diagnostic yield of peripheral pulmonary lesions: a randomized trial. Chest 136(1), 229–236 [PubMed: 18812446]
• Dango S, Guenter J, and Passlick B (2010) Endobronchial ultrasound-guided transbronchial needle aspiration and its role in non-small cell lung cancer: Diagnostic impact and limitations. Thoracic Cancer 1(2), 70–76 [PubMed: 27755780]
• Darwiche K, Zarogoulidis P, Baehner K, Welter S, Tetzner R, Wohlschlaeger J, Theegarten D, Nakajima T, and Freitag L (2013) Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging. Annals of Oncology 24(11), 2866–70 [PubMed: 24026539]
• Ernst A, Anantham D, Eberhardt R, Krasnik M, and Herth F J (2008) Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 3(6), 577–82 [PubMed: 18520794]
• Fritscher-Ravens A (2003) Endoscopic ultrasound evaluation in the diagnosis and staging of lung cancer. Lung Cancer 41(3), 259–67 [PubMed: 12928117]
• Fritscher-Ravens A, Bohuslavizki K H, Brandt L, Bobrowski C, Lund C, Knofel W T, and Pforte A (2003) Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 123(2), 442–51 [PubMed: 12576364]
• Godbout K, Martel S, Simon M, Lampron N, and Delage A (2016) Evaluation of pulmonary nodules using the spyglass direct visualization system combined with radial endobronchial ultrasound: A clinical feasibility study. Open Respiratory Medicine Journal 10, 79–85 [PMC free article: PMC5220169] [PubMed: 28144366]
• Gompelmann D, and Herth F J (2014) Role of endobronchial and endoscopic ultrasound in pulmonary medicine. Respiration 87(1), 3–8 [PubMed: 24296947]
• Govert J A, Dodd L G, Kussin P S, and Samuelson W M (1999) A prospective comparison of fiberoptic transbronchial needle aspiration and bronchial biopsy for bronchoscopically visible lung carcinoma. Cancer 87(3), 129–34 [PubMed: 10385443]
• Grah C, Griff S, Mairinger T, Bollmann L, Temme H, Seiberth R, and Vogelbusch M (2011) Comparison of 21 gauge and 22-gauge aspiration needle during endobronchial ultrasound-guided transbronchial needle aspiration: a randomised trial. Journal of thoracic oncology. 6(6 suppl. 2), S1148
• Gu P, Zhao Y Z, Jiang L Y, Zhang W, Xin Y, and Han B H (2009) Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. European Journal of Cancer 45(8), 1389–96 [PubMed: 19124238]
• Hassan M Q, Ahamad M S, Ahmed S, and Chowdhury M A (2010) Comparative study of efficacy of brush cytology and transthoracic fine needle aspiration cytology in the diagnosis of bronchogenic carcinoma. Bangladesh Medical Research Council Bulletin 36(1), 37–9 [PubMed: 21280559]
• Herth F, Becker H D, and Ernst A (2004) Conventional vs Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: A Randomized Trial. Chest 125(1), 322–325 [PubMed: 14718460]
• Herth F J. F, Lunn W, Eberhardt R, Becker H D, and Ernst A (2005) Transbronchial versus transesophageal ultrasound-guided aspiration of enlarged mediastinal lymph nodes. American Journal of Respiratory and Critical Care Medicine 171(10), 1164–1167 [PubMed: 15665318]
• Hwangbo B, Lee G K, Lee H S, Lim K Y, Lee S H, Kim H Y, Lee H S, Kim M S, Lee J M, Nam B H, and Zo J I (2010) Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer. Chest 138(4), 795–802 [PubMed: 20348194]
• Jiang J, Browning R, Lechtzin N, Huang J, Terry P, and Wang K P (2014) TBNA with and without EBUS: A comparative efficacy study for the diagnosis and staging of lung cancer. Journal of Thoracic Disease 6(5), 416–420 [PMC free article: PMC4015015] [PubMed: 24822097]
• Kramer H, and Groen H J. M (2003) Current Concepts in the Mediastinal Lymph Node Staging of Nonsmall Cell Lung Cancer. Annals of Surgery 238(2), 180–188 [PMC free article: PMC1422673] [PubMed: 12894010]
• Lardinois D (2011) Pre- and intra-operative mediastinal staging in non-small-cell lung cancer. Swiss Medical Weekly 141(MARCH), [PubMed: 21384283]
• Micames C G, McCrory D C, Pavey D A, Jowell P S, and Gress F G (2007) Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis. Chest 131(2), 539–48 [PubMed: 17296659]
• Mullan C P, Kelly B E, Ellis P K, Hughes S, Anderson N, and McCluggage W G (2004) CT-guided fine-needle aspiration of lung nodules: effect on outcome of using coaxial technique and immediate cytological evaluation. Ulster Medical Journal 73(1), 32–6 [PMC free article: PMC2475445] [PubMed: 15244123]
• Oezkan F, Wolters C, Franzen D, Hager T, Eisenmann S, Freitag L, He K, Weinreich G, and Darwiche K (2017) Feasibility study of using 19G needle for EBUS-TBNA: a prospective-randomized comparison of 19G and 22G EBUS-needles. American journal of respiratory and critical care medicine. Conference: american thoracic society international conference, and ATS 2017. United states 195(no pagination),
• Ost D E, Ernst A, Lei X, Kovitz K L, Benzaquen S, Diaz-Mendoza J, Greenhill S, Toth J, Feller-Kopman D, Puchalski J, Baram D, Karunakara R, Jimenez C A, Filner J J, Morice R C, Eapen G A, Michaud G C, Estrada Y Martin R. M, Rafeq S, Grosu H B, Ray C, Gilbert C R, Yarmus L B, Simoff M, and Registry A QuIRE Bronchoscopy (2016) Diagnostic Yield and Complications of Bronchoscopy for Peripheral Lung Lesions. Results of the AQuIRE Registry. American Journal of Respiratory & Critical Care Medicine 193(1), 68–77 [PMC free article: PMC4731617] [PubMed: 26367186]
• Paone G, Nicastri E, Lucantoni G, Della Iacono, R, Battistoni P, D’Angeli A L, and Galluccio G (2005) Endobronchial ultrasound-driven biopsy in the diagnosis of peripheral lung lesions. Chest 128(5), 3551–3557 [PubMed: 16304312]
• Puri R, Vilmann P, Saftoiu A, Skov B G, Linnemann D, Hassan H, Garcia E S. G, and Gorunescu F (2009) Randomized controlled trial of endoscopic ultrasound-guided fine-needle sampling with or without suction for better cytological diagnosis. Scandinavian Journal of Gastroenterology 44(4), 499–504 [PubMed: 19117242]
• Roth K, Eagan T M, Andreassen A H, Leh F, and Hardie J A (2011) A randomised trial of endobronchial ultrasound guided sampling in peripheral lung lesions. Lung Cancer 74(2), 219–25 [PubMed: 21481486]
• Saji J, Kurimoto N, Morita K, Nakamura M, Inoue T, Nakamura H, and Miyazawa T (2011) Comparison of 21-gauge and 22-gauge Needles for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration of Mediastinal and Hilar Lymph Nodes. Journal of Bronchology and Interventional Pulmonology 18(3), 239–246 [PubMed: 23208567]
• Schreiber G, and McCrory D C (2003) Performance characteristics of different modalities for diagnosis of suspected lung cancer: Summary of published evidence. Chest 123(1 SUPPL.), 115S–128S [PubMed: 12527571]
• Soja J, Szlubowski A, Kocon P, Czajkowski W, Grzanka P, Tomaszewska R, Cmiel A, and Kuzdzal J (2010) Usefulness of transbronchial needle aspiration for initial lung cancer staging. Polskie Archiwum Medycyny Wewnetrznej 120(7–8), 264–269 [PubMed: 20693956]
• Szlubowski A, Soja J, Kocon P, Talar P, Czajkowski W, Rudnicka-Sosin L, Cmiel A, and Kuzdzal J (2012) A comparison of the combined ultrasound of the mediastinum by use of a single ultrasound bronchoscope versus ultrasound bronchoscope plus ultrasound gastroscope in lung cancer staging: a prospective trial. Interactive Cardiovascular & Thoracic Surgery 15(3), 442–6; discussion 446 [PMC free article: PMC3422922] [PubMed: 22623626]
• Trisolini R, Cancellieri A, Tinelli C, de Biase, D, Valentini I, Casadei G, Paioli D, Ferrari F, Gordini G, Patelli M, and Tallini G (2015) Randomized Trial of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration With and Without Rapid On-site Evaluation for Lung Cancer Genotyping. Chest 148(6), 1430–7 [PubMed: 26158441]
• Wagner E D, Ramzy I, Greenberg S D, and Gonzalez J M (1989) Transbronchial fine-needle aspiration. Reliability and limitations. American Journal of Clinical Pathology 92(1), 36–41 [PubMed: 2750706]
• Xi Y, Fan J, Che D, Zhai K, Ren T, Feng X, Shang L, Hu J, Yu Y, and Meng Q (2017) Distant metastasis and survival outcomes after computed tomography-guided needle biopsy in resected stage I-III non-small cell lung cancer. Journal of Cancer 8(16), 3356–3361 [PMC free article: PMC5665052] [PubMed: 29158808]
• Yarmus L, Kloot T, Lechtzin N, Napier M, Dressel D, and Feller-Kopman D (2011) A randomized prospective trial of the utility of rapid on-site evaluation of transbronchial needle aspirate specimens. Journal of bronchology & interventional pulmonology 18(2), 121–127 [PubMed: 23169079]
• Yarmus L, Akulian J, Ortiz R, Thompson R, Oakjones-Burgess K, Arias S, Semaan R, Feller-Kopman D, Lee H, and Wang Kp (2015) A randomized controlled trial evaluating airway inspection effectiveness during endobronchial ultrasound bronchoscopy. Journal of thoracic disease 7(10), 1825–1832 [PMC free article: PMC4635275] [PubMed: 26623106]
• Yasuda I, Kato T, Asano F, Okubo K, Omar S, Kako N, Yasuda S, Sano K, Soehendra N, and Moriwaki H (2009) Mediastinal lymph node staging in potentially resectable non-small cell lung cancer: a prospective comparison of CT and EUS/EUS-FNA. Respiration 78(4), 423–31 [PubMed: 19672051]
• Zhang R, Ying K, Shi L, Zhang L, and Zhou L (2013) Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal lymph node staging of lung cancer: a meta-analysis. European Journal of Cancer 49(8), 1860–7 [PubMed: 23481511]

Health Economic studies – Included

• Luque, M., Díez, F. J., & Disdier, C. (2016). Optimal sequence of tests for the mediastinal staging of non-small cell lung cancer. BMC medical informatics and decision making, 16(1), 9. [PMC free article: PMC4727341] [PubMed: 26813400]
• Navani, N., Nankivell, M., Lawrence, D. R., Lock, S., Makker, H., Baldwin, D. R., … & Janes, S. M. (2015). Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. The Lancet Respiratory Medicine, 3(4), 282–289. [PMC free article: PMC4648022] [PubMed: 25660225]
• Sharples, L. D., Jackson, C., Wheaton, E., Griffith, G., Annema, J. T., Dooms, C., … & Buxton, M. (2012). Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. [PubMed: 22472180]
• NICE (2011) Clinical Guideline 121 Lung cancer: diagnosis and management. Appendix 4: Economic model to compare different testing strategies to stage the mediastinum in patients with NSCLC

Health Economic studies – Excluded

• Bongers, M. L., Coupé, V. M., De Ruysscher, D., Oberije, C., Lambin, P., & Uyl-de Groot, C. A. (2015). Individualized Positron Emission Tomography–Based Isotoxic Accelerated Radiation Therapy Is Cost-Effective Compared With Conventional Radiation Therapy: A Model-Based Evaluation. International Journal of Radiation Oncology* Biology* Physics, 91(4), 857–865. [PubMed: 25752401]
• Czarnecka-Kujawa, K., Rochau, U., Siebert, U., Atenafu, E., Darling, G., Waddell, T. K., … & Yasufuku, K. (2017). Cost-effectiveness of mediastinal lymph node staging in non–small cell lung cancer. The Journal of Thoracic and Cardiovascular Surgery, 153(6), 1567–1578. [PubMed: 28283236]
• Deppen, S. A., Davis, W. T., Green, E. A., Rickman, O., Aldrich, M. C., Fletcher, S., … & Grogan, E. L. (2014). Cost-effectiveness of initial diagnostic strategies for pulmonary nodules presenting to thoracic surgeons. The Annals of thoracic surgery, 98(4), 1214–1222. [PMC free article: PMC4186897] [PubMed: 25087933]
• Dietlein, M., Weber, K., Gandjour, A., Moka, D., Theissen, P., Lauterbach, K. W., & Schicha, H. (2000). Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. European journal of nuclear medicine, 27(11), 1598–1609. [PubMed: 11105815]
• Dietlein, M., Weber, K., Gandjour, A., Moka, D., Theissen, P., Lauterbach, K. W., & Schicha, H. (2000). Cost-effectiveness of FDG-PET for the management of solitary pulmonary nodules: a decision analysis based on cost reimbursement in Germany. European journal of nuclear medicine, 27(10), 1441–1456. [PubMed: 11083532]
• Esnaola, N. F., Lazarides, S. N., Mentzer, S. J., & Kuntz, K. M. (2002). Outcomes and cost-effectiveness of alternative staging strategies for non–small-cell lung cancer. Journal of clinical oncology, 20(1), 263–273. [PubMed: 11773178]
• Han, Y., Xiao, H., Zhou, Z., Yuan, M., Zeng, Y., Wu, H., & Fang, Y. (2015). Cost-effectiveness analysis of strategies introducing integrated 18F-FDG PET/CT into the mediastinal lymph node staging of non-small-cell lung cancer. Nuclear medicine communications, 36(3), 234–241. [PubMed: 25460305]
• Lejeune, C., Al Zahouri, K., Woronoff-Lemsi, M. C., Arveux, P., Bernard, A., Binquet, C., & Guillemin, F. (2005). Use of a decision analysis model to assess the medicoeconomic implications of FDG PET imaging in diagnosing a solitary pulmonary nodule. The European Journal of Health Economics, 6(3), 203–214. [PubMed: 15834623]
• Gómez León, N., Escalona, S., Bandrés, B., Belda, C., Callejo, D., & Blasco, J. A. (2014). 18f-fluorodeoxyglucose positron emission tomography/computed tomography accuracy in the staging of non-small cell lung cancer: Review and cost-effectiveness. Radiology Research and Practice, 2014. [PMC free article: PMC4238277] [PubMed: 25431665]
• Medford, A. R. L., Agrawal, S., Free, C. M., & Bennett, J. A. (2010). A prospective study of conventional transbronchial needle aspiration: performance and cost utility. Respiration, 79(6), 482–489. [PubMed: 20110643]
• Meyers, B. F., Haddad, F., Siegel, B. A., Zoole, J. B., Battafarano, R. J., Veeramachaneni, Patterson, G. A. (2006). Cost-effectiveness of routine mediastinoscopy in computed tomography–and positron emission tomography–screened patients with stage I lung cancer. The Journal of thoracic and cardiovascular surgery, 131(4), 822–829. [PubMed: 16580440]
• Navani, N., & Janes, S. M. (2013). Endobronchial Ultrasound–guided Transbronchial Needle Aspiration for Lymphoma: The Final Frontier. [PMC free article: PMC3863735] [PubMed: 24236584]
• Navani, N., Nankivell, M., Woolhouse, I., Harrison, R. N., Munavvar, M., Oltmanns, Janes, S. M. (2011). Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of intrathoracic lymphadenopathy in patients with extrathoracic malignancy: a multicenter study. Journal of Thoracic Oncology, 6(9), 1505–1509. [PMC free article: PMC3361007] [PubMed: 21792077]
• Navani, Neal, et al. “Endobronchial ultrasound–guided transbronchial needle aspiration prevents mediastinoscopies in the diagnosis of isolated mediastinal lymphadenopathy: a prospective trial.” American journal of respiratory and critical care medicine 186.3 (2012): 255–260. [PMC free article: PMC3423452] [PubMed: 22652031]
• Rintoul, Robert C., et al. “Cost effectiveness of endosonography versus surgical staging in potentially resectable lung cancer: a health economics analysis of the ASTER trial from a European perspective.” Thorax (2013): thoraxjnl-2013. [PubMed: 24064440]
• Sari, A. A., Ravaghi, H., Mobinizadeh, M., & Sarvari, S. (2013). The cost-utility analysis of PET-scan in diagnosis and treatment of non-small cell lung carcinoma in Iran. Iranian Journal of Radiology, 10(2), 61. [PMC free article: PMC3767016] [PubMed: 24046780]
• Schreyögg, J., Weller, J., Stargardt, T., Herrmann, K., Bluemel, C., Dechow, T., … & Buck, A. K. (2010). Cost-effectiveness of hybrid PET/CT for staging of non–small cell lung cancer. Journal of Nuclear Medicine, 51(11), 1668–1675. [PubMed: 21051648]
• Scott, W. J., Shepherd, J., & Gambhir, S. S. (1998). Cost-effectiveness of FDG-PET for staging non–small cell lung cancer: a decision analysis. The Annals of thoracic surgery, 66(6), 1876–1884. [PubMed: 9930463]
• Søgaard, R., Fischer, B. M. B., Mortensen, J., Rasmussen, T. R., & Lassen, U. (2013). The Optimality of Different Strategies for Supplemental Staging of Non–Small-Cell Lung Cancer: A Health Economic Decision Analysis. Value in health, 16(1), 57–65. [PubMed: 23337216]
• van Loon, J., Grutters, J. P., Wanders, R., Boersma, L., Dingemans, A. M. C., Bootsma, G., … & Snoep, G. (2010). 18 FDG-PET-CT in the follow-up of non-small cell lung cancer patients after radical radiotherapy with or without chemotherapy: an economic evaluation. European Journal of Cancer, 46(1), 110–119. [PubMed: 19944595]
• Wang, Y. T., & Huang, G. (2012). Is FDG PET/CT cost-effective for pre-operation staging of potentially operative non-small cell lung cancer?–from Chinese healthcare system perspective. European journal of radiology, 81(8), e903–e909. [PubMed: 22698711]