In patients with lung cancer is combined endobronchial ultrasound and endoscopic ultrasound superior to conventional mediastinoscopy in staging the mediastinum?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was ‘In patients with lung cancer, is combined endobronchial ultrasound and endoscopic ultrasound (EBUS + EUS) superior to cervical mediastinoscopy (CM) in staging the mediastinum?’ Altogether more than 110 papers were found, of which one meta-analysis, two RCTs, and two cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Studies directly comparing EBUS + EUS and CM are limited in number and quality, with the majority of studies focusing on comparing endosonographic techniques or a single technique with surgical staging. Moreover, in four out of five studies, surgical staging of the mediastinum was undertaken following a negative EBUS + EUS result, limiting the utility of comparing endosonography alone. Regardless of this, the initial EBUS + EUS approach followed by surgical staging if negative resulted in greater sensitivity and detection of N2/3 metastases as well as greater sampling in the majority of studies, resulting in higher likelihood of upstaging and treatment alterations for patients. There was also improved quality of life demonstrated in the EBUS + EUS group with significant reductions in futile thoracotomies and less complications when compared with exclusive CM staging. We conclude that a combined approach of combined endosonography in the first instance, followed by CM staging of the mediastinum results in greater sensitivity of nodal disease and subsequent greater accuracy in upstaging and determining treatment plans with a concurrent reduction in complication rates and futile procedures.


Introduction
A best evidence topic was constructed according to a structured protocol. This is fully described in the IJS [1].

Clinical scenario
You attend a lung cancer multidisciplinary meeting involving respiratory physicians, oncologists and thoracic surgeons where they are discussing a 62-year-old man with a 45 mm right upper lobe non-small cell lung carcinoma. Positron-Emission Tomography (PET) reveals low grade uptake of flurodeoxyglucose (FDG) at stations 4R and 7. A colleague suggests that combined endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) would be less invasive and more accurate than proceeding directly to cervical mediastinoscopy (CM), the gold standard staging procedure. You resolve to review the scientific literature to inform your plan.

Search strategy
A literature search was performed on MEDLINE database (from 1946 to present) using the OVID interface with the terms: (EBUS OR endobronchial) AND (EUS OR endoscopic) AND (combined OR endosonography OR ((ultrasonography) OR (ultrasound))) AND mediastinoscopy AND staging AND (lung neoplasms OR lung cancer). Only papers published in English were reviewed. The reference lists of initially identified papers were searched for relevant studies.

Search outcome
A total of 110 papers were found using the reported search. From these, five papers were identified that were deemed to provide the best evidence to answer the question. These are presented in Table 1.

Results
The results of the five papers (one meta-analysis, two RCTs, and two cohort studies) are summarised in Table 1.
Liberman et al. [3] conducted a single-centre prospective study in 166 patients comparing EBUS + EUC with CM. All patients in the study had EBUS + EUS first followed by CM -acting as a control for themselves. The sensitivity of EBUS + EUS was 91% with a further 5 patients diagnosed with N2 disease following CM. EBUS + EUS found an additional 24 patients (14.4%) with N2/N3 disease over CM, which may have prevented futile thoracotomies in a significant proportion of patients. The negative predictive value and diagnostic accuracy were similar among the techniques (92% vs. 89%, p = NR; 91% vs. 89%, p = NR), with more complications occurring during the CM procedure (0 vs. 15, p = NR). Unfortunately, statistical analysis was not performed directly comparing the two techniques, thus limiting the utility of this study.
Sehgal et al. [4] performed a meta-analysis including 9 studies between 2005 and 2015 that included 960 patients. The authors demonstrated equivalence between EBUS + EUS and CM with a pooled risk difference (RD) for diagnostic sensitivity of 0.11 (CI 0.07-0.29) across all studies. Additionally, endosonography had a higher pooled RD in terms of complications with a 6.8% increase compared with CM (CI 4.3-9.8). Significantly greater sensitivities were reported for lymph node stations 2R and 4L (RD 0.16, p = 0.03; RD 0.19, p = 0.002), however, there were similar outcomes in stations 7 and 4R.
Sharples et al. [6] completed an RCT with 241 patients involving four districts in the UK between 2007 and 2009. Patients were randomised to undergo EBUS + EUS or CM alone, with patients proceeding to CM if EBUS + EUS was negative. This RCT demonstrated that using combined EBUS + EUS, followed by CM if negative, had a higher sensitivity and negative predictive value than CM alone (94% vs. 79%, p = 0.02; 93% vs. 86%, p = 0.18). Conversely, when the diagnostic accuracy of EBUS + EUS alone is assessed, without additional CM, the results were not statistically significant (sensitivity 85% vs. 79%, p = 0.62; NPV 85% vs. 86%, p = 1.00). CM was avoided in 47% of patients due to positive endosonography findings. Additionally, unnecessary thoracotomy was higher in the CM staging group (7% vs. 18%, p = 0.02), however, complications were similar between the groups (5% vs. 6%, p = 0.78).
There was no difference in survival at 6 months for EBUS + EUS compared with CM (9 vs. 11 deaths, p = 0.57). Quality of life was significantly improved in the EBUS/EUS cohort as demonstrated by a higher European quality of life staging score (EQ-5D 0.117, p = 0.003).

Clinical bottom line
Studies directly comparing EBUS + EUS and CM are limited in number and quality, with the majority of studies focusing on comparing endosonographic techniques or a single technique with cervical mediastinoscopy. Moreover, in four out of five studies CM was undertaken following a negative EBUS + EUS result, limiting the utility of comparing endosonography alone. Regardless of this, the initial EBUS + EUS approach followed by surgical staging if negative resulted in greater sensitivity and detection of N2/3 metastases as well as greater sampling in the majority of studies, resulting in higher likelihood of upstaging and treatment alterations for patients. There was also improved quality of life demonstrated in the endosongraphy group with significant reductions in futile thoracotomies and less complications when compared with exclusive CM surgical staging. We conclude that a combined approach of endosongraphy (EBUS + EUS) in the first instance, followed by surgical staging of the mediastinum with CM results in greater sensitivity of nodal disease and subsequent greater accuracy in upstaging and determining treatment plans with a concurrent reduction in complication rates and futile procedures.

Provenance and peer review
Not commissioned, externally peer reviewed.

Declaration of competing interest
None declared.