1. Clinical utilization of endobronchial ultrasound (EBUS) to stage lung cancer Francisco A. Almeida, MD, MS, FCCP Associate Staff Member Respiratory Institute Cleveland Clinic

2. Clinical utilization of endobronchial ultrasound (EBUS) to stage lung cancer No conflicts of interest

3. EBUS staging in NSCLC RADIAL-PROBE EBUS CONVEX-PROBE EBUS

4. EBUS staging in NSCLC

5. Lymph node map and lung cancer staging

6. Rusch V, Asamura H, Watanabe H et al. J Thorac Oncol. 2009;4: 568–577 IASLC Lymph node map

7. Detterbeck F, Postmus P, Tanoue L. Chest 2013: 143(5)(Suppl):e191S–e210S

8. Yasufuku K, Nakajima T, Motoori K et al. Chest 2006;130;710-718

9. EBUS vs Mediastinoscopy

10. Prospective, crossover trial Consecutive subjects with clinically suspected NSCLC Inclusion criteria: - Resectable disease - PET not used and histology unconfirmed at enrollment - Mediastinal adenopathy (10 mm) on CT had to be confined to lymph node stations 2, 4 or 7 J Thorac Oncol 2008;3:577-582

11. EBUS performed as separate procedure 1 week before mediastinoscopy or at the time of mediastinoscopy Only pathologically enlarged nodes on CT biopsied Two passes only NO ROSE Patients with negative EBUS-TBNA and mediastinoscopy: surgical resection J Thorac Oncol 2008;3:577-582

12. 66 pts met inclusion criteria 120 enlarged nodes Mean large node/patient: 1.8 ± 0.1 (1–4) 51 pts had surgery Overall agreement: 78%

13. Sensitivities: - EBUS: 87% - Mediastinoscopy: 68% In a per patient analysis, the overall diagnostic yield: -EBUS-TBNA was 59/66 (89%) -Mediastinoscopy was 52/66 (79%; p 0.1) Prediction of correct pathologic N stage in the 57 patients with NSCLC: - EBUS-TBNA: 53/57 (93%) - Mediastinoscopy: 47/57 (82%; p 0.083) J Thorac Oncol 2008;3:577-582

14. Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252

15. Eligibility: patients with potentially resectable NSCLC and indication for mediastinal nodal sampling - mediastinal nodes with short axis ≥ 10 mm - PET-positive mediastinal or hilar nodes - centrally located lung tumor 4 participating European hospitals Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252

16. Patients randomly assigned (1:1) to either - surgical staging alone (surgical staging group: mediastinoscopy) - endosonography (combined EUS-FNA and EBUS-TBNA) followed by surgical staging if no nodal metastases Patients without evidence of mediastinal Dz following surgical staging in either study group: - thoracotomy with complete lymph node dissection was performed Endosonography of the mediastinum: under moderate sedation Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252

17. Surgical staging - Sensitivity: 79% (41/52; 95% CI, 66%-88%) - NPV: 86% (66/77; 95% CI, 76-92%) Endosonographic staging - Sensitivity: 85% (56/66; 95% CI, 74%-92%) - NPV: 85% (57/67; 95% CI, 75-92%) (p >.99) Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252

18. Prospective, controlled trial performed in patients with confirmed or suspected NSCLC who required a mediastinoscopy Patients were candidates for surgical resection Under general anesthesia: EBUS staging followed by mediastinoscopy on the same setting Operator was blinded to EBUS on-site results If path negative for N2 or N3 Dz after EBUS and mediastinoscopy: thoracotomy with nodal dissection at the same setting of later Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400

21. Mean short axis of the nodes Bx’ed by EBUS-TBNA: 6.9 ± 2.9 mm False-negative: 8 on EBUS-TBNA vs 14 on mediastinoscopy Sensitivity, negative predictive value, and diagnostic accuracy: - EBUS-TBNA: 81%, 91%, 93% - Mediastinoscopy: 79%, 90%, 93% (McNemar’s test, P=.78) Minor complications from mediastinoscopy observed in 4 patients (2.6%) (hematoma in 2, left recurrent nerve injury in 1, and wound infection in 1) Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400

22. EBUS and PET-CT

23. 78 out of 102 study patients underwent surgery Chest 2006;130;710-718 p < 0.00001

24. EBUS-TBNA results: Small cell lung cancer in 9 (12%) Adenocarcinoma in 25 (33%) Squamous cell carcinoma in 20 (25%) Non small cell lung cancer (unspecified) in 23 (30%) cases In 42 (55%) of the 77 cases EBUS-TBNA showed malignancy: primary tissue diagnosis in addition to giving staging information J Thorac Oncol 2009;4:44-48

25. For the 96 cases with definitive reference pathology, the EBUS-TBNA per patient basis: Sensitivity: 91% (95% CI 82–95) Diagnostic accuracy: 92% Specificity: 100% (95% CI 73–100), assuming no FP PPV: 100% (95% CI 95–100) NPV: 60% (95% CI 36–80) EBUS-TBNA obviated the need for further surgical staging procedures in 71% J Thorac Oncol 2009;4:44-48

26. Chest 2009;135;1280-1287

27. Normal mediastinum on PET/CT in 61 patients: 9 found to have mediastinal metastasis, 6 on EBUS-TBNA Sensitivity 75%; Specificity 100%; NPV 94%

28. Stations 2, 4, 7, 10, and 11: short-axis diameter measured in 97 pts All visualized nodes 5 to 10 mm were punctured TWICE: 7.9 ± 0.7 mm Sensitivity: 89% Specificity: 100% NPV: 99% Chest 2008;133;887-891 Missed by EBUS-TBNA

29. EBUS scope for “complete” mediastinal staging

30. Chest 2010; 138:795-802 Combining EUS-B-FNA + EBUS-TBNA: the proportion of accessible mediastinal nodal stations was increased from 78.6% (372/473) to 84.8% (401/473) (p=0.015)

31. Chest 2010; 138:790-794

32. EBUS: meta-analysis Adams K, Shah PL, Edmonds L et al. Thorax 2009;64:757-762 Gu P, Zhao Y, Jiang L et al. Eur J Cancer 2009;45(8):1389-1396

33. EBUS vs other invasive tests in lung cancer: - diagnosis and staging

34. Almeida F, Casal R, Jimenez C et al, Chest, in press 64%

35. Almeida F, Casal R, Jimenez C et al, Chest, in press

36. EBUS and NSCLC subtyping and biomarkers

37. Navani N, Brown JM, Nankivel M et al. Am J Respir Crit Care Med 2012;185(12):1316-1322 Data not described: -434 final EBUS cancer Dx -Specific subtype in 333 (76.7%)

38. Esterbrooka G, Anathhanama S, Plantb PK. Lung Cancer 2013;80(1):30-34 Specific subtype in NSCLC: - 118 of 149 (79.2%)

39. EBUS and Biomarkers EGFR gene mutation analysis EBUS-TBNA samples of metastatic AdenoCA of hilar and/or mediastinal lymph node from 156 patients 1 - Recut sections of the paraffin-embedded samples yielded tumor cells in 154 - EGFR positive in 42 (26.9%) - “Enough” tumor for other testing (113): 4 with K-ras and 47 with p53 EGFR gene analysis feasible in 26 (72.2%) out of the 36 patients 2 - EGFR positive in 2 out of 20 patients with adenocarcinoma 1.Nakajima T, Yasufuku K, Nakagawara A et al. Chest; Prepublished online April 28, 2011; DOI 10.1378/chest. 10-3186 2.Garcia-Olive I, Monso E, Andreo F et al. Eur Respir J 2010; 35: 391-395

40. EBUS and Biomarkers EML4-ALK Fusion Gene Assessment: FISH EML4-ALK Fusion Gene Assessment in “metastatic” lymph nodes 1 - Re-sliced specimens for histologic examination available in 109 out 112 - ALK positive in 7: all adenoCA and EGFR negative EML4-ALK Fusion Gene Assessment in lymph nodes showing adenocarcinoma or NSCLC NOS and negative for EGFR 2 - FISH analysis successful in 52 of 55 samples (94.5%) - ALK positive in 3 of 52 (5.7%) 1.Sakairi Y, Nakajima T, Yasufuku K et al. Clin Cancer Res 2010;16:4938-4945 2.Neat MJ, Foot NJ, Hicks A et al. Cytopathology 2013 doi: 10.1111/cyt.12060. [Epub ahead of print]

41. EBUS-TBNA, EUS-FNA and histological samples available in 43 patients - KRAS mutation: 6 patients - EGFR mutation: 1 patient - PIK3CA mutation: 1 patient 100% concordance between cytological and histological specimens PLoS ONE 6(3): e17791. doi:10.1371/journal.pone.0017791

42. EBUS, ROSE and needle gauge

43. Oki M, Saka H, Kitagawa C et al. Respiration 2013 [Epub ahead of print]

44. EBUS: 21g vs 22g needle Oki M, MD, Saka H, Kitagawa C et al. J Bronchol Intervent Pulmonol 2011;18:306-310 Nakajima T, Yasufuku, Takahashi R et al. Respirology 2011; 16:90-94

45. EBUS: 21g vs 22g needle Yarmus L, Akulian J, Lechtzin N et al. CHEST 2013; 143(4):1036-1043

46. EBUS and ultrasound characteristics

47. J Bronchol Intervent Pulmonol 2011;18:322-328

48. Lack of CIV: increase in the likelihood of malignancy [OR, 49.7; 95% confidence interval, 15.1-163.9] Presence of a CIV for benign cytology - Sensitivity: 83.0% - Specificity: 91.1% PPV of CIV predicting nonmalignant cytology: 88.6% The presence or absence of a CIV accurately predicted cytology results in 90 out of the 103 LNs sampled (87.4%). J Bronchol Intervent Pulmonol 2011;18:322–328

49. CHEST 2010; 138(3):641-647

52. Initial Lung Cancer Evaluation

53. Curr Opin Pulm Med 2010; 16(4):307-14

54. Summary EBUS and mediastinoscopy: both superior to current imaging modalities for NSCLC mediastinal staging EBUS and mediastinoscopy appear to be equivalent for mediastinal staging of NSCLC patients: local expertise defines choice Standard bronchoscopy + EBUS probably the ideal initial test for diagnosis and staging of lung cancers radiographically limited to the chest

55. Summary Nodal sonographic characteristics not ready for primetime but may add to EBUS staging (will it increase sensitivity?) EBUS alone (in expert hands) is sufficient for the MAJORITY of mediastinal staging cases: - Combined EBUS and mediastinoscopy provides best yield, and should be viewed as complimentary Role of cytology (EBUS) in minimally invasive lung cancer staging is extremely important - Likely to become the norm in many centers