Mediastinal Staging for Lung Cancer

1. Mediastinal Staging for Lung Cancer Victor van Berkel, MD/PhD Medical Oncology Conference 5/26/2011

2. Overview • Relevance of Staging • What question are we answering? • Rule in versus rule out • Radiologic staging • CT scan • PET scan • Invasive Staging • Mediastinoscopy • Minimally invasive staging • EBUS/TBNA • When to use which modality

3. Lung Cancer Staging • Tumor-Node-Metastatis system (TNM) • Originally put into use in 1986 • Has undergone seven revisions, most recent one January 2010 Goldstraw et al., J. Thoracic Oncology, 2007

4. Mediastinal Lymph Nodes Mountain et al., Chest, 1997

5. Mediastinal Lymph Nodes N1: Hilar nodes (double digit ) N2: Ispilateral central nodes (single digit) N3: Contralateral nodes, or supravlavicular

6. Treatment of Stage III NSCLC • Two trials in early 90s showed improved survival with pre-op chemotherapy versus surgery alone Roth et al., Lung Cancer, 1998 Rosell et al., Lung Cancer, 1999

7. Warning: Statistics Ahead • Sensitivity = Actual positives correctly identified • Specificity = Actual negatives correctly identified • Positive Predictive Value = Proportion of patients with positive results that are correctly diagnosed • Negative Predictive Value = Proportion of patients with negative results that are correctly diagnosed Positive and negative predictive value are greatly influenced by pre-test probability

8. A Ridiculous Example • Problem: How do you identify a Red Sox fan? • Diagnostic Test: Presence of Red Sox hat • Sensitivity: Poor – Many Red Sox fans not wearing hats • Specificity: Excellent – Few non-fans wearing hats • Positive Predictive Value: Excellent; +Hat = Go Sox • Negative Predictive Value: Depends on city • In Louisville: 1.2 million people, ~1000 Red Sox fans • Negative predictive value 99.96% • In Boston: 4.6 million people, ~ 2.6 million Red Sox fans • Negative predictive value 52.63%

9. A More Relevant Example • 74 year old female • Lifetime smoker • Cough/hemoptysis • 4.2 cm, spiculated mass • Bulky lymph nodes

10. A More Relevant Example • 50 year old male • Distant hx of tobacco • Asymptomatic • 1.2cm peripheral mass • No lymph nodes identified on CT

11. Staging Considerations • When evaluating staging options, there are two distinct scenarios to consider • Ruling in clinically evident N2/N3 disease • Ruling out N2/N3 disease not clinically present

12. Overview • Relevance of Staging • What question are we answering? • Rule in versus rule out • Radiologic staging • CT scan • PET scan • Invasive Staging • Mediastinoscopy • Minimally invasive staging • EBUS/TBNA • When to use which modality

13. Chest CT • Easy to get • Confirms presence, size, location of primary tumor • Assess growth of primary tumor into contiguous structures • Evaluate metastases in liver, adrenals • Assessment of size of mediastinal lymph nodes • Standard criteria is LN > 1cm in size is abnormal

14. Chest CT • Prospective study – 143 patients • CT scan followed by surgical staging • Sensitivity 64%, Specificity 62% • PPV 43%, NPV 79% McLoud et al, Radiology, 1992

15. PET-FDG • Fluorodeoxyglucose • D-glucose analog labeled with F18 • Taken up, phosphorylated, not metabolized • Accumulation proportional to metabolism • Malignancy • Infection • Inflammation • Numerous studies examining PET for staging the mediastinum

16. PET-FDG • Retrospective analysis of 202 patients • PET followed by mediastinoscopy • Sensitivity 64%, Specificity 77% • PPV 44%, NPV 88% Gonzalez-Stawinski et al, JTCVS, 2003

17. PET-FDG • Prospective, multicenter trial, 303 patients • CT scan, then PET, then surgical staging • N2/N3 Sensitivity 61%, Specificity 84% • N2/N3 PPV 56%, NPV 87% • Distant metastases identified in 6% • PPV 36%, NPV 99% Reed et al, JTCVS, 2003

18. PET/CT in Stage I disease • Retrospective analysis of 248 patients • Clinical stage I based on CT and PET • 5.6% demonstrated to have occult N2 • Invasive staging (mediastinoscopy) not cost effective • 0.008 years of life expectancy gained • Sensitive to prevalence of N2 disease Meyers et al, JTCVS, 2006

19. CT and PET • Provide important initial information • Good at identifying distant disease • Confirmatory studies still required • CT/PET is insufficient for staging • Positive studies need verification • Negative studies do not preclude N2/N3 • In right population, can avoid invasive staging

20. Overview • Relevance of Staging • What question are we answering? • Rule in versus rule out • Radiologic staging • CT scan • PET scan • Invasive Staging • Mediastinoscopy • Minimally invasive staging • EBUS/TBNA • When to use which modality

21. Mediastinoscopy • Cervical mediastinoscopy • Carlens 1959, Pearson 1965 • Outpatient procedure, general anesthesia Siracuse, OTTCVS, 2009

22. Mediastinoscopy Siracuse, OTTCVS, 2009

23. Mediastinoscopy Siracuse, OTTCVS, 2009

24. Mediastinoscopy • Advantages • Extensive reported experience • Low morbidity (0.6%) and mortality (0.05%) • Hammoud et al., JTCVS, 1999 • Able to sample the most common sites of nodal disease (levels 2,4,7) • Sensitivity 81%, Specificity 100%, NPV 91% • Toloza et al., Chest, 2003

25. Mediastinoscopy • Disadvantages • General anesthesia, OR time • Unable to assess levels 5,6,8,9 • Difficult to perform re-do mediastinoscopy • Good sensitivity/specificity may be limited to centers of expertise

26. Mediastinoscopy • Patient care survey of 729 hospitals • 40,090 patients, 11,668 treated surgically • Only 27% underwent mediastinoscopy • Only 46% resulted in lymph node tissue Little et al., Annals of Thoracic Surgery, 2005

27. Overview • Relevance of Staging • What question are we answering? • Rule in versus rule out • Radiologic staging • CT scan • PET scan • Invasive Staging • Mediastinoscopy • Minimally invasive staging • EBUS/TBNA • When to use which modality

28. EBUS-TBNA • Practice started with blind TBNA in mid 1980s • Diagnostic yield low (20-60%), vascular injuries • Evolved to radial EBUS to identify lesion, with subsequent needle biopsy • Yield better (60-80%), highly operator dependent • Real time EBUS-TBNA began in 2003-2004 Crabtree, OTTCVS, 2009

29. EBUS-TBNA • General anesthesia with #4 LMA or #8 ET tube • On-site cytopathologist • Similar range of access as mediastinoscopy, improved distal (10,11) and posterior level 7 • Color doppler to avoid vascular injury • Diagnostic yield improves with 3-4 passes per node Crabtree, OTTCVS, 2009

30. EBUS-TBNA Crabtree, OTTCVS, 2009

31. EBUS-TBNA Crabtree, OTTCVS, 2009

32. EBUS in a Favorable Population • 502 patients enrolled: CT scan, EBUS, surgical staging • EBUS was diagnostic in 94% of patients • 35 of 37 missed were malignant on surgical biopsy • Sensitivity 94%, Specificity 100%, NPV 11% • 493 of 502 patients (98%) had malignant nodes Herth et al., Thorax, 2006

33. EBUS in a PET+ population • 109 patients underwent EBUS of PET+ nodes • Malignancy detected by EBUS in 71% • Biopsy performed in 19 of 32 EBUS negative • 7 of 19 positive for malignancy • Sensitivity 91%, Specificity 100%, NPV 60% • 84 out of 96 (88%) patients with malignant nodes Rintoul et al., Journal of Thoracic Oncology, 2009

34. EBUS in a PET+ population • 106 patients underwent EBUS of PET+ nodes • Malignancy detected by EBUS in 56% • Biopsy performed in 30 of 46 EBUS negative • 3 of 30 positive for malignancy • Sensitivity 93%, Specificity 100%, NPV 91% • 63 out of 90 (70%) patients with malignant nodes Bauwens et al., Lung Cancer, 2008

35. EBUS in a CT - population • 100 patients underwent EBUS of CT- nodes (<1cm) • T1-T4 tumors, no mention of proportions • Malignancy detected by EBUS in 19% • Biopsy or resection performed in all, 2 additional + found • Sensitivity 91%, Specificity 100%, NPV 98% • 21 out of 100 (21%) patients with malignant nodes Herth et al., Eur Resp Journal, 2008

36. Overview • Relevance of Staging • What question are we answering? • Rule in versus rule out • Radiologic staging • CT scan • PET scan • Invasive Staging • Mediastinoscopy • Minimally invasive staging • EBUS/TBNA • When to use which modality

37. Recent Guidelines • Mediastinoscopy still the gold standard • Invasive procedures can be omitted for peripheral tumors and radiologically negative nodes • Central tumors, PET+ hilar N1, and LN ≥ 16 mm need invasive mediastinal node evaluation • EUS-FNA, EBUS-FNA have high specificity but negative predictive value is low. If negative, surgical staging is indicated De Leyn et al., Eur Journal of CTS, 2007

38. Dissent • 66 patients, enlarged level 2,4,or 7 lymph nodes • EBUS, then mediastinoscopy, then surgical resection • Very high rate of positive nodes (59/66 patients) • Med Sensitivity 68%, Specificity 100%, NPV 59% • EBUS Sensitivity 87%, Specificity 100%, NPV 78% • Largest difference in Med vs. EBUS at level 7 nodes Ernst et al., J Thoracic Oncology, 2008

39. Rebuttal • 234 patients, enlarged level 2,4, 5 or 7 lymph nodes • EBUS done by pulmonologists • One method first, then other if negative • Disease less prevalent – 108/234 patients positive • Med Sensitivity 88%, Specificity 100%, NPV 93% • EBUS Sensitivity 57%, Specificity 100%, NPV 79% Cerfolio et al., Ann Thorac Surg, 2010

40. Practical Considerations • Investment in time (learning and OR) • Cost of equipment purchase and upkeep • Performed by pulmonologist vs. surgeon • Presence of skilled cytopathologist • ROSE vs. non-ROSE • One or two trips to the OR

41. Adapt to Your Needs • Radiology is Necessary, but not Sufficient • T1a disease with negative nodes by PET/CT • EBUS is a sensitive, non-invasive tool • For clinical N2 that may need restaging later • Need tissue diagnosis on clinical N1,N2,N3 • Mediastinoscopy remains the final word • For clinically evident disease, negative EBUS • For staging and resection at same OR trip