Lung cancer staging in 2011: use of pet Scan and other modalities Nicole Bouchard MD FRCPC Pulmonologist April 29, 2011

Disclosure I cannot identify any potential conflict of interest.

Objectives 1) Select the appropriate diagnostic tests to accurately stage lung cancer 2) Understand the strengths and weaknesses of PET Scan for lung cancer staging 3) Propose a rational approach to optimally stage mediastinal lymph nodes

TNM Lababede O, Chest 2011; 139: 183-189

Diagnostic tests CT scan: PET-CT: Pulmonary function testing chest and upper abdomen PET-CT: if a radical treatment is considered Pulmonary function testing Imaging of the head (MRI): if symptoms for small cell lung cancer maybe in stage 3 disease NSCLC Lim E, Thorax 2010; 65 (Suppl III); iii1-iii27 Alberts WM, Chest 2007; 132; 1S-19S

Diagnostic tests Bone scintigraphy? PET is more sensitive to avoid an unnecessary PET-CT PET: from base of skull to upper thighs

Diagnostic tests Least invasive approach that provides both the diagnostic and the stage bronchoscopy, transthoracic CT guided needle biopsy, radial probe EBUS EBUS, EUS, mediastinoscopy, VATS US guided needle aspiration: thoracentesis, cervical lymph node, liver EUS: left adrenal metastasis

Diagnostic tests → Adequate sample IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma NSCLC are to be classified into adenocarcinoma or squamous cell carcinoma gefitinib, pemetrexed, bevacizumab Travis WD, Journal of Thoracic Oncology 2011; 6: 244-285

Diagnostic tests Wait times and costs 2852 patients provincial cancer registry: Manitoba ≥ 25% of patients waited more than 55 days Cheung WY, Lung Cancer 2010 Sep [ Epub ahead of print ]

Diagnostic tests Multidisciplinary team 1222 patients with NSCLC, 2001-2007 survival? prior after complete staging 79% 93% multidisciplinary evaluation prior to surgery 62% 96% adherence to guidelines 81% 97% mean days from diagnosis to treatment 29 days 17 days Freeman RK, Eur J Cardiothoracic Surg 2010; 38: 1-5

PET-CT Scan Preoperative PET-CT prospective, randomized study 189 patients, NSCLC conventional staging (CT of the abdomen, bronchoscopy) or conventional staging plus PET-CT PET-CT: reduced the number of futile thoracotomies, had no effect on survival Fischer B, NEJM 2009; 361: 32-39

PET-CT Scan Preoperative PET-CT prospective, randomized trial 337 patients, stage 1-3A NSCLC PET-CT or conventional (abdominal CT & bone scan) cranial imaging PET-CT: spares more patients from inappropriate surgery, but also incorrectly upstaged disease Maziak DE, Ann Intern Med 2009; 151: 221-228

PET-CT Scan T stage (SUVmax 2,5) false positive: infectious and inflammatory lesions false negative: carcinoid, certain adenocarcinomas, uncontrolled diabetes, cavity with necrotic center, lesion < 8 mm Lim E, Thorax 2010; 65 (Suppl III); iii1-iii27

PET-CT Scan Solitary pulmonary nodule (8 - 30 mm) and an initial SUVmax  2.6 retrospective study, CHUS, PET-CT 20 / 65 (31%) patients: diagnosis of cancer; mostly adenocarcinomas risk factors for malignancy: higher 18F-FDG uptake, spiculated nodule SUVmax  1: new threshold? Houle MA, Can Respir J 2010; 17, suppl B: 6B

PET-CT Scan N stage CT > 10 mm in short axis diameter sensitivity 57-61%, specificity 79-82% PET sensitivity 84%, specificity 89% false negative: small volume, low metabolic activity false positive: inflammation → sampling size of the lymph node is important Lim E, Thorax 2010; 65 (Suppl III); iii1-iii27 Alberts WM, Chest 2007; 132; 1S-19S

PET-CT Scan M stage sensitivity 93%, specificity 96% detect metastases: 15%, more with advanced stage Lim E, Thorax 2010; 65 (Suppl III); iii1-iii27

PET-CT Scan Sample of any isolated distant lesion 350 patients 21% had a solitary lesion: 46% had a benign lesion or another cancer (second cancer or recurrence) Lardinois D, J Clin Oncol 2005; 23: 6846-6853

Mediastinal lymph nodes (LN) No lymph node sampling if uptake is within normal limits on PET-CT and < 1 cm false negative rate: 5-7% for a peripheral tumor if central tumor, N1 enlargement? N2 or N3 ≥ 1 cm but PET negative? Lymph node sampling if PET uptake is positive, to avoid false positive results EBUS/EUS; +/- mediastinoscopy if negative

Mediastinal lymph nodes (LN) EBUS: 2, 4, 7, 10, 11 EUS: 2L, 4L, 7, 8, 9 mediastinoscopy: 2R, 4R, anterior part of 7 Goldstraw P, IASLC Staging Manual in Thoracic Oncology, 2009

EBUS: meta-analysis (1) Study caracteristics Adams K, Thorax 2009; 64: 757-762

EBUS: meta-analysis (1) Study results

EBUS: meta-analysis (1) Sensitivity 88% Specificity 100%

EBUS: meta-analysis (2) Sensitivity 93% Specificity 100% Only 2 complications 2 / 1299 patients (0,15%) pneumothorax patient with COPD: hypoxemia during the procedure Gu P, European Journal of Cancer 2009; 45: 1389-1396

EBUS: false negative rate False negative rates 20-25% External validity other studies have been published

EBUS: learning curve Learning curves 500 patients 5 EBUS operators no learning from prior experience operators 3 & 5: still in the learning phase after 100 procedures Kemp SV, Thorax 2010; 65: 534-538

EBUS: cost effectiveness cost-beneficial in comparison with surgical mediastinoscopy, for a prevalence as low as 30% negative results confirmed by mediastinoscopy: cost-beneficial according to the prevalence of LN metastases (>79%) Steinfort D, J Thorac Oncol 2010; 5: 1564-1570

EBUS: how many aspirations? 650 aspirations (163 MLN stations) in 102 patients, ROSE not available best diagnostic value: 3 aspirations (sensitivity: 69.8%, 83.7%, 95.3%, 95.3%) 2 aspirations: when at least one tissue core Lee H, Chest 2008; 134: 368-374

EBUS: which needle? 21-gauge versus 22-gauge aspiration needle 45 lesions same diagnostic yield 21G: better histological preservation but more blood contamination Nakajima T, Respirology 2010 Sep [ Epub ahead of print ]

EBUS: mutations and SCLC Mutation analysis EGFR and KRAS mutations can be performed in cytologic specimens (EUS/EBUS) also EML4-ALK fusion gene SCLC: high diagnostic yield Schuurbiers OC, J Thorac Oncol 2010: 5: 1664-1667 Nakajima T, J Thorac Oncol 2011; 6: 203-206 Wada H, Ann Thorac Surg 2010; 90: 229-234

EUS: meta-analysis 18 studies No major complications; minor complications: 10 cases (0.8%), Sensitivity Specificity 18 studies 83% 97% 8 studies (abnormal MLN on CT scans) 90% 4 studies (no abnormal MLN on CT scans) 58% - Micames CG, Chest 2007; 131: 539-548

TBNA, EBUS, EUS 138 consecutive patients known or suspected lung cancer on CT Sensitivity Negative predictive value Blind TBNA 36% (15/42) 78% (96/123) EUS-FNA 69% (29/42) 88% (96/109) EBUS-FNA EUS-FNA + EBUS-FNA 93% (39/42) 97% (96/99) Wallace MB, JAMA 2008; 299: 540-546

EBUS & EUS: single scope 139 consecutive patients, enlarged LN (CT) EBUS & EUS: single linear US bronchoscope by one operator Number of nodes sampled Sensitivity Specificity Negative predictive value EUS 229 (37%) 63 (89%) 100% 82% EBUS 390 (63%) 65 (91%) 92% Combined 619 (100%) 68 (96%) 96% Herth FJ, Chest 2010: 138: 790-794

EBUS & EUS: single scope 150 potentially operable patients, prospective study EBUS +/- EUS used for MLN inaccessible or difficult to access by EBUS 2 false negative (by mediastinoscopy) Sensitivity Specificity Negative predictive value Accuracy EBUS 84% (38/45) 100% 93% 95% EBUS + EUS 91% (41/45) 96% 97% p value 0.332 - 0.379 0.360 Hwangbo B, Chest 2010; 138: 795-802

EBUS versus mediastinoscopy 66 patients, prospective crossover trial Prevalence of malignancy: 89% Diagnostic yield EBUS: 91% versus mediastinoscopy: 78% (p=0.007) disagreement: subcarinal lymph nodes (24%; p=0.011) no difference: true pathologic N stage (per patient) Ernst A, Journal of Thoracic Oncology 2008; 3; 577-582

ASTER study Randomized controlled multicenter trial 241 patients Lung or mediastinal abnormality on CT, no extrathoracic metastases EUS & EBUS (systematic sampling) and surgical staging if negative or surgical staging (mediastinoscopy): N2 & N3 Annema JT, JAMA 2010; 304: 2245-2252

ASTER study Nodal metastases Thoracotomy unnecessary 62 patients by combined staging (p=0.02) 41 patients by surgical staging mediastinoscopy: 11 patients to identify 1 with nodal metastasis Thoracotomy unnecessary 21patients in the mediastinoscopy group 9 patients in the combined group (p = 0.02) No increase rate of complications

Conclusion PET-CT: before surgery and radiotherapy When N2 or N3 is suspected on PET: EBUS; mediastinoscopy if negative Complete mediastinal staging: EBUS +/- EUS; role of mediastinoscopy? Further studies are ongoing preoperative EBUS, EBUS vs mediastinoscopy, surgical staging vs endosonography