Treatment of Clinical Stage I Lung Cancer: Thoracoscopic Lobectomy is the Standard

Treatment of Clinical Stage I Lung Cancer: Thoracoscopic Lobectomy is the Standard AATS General Thoracic Surgery Symposium May 5, 2010 Thomas A. D Amico MD Professor of Surgery, Duke University Medical Center Program Director, Thoracic Surgery Co-Director, Thoracic Oncology Research Laboratory Director, Clinical Oncology, Duke Comprehensive Cancer Center

Disclosure Consultant Covidien Scanlan No conflicts related to this presentation

The Debate: SBRT/RFA vs Lobectomy in Clinical Stage I NSCLC Not a debate about the efficacy of SBRT/RFA in selected patients Not a debate about the role of thoracic surgeons in evaluating or using SBRT/RFA Not a debate regarding the superiority of lobectomy over lesser resection

Lobectomy for c-stage I NSCLC 1. Inaccurate staging: c-stage I p-stage I 2. Thoracoscopic lobectomy/segmentectomy achieves complete resection and nodal staging, with low complication rates 3. Without tissue, biologic staging and treatment strategies are less effective

Staging Lung Cancer 1. Clinical staging of lung cancer is inaccurate 5-year survival Clinical Stage I 57% Pathologic Stage I 67% A substantial fraction of patients with c-stage I NSCLC are not p-stage I NSCLC

CT: Induction Freidman Clinical Stage I by CT and PET

CT: Induction Freidman N3 at Mediastinoscopy

Mediastinal Staging with PET Study N Sensitivity Specificity Iowa (Ann Thorac Surg 2002;73:394) Duke University Medical Center (J Thorac Cardiovasc Surg 2003; 126: 1900-5) ACOSOG Z0050 (J Thorac Cardiovasc Surg 2003;126:1943-1951) 237 82% 82% 203 64% 77% 287 61% 84% 727 68% 81%

Mediastinal Staging with PET Study N Sensitivity Specificity Iowa (Ann Thorac Surg 2002;73:394) 237 82% 82% Duke University Medical Center (J Thorac Cardiovasc Surg 2003; 126: 1900-5) ACOSOG Z0050 (J Thorac Cardiovasc Surg 2003;126:1943-1951) 203 64% 77% 25% 287 61% 84% Under-staged 727 68% 81%

Serum CEA in Surgically Resected Clinical Stage I Patients With NSCLC Sawabata N et al Ann Thorac Surg 2002;74:174-179 N=297 IA 156 53% IB 79 27% IIA 6 2% IIB 12 4% IIIA 23 8% IIIB 13 4% IV 8 3%

Serum CEA in Surgically Resected Clinical Stage I Patients With NSCLC Sawabata N et al Ann Thorac Surg 2002;74:174-179 N=297 IA 156 53% IB 79 27% IIA 6 2% IIB 12 4% 20% IIIA 23 8% IIIB 13 4% Under-staged IV 8 3%

Risk Factors For Occult Mediastinal Metastases In Clinical Stage I NSCLC Lee PC et al. Ann Thorac Surg 2007;84:177-181 N=224 IA 118 53% IB 51 23% IIA 6 3% IIB 16 7% IIIA 12 5% IIIB 18 8% IV 3 1%

Risk Factors For Occult Mediastinal Metastases In Clinical Stage I NSCLC Lee PC et al. Ann Thorac Surg 2007;84:177-181. N=224 IA 118 53% IB 51 23% IIA 6 3% IIB 16 7% 24% IIIA 12 5% IIIB 18 8% Under-staged IV 3 1%

Clinical staging will underestimate extent of disease in 20-25% of patients Strategies that attempt local control without pathologic staging will be inadequate, especially disappointing in patients with curable N1 and N2 disease

2. The risks of surgery may be overestimated in patients that undergo thoracoscopic lobectomy, which should be feasible in nearly all patients with clinical stage I NSCLC that would be candidates for SBRT/RFA

Thoracoscopic Lobectomy is Associated with Fewer Postoperative Complications Villamizar N, et al. J Thorac Cardiovasc Surg 2009; 138: 419 425 Western Thoracic Surgical Association 2008 Compared outcomes after lobectomy (n=1079) Thoracoscopic (n=697) vs Thoracotomy (n=382) Propensity analysis (n=284 each) matching preoperative variables and stage Analysis of postoperative complications

Propensity Matching: Greedy 5 to 1 Algorithm Demographics Fx Status Co-morbidity PFTS Other Age Zubrod score HTN FEV1 Stage Gender ASA CAD FVC Smoking BMI CHF DLCO Steroid Use DM Preop Chemo CVD Preop XRT CRI Elective Status Thoracotomy N=284 Thoracoscopy N=284

Outcomes: Propensity Matched Feature THOR (n=284) VATS (n=284) P No Complication, n (%) 144 (51%) 196 (69%) 0.0001 Atrial Fibrillation, n (%) 61 (21%) 37 (13%) 0.01 Atelectasis, n (%) 34 (12%) 15 (5%) 0.006 Prolonged air leak, n (%) 55 (19%) 37 (13%) 0.05 Pneumonia, n (%) 27 (10%) 14 (5%) 0.05 Transfusion, n (%) 36 (13%) 11 (4%) 0.02 Renal Failure, n (%) 15 (5%) 4 (1.4%) 0.02 Death, n (%) 15 (5%) 8 (3%) 0.20 Chest tube duration (days) 4 3 0.0001 Length of stay (days) 5 4 0.0001

Thoracoscopic Lobectomy is Associated with Lower Morbidity than Open Lobectomy: A Propensity-Matched Analysis from the STS Database AATS 2009 J Thorac Cardiovasc Surg 2010: 139:366-78 Subroto Paul MD, Jeffrey L. Port MD, Shubin Sheng PhD, Paul C. Lee MD, David H. Harpole MD, Mark W. Onaitis MD, Brendon M. Stiles MD, Nasser K. Altorki MD, Thomas A. D Amico MD

STS-GTD (2002-2007) 6365 Patients 6323 Patients Exclude Prior Thoracic Surgery (8) Missing Age or Gender Data (17) Other (17) Thoracotomy N=5042 Thoracoscopy N=1281

Postoperative Complication Thoracotomy (n=1281) Outcomes Thoracoscopy (n=1281) P Value* No complications 847 (65%) 945 (74%) <0.0001* All Cardiovascular 167 (13%) 106 (8%) 0.0002* Atrial Arrhythmia 147 (12%) 93 (7%) 0.0004* All Pulmonary 156 (12%) 97 (7%) 0.0001* Reintubation 40 (3.1%) 18 (1.4%) 0.0046* Postoperative Blood Transfusion 60 (4.7%) 31 (2.4%) 0.0028*

Thoracoscopic Lobectomy in High Risk Patients Under 70 Poor PFT n=207 (22%) Over 70 Poor PFT n=135 (14%) Over 70 Good PFT n=203 (22%) Low Risk n=398 (42%)

Thoracoscopic Lobectomy is Associated with Fewer Postoperative Complications in Patients >70 years Berry MF, et al Ann Thorac Surg 2009; 88: 1093-1099 Thoracotomy VATS p No Cx 36% 61% 0.0001 A-fib 28% 18% 0.04 Respiratory Cx 12% 5% 0.03 Transfusion 16% 7% 0.01 Delirium 13% 5% 0.03

Thoracoscopic Lobectomy in High Risk Patients Under 70 Poor PFT n=207 (22%) Over 70 Poor PFT n=135 (14%) Over 70 Good PFT n=203 (22%) Low Risk n=398 (42%)

Pulmonary Function Tests Do Not Predict Complications after Thoracoscopic Lobectomy Berry MF et al. Ann Thorac Surg 2010; 89:1044-51 Southern Thoracic Surgical Association 2009 Compared outcomes after lobectomy in patients with FEV1 or DLCO <60% predicted Propensity analysis, matching preoperative variables and stage Analysis of overall postoperative complications

Incidence of Pulmonary Complications by Approach DLCO FEV1

Thoracoscopic Lobectomy: Lower Morbidity Thoracoscopic Lobectomy Thoracotomy Relative Advantage No Cx (all) 72% 58% 25% No Cx (>70 yrs) 61% 36% 66% A-Fib (all) 9% 22% 130% A-Fib (>70 yrs) 18% 28% 60%

Pulmonary Segmentectomy Potential advantages of segmentectomy Preservation of pulmonary function (segmentdependent) compared to lobectomy Improved oncologic outcomes compared wedge resection

Pulmonary Segmentectomy Indications? Small T1 lesions Advanced COPD with lower lobe tumor Previous resections Central pulmonary metastases

Effect of tumor size on prognosis in patients with NSCLC: The role of segmentectomy Okada et al. J Thorac Cardiovasc Surg 2005;129:87-93 1272 patients 5-year survival Stage I > 10 mm 50 100% 100% 11 to 20 mm 273 83.5% 92.6% 21 to 30 mm 368 76.5% 84.1% >30 mm 581 57.9% 76.4%, >30 mm lobectomy 81.3% >30 mm segment 62.9%

Effect of tumor size on prognosis in patients with NSCLC: The role of segmentectomy Okada et al. J Thorac Cardiovasc Surg 2005;129:87-93 Male, age, tumor size, stage adversely affected survival Authors conclude: < 20 mm Consider segmentectomy 21-30 mm Further study > 30 mm Lobectomy

<20mm Disease-Free Survival <21-30mm Overall Survival >30mm

Radical sublobar resection for small-sized non small cell lung cancer: A multicenter study Okada et al. J Thorac Cardiovasc Surg 2006;132:769-775 Peripheral ct1n0m0 <2 cm (from 3 institutions) 5-year survival Sublobar (n = 305) 85.9% Lobar (n = 262) 83.4% Sublobar resection should be considered as an alternative for stage IA NSCLC 2 cm or less

Sublobar Resection for Patients With Peripheral Small Adenocarcinomas of the Lung: Surgical Outcome is Associated With Features on CT Nakayama et al Ann Thorac Surg 2007;84:1675-1679 63 patients with adenocarcinoma underwent sublobar resection of c-stage IA tumors measuring 2 cm or less Classified as "air-containing type" (46 patients) or "solid-density type" (17 patients) according to the tumor shadow disappearance rate on highresolution CT

Sublobar Resection for Patients With Peripheral Small Adenocarcinomas of the Lung: Surgical Outcome is Associated With Features on CT Nakayama et al Ann Thorac Surg 2007;84:1675-1679 Air-containing tumors 38 BAC and 8 non-bac No patient with air-containing tumors had recurrence (median f/u 70 months) 5-year survival Air-containing tumors 95% Solid-density tumors 57%

Pulmonary Segmentectomy: Thoracotomy Or Thoracoscopy Atkins BZ, et al. Ann Thorac Surg 2007 84: 1107-1113 77 sub-lobar anatomic resections (2000-06) Thoracotomy (OS) 29 patients Thoracoscopy (TS) 48 patients Retrospective review of prospectively-maintained thoracic surgery database

Thoracoscopic Segmentectomy: Outcomes OS (n=29) TS (n=48) Mortality 2 (7%) 0 Atrial arrhythmias 3 (10%) 7 (14%) Bleeding 1 (3%) 0 Prolonged air leak (>7d) 2 (7%) 5 (10%) Locoregional recurrences 1 (8%) 2 (8%) Distant recurrences 2 (17%) 0

Thoracoscopic Segmentectomy Compares Favorably With Thoracoscopic Lobectomy For Patients With Small Stage I Lung Cancer Shapiro M, et al. J Thorac Cardiovasc Surg 2009;137:1388-1393 Segmentectomy 31 pts and lobectomy 113 pts No difference in # of nodes/stations resected 5 (17%) recurrences after segmentectomy and 23 (20%) after lobectomy (P =.71); locoregional recurrence rates of 3.5% and 3.6%, respectively Pts after segmentectomy had lower FEV1 than after lobectomy (83% vs 92%, P =.04)

Lobectomy vs Limited Resection NCCN guidelines: Lobectomy is preferred over limited resection Segmentectomy preferred over wedge resection Segmentectomy: selected patients with tumors <2cm Tumor type (BAC) and location Age/Performance status Pulmonary function

CALGB 140503: Phase III Trial of Lobectomy vs Sub-Lobar Resection for <2cm Peripheral NSCLC Pre-registration Surgery: Confirm pathologic dx of NSCLC and N0 status by frozen section of R4, 7, 10 or L5, 6, 10 R an d o m iz a ti o n Lobectomy Limited resection (segmentectomy or wedge)

3. Patients who undergo SBRT/RFA may not be eligible to be evaluated with biologic staging with state of the art techniques, and may not receive the benefits of adjuvant therapy

Metagene 5-year survival 90% 5-year survival <10%

Metagene

CALGB 30506 Resection: Stage I Randomize (2:1) Adjuvant Chemotherapy Observation Genomic Risk Analysis High Risk Low Risk High Risk Low Risk

Improving Outcomes with Stage I Lung Cancer Clinical staging is insufficient to define stage I disease; a significant fraction (20-25%) of c-stage I patients are undertreated by SRS/RFA The risks of surgical therapy in high-risk patients may be overestimated Biologic staging and treatment strategies are currently dependent on tissue acquisition

Caveats Surgical resection without appropriate management of hilar and mediastinal lymph nodes, both preoperatively and intraoperatively, is worse than SBRT/RFA In the future, it is possible that biologic techniques would identify which patients could benefit from SBRT/RFA