1. Rodney J. Landreneau, MD Professor of Surgery Heart, Lung & Esophageal Surgery Institute University of Pittsburgh Medical Center Management of Non-Small Cell Lung Cancer St. Margaret Grand Rounds September 10,2009

2. Management of Non-Small Cell Lung Cancer CT surveillance for lung cancer Sublobar Resection vs. Lobectomy Role of surgical resection for regionally advanced lung cancer Adjuvant Systemic Therapy for regionally advanced “resectable” lung cancer CT surveillance for lung cancer Sublobar Resection vs. Lobectomy Role of surgical resection for regionally advanced lung cancer Adjuvant Systemic Therapy for regionally advanced “resectable” lung cancer

3. Lung Cancer Surveillance

4. Original Article Survival of Patients with Stage I Lung Cancer Detected on CT Screening The International Early Lung Cancer Action Program Investigators N Engl J Med Volume 355(17):1763-1771 October 26, 2006

5. Kaplan-Meier Survival Curves for 484 Participants with Lung Cancer and 302 Participants with Clinical Stage I Cancer Resected within 1 Month after Diagnosis The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771

6. Conclusion ● Annual spiral CT screening can detect lung cancer that is curable ● Comparable screening efficacy as mammographic screening for breast cancer (prevalence 1.6%; incidence 0.6%) ● Cost effective - low energy, fast scanning about $200 ● Treatment of early stage disease less expensive than advanced disease

7. Controversy

8. CT scans have radiation risks and sometimes detect cancers that would not have progressed, leading to risky procedures like biopsies and lung surgery when not needed. lung surgery lung surgery

9. The National Cancer Institute started in 2002 the $200 million “National Lung Screening Trial” comparing death rates among 55,000 people randomly assigned to have CT scans or chest X- rays. Results are not expected until 2010.

10. “Sublobar Resection” or “Lobectomy” for stage I lung cancer

11. Standard of Care For Peripheral Nodules 1940’s Pneumonectomy 1960’s Lobectomy 1990’s ?Segmentectomy/Wedge (and adjuvant local/systemic Rx) Surgical Resection of the Lung

22. Errett LE et al J Thorac Cardiovasc Surg. 1985 Nov;90(5):656-61 Sublobar Resection vs. Lobectomy for Stage 1 Non-Small Cell Lung Cancer

24. Randomized Trial of Lobectomy Versus Limited Resection for T1 N0 Non-Small Cell Lung Cancer (125 Lobectomy, 122 Limited Resection) RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23

25. Lobectomy vs Limited Resection Time to death (from any cause) by treatment logrank p=0.088 (one-tailed) Ginsberg and Rubinstein Ann Thorac Surg

26. Wedge Resection Versus Lobectomy for Stage I (T1 N0 M0) Non-Small Lung Cancer Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

27. Wedge vs Lobectomy for Stage I NSCLC p=0.889 Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

28. Wedge vs Lobectomy for Stage I NSCLC Open WR VATS WR Vs.LobeP< Op Mortality (%)00Vs.3.30.20* Postop Stay (days) 7.76.5Vs.10.10.0002* Local Recur (%) 1715 Vs. 5 0.08* Local/Systemic Recurrence (%) 2423vs.170.43* *- all WR (n=95) vs. Lobe (n=124) Statistical Methods: Life Table Analyses Obtained by Log Rank and Wilcoxson Tests Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

29. ! Local Recurrence !

30. Adjuvant Radiation Therapy ● External beam radiation therapy - Potential risk of increased injury to surrounding pulmonary parenchyma ● What is efficacy of intraoperative brachytherapy when external beam radiation may otherwise be applied?

31. Intraoperative Brachytherapy ● Not a new concept for lung cancer ● Mostly used for Stage IIIA disease - close or positive margins ● Improved local control ● What is it’s role in high risk patients with totally resectable disease where lobar resection is not feasible and adjuvant radiotherapy is recommended?

41. Comparison Between Sublobar Resection and 125Iodine Brachytherapy After Sublobar Resection in High-Risk Patients with Stage I Non–Small-Cell Lung Cancer Comparison Between Sublobar Resection and 125Iodine Brachytherapy After Sublobar Resection in High-Risk Patients with Stage I Non–Small-Cell Lung Cancer R. Santos, A. Colonias, D. Parda, M. Trombetta, RH Maley, R. Macherey, S. Bartley, T. Santucci, RJ Keenan, RJ Landreneau Surgery 2003, Oct;134(4): 691-7

42. Sublobar Resection (n=102) Sublobar Resection With Brachy (n=96) Local Recurrence19 (18.6%)1 (1%) p=.0001 Hospital Mortality0 (0%)3 (3%) p=ns Hospital Stay7 days8 days p=ns Survival % 1, 2, 3 and 4 year93, 73, 68, 60%96, 82, 70, 67% p=ns Systemic Recurrence 29 (28.4)22 (23%) p=ns Pre-op FEV 1% predicted 65%53% p=nsResults The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-up

44. Lobectomy vs Sublobar Resection “Effect of Tumor Size on Prognosis in Patients with Non-Small Cell Lung Cancer: The Role of Segmentectomy as a Type of Lesser Resection” “Effect of Tumor Size on Prognosis in Patients with Non-Small Cell Lung Cancer: The Role of Segmentectomy as a Type of Lesser Resection” Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T, Nakagawa A, Tsubota N. “J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93” An evaluation of surgical resection in 1272 NSCLC patients

45. TUMOR SIZE Segmental ResectionLobectomy Wedge Resection 20 mm or less96.792.485.7 20-30 mm84.687.439.4 More than 30 mm 62.981.30 Lobectomy vs Sublobar Resection 5 Year Cancer Specific Survival “Stage I” “Okada, M, et al J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”

46. Efficacy of Anatomic Segmentectomy in the Treatment of Stage I NSCLC Matthew J. Schuchert M.D., Brain L. Pettiford M.D., Samuel Keeley M.D., Thomas A. D’Amato M.D., Ph.D., Arman Kilic B.S., Hiran C. Fernando M.D., John Close M.A., Ricardo Santos M.D., James R. Landreneau, James D. Luketich M.D., Rodney J. Landreneau M.D. Division of Thoracic Surgery Heart, Lung and Esophageal Surgery Institute UPMC Health System Pittsburgh, Pennsylvania

47. Patient and Tumor Characteristics Stage IA Anatomic Segmentectomy (n=182) Lobectomy (n=246) Stage IA109 (60%) 114 (46%) Tumor Size Mean (cm) Range (cm) 1.71.9 Schuchert MJ., et. Al.; STS 2007

48. Stage IA – Segmentectomy vs Lobectomy Cumulative Survival Time (months) Lobectomy Segmentectomy log rank = 0.780 Schuchert MJ., et. Al.; STS 2007 Overall Survival

49. Recurrence Patterns - Stage IA Anatomic Segmentectomy (n=109) Lobectomy (n=114) P Value NED 97 (89%) 102 (83.3%) NS Recurrence Locoregional Distant 12 (11.0%) 5 (4.6%) 7 (6.4%) 12 (10.5 %) 6 (5.3%) NS Follow-Up (Mos)18.330.0<0.05 Schuchert MJ., et. Al.; STS 2007

50. Anatomic Segmentectomy Favorable Criteria for Anatomic Segmentectomy Peripheral location (outer 1/3) Small Tumors: < 2 cm in diameter Pathologic Margin > 1 cm (Margin/Tumor ratio>1) Age >75 Marginal pulmonary function Ground glass opacities – Bronchoalveolar UPMC Experience 452 Anatomic Segmentectomies - 224 Stage I NSCLC - 114 Stage II-III NSCLC - 31 Metastasectomies - 9 Benign Neoplasms - 53 Inflammatory/Granulomatous - 15 Bullous Disease - 5 Infection/Abscess - 1 Trauma ACOSOG Z0030: Mortality 3%; Complications 46% UPMC: Mortality 1.1%; Complications 32%

51. Sublobar Resection?

52. Sublobar Resection vs. Lobectomy?

54. Induction (pre-operative ) Chemo-radiotherapy for Stage III-a non-small cell lung cancer Standard of Care ???

56. Intergroup trial 0139 Chemo-radiation vs Chemo- radiation followed by surgical resection of Stage IIIa NSCLC Kathy Albain et al. ASCO 2005 Lancet 2009;374:379-86

62. Adjuvant Chemotherapy in NSCLC: A new standard of care?

63. N Engl J Med 2004;350:351-60

64. New Engl J Med 2004;350:351-60 4%

66. NEJM 2004;350:351-60 Chemotherapy better

67. ASCO 2004 CALGB 9633 Chemotherapy Observation 71% 59% HR 0.62 p=0.028 NCIC BR 10 Chemotherapy Observation 69% 54% HR 0.7 p=0.012 YRS 5yrs 4yrs

69. ASCO 2005 ANITA : OS months Survival Distribution Function 1.00 0.75 0.50 0.25 0 020406080100120 0.79 [0.66 - 0.95] Hazard Ratio 0.013P-value 65.843.8 Median months NVB + CDDP OBS. Obs NVB + CDDP

70. ChemotherapyObservation MOS 95 months 78 months P value 0.10 HR (90% CI) 0.80 (0.60-1.07) 02468 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0123456789 ASCO 2006 (137/155 of total events) ABSTR #7007 CALGB 9633 - OVERALL SURVIVAL

72. Adjuvant Chemotherapy Standard of Care - Stages IIA-B - IIIA NSCLC - Maybe Larger IB ??? ● Good performance status patients with “R0” Anatomic Resection - Stages IIA-B - IIIA NSCLC - Maybe Larger IB ???

75. City of Pittsburgh Pennsylvania Thank You

77. Still Empiric Therapy Approach!!

79. Drug Resistance Testing

80. Clinical Correlation in Non-Small Cell Lung Cancer

81. 9 LDR IDR EDR

82. 10

83. Completely Resected Stage IB-IIIA NSCLC + EDR-Assay Randomize Assay Directed Standard Therapy Correlative Studies Molecular Markers Proteomics Genomics Correlative Studies Molecular Markers Proteomics Genomics Registration vs. Survival Disease Free Survival Survival Disease Free Survival Schema for Future Clinical Trials

84. Future Directions Patients with micrometastisis Responders to Chemotx STD AD Improvement ?

87. Randomized Trial of Induction Chemotherapy Followed by Anatomic Lung Resection – Stage IIIA – SWOG 9900 Eric Vallieries 2007

88. S9900 S9900 Study Design ELIGIBLEELIGIBLE RANDOMIZEDRANDOMIZED PACLITAXEL CARBOPLATIN x3 cycles SURGERY ● Clinical Stage T2N0, T1-2N1, T3N0-1 ● Mediastinoscopy if LN > 1 cm on CT ● Stratification: IB/ IIA vs. IIB/ IIIA Pisters, et. Al. – ASCO 2005

89. Surgical Results Preop PCb N=168 Surgery Only N=167 Explored 149 (89%)* 162 (97%)** R0 Intent to Treat 84%84% Explored Explored94%89% Pneumonectomy16%16% Lobectomy68%68% Wedge/Segment5%11% Open/Close3%4% Incomplete Data 8%1% Path CR 10%- *19: Refusal, POD, death, medical, wrong arm, n/a **5: Medical, refusal, MD decision, n/a S9900 Pisters, et. Al. – ASCO 2005

90. Progression-Free Survival by Treatment Arm 05/09/2005, median F/U 31 mo Pisters, et. Al. – ASCO 2005

91. Overall Survival by Treatment Arm 05/09/2005, median F/U 31 mo Pisters, et. Al. – ASCO 2005

92. CS (n=154)S Only (n=160) N=7* (.045)N=4 (.025) Lobectomy Pneumonectomy 3 (.02) 4/24 (.17) Lobectomy Pneumonectomy 4 (.035) 0/26 [2R, 2L] *p=0.32 From: Eric Vallieries 2007 Randomized Trial of Induction Chemotherapy Followed by Anatomic Lung Resection – Stage IIIA – SWOG 9900

93. Depierre Randomized Preop Trial Preop Trial ● N=355 eligible, stages IB, II and IIIA (35% N2) ● MIP x2 Surgery (+2 adj: PR/path CR) Surgery alone ● Median survival 37 vs 26 months, p=0.15 Depierre JCO 2002

94. ● Disease free survival 27 vs 13 mo, p=0.033 ● Risk of DM=0.54 [0.33-0.88], p=0.01 ● Stage I-II: Risk death= 0.68 [0.49-0.96], p=0.027 Depierre Randomized Preop Trial Preop Trial Continued Depierre JCO 2002

95. Results Overall Survival BLOTS9900Depierre PreopControlPreopControl Median OS (months) 4347403726 1 year (%) 8482797773 2 year (%) 6869635952 Pisters, et. Al. - ASCO 2005; JCO 2002

96. Management of Non-Small Management of Non-Small Cell Lung Cancer Lung Cancer Survival

98. Still Empiric Therapy Approach!!

99. Dr. Henschke has asserted that allowing hundreds of thousands of people to die in the meantime is unethical. Therefore, “off study” CT screening should be approved by insurance for high risk patients!