1. Adjuvant Radiation is Not Associated with Improved Survival in Patients with Positive Margins Following Lobectomy for Stage I & II Non-Small Cell Lung Cancer Brian C Gulack, MD; Jeffrey Chi-Fu Yang, MD; Paul J Speicher, MD, MHS; H. Volkan Kara, MD; Thomas A D’Amico, MD; Mark F Berry, MD, MHS; Matthew G Hartwig, MD 1

2. Disclosures Dr. Thomas D’Amico serves as a consultant for Scanlan. The other authors have no conflicts of interest to report. The National Cancer Data Base is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The COC and the ACS are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data. 2

3. Background Lobectomy –Most common surgical procedure performed for stage I or II NSCLC. –4-6% associated with positive margins. Current NCCN guidelines for positive margins: –Re-resection +/- chemotherapy (preferred). –Adjuvant radiation +/- chemotherapy. –Based on limited data. Reviewed the National Cancer Data Base (NCDB) in order to better guide therapy for this clinical scenario. –Hypothesis: Significant benefit from adjuvant XRT 3

4. Methods National Cancer Data Base –Collects information from over 1500 Commission-on- Cancer accredited hospitals. –Captures roughly 70% of newly diagnosed cancers in the United States each year. 4

5. Methods Inclusion Criteria: Lobectomy or Pneumonectomy for Clinical Stage I or II NSCLC from 1998-2006. Exclusion Criteria: Unknown follow-up. Known neoadjuvant therapy. Patient receiving a lobectomy who died within 30 days of surgery. 5

6. 6 Lobectomy for Stage I or II NSCLC Negative Margins Positive Margins Included: -R1 Disease -R2 Disease -Positive Margins NOS Methods

7. 7 Lobectomy for Stage I or II NSCLC Negative Margins Positive Margins Methods Adjuvant Radiation No Adjuvant Radiation

8. 8 Lobectomy for Stage I or II NSCLC Negative MarginsPositive Margins Adjuvant Radiation No Adjuvant Radiation Adjuvant Radiation Pneumonectomy Propensity Match Methods

9. Results 9 Variable Negative Margins Positive Margins P-value N48051 (96.1%)1959 (3.9%) Age (years) 68 (61, 74)68 (61, 75)0.28 Female Sex 50.2% 45.9%< 0.01 Race <0.01 White 90.1%87.8% Black 7.0%9.1% Other/Unknown 2.9%3.1% Private Insurance Status 35.3%34.6%0.55 Academic Center 33.8%27.5%< 0.01

10. Results 10 Variable Negative Margins Positive Margins P-value N48051 (96.1%)1959 (3.9%) Age (years) 68 (61, 74)68 (61, 75)0.28 Female Sex 50.2% 45.9%< 0.01 Race <0.01 White 90.1%87.8% Black 7.0%9.1% Other/Unknown 2.9%3.1% Private Insurance Status 35.3%34.6%0.55 Academic Center 33.8%27.5%< 0.01

11. Results 10 Variable Negative Margins Positive Margins P-value N48051 (96.1%)1959 (3.9%) Age (years) 68 (61, 74)68 (61, 75)0.28 Female Sex 50.2% 45.9%< 0.01 Race <0.01 White 90.1%87.8% Black 7.0%9.1% Other/Unknown 2.9%3.1% Private Insurance Status 35.3%34.6%0.55 Academic Center 33.8%27.5%< 0.01

12. Results 11 Variable Negative Margins Positive MarginsP-value N 48051 (96.1%)1959 (3.9%) Tumor Size > 5.0 cm 11.8%21.7%< 0.01 Clinical Stage II 10.5%28.7%<0.01

13. Results 11 Variable Negative Margins Positive MarginsP-value N 48051 (96.1%)1959 (3.9%) Tumor Size > 5.0 cm 11.8%21.7%< 0.01 Clinical Stage II 10.5%28.7%<0.01

14. Results 11 Variable Negative Margins Positive MarginsP-value N 48051 (96.1%)1959 (3.9%) Tumor Size > 5.0 cm 11.8%21.7%< 0.01 Clinical Stage II 10.5%28.7%<0.01

15. Results Negative Margin 34.5% P < 0.001 57.2% Positive Margin Adjusted HR: 1.46 (95% CI: 1.33, 1.60) Covariates included in adjustment: age, sex, race, insurance status, Charlson/Deyo comorbidity index, pathologic grade, pathologic stage.

16. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001

17. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001

18. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001

19. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001

20. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001

21. Results 13 Variable No Adjuvant Radiation Adjuvant Radiation p-value N949 (61.8%)587 (38.2%) Age70 (62, 76)67 (60, 73)< 0.001 Female47.0%41.6%0.043 Academic Center 30.9%19.6%< 0.001 Tumor Size > 5.0 cm 19.0%27.5% < 0.001 Clinical Stage II 20.4%37.5% < 0.001 Pathologic Stage II 36.4%61.4% < 0.001 Adjuvant Chemotherapy27.3%57.1%< 0.001 No significant differences in insurance status, or Charlson/Deyo Comorbidity Index.

22. Results No Adjuvant Radiation P = 0.009 Adjuvant Radiation Adjusted HR: 1.08 (95% CI: 0.88, 1.32) Covariates included in adjustment: age, sex, race, insurance status, Charlson/Deyo comorbidity index, pathologic grade, pathologic stage.

23. Results 15 VariablePneumonectomyLobectomyp-value N 450225 Age 68 (59.2, 74)67 (60, 74)0.85 Female 42.4%42.2%0.99 Charlson/Deyo Comorbidity Index 0.96 0 56.9%57.8% 1 32.7%31.6% 2 10.4% 10.7% Tumor Size > 5.0 cm 21.8% 0.99 Pathologic Stage II 57.6%59.1% 0.79

24. Results 16 Pneumonectomy Lobectomy w/XRT

25. Results 16 Pneumonectomy Lobectomy w/XRT Pneumonectomy vs Lobectomy HR: 0.96, 95% CI: 0.77, 1.20

26. Results 16 Pneumonectomy Lobectomy w/XRT Pneumonectomy vs Lobectomy HR: 0.73, 95% CI: 0.60, 0.89

27. Results 16 Pneumonectomy Lobectomy w/XRT Pneumonectomy vs Lobectomy 5-Year: HR: 0.50, 95% CI: 0.38, 0.66 45.3% 33.7%

28. Limitations –Potential for unobserved confounding. Details of treatment decisions regarding adjuvant therapy and deferring re-resection not available. –Radiation therapy for other indications. –Limited ability to assess the impact of adjuvant chemotherapy. 18

29. Summary –Lobectomy for Stage I or II NSCLC is associated with a 4% positive margin rate. –Positive margins are associated with reduced survival. –Adjuvant Radiation therapy is not associated with a significant survival benefit. –Re-resection, when feasible, may be a superior treatment option. 17