1. Giving Induction Radiation in Addition to Chemotherapy Is Not Associated with Improved Survival of NSCLC Patients with Operable Mediastinal Nodal Disease Chi-Fu Jeffrey Yang MD, Brian Gulack MD, Paul Speicher MD, Xiaofei Wang PhD, Mark Onaitis MD, David Harpole MD, Thomas D’Amico MD, Mark Berry MD, Matthew Hartwig MD Duke Cancer Institute Durham, NC

2. Disclosures  Dr. Thomas D’Amico is a consultant for Scanlan  No conflicts related to this presentation

3. Introduction  For patients selected for surgery for stage IIIA-N2 non-small cell lung cancer (NSCLC), the optimal induction therapy strategy is not well-established 1 1. J Natl Compr Canc Netw 2012; 10: 599-613

4. Introduction  For patients selected for surgery for stage IIIA-N2 non-small cell lung cancer (NSCLC), the optimal induction therapy strategy is not well-established 1  Few prospective studies have evaluated induction therapy regimens 1. J Natl Compr Canc Netw 2012; 10: 599-613

5. Introduction  For patients selected for surgery for stage IIIA-N2 non-small cell lung cancer (NSCLC), the optimal induction therapy strategy is not well-established 1  Few prospective studies have evaluated induction therapy regimens  Previous studies have shown that the addition of radiation to chemotherapy enhances mediastinal nodal down-staging but does not improve survival when compared to induction chemotherapy alone 2 2. Ann Thorac Surg 2012; 93:1807-12 1. J Natl Compr Canc Netw 2012; 10: 599-613

6. Objective  Assess outcomes of patients with operable stage IIIA-N2 disease who received induction chemotherapy (Chemo) vs induction chemoradiation (ChemoRT)  National Cancer Data Base

7. Objective  Assess outcomes of patients with operable stage IIIA-N2 disease who received induction chemotherapy (Chemo) vs induction chemoradiation (ChemoRT)  National Cancer Data Base  Hypothesis: No significant improvement would be observed with the addition of radiation to induction chemotherapy

8. Methods  National Cancer Data Base (NCDB)  Prospective database jointly sponsored by the American College of Surgeons and the American Cancer Society,  Data abstracted by certified tumor registrars from approved Tumor Registries  Captures ~70% of cancer cases in the U.S.

9.  Inclusion Criteria:  Patients with cT1-3, N2 NSCLC from 2003-2006  All patients underwent induction chemotherapy or induction chemoradiation  Patients had at least a lobectomy or pneumonectomy (n=1362)  Post-resection pathologic nodal data collected  Start: Comorbidity data available since 2003  End: Long-term survival data available for patients diagnosed until the end of 2006 Methods

10.  Exclusion Criteria:  History of previous unrelated malignancy in last 5 years  Patients with T4 or N3 NSCLC  Statistical analyses  Kaplan-Meier Analysis  Multivariable Cox proportional hazards modeling Methods

11. Patient Characteristics No significant differences observed between induction chemotherapy and induction chemoradiation for: Gender Race Co-morbidity scores

12. Patient Characteristics Variable Chemo (N = 528) Chemo+RT (N = 834) p-value Age, mean ± SD 62 ± 1060 ± 10<0.01 Facility Type (% of total)<0.01 Academic/Research Program 56% 43% Non Academic Program 44% 57% Induction chemoradiation patients were younger More patients in the induction chemoradiation group were treated at community cancer programs

13. Clinical T Status Variable Chemo (N = 528) Chemo+RT (N = 834) p-value Clinical T Status (% of total)<0.01 T1 30% 21% T2 60% 61% T3 10% 18% Induction chemotherapy group had lower clinical T status

14. Perioperative Outcomes Variable Chemo (N = 528) Chemo+RT (N = 834)p-value Type of Surgery (% of total)0.04 Pneumonectomy 16%20% Lobectomy 84%80% More patients in the induction chemoradiation group underwent pneumonectomy

15. Perioperative Outcomes Variable Chemo (N = 528) Chemo+RT (N = 834) p-value Perioperative Mortality (% of total) Lobectomy1%3%0.14 Pneumonectomy8%6%0.59 Re-admission in 30 days (% of total)6%7%0.38 Length of Stay Median, IQR6 (4, 8) 0.37 No significant differences in perioperative mortality, length of stay and hospital re-admission between the groups

16. Pathologic Results Variable Chemo (N = 528) Chemo+RT (N = 834) p-value Size of Tumor (cm) Median, IQR3.5, (2.5, 5.0)4 (2.6, 6.0)<0.01 Lymph Nodes Examined Median, IQR10 (5, 16)7 (5, 16)<0.01 Positive Margin8%7%0.55 Patients that underwent induction chemotherapy alone had smaller tumor size Induction radiation was associated with fewer nodes examined

17. Down-staging Variable Chemo (N = 528) Chemo+RT (N = 834) p-value T stage down-staging 24%38%<0.01 N2 to N0/N1 down-staging 46%58%<0.01 T stage down-staging was more common with induction chemoradiation Nodal down-staging from N2 to N1/N0 was more common with the induction chemoradiation

18. Overall Survival of Patients with Operable N2 NSCLC who Underwent Induction Chemotherapy vs. Induction Chemoradiation p = 0.78 TreatmentMedian survival 5-year survival Induction CRT3.3 years41.4 % Induction CT3.4 years40.8 % Induction CRT – 834 698 533 406 356 299 205 110 49 Induction CT – 528 445 341 278 227 188 130 62 29

19. Impact of Induction Therapy in Multivariable Analysis * Adjusted for: age, sex, race, comorbidity score, facility type, insurance type, clinical T status, type of operation, histology and tumor location Induction Chemoradiation vs Chemotherapy

20. p = 0.54 Overall Survival after Induction Therapy Followed by Lobectomy TreatmentMedian survival 5-year survival Induction CRT3.9 years44.0 % Induction CT3.6 years42.3 % Induction CRT – 666 573 447 346 305 255 169 89 39 Induction CT – 445 388 300 243 201 167 115 56 27 aHR 1.01; 95% CI: 0.86-1.18

21. Overall Survival after Induction Therapy Followed by Pneumonectomy p = 0.99 TreatmentMedian survival 5-year survival Induction CRT2.1 years32 % Induction CT2.4 years33 % IC – 83 57 41 35 26 21 15 6 2 ICR – 168 125 86 60 51 44 36 21 10 aHR 1.15; 95% CI: 0.80-1.65

22. Limitations  Retrospective study  No histologic verification of N2 disease prior to induction therapy  No data on type of N2 disease (multi-station vs single station)  Survival was not cancer-specific and no data on location of recurrence

23. Summary  No significant differences in perioperative mortality between induction chemotherapy and induction chemoradiation

24. Summary  No significant differences in perioperative mortality between induction chemotherapy and induction chemoradiation  Induction chemoradiation was associated with a higher rate of primary tumor (T) and mediastinal nodal down-staging  However, there was no survival benefit associated with addition of radiation to induction chemotherapy

25. Conclusion  The addition of radiation to induction chemotherapy for operable stage IIIA-N2 NSCLC is not associated with a significant improvement in overall survival

26. Conclusion  The addition of radiation to induction chemotherapy for operable stage IIIA-N2 NSCLC is not associated with a significant improvement in overall survival  The use of induction chemoradiation should be reexamined in the context of randomized trials

27. Conclusion  The addition of radiation to induction chemotherapy for operable stage IIIA-N2 NSCLC is not associated with a significant improvement in overall survival  The use of induction chemoradiation should be reexamined in the context of randomized trials  Future studies should focus on identifying characteristics that can be used to indicate if and when radiation is needed in addition to chemotherapy

28. Notes