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Jeffrey D. Bradley, M.D. S. Lee Kling Professor of Radiation Oncology

Approaching Early-Stage Disease: Strategizing Various T herapeutic Options (Surgery vs. SBRT vs. RFA). Jeffrey D. Bradley, M.D. S. Lee Kling Professor of Radiation Oncology Alvin J Siteman Cancer Center. Disclosures. No financial relationships to disclose

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Jeffrey D. Bradley, M.D. S. Lee Kling Professor of Radiation Oncology

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  1. Approaching Early-Stage Disease: Strategizing Various Therapeutic Options (Surgery vs. SBRT vs. RFA) Jeffrey D. Bradley, M.D. S. Lee Kling Professor of Radiation Oncology Alvin J Siteman Cancer Center

  2. Disclosures • No financial relationships to disclose • Chair of NRG Oncology Lung Cancer Committee (modest stipend)

  3. Case 1: LB • Referred by cardiologist to Dr. Meyers for evaluation of a LUL lung nodule • Recent drug-eluting stent placed in coronary artery. On clopidrogel • FDG-PET showed moderately increased FDG uptake with max SUV of 2.5. No other findings • PFTs showed FEV1 of 2.64 (83%) and FEV1/FVC of 74.7 (100%) • CT-guided needle Bx: NSCLC favor SCCA

  4. LB SABR Images

  5. LB: 5 Year Follow-up Images

  6. Surgery Lobectomy/ pneumonectomy Sublobar resection (segmentectomy, wedge) Radiation SBRT EBRT Observation Stage I NSCLC - Options Medically operable ??? Borderline medically operable ?? Medically inoperable ? Wouldn’t touch with a 10-foot pole

  7. Results of Surgery • IASLC project – AJCC 7th addition • 100,869 patients from 46 sources from 19 countries • 67,725 NSCLC treated between 1990-2000 • American College of Surgeons Z4032 • Randomized Phase III study of sublobar resection +/- brachytherapy in high-risk patients with NSCLC, 3 cm or smaller (ongoing)

  8. 5y LR (LCSG 1995) 6% 18% Stage I NSCLC - Options • Surgery

  9. ACOSCOG Z0432

  10. Stereotactic Body Radiation Therapy • Not a machine, but a type of radiation delivery. • Stereotactic = precise positioning of the target volume in 3 dimensions. • Has become synonymous with high dose per fraction. • Different delivery techniques (arcs, static fields, protons)

  11. 1 failure within PTV, 0 within 1 cm of PTV 36 month Primary tumor control = 98% (CI: 84-100%) Challenges?......What Challenges?RTOG 0236 Lobar tumor control = 94% Timmerman et al. JAMA 2010

  12. Thermal Ablation for lung cancers

  13. Radiofrequency Ablation – Schneider et al. 2013

  14. Radiofrequency Ablation • Follow up data are now projecting 5-year results for percutaneous thermal ablation • Pneumothorax and chest drain rates are very high • Local recurrence rates are poor (11-57%) • Industry and investigators are evaluating bronchoscopic ablation techniques • Consider for SBRT failures? • First-line RFA cannot be recommended

  15. Randomized Trials comparing surgery to SBRT • Lobectomy • Netherlands ROSEL Trial – closed due to lack of accrual • Accuray Cyberknife – closed due to lack of accrual • High Risk • ACOSOG Z4099/RTOG 1021 – closed due to lack of accrual • TMSC rejected amendment for cluster randomization (5/9/13) • One last hope? VA Medical System – VALOR Trial Lobectomy vs SBRT Drew Moghanaki - PI

  16. ACOSOG Z4099/RTOG 1021 Phase III Trial for High-risk patientsOpened June 2011 ARM 1: Sublobar Resection ± Brachytherapy (SR) Histological confirmation NSCLC and confirmation N2/N3 negative lymph nodes F O L L O W U P Registration and Randomization ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy Endpoint: 3 year OS Accrual = 420 patients

  17. ACOSOG Z4099/RTOG 1021 Phase III Trial for High-risk patientsOpened June 2011 ARM 1: Sublobar Resection ± Brachytherapy (SR) Histological confirmation NSCLC and confirmation N2/N3 negative lymph nodes F O L L O W U P Registration and Randomization ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy Closed Endpoint: 3 year OS Accrual = 420 patients

  18. Rough comparison of OS SBRT vs. surgery for clinical stage I NSCLC

  19. SBRT vs. surgery for clinical stage I NSCLC • Problem #1. . . • Treatment groups are inherently different! Vs.

  20. SBRT vs. surgery for clinical stage I NSCLC • Problem #2. . . • Definition of “medically operable”? FVC FEV1 Smoking Diabetes ??? Performance Status DLCO Cardiac Co-morbidity Predicted Postoperative Pulmonary Reserve

  21. SBRT vs. surgery for clinical stage I NSCLC • Medically operable • Uematsu, IJROBP 2001 • Onishi, J Thorac Oncol 2007 / IJROBP 2010 • Medically inoperable / High risk operable • William Beaumont • Grills, JCO 2010 - Wedgevs. SBRT • Cornell • Parashar, Cancer 2010 –Wedge+Brachyvs. SBRT • Wash U • Crabtree, J Thorac Cardiovasc Surg 2010 - Any surgeryvs. SBRT • Robinson, JTO 2012– Lobectomy/Pneumonectomyvs. SBRT

  22. SBRT vs. surgery for clinical stage I NSCLC Medically operable - Onishi, J Thorac Oncol 2007 • Median F/U 38 mo (2-128 mo) All 257 pts OS by medical operability 3y ~70%, 5y 64.8% 3y ~40%, 5y 35%

  23. SBRT vs. surgery for clinical stage I NSCLC Medically operable - Onishi, J Thorac Oncol 2007 Control rates by BED10 for all pts ≥ 100Gy = 64.8% 19.7% sig 53.9% 5y overall survival

  24. What dose for peripheral lung cancers? Medically operable - Onishi, J Thorac Oncol 2007 5y OS by BED10 in medically operable ≥100 Gy 3y 80.4%, 5y 70.8% BED = nd(1+d//) Schemes >100 Gy: 16 Gy x 3 12 Gy x 4 10 Gy x 5 <100Gy 3y ~65%, 5y ~50%

  25. SBRT vs. surgery for clinical stage I NSCLC Medically operable - Onishi, IJROBP 2010 • 87 pts w/medically operable, path proven T1 (n=65) or T2 (n=22) N0 NSCLC tx’d w/SBRT to BED > 100Gy from 1995-2004 at 14 Japanese institutions. • Subset from original 2007 study with longer follow-up. • SBRT was 42-72.5 Gy / 3-10 fx via a variety of stereotactic techniques. • No chemo

  26. SBRT vs. surgery for clinical stage I NSCLC Medically operable - Onishi, IJROBP 2010 • Median F/U 55 mo Local control Overall survival 5y LC 86.7% (All) 5y OS 69.5% (All) CSS 76.l%

  27. Local Recurrence by Prescription Dose 2-year LR of 15% for low dose vs 4% for high dose Grills IS et al. JTO 2012;7(9):1382-93 Elekta Consortium 1.0 0.8 0.6 Local Recurrence Rx BED10< 105 Gy 0.4 p<0.001 0.2 Rx BED10≥ 105 Gy 0 0 2 4 6 8 Time (Years)

  28. SBRT vs. surgery for clinical stage I NSCLC Medically operable - Onishi, IJROBP 2010 • Median F/U 55 mo Local control Overall survival 5y LC 86.7% (All) 5y OS 69.5% (All) CSS 76.l%

  29. SBRT vs. surgery for clinical stage I NSCLC Medically inoperable / High risk operable -Grills, JCO 2010 • Median potential F/U 30 mo

  30. J Thorac Oncol 2013; 8:192-201

  31. RTOG 0915 Overall Survival Videtic et al. ASTRO and IASLC 2013

  32. Centrally-located lung cancers

  33. Reported Toxicity for Central Lung Cancers Timmerman et al. JCO 2006 Timmerman R. et al JCO 2006

  34. RTOG 0813 - SBRT Dose LevelsTrial completed, await f/u Phase I/II Dose Escalation study (N=94) Level 1 10 Gy x 5 50 Gy Level 2 10.5 Gy x 5 52.5 Gy Level 3 11 Gy x 5 55 Gy Level 4 11.5 Gy x 5 57.5 Gy Level 5 12 Gy x 5 60 Gy Design: Continual Reassessment Monitoring (CRM) Endpoints: Phase I – Any Tx-related Grade 3 or greater toxicity Phase II – 2-year primary tumor control rate

  35. WU Data on Local Control Olsen, Robinson, Bradley et al. IJROBP 2011

  36. Conclusions: Surgery versus SBRT • Surgery is the gold standard for operable patients • For inoperable or marginally operable patients with Stage I lung cancer, SBRT offers excellent local control and similar survival to surgical approaches • SBRT results will be similar, regardless of delivery device. Differences are method of imaging, +/- fiducials, treatment time, etc. • Randomized trials have failed to accrue for various reasons; patients and surgeons

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