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

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

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

LB SABR Images

LB: 5 Year Follow-up Images

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

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)

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

ACOSCOG Z0432

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)

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

Thermal Ablation for lung cancers

Radiofrequency Ablation – Schneider et al. 2013

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

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

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

ACOSOG Z4099/RTOG 1021 Phase III Trial for High-risk patients Opened June 2011 Histological confirmation NSCLC and confirmation N2/N3 negative lymph nodes Registration and Randomization ARM 1: Sublobar Resection ± Brachytherapy (SR) ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy F O L W U P Closed Endpoint: 3 year OS Accrual = 420 patients 19

SBRT vs. surgery for clinical stage I NSCLC Rough comparison of OS cT1N0 cT2N0 3y OS 5y OS Surgery AJCC 6th ed 71% 61% 46% 38% AJCC 7th ed ~68% (1a) ~58% (1b) 53% (1a) 47% (1b) ~50% (2a) ~45% (2b) ~30% (3; ≥ 7 cm) 43% (2a) 36% (2b) 26% (3; ≥ 7 cm) SBRT RTOG 0236 (60Gy/3) (55.8%; T1/T2) ? U. Indiana (60-66Gy/3) ~50% ~20% ~35%

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

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

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 - Wedge vs. SBRT Cornell Parashar, Cancer 2010 – Wedge+Brachy vs. SBRT Wash U Crabtree, J Thorac Cardiovasc Surg 2010 - Any surgery vs. SBRT Robinson, JTO 2012– Lobectomy/Pneumonectomy vs. SBRT

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 5y OS 56.8% 47.2% CSS 76.9% 73.2% 3y ~70%, 5y 64.8% Only compared OS by medical operability. 3y ~40%, 5y 35%

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% 5y overall survival 19.7% 53.9% sig

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% Best case scenario – optimal dose SBRT, medically operable. Implications for other studies, which did not correct for BED.

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

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%

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 2 4 6 8 Time (Years)

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%

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

J Thorac Oncol 2013; 8:192-201

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

Centrally-located lung cancers

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

RTOG 0813 - SBRT Dose Levels Trial completed, await f/u Phase I/II Dose Escalation study (N=94) RTOG 0813 - SBRT Dose Levels Trial completed, await f/u 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

WU Data on Local Control Olsen, Robinson, Bradley et al. IJROBP 2011 38 38

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