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. 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

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

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

11. ACOSCOG Z0432

12. 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)

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

14. Thermal Ablation for lung cancers

15. Radiofrequency Ablation – Schneider et al. 2013

16. 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

17. 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

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
Endpoint: 3 year OS
Accrual = 420 patients 18

19. 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

20. 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%

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

22. 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

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

24. 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%

25. 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

26. 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.

27. 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 at 14 Japanese institutions.
Subset from original 2007 study with longer follow-up.
SBRT was Gy / 3-10 fx via a variety of stereotactic techniques.
No chemo

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 % (All)
5y OS % (All)
CSS l%

29. 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):
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)

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

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

32. J Thorac Oncol 2013; 8:

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

35. Centrally-located lung cancers

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

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

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

39. 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