1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

2. Case History 84-year-old with poor pulmonary function, smoking history, and recent thromboembolic event Underwent serial CT scans with these findings

3. CP1066773-47

4. Case History PET Positive there at SUV 10.1 OK elsewhere FNA performed: Result C/W NSCLC Patient considered unsuitable for lobectomy due to co-morbidities

5. Treatment Options 1. Observation? 2. Wedge Resection (VATS or Not)? 3. Radiofrequency Ablation? 4. Systemic Therapy? Chemo or Oral TKI? 5. Radiosurgical Ablation?

6. Subsequent Course The patient received SBRT at 18 Gy times 3 without difficulty. On six -month follow-up, CT chest revealed a new moderate-sized ipsilateral pleural effusion and “scarring” at the primary tumor.

7. Final Question This pleural effusion should be: 1.Tapped 2.Drained and Treated 3.Evaluated with PET 4.Evaluated with Thoracoscopy 5.Treated with Chemotherapy

8. Walter J Curran, Jr, MD Executive Director Winship Cancer Institute of Emory University Group Chairman Radiation Therapy Oncology Group Stereotactic RT in Early Stage Lung Cancer Current and Future Applications???

9. Technology Enabling SBRT

10. What is SBRT? Potentially highly effective Potentially extremely dangerous

11. RT Fractionation Options Conventionally Fractionated RT - small daily doses - go to very high cumulative doses - tolerable for most normal tissues Hypofractionated RT - larger daily doses (3-8 Gy) - used mostly for palliation Ablative RT (Stereotactic) - very high daily doses (8-20 Gy) - overwhelm tumor repair - causes “late” effects that may be intolerable

12. Ablative Treatments (Stereotactic) Must Exclude Normal Tissue Requirements for ablative hypofractionation: – Abandon prophylactic treatment – Account for organ motion – Achieve sharper dose fall-off gradients to normal tissue (mimic radiosurgery) These requirements need advanced technology

13. Phase I Dose Response for Local Control

14. First North American cooperative group trial testing SBRT Non-small cell lung cancer - biopsy proven T1, T2 (  5 cm) and T3 (chest wall only,  5 cm), N0, M0 Medical problems precluding surgery (e.g. emphysema, heart disease, diabetes) No other planned therapy Robert Timmerman, MD; Rebecca Paulus, BS; James Galvin, PhD; Jeffrey Michalski, MD; William Straube, PhD; Jeffrey Bradley, MD; Achilles Fakiris, MD; Andrea Bezjak, MD; Gregory Videtic, MD;David Johnstone, MD; Jack Fowler, PhD; Elizabeth Gore, MD; Hak Choy, MD Robert Timmerman, MD; Rebecca Paulus, BS; James Galvin, PhD; Jeffrey Michalski, MD; William Straube, PhD; Jeffrey Bradley, MD; Achilles Fakiris, MD; Andrea Bezjak, MD; Gregory Videtic, MD;David Johnstone, MD; Jack Fowler, PhD; Elizabeth Gore, MD; Hak Choy, MD :RTOG 0236

15. Compact Dose Deposition Pulmonary Vein BronchusBronchus EsophagusEsophagus CordCord SkinSkin ChestwallChestwall LungLung

16. Local Tumor Control Rate: RTOG 0236 1 failure within PTV, 0 within 1 cm of PTV 36 months local control = 98% (CI: 84 -100%)

17. Regional and Disseminated Recurrence: RTOG 0236 2 patients have reported a regional failure, both after 2 years (2.8 and 3.0 years) Eleven patients (20%) have experienced disseminated failure

18. n=55 Complete Response23 (42%) Partial Response22 (40%) Stable9 (16%) Not evaluated1 (2%) RTOG 0236 : Best Observed Response

19. Post-SBRT Treatment Lung Reaction

20. Grade 3-5 Toxicity: Location, Location

21. RTOG 0618: SBRT for Operable Stage I NSCLC: Accrual complete RTOG 0813: SBRT for Central Early Stage NSCLC: Nearly done Other RTOG Phase I/II Trials SBRT Future Plans

22. Japanese Pooled Retrospective Experience with SBRT in OPERABLE Patients Stage IA (n=63), 5y OS 75% (95% CI 63-87%) Stage IB (n=24), 5y OS 70% (95% CI 49-90%)

23. Legitimate Alternative to Lobectomy for Stage I NSCLC?????? Requirements: -Local control 90% or more at 5 years (actuarial) -Survival 60-80% at 5 years (actuarial) -Grade III or higher toxicity <15-20% -Ideally less invasive than thoracotomy -Ideally more convenient -Ideally less costly -All proven by prospective testing

24. Phase III Study of Sublobar Resection (SR) versus SBRT in High Risk Patients with Stage I NSCLC Z4099 / R1021 Joint Trial between ACOSOG and RTOG To ascertain whether patients treated by SBRT have 3- year overall survival (OS) rate that is no more than 10% less than patients treated with Surgery.

25. Phase III Study of Sublobar Resection versus SBRT in High Risk Patients with Stage I NSCLC Z4099 / R1021

26. Phase III Study of Surgery vs SBRT in High Risk Pts with Stage I NSCLC: Z4099 / R1021 Non-Inferiority Survival Design: 80% +/-10% 420 Pts to be Enrolled Activated 3/11 Brachytherapy with Sublobar Resection

27. What is the Real Debate Question? Are American Docs Disciplined Enough to Enroll and Randomize Patients into this Surgery vs SBRT Trial? Historic Record is Spotty Likely Possible at Lower Velocity than Projected NCI Early Stopping Rules will be an Issue!

28. Summary SBRT is a new Standard for Medically Inoperable Stage I NSCLC Operable Patients: Data from Phase II and Phase III Trials Necessary Central Lesions: Data on RT Dose Pending

30. Sunday, February 12, 2012 Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Walter J Curran Jr, MD David Jablons, MD Mark G Kris, MD Suresh Ramalingam, MD Alan B Sandler, MD