Gregory M. M. Videtic, MD, CM, FRCPC Associate Professor,

1. “Stereotactic body radiotherapy (SBRT) for early stage lung cancer”3rd Annual Atlantic Canada Thoracic Oncology ConferenceOctober 20-21, 2011Pier 21, Halifax, NS Gregory M. M. Videtic, MD, CM, FRCPC Associate Professor, Cleveland Clinic Lerner College of Medicine; Section Head for Thoracic Malignancies, Dept. of Radiation Oncology, Taussig Cancer Institute The Cleveland Clinic

2. CONFLICTS OF INTEREST • NONE

3. OBJECTIVES • To review the nature and the problem of early stage lung cancer • To review the standard of care with respect to managing early stage lung cancer • To review the principles and practice of stereotactic body radiotherapy (SBRT) as they apply to early stage lung cancer • To review SBRT experience at the Cleveland Clinic

4. SBRT for Early Lung Cancer: The Cleveland Clinic program • Program initiated in 6/04 • ~500 medically inoperable early stage NSCLC pts treated to date • Some oligometastatic cases (~50) • 7 stage I SCLC cases (!)

5. A little background first…

6. Epidemiology of Lung Cancer • 0 • Leading cause of cancer-related deaths worldwide • Most common malignancy worldwide • over 1 million cases now being diagnosed yearly • USA Cancer Statistics 2009 • Estimated new cases: 219,440 • 15% of all new cancer diagnoses • Estimated Deaths: 159,390 • 29% of all cancer deaths • (#1 Cancer Killer of Men and Women) Jemal A et al. CA Cancer J Clin. 2009; 59:225

7. INTRODUCTION • Definition of Early Stage Non-Small Cell Lung Cancer (NSCLC) • Confined to lung, about 15-20% of total cases [30-40,000 cases annually] • By TNM staging: IA or IB • Thus, No LOCOREGIONAL lymph nodes • Standard of care • Surgery: 5-year survival 50-70%

8. EARLY STAGENode Negative Lung Cancer Gold Standard Rx = Surgery • Time honored position • Patient selection - proper staging (pathologic node negative ) - adequate pulmonary reserve - absent or controlled medical problems • Effective treatment - impressive local control (65-90%) - overall survival 60-80% at 5 years

9. EARLY STAGE LUNG CANCER • “Surgical resection remains the gold standard for treatment of patients with stage I and II NSCLC…” • Ginsberg RJ & Pot JL. Surgical therapy of stage I and non-T3N0 stage II non-small cell lung cancer. In: “Lung Cancer-Principles and Practice”. Eds. Pass HI et al. Lippincott, Williams and Wilkins, Philadelphia, PA; 2000. p. 691. • Mountain CF. Semin. Surg. Oncol. 18:106–115, 2000. • 5-year Overall Survival for stage I NSCLC • clinical stage IA-61% vs. pathologic stage IA-67% • clinical stage IB-38% vs. pathologic stage IB-57%

10. Randomized Trial of Lobectomy Versus Limited Resection for T1 N0 Non-Small Cell Lung Cancer. Ginsberg and Rubinstein • Conclusions • Compared with lobectomy, limited pulmonary resection does not confer improved perioperative morbidity, mortality, or late postoperative pulmonary function. Because of the higher death rate and locoregional recurrence rate associated with limited resection, lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1 N0 non-small cell lung cancer.

11. Lung Cancer Study GroupGinsberg, et al. Ann Thorac Surg. 1995 Sep;60(3):615-22

12. How Good is “Gold”? • Surgery is a very good but non-perfect treatment • NB: path stage I 5-yr OS is “ONLY” 60-70% • Local failures, death from cancer (even controlling for pathological staging) • Toxicity, pain and suffering • Expense - hospitalization, recovery, lost work/income, etc. • Surgery not appropriate for many!

13. INTRODUCTION • Many early stage pts [30-50%] potentially resectable but MAY have reasons for being medically inoperable • Co-morbidities preventing surgical resection include • COPD • Cardio-vascular Disease • Poor performance status • Doing “nothing” is not good in med inop pts • McGarry et al. (Chest 2002): Lung cancer cause of death in 53% of 75 stage I medically inoperable pts treated with observation alone

15. EARLY STAGE LUNG CANCER • Management of the medically inoperable early lung cancer pt • O.S. with primary conventional daily fractionated RT historically poor • BUT O.S. with RT confounded by • Patient co-morbidities (competing death causes) • RT interacting with co-morbidities • e.g. COPD exacerbation

16. 3-5 Year Survival in Early Stage Lung Cancer Rx Modality% alive • Stage I Surgery 60-80%Stage I* Radiotherapy (RT) 15-45% • Stage II Surgery 30-50%Stage II* RT 10-30% *clinically staged and mostly medically inoperableRT generally 60 Gy delivered in 6 weeks

17. SELECTION LUCK? “The real reason we use conventionally fractionated RT is in fact because of the normal tissues, not the tumor.” Bob Timmerman, 2007 “OLD-SCHOOL” RADIOTHERAPY ALONE CAN CURE LUNG CANCER!

18. Local Progression-Free Survival Is a Function of Dose • 0 ~ 84 Gy would be needed for ~ 50% local progression- free survival in 30 months Mehta M, Manon R. Sem Oncol. 2005;(Suppl 3):s25–s34.

19. 87 yo WF, T2 lesion RUL, bx=adenoCA, PET SUV=16.92 at lesion, medically inoperable EBRT 70 Gy/35fx: per plan to the 97% isodose line using 10 MV photons via LAO/POST/RPO field set ups. • Pre-RT CT 4/28/04 Post-RT scan of 4/7/10

20. RT and lung cancer • The efficacy and safety of RT reflect the interplay between • total dosedelivered to the malignant tumor • the rate of dose delivery (daily fractionation) • the volume (and type) of tumor-bearing organ irradiated. • The intrinsic tolerance of the tissue irradiated

21. Improving RT Results in the Inoperable Early Lung CA patient Examples of isodose coverage for a patient w/ peripheral stage I lung carcinoma comparing a simple parallel-opposed beam arrangement versus a conformal four-field-technique.. From: Principles and Practice of Radiation Oncology, 4th edition, C. Perez, L. Brady, E. Halperin and R Schmidt-Ullrich, editors, 2004

24. Spread out the Entrance Dose/focus on the target

25. The origins of lung stereotactic body radiotherapy (SBRT) • Modeled after brain radiosurgery principles • Multiple convergent beams • Rigid patient immobilization • Precise localization via stereotactic coordinate system • Single fraction treatment • Size-restriction for target

26. INTRODUCTION • What is SBRT? Technical • Multiple convergent beams of RT aimed at target • Requires rigid patient immobilization • MUST account OR compensate for organ motion • Precise localization of target via stereotactic coordinate system • Size-restriction for target

27. INTRODUCTION • What is SBRT? Technical • Typically few-fraction (1 to 5) RT using large individual fraction doses • High dose conformality, i.e., “tight around target” • Rapid dose fall-off from target to surrounding normal tissue.

28. Many ways to skin a cat…

29. INTRODUCTION Use of “Image Guidance”- Technology for frequent 2D and 3D imaging, during RT, to verify/direct radiation therapy checked against the “standard” : Imaging coordinates set by images set at simulation and used for planning

30. Treatment Verification • Re-align to eliminate error between and during treatment

31. Pulmonary Vein Bronchus Lung Esophagus Chestwall Cord Skin Compact Dose Deposition

32. Lung tumors move with time

33. Lung tumors move in space

34. How do we deal with tumor motion? • Solutions (is there just one??) • Tumor factors • Stop the tumor from moving..somehow • Follow the tumor as it is moving and treat as it moves • Patient factors • Stop the patient from breathing (!) • Control the patient’s breathing • Machine factors • Turn on machine only when it “sees” tumor

36. SBRT and Early Lung Cancer CLINICAL EXPERIENCE Numerous series document efficacy and safety of SBRT in early lung cancer Recent review of rationale, techniques, applications and optimization of SBRT for various extracranial sites (Song et al. Oncology, 2004) -Includes lung cancer (primary/metastatic)

37. SBRT and Early Lung Cancer- Numerous studies report excellent local control.

38. SBRT and Early Lung Cancer-The radiobiological dose matters, I.e., >100Gy equivalent

39. SBRT and Early Lung Cancer • Treatment Toxicities • Reported rates generally low • > grade 3 pneumonitis, hypoxia: < 5% • Related to tumor location • RTOG SBRT eligibility • Tumors must be at “2 cm or beyond the zone of the proximal bronchial tree” • Restriction due to high bronchial injury rates • Based on work of Timmerman et al at U Indiana

40. SBRT and Early Lung Cancer • Interesting SBRT data from Japan in operable pts who declined surgery (Onishi et al) • 5 year survivals for stage IA and IB comparable to surgery • Stage IA=77% • Stage IB=68%

41. SBRT for Early Lung Cancer: The Cleveland Clinic program

42. SBRT for Early Lung Cancer: The Cleveland Clinic program • Program initiated in 6/04 • ~500 medically inoperable early stage NSCLC pts treated to date • Some oligometastatic cases (~50) • 7 stage I SCLC cases (!)

44. SBRT for Early Lung Cancer: The Cleveland Clinic program • PATIENT SELECTION Defined as early stage AND medically inoperable following • Review by the Thoracic Multidisciplinary Lung Team • Surgeon • Pulmonologist • Radiation Oncologist • Medical Oncologist • (Cardiothoracic service/Cardiology) • Staging (complete) to include • PET • +(/-) Mediastinoscopy • +(/-) Biopsy- morbidity of procedure of importance

45. SBRT for Early Lung Cancer: The Cleveland Clinic program • Treatment Regimen Model • Uematsu et al. IJROBP 2001; 51:666-670 • 5 yr. reported experience with Stage I NSCLC • 50 patients (medically inoperable / refused surgery) • Dose 50-60 Gy / 5-10# /1-2 wks • T size 0.8-5.0 cm • Staged by CXR, CT chest, no PET, no mediastinoscopy • Results: • 3 yr o.s. 66% for 50 patients • 3 yr o.s. 86% for the 29 medically inoperable patients • 3 yr c.s.s. 80% for 50 patients

46. SBRT for Early Lung Cancer: The Cleveland Clinic program • Treatment Unit Novalis BrainLab System • 6MV Linac • Special characteristics “Automated image-guided radiation therapy system, utilizes high-resolution X-rays to pinpoint internal tumor sites seconds before treatment, robotically corrects patient set-up errors and tracks any patient movement throughout the treatment, all within a standard treatment time slot”

47. SBRT for Early Lung Cancer: The Cleveland Clinic program • SBRT on NOVALIS • By restriction (immobilization) • By tumor motion studies • By creating reference frame to provide real-time verification of patient positioning and set-up

48. SBRT for Early Lung Cancer: The Cleveland Clinic program • Novalis patient immobilization BodyFix Stereotactic Immobilizer

49. SBRT for Early Lung Cancer: The Cleveland Clinic program • Abdominal compression/breathing restriction

50. SBRT for Early Lung Cancer: The Cleveland Clinic program • Abdominal compression/breathing restriction