AATS Focus on Thoracic Surgery : Lung Cancer November 17,2012 Session VII: SBRT

1. AATS Focus on Thoracic Surgery : Lung Cancer November 17,2012 Session VII: SBRT Strategies for Treating Failed SBRT or Other Ablative Therapies James D. Luketich MD, FACS Henry T. Bahnson Professor and Chairman, Department of Cardiothoracic Surgery University of Pittsburgh Medical Center

2. Presenter DisclosureJames D. Luketich, MD The following relationships exist related to this presentation: Accuray- Grant/Research Support Acknowledgements: UPMC Faculty (Arjun Pennathur, Matt Schuchert) and Staff

3. Overview • Overview of SRS • Factors associated with failure after SRS • Poor choice of tumor and/or contouring problems • Poor choice of technology • Inadequate staging pre-SRS • Initial dosing (< or > 100gy BED) • Approach to and management of recurrent disease

4. Ideal Candidate for Ablative Therapy • Pathologically similar in concept to the ideal candidate for sub-lobar resection • Small tumor (<3 cm, better if less than 2cm ) • Adequate loco-regional staging (Clinical Stage Ia, Ib) • PET-CT • Mediastinscopy if indicated • Favorable initial assessment of a local tumor that is deemed inoperable by an experienced Thoracic Surgeon

5. Case Example of a Localized tumor, with Adequate Planning and BED dose Greater than 100Gy

6. American Association for Thoracic Surgery 87th Annual Meeting , Washington, DC General Thoracic Surgery Scientific Session Stereotactic Radio Surgery For The Treatment Of Stage I Non-small Cell Lung cancer In High-Risk Patients Arjun Pennathur, James D. Luketich, Steve A. Burton, Ghulam Abbas, Mang Chen, Dwight E. Heron, William E. Gooding, Cihat Ozhasoglu, Rodney J. Landreneau, Neil A. Christie University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Pennathur A, Luketich et al JTCVS 2009

7. Factors associated with recurrent disease: Dose • Dose administered during treatment with SRS/SBRT is associated with local control. • We initially reported the results medically inoperable patients with Stage I non-small cell lung carcinoma who were treated with a median dose of 20 Gray in a single fraction. (BED < 60gy) • At a mean follow-up of 24 months, the estimated probability of survival at 1-year was 81% (CI 0.73-.90). • Local progression occurred in 9 patients (42%), at a mean follow-up of 24 months with this dose. The median time to local progression was 12.3 months

8. Factors associated with recurrent disease: Dose • Dose escalation and increase in BED is associated with improved local control • In a multi-institutional study from Japan, higher doses were again associated with better response rates. • Median follow- up was 24 months. • Stratification of their results according to biologically effective dose (BED) greater than 100 Gy vs. less than 100 Gy

9. Japanese Multi-institutional Study • 245 patients with Stage I NSCLC • Stage I A 155, I B 90 • Median Age 76 years • Median Biologically effective dose 108 Gy • Inoperable158 patients; Operable 87 patients • Median follow-up 24 months Onishi H et al Cancer, 2004

10. Japanese Study: Progression and BED • Local progression (all Patients) 13.5% • BED <100 Gy: Local Progression 26.4% IA 16.3%; IB: 44% • BED >100 BED: Local progression 8.1%

11. Japanese Study Update5 year Local Control 84% Onishi et al; J Thorac Oncol. 2007;2: Suppl 3, S94–S100

12. CyberKnife SRS Multicenter Study for Stage I medically inoperableInitial Results Presented at ASTRO 2012 University of Pittsburgh- PI site (PI: Luketich MD) Primary Aims: • To assess clinical response rate, local control, progression-free survival and overall survival, following CyberKnife SRS for patients with early stage NSCLC. • Peripheral lesion-accrual complete; Central-ongoing Dose : Peripheral Lesion: 60 Gy in 3 fractions Central Lesion: 48 Gy in 4 fractions BED is about 105 gy for 48, 60 is in excess of 110

13. Institutions University of Pittsburgh Medical Center, PA Stanford University, CA Baylor University Medical Center, TX Georgetown University Hospital, Washington, DC St. Joseph’s/Barrow Neurological Institute, AZ Fresno Community Regional Medical Center, CA St. Catherine Hospital, IN St. Anthony Hospital, OK North Florida Regional Medical Center, FL Sinai Hospital of Baltimore, MD St. Luke’s/Aurora Medical Center, WI Naples Community Hospital, FL North West Community Hospital, IL

14. CyberKnife Multicenter Study: Initial Results - A total of 78 peripheral NSCLC patients, 62 with stage IA and 16 with stage IB, treated with SRS- 60 Gy in three fractions • There was no peri-treatment mortality. • Median follow-up was 26 months • The probability of 2-year cancer specific-survival (CSS) for the entire group was 79% (95% confidence interval 69%-90%). • During follow-up, 26 patients had recurrence: • Local only 3 (3.8%), and 23 (29%) with regional and/or distant progression. The median recurrence-free survival was not reached.

15. Factors associated with recurrent disease: Size T1 vs. T2 • Dunlap et al. evaluated Local control in T1 (n=27) vs. T2 (n=13) tumors • Median dose was 60 Gy in 3 to 5 fractions (BED > 100gy) • Median follow-up 12.5 months • Increasing tumor size correlated with worse local control and overall survival. Dunlap et al. J Thorac Cardiovasc Surg 2010;140:583-9

16. Factors associated with recurrent disease: Size T1 vs. T2 • Median recurrence-free survival for T1 tumors was 30.6 months and T2 tumors was 20.5 months • Local control at 2 years was 90% for T1 tumors vs. 70% for T2 tumors (P= 0. 03). • Conclusions: Stereotactic body radiation therapy for T2 non–small-cell lung cancer has a higher local recurrence rate and trended toward a worse survival than did T1 lesions. • Tumor size is an important predictor of response to stereotactic body radiation therapy and should be considered in treatment planning. Dunlap… Jones DA . J Thorac Cardiovasc Surg 2010;140:583-9

17. Local control by T-stage grouping: Size- T1 vs. T2 P= 0. 03 Dunlap et al; J Thorac Cardiovasc Surg 2010

18. Overall survival by T-stage grouping Size- T1 vs. T2 Dunlap et al; J Thorac Cardiovasc Surg 2010

19. Approach to Recurrent Disease • Re-evaluation of the original decision not to operate • Re-Staging starting with tissue confirmation (optional) of the patient with suspected recurrent disease • Define the location/s of recurrence, is it truly local only? • EBUS/ Mediastinoscopy for locoregional staging • PET- CT scan- R/O distant disease, consider brain MRI

20. Functional and Operability Evaluation • Re-evaluate Loco-regional and distant staging • Functional evaluation of the patient • Repeat Pulmonary Function Tests • Quantitative V/Q • Consider short period of pulmonary rehab to improve surgical outcomes • Cardiac Evaluation • Consider intervention, stent, etc if indicated

21. Approach: Local RecurrenceEvaluate Operative Risk • Important to recognize that “medical operability” status can change- example acute coronary event, stroke etc • Resect if patient is operable • Consider ablative therapy if inoperable Evaluate dose given previously- ? SRS Image-guided ablation- Radiofrequency Ablation

22. Case 1: NSCLC Treated With RFA with Progression POD 1 Post-RFA-3 months Pre-RFA

23. Ablated Cancer

24. Necrotic Tumor Viable Tumor Viable Tumor

25. Case 2: Pre SRS lesion

26. Recurrent Lesion post SRS at 7 months

27. Resected with Lobectomy Pathology with viable tumor Viable Tumor

28. Results of Salvage Surgery - 1 Allibhai e al. Eur Respir J 39, 1039-1042, 2012 • 209 patients treated with SBRT due to medical inoperability • Local recurrence developed in 6 patients, and in four patients no other site of recurrence • All 4 patients were determined to be medically operable • Underwent Lobectomy with lymph node sampling

29. Results of Salvage Surgery - 2 Chen et al J Thorac Oncol 5, 1999-2002, 2010 • Total of 144 patients undergoing SRS during a 10-year period • Biologic effective dose of 105.6 Gy • Median follow-up of 31.5 months • Local recurrence was detected in 24 patients (16.7%). • Increase in PET FDG uptake in all the patients • Five patients underwent salvage surgical resection- Lobectomy with nodal dissection • No major technical difficulties or increased postoperative morbidity.

30. Results of Salvage Surgery 3 Neri et al J Thorac Oncol 5, 2003-2007, 2010 • Reviewed 81 patients with stage I disease and 46 patients with lung metastases. • Local recurrence was detected in 18 patients (14.1%) • Seven (NSCLC=2; Metastases= 5) of these 18 patients underwent salvage surgery • Six patients underwent lobectomy and one segmentectomy • Postoperatively, one patient had a broncho-pulmonary fistula requiring reoperation and pleurodesis

31. Salvage Surgery: Summary • It is important to recognize that “medical operability” status can change- examples, pulmonary rehab, V/Q assessment, recovery from an acute coronary event, stroke etc, • Critically assess original treatment details, was SRS dosing adequate, can additional RT be given, was the RFA needle centrally deployed • “Operability” may vary considerably depending on knowledge and experience of who is doing the evaluation, (eg. upper lobe tumors in setting of emphysema) • Re-stage the recurrent disease: rule out mets, is it in the central portion of the tumor, the periphery or in the local nodes that may not have been well addressed by SRS or RFA • In some cases, we plan RFA initially and place fiducials if we think the recurrence risk is high, and perform sequential SRS • The peri-operative morbidity of surgery post-SRS is acceptable in a few case reports (broncho pleural fistula with air leak has been reported)

32. Conclusions • Thoracic surgeons should have been involved in the initial work-up, decision making and treatment planning • Thoracic Surgeons should redo the work-up in patients with failures after SRS • Re- Stage the patient completely • Review all the old records including treatment plan, and prior dose administered • Re-Evaluate the patient and determine the risk for limited pulmonary resection • For isolated local recurrence consider resection or ablative therapies for treatment of recurrence • Rule of Systemic recurrence

33. Thank You