Pulmonary Stereotactic Ablative Radiotherapy: Current Implementation and Future Directions

1. Pulmonary Stereotactic Ablative Radiotherapy: Current Implementation and Future Directions CTOP Conference 2014 Philip Schaner M.D., Ph.D

2. I have no conflicts of interest to report

3. Definition of Stereotactic Body Radiotherapy • Method of delivering external beam radiotherapy (EBRT) • Particles (proton) or photon • Accurately delivers EBRT with a high degree of conformality • Spatial and Temporal resolution of target and organs at risk • Maintenance of high spatial targeting accuracy throughout the entire treatment • Immobilization • High frequency position monitoring through integrated image guidance • Respiratory Motion Management • Dose per Fraction: at least equivalent to radical doses in conventional fractionation: 5 – 34 gray (Gy) [Conventional Fractionation: 1.8 – 2 Gy] • Few fractions: 1 - 10 • Nomenclature: • Stereotactic ablative radiotherapy (SABR) • Stereotactic body radiotherapy (SBRT)

4. SBRT LUNG

5. Subset of NSCLC appropriate for SBRT • Stage I subset: • typically < 5 cm in maximal dimension • Not invading outside the chest (can be touching pleura) • Not invading into lobar bronchus • Minimal associated lung collapse • Mass well delineated

6. Subset of NSCLC appropriate for SBRT • Mass too large, invading into nearby structures • Primary acceptable but nodal disease present

7. Treatment Planning • Highly conformal dose distribution with rapid dose fall off • Maximally spare adjacent organs • Low dose spill • High dose spill

8. Accurate Delivery • Target localization • Lung cancer is a moving target….

9. 4D Treatment Delivery • Patient Breaths Normally – Control when XRT is on

10. Clinical • Multi-institutional Phase II Data: RTOG 0236 • Inclusion: • NSCLC • T1 or T2, N0,M0 • Peripheral: > 2 cm from proximal bronchial tree • Medically inoperable: FEV1 <40%, DCLO < 40% • Methodology: • All tumors received 18 Gyx 3 fractions (54 Gy) • Accrual: 55 pts Timmerman et al. JAMA 2010

11. Clinical • RTOG 0236 • Results: • Local control: • 3 yr = 97.3% (one T2 tumor progressed in-field) • Regional control: • 3 yr = 87.2%% (2 nodal failures, both around 35 months post SABR) • Distant Failure: • 3 yr T1: 14.7% • 3 yr T2: 47% • Toxicity: • 12.7% Grade 3 toxicity • 3.6% Grade 4 toxicity Timmerman et al. JAMA 2010

12. Clinical • Treatment of oligometastatic disease: Stage IV cancer with ≤ 5 metastatic lesions • Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases • Inclusion: • Any primary tumor except germ cell, leukemia, lymphoma • Max cumulative tumor diameter < 7 cm • Extrathoracic disease allowed: low burden, potentially treatable with 1st or 2nd line standard therapy • Adequate lung function: FEV1 >40%, DCLO >40% • Methodology: • Dose escalation to 20 Gyx 3 fractions (60 Gy) • Accrual: 38 pts => 63 lesions Rusthoven et al. JCO 2009

13. Clinical • Results: • Local control: • 2 yr = 96% • Patient characteristics • Toxicity: • Grade 3: 8% • Grade 4-5: 0% Rusthoven et al. JCO 2009

14. Areas of Investigation • What is the appropriate SABR dose for peripheral lesions?

15. Areas of Investigation • RTOG 0915 interim outcomes: • N=94 • Median FU 20.6 months • No significant difference with respect to toxicity in both arms: • 9.8% 34 Gyvs 13.3% 48 Gy > Gr 3 toxicities. • Local Control at 1 yr 97% both arms. • Winner? Need longer term follow up • Local Failure increases over time in many series, one year is not enough follow up.

16. Areas of Investigation • What is the appropriate SABR dose for centrally located lesions?

17. ARM 1: Anatomical surgical resection with LN dsxn Stage IA NSCLC Peripheral lesion F O L L O W U P ARM 2: SABR 20 Gyx 3 12 Gyx 5 Areas of Investigation • Measuring SABR against Surgery ROSEL Trial (Netherlands) Terminated due to poor accrual

18. ARM 1: Lobectomy or pneumonectomy • Stage I NSCLC • < 4 cm • Good surgical candidate • FEV1 > 40% pred • DLCO > 40% pred • Post-op predicted FEV1 > 30% F O L L O W U P ARM 2: SABR using Cyberknife Peripheral: 20 Gyx 4 Central: 15 Gyx 4 Areas of Investigation • Measuring SABR against Surgery Lung Cancer STARS trial: phase III, endpoint 3 yr OS

19. ARM 1: Sublobar Resection ± Brachytherapy (SR) Histological confirmation NSCLC and confirmation N2/N3 negative lymph nodes • T < 3 cm • Peripheral • High risk for surgery • Major • FEV1 ≤50% pred • DLCO ≤50% pred • Minor • Age ≥75 years • FEV1 51-60% pred • DLCO 51-60% pred F O L L O W U P ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy Areas of Investigation • Measuring SABR against Surgery ACOSOG Z4099/RTOG 1021 Phase III TrialOpened June 2011

20. Areas of Investigation • Combining radiofrequency ablation with SABR • UNM: RFA combined with SABR for large lung tumors • T2-4N0 > 3 cm; N1-3 if M1 eligible • 40 Gy/5 fractions escalating to 50 Gy/5 fractions f/b RFA procedure • Using SBRT as a boost for Stage II/III NSCLC • U Kentucky: Stage IIA – selected III-B • 59.4 Gychemoradiotherapy => if residual disease: boost 10 Gyx 2 (peripheral) • Proton vs Photon SBRT • SBRT combined with chemotherapy • Maintenance chemotherapy vs consolidative SBRT for Stage IV NSCLC • UTSW: 1st line chemo (no biologics) => up to six discrete extracranial lesions • U Kentucky: T1-T3N0 NSLC => SBRT then adjuvant cisplatin + docetaxel or pemetrexed

21. Questions….