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

I have no conflicts of interest to report

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)

SBRT LUNG

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

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

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

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

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

Multi-institutional Phase II Data: RTOG 0236 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 Gy x 3 fractions (54 Gy) Accrual: 55 pts Timmerman et al. JAMA 2010

3 yr = 97.3% (one T2 tumor progressed in-field) 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

Any primary tumor except germ cell, leukemia, lymphoma 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 Gy x 3 fractions (60 Gy) Accrual: 38 pts => 63 lesions Rusthoven et al. JCO 2009

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

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

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 Gy vs 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.

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

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

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

ACOSOG Z4099/RTOG 1021 Phase III Trial Opened June 2011 Areas of Investigation Measuring SABR against Surgery ACOSOG Z4099/RTOG 1021 Phase III Trial Opened June 2011 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 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

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 Gy chemoradiotherapy => if residual disease: boost 10 Gy x 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

Questions….