2011 Trial Update RTOG Lung Cancer Committee Chair: Jeffrey - PowerPoint PPT Presentation

RTOG Lung Cancer 2011 Trial Update RTOG Lung Cancer Committee Chair: Jeffrey Bradley, M.D. Kling Associate Professor Department of Radiation Oncology Washington University School of Medicine

RTOG Lung Committee • Small Cell Lung Cancer ▫ Limited Stage (Intergroup Trial) ▫ Extensive Stage (RTOG 0937) • Early Stage NSCLC ▫ In-operable (0813 and 0915) ▫ Operable (RTOG 1021/ACOSOG Z4099) • Locally advanced NSCLC ▫ Stage IIIA/B (Intergroup Trial -0617) ▫ Stage IIIA with minimal N2 disease (0839) ▫ Stage IIIA – Individualized RT Rx with PET-adapted boost (1106)

Monthly RTOG Lung Accrual

Phase III Comparison of Thoracic Radiotherapy Regimens in Limited-stage Small Cell Lung Cancer CALGB 30610 RTOG 0538 Principal Investigator: Jeff Bogart, MD RTOG PI: Ritsuko Komaki, MD

RTOG 0538 / CALGB 30610 R 45 Gy 1.5 Gy BID A CDDP CDDP CDDP CDDP VP-16 VP-16 VP-16 VP-16 N D 61.2 Gy, 1.8 Gy QD FB Con bst O PCI M CDDP CDDP CDDP CDDP VP-16 VP-16 VP-16 VP-16 I Z 70 Gy Gy, 2.0 Gy QD E CDDP CDDP CDDP CDDP VP-16 VP-16 VP-16 VP-16

RTOG 0538/CALGB 30610 • Status ▫ Accrual thru 8/11: 185/670 patients  1/3 by RTOG ▫ Interim analysis after initial 30 and 50 patients on each arm showed no difference in toxicity ▫ Accrual continuing to 70 patients per arm for next interim toxicity analysis

Prophylactic cranial irradiation in extensive disease small cell lung cancer (EORTC 08993-22993) Slotman et al. NEJM 2007 Study Design PCI 20-30 Gy in No response Chemotherapy 5-12 fractions (4-6 cycles) Random Any response No PCI < 5 weeks 4-6 weeks Stratification: Performance score and Institute

Prophylactic cranial irradiation in extensive disease small cell lung cancer Overall survival 100 90 1 year: VS. 13.3% 27.1% 80 HR: 0.68 (0.52-0.88) p=0.003 70 60 50 40 30 PCI 20 Control 10 0 (months) 0 4 8 12 16 20 24 28 32 36 Slotman et al. NEJM 2007

Phase II Study of PCI and consolidative Extra-Cranial Radiation for ED-SCLC (RTOG 0937) IF RT Study Design Chest and Other Sites PCI Random Chemotherapy Any response 25 Gy in 10 fx (4-6 cycles) Observation Stratify: PR vs CR 1 vs 2-3 mets PI: Elizabeth Gore, MD

RTOG 0937 Specifics • Primary Objective: To compare 1-year median survival • Eligibility: ▫ ES-SCLC, excluding brain metastases AND ▫ Only 1-3 metastatic sites prior to platinum-based chemotherapy AND ▫ Radiographic PR or CR • Sample size = 154 • Radiation therapy dosing ▫ PCI given in 2.5 Gy fractions to 25 Gy ▫ Metastases dosing is 3 Gy fractions to 45 Gy ▫ Acceptable alternative is 4 Gy fractions to 40 Gy

RTOG Lung Committee • Small Cell Lung Cancer ▫ Limited Stage (Intergroup Trial) ▫ Extensive Stage (RTOG 0937) • Early Stage NSCLC ▫ In-operable ▫ Operable (RTOG 1021 / ACOSOG Z4099) • Locally advanced NSCLC ▫ Stage IIIA/B (Intergroup Trial -0617) ▫ Stage IIIA with minimal N2 disease (0839) ▫ Stage IIIA with PET-adapted boost

Early Ea rly St Stage ge NSC SCLC LC Stereotactic Body Pulmonary Vein Bronchus Radiation Lung Therapy Esophagus Chestwall (SBRT) Cord Skin Physical Targeting

• RTOG 0236 trial for medically inoperable ▫ Very high tumor control (similar to surgery)(94%) ▫ 56% 3-year survival • SBRT has become a standard of care for medically inoperable patients ▫ Up to 10,000 patients per year in US • RTOG 0236 has become a model for expansion of oligofractionated ablative radiotherapy

RTOG 0236: Local Control 100 100 / / / / / / / / / / // / / / / / / / / / / / / / /// / / / 36 month local control = 98% (CI: 84-100%) Local Control (%) 75 75 50 50 1 failure within PTV, 1 within same lobe 25 25 Fail: 1 Total: 55 0 0 0 0 6 6 12 12 18 18 24 24 30 30 36 36 Months after Start of SBRT Patients at Risk 55 54 47 46 39 34 23 Timmerman et al. : JAMA 2010

RTOG: 0236 Disseminated Recurrence • 6 patients (11%) disseminated within 1 year of Rx 100 100 Disseminated Recurrence (%) Fail: 11 75 75 Total: 55 50 50 36 month disseminated recurrence = 22% (CI: 12-38%) 25 25 / / / / / / / / / / / / / / / / / / / / / / / / 0 0 0 0 6 6 12 12 18 18 24 24 30 30 36 36 Months after Start of SBRT Patients at Risk 55 51 44 43 38 33 21 Timmerman et al .JAMA 2010

Overall Survival • Median survival is 48.1 months 100 100 Overall Survival (%) 75 75 / 36 month / / / / / / overall survival = 56% (CI: 42-68%) 50 50 Dead: 26 25 25 Total: 55 MST: 48.1 (95% CI): (29.6, not reached) 0 0 0 0 6 6 12 12 18 18 24 24 30 30 36 36 Months after Start of SBRT Patients at Risk 55 54 47 46 40 35 24

0236 Severe Toxicity • No grade 5 toxicities (treatment deaths) • Two (4%) grade 4 protocol specified toxicity (decline in PFTs to <25% predicted & hypocalcemia) • Seven (13%) grade 3 protocol specified toxicities

Rough Comparisons Treatment Patient Local 3-year Category Control Overall Survival Lobectomy/Pneumonectomy Standard risk 95+% 75-90% operable Sublobar resection Standard risk 75-95% 61-90% operable Sublobar resection High risk 75-95% 60-80% operable Sublobar+brachytherapy High risk 90-95% 65-80% operable SBRT High risk 90-95%* ?? but likely at operable least 55% SBRT Medically 90-95%* 55% inoperable

RTOG 0618 • Small pilot study in operable patients (N=33) • Primary objective = 2 year local control, secondary objectives survival and toxicity • Target local control = 90% (similar to lobectomy) justifying treatment dose • Initial analysis planned for 2012

Physical Targeting with SBRT RTOG 0813 Phase I/II study of SBRT for early stage centrally located NSCLC in medically inoperable pts Physical Targeting: Current & Planned Trials

0813 - SBRT Dose Levels Level 5 10 Gy x 5 50 Gy Level 6 10.5 Gy x 5 52.5 Gy Level 7 11 Gy x 5 55 Gy Level 8 11.5 Gy x 5 57.5 Gy Level 9 12 Gy x 5 60 Gy

RTOG 0915-SBRT for early stage medically inoperable lung cancer PI: Videtic R R a Primary Endpoint 34 Gy X 1 e n > grade 3 rates of Toxicity g Respiratory d Soft tissue/chest wall VS. i Skin o s m t 12 Gy x 4 Secondary Endpoints i 12 Gy X 4 e LC/OS/DFS z PET response r e PFTs Biomarkers

RTOG SBRT Plan • Medically Inoperable Early Stage NSCLC SBRT (18 Gy X 3) Randomize III Altered Fx SBRT SBRT 34 Gy X 1 Randomize II RTOG 0915 SBRT 12Gy X4 Physical Targeting: Future Plans

ROSEL: Radiosurgery or Surgery for operable stage I NSCLC Netherlands Trial PI: Suresh Senan, MD CLOSED!!! Failed to accrue

Cyberknife Trial (STARS) • Randomized trial comparing surgery (lobectomy) to SBRT for Stage I NSCLC • SBRT dose: 12.5 Gy x 4 fractions • Cyberknife users only • Multi-institutional • PI: Jack Roth, M.D • Lobectomy candidates

ACOSOG Z4099/ RTOG 1021 Hiran C. Fernando, MD (ACOSOG); Robert Timmerman, MD (RTOG ) ARM 1: Sublobar Histological F Resection ± confirmed O Brachytherapy Stage I L (SR) Registration NSCLC L and O Randomization High-risk W ARM 2: Stereotactic U Body P Radiation Therapy (SBRT) 18 Gy Activated May 2011 X 3 = 54 Gy

ACOSOG Z4099/ RTOG 1021 • 400+ patient randomized trial ▫ Enrolled in 4-5 years (8 patient/month) • Primary endpoint is 3 year overall survival • Randomize prior to treatment ▫ Intent to treat ▫ +/- brachytherapy is optional in surgery arm • CTC Version 4 toxicity assessment for both arms

Realities • Trials in average risk patients have struggled to accrue ▫ Surgeons are uncomfortable ▫ Strategy: high risk operable patients only • Patients struggle with a surgical vs. non-invasive randomization ▫ Use less ‘radical’ option ( sublobar anatomical, wedges) ▫ Can be done through a scope • Now is the time to do this trial! ▫ SBRT momentum for off-protocol therapy will increase

SBRT Workshops • Held at next few RTOG Semi-annual meetings • Experts: ▫ Timmerman (PI) ▫ Galvin (RTOG medical physics) ▫ Straube and Bosch (ATC) ▫ Dosimitrist • Participants: ▫ Targeted radiation oncologists and physicists • Agenda ▫ How to become credentialed ▫ Plan cases to meet RTOG constraints Organized by Betty O’Meara at RTOG

RTOG Lung Cancer Strategy • Small Cell Lung Cancer ▫ Limited Stage ▫ Extensive Stage • Early Stage NSCLC ▫ In-operable ▫ Operable • Locally advanced NSCLC ▫ Stage IIIA/B ▫ Stage IIIA with minimal disease ▫ Stage IIIA with PET-adapted boost

Molecular Targeting with Chemoradiation and Surgery Trimodality Therapy for Stage IIIA Minimal N2 Dz. RTOG 0229 NSCLC IIIA CBDCA AUC =2.0 Paclitaxel 50 mg/m2 XRT 61.2 Gy (1.8 Gy/d) Y Resectable N • Anatomic lobectomy or CBDCA AUC=6 pneumonectomy Paclitaxel 225 mg/m 2 • Muscle flap for bronchial x 2 cycles stump Pathological mediastinal nodal clearance rate = 63% ASTRO 2010: Mohan et al.

RTOG 0229: Patient Eligibility • Pathologically proven IIIA or IIIB (N3 excluding SCLV) NSCLC • Must be considered potential surgical candidate prior to therapy • Mediastinal LN must be assessed with biopsy proven N2 or N3 • Zubrod 0-1 • Projected post op FEV 1 at least 800 cc based on FEV 1 = FEV1 X % perfusion to uninvolved lung from quant V/Q scan