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

CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16 70 Gy Gy, 2.0 Gy QD 61.2 Gy, 1.8 Gy QD FB Con bst CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16

PCI

45 Gy 1.5 Gy BID CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16

R A N D O M I Z E

RTOG 0538 / CALGB 30610

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

Study Design

PCI 20-30 Gy in 5-12 fractions No PCI Random Any response Stratification: Performance score and Institute

< 5 weeks 4-6 weeks

No response

Chemotherapy (4-6 cycles)

Prophylactic cranial irradiation in extensive disease small cell lung cancer (EORTC 08993-22993)

Slotman et al. NEJM 2007

(months) 4 8 12 16 20 24 28 32 36 10 20 30 40 50 60 70 80 90 100

PCI Control 1 year: VS. HR: 0.68 (0.52-0.88) p=0.003

Overall survival Prophylactic cranial irradiation in extensive disease small cell lung cancer

13.3% 27.1% Slotman et al. NEJM 2007

Study Design

PCI 25 Gy in 10 fx IF RT Chest and Other Sites Random Any response

Chemotherapy (4-6 cycles)

Phase II Study of PCI and consolidative Extra-Cranial Radiation for ED-SCLC (RTOG 0937)

Observation PI: Elizabeth Gore, MD Stratify: PR vs CR 1 vs 2-3 mets

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

Stereotactic Body Radiation Therapy (SBRT)

Pulmonary Vein Bronchus Esophagus Cord Skin Chestwall Lung

Physical Targeting

Ea Early rly St Stage ge NSC SCLC LC

• 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
• ligofractionated ablative radiotherapy

RTOG 0236: Local Control

36 month local control = 98% (CI: 84-100%)

Timmerman et al. : JAMA 2010 1 failure within PTV, 1 within same lobe

Local Control (%) 25 50 75 100 Months after Start of SBRT 6 12 18 24 30 36 25 50 75 100 6 12 18 24 30 36 Patients at Risk 55 54 47 46 39 34 23 Fail: 1 Total: 55

/ / / / / / / / / / // / / / / / / / / / / / / / /// / / /

RTOG: 0236 Disseminated Recurrence

36 month disseminated recurrence = 22% (CI: 12-38%)

• 6 patients (11%) disseminated within 1 year of Rx

Timmerman et al .JAMA 2010 Disseminated Recurrence (%) 25 50 75 100 Months after Start of SBRT 6 12 18 24 30 36 25 50 75 100 6 12 18 24 30 36 Patients at Risk 55 51 44 43 38 33 21 Fail: 11 Total: 55

/ / / / / / / / / / / / / / / / / / / / / / / /

Overall Survival (%) 25 50 75 100 Months after Start of SBRT 6 12 18 24 30 36 25 50 75 100 6 12 18 24 30 36 Patients at Risk 55 54 47 46 40 35 24 Dead: 26 Total: 55 MST: 48.1 (95% CI): (29.6, not reached)

/ / / / / / /

Overall Survival

36 month

• verall survival = 56% (CI: 42-68%)
• Median survival is 48.1 months

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

Treatment Patient Category Local Control 3-year Overall Survival

Lobectomy/Pneumonectomy Standard risk

• perable

95+% 75-90% Sublobar resection Standard risk

• perable

75-95% 61-90% Sublobar resection High risk

• perable

75-95% 60-80% Sublobar+brachytherapy High risk

• perable

90-95% 65-80% SBRT High risk

• perable

90-95%* ?? but likely at least 55% SBRT Medically inoperable 90-95%* 55%

Rough Comparisons

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

Physical Targeting: Current & Planned Trials

RTOG 0813

Phase I/II study of SBRT for early stage centrally located NSCLC in medically inoperable pts

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

12 Gy x 4 R e g i s t e r 34 Gy X 1

Primary Endpoint > grade 3 rates of Toxicity

Respiratory Soft tissue/chest wall Skin

Secondary Endpoints LC/OS/DFS PET response PFTs Biomarkers

R a n d

• m

i z e

VS.

PI: Videtic 12 Gy X 4

• Medically Inoperable Early Stage NSCLC

RTOG SBRT Plan

Physical Targeting: Future Plans

Randomize III SBRT 34 Gy X 1 SBRT 12Gy X4 SBRT (18 Gy X 3) Altered Fx SBRT Randomize II RTOG 0915

ROSEL: Radiosurgery or Surgery for

• perable 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

Histological confirmed Stage I NSCLC High-risk Registration and Randomization ARM 1: Sublobar Resection ± Brachytherapy (SR) ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy F O L L O W U P

ACOSOG Z4099/ RTOG 1021

Hiran C. Fernando, MD (ACOSOG); Robert Timmerman, MD (RTOG)

Activated May 2011

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

NSCLC IIIA

CBDCA AUC =2.0 Paclitaxel 50 mg/m2 XRT 61.2 Gy (1.8 Gy/d)

Resectable

Y N

• Anatomic lobectomy or

pneumonectomy

• Muscle flap for bronchial

stump

CBDCA AUC=6 Paclitaxel 225 mg/m2 x 2 cycles

Molecular Targeting with Chemoradiation and Surgery Trimodality Therapy for Stage IIIA Minimal N2 Dz.

RTOG 0229

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
• r 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

Tumor Characteristics

(n=57) Histology

Squamous Cell Carcinoma 11 (19.3%) Adenocarcinoma 29 (50.9%) Large cell undifferentiated 1 ( 1.8%) NSCLC, NOS 16 (28.1%)

AJCC Stage

IIIA 56 (98.2%) IIIB 1 ( 1.8%)

T-Stage

T1 18 (31.6%) T2 28 (49.1%) T3 11 (19.3%)

N-Stage

N2 56 (98.2%) N3 1 ( 1.8%)

0229 Mediastinal Nodal Clearance

Residual Mediastinal Disease Mediastinal nodal clearance

Patients Eligible for Assessment of Primary Endpoint Surgery Performed Reasons for No Surgery Residual Mediastinal Nodes Primary Unresectable Medical contraindications MD refusal Died prior to Surgery Progressive disease Other

(N=43*) 16 (37%) 27 (63%)

43 Pts 37 pts 20 pts 6 pts 2 pts 5 pts 1 pt 1 pt 1 pt 4 pts

RTOG 0229 Survival

Time (Months) Overall Survival % Alive (95% Cl) # at Risk Progression-Free Survival %Alive (95% Cl) # at Risk

6 12 18 24 100% 57 87.7% (76.0, 93.9) 50 77.2% (64.0, 86.1) 43 66.4% (52.5, 77.1) 37 53.8% (40.0, 65.8) 29 100% 57 75.4% (62.1, 84.7) 43 50.8% (37.2, 62.9) 28 38.1% (25.6, 50.5) 21 32.7% (20.9, 45.0) 17 Fail/Total Median (95% Cl) 32/57 26.6 months (18.5, ∞) 45/57 12.9 months (8.0, 18.8)

Overall Survival by Mediastinal Nodal Clearance Status (RTOG 0229)

Time (Months)

No Mediastinal Nodal Clearance

% Alive (95% Cl) # at Risk

Mediastinal Nodal Clearance

% Alive (95% Cl) # at Risk

6 12 18 24 100 % 16 87.5% (58.6, 96.7) 14 81.3% (52.5, 93.5) 12 60.9% (32.7, 80.3) 9 54.2% (27.1, 75.0) 8 100% 27 100% 27 92.6% (73.5, 98.1) 25 81.5% (61.1, 91.8) 22 66.7% (45.7, 81.1) 17 Fail/Total Median Survival Time (95% Cl) 8/16 32.7 months (13.8, ∞) 12/27 Not Reached

NSCLC IIIA

CBDCA AUC =2.0 Paclitaxel 50 mg/m2 XRT 61.2 Gy (1.8 Gy/d) Panitumumab

Resectable

Y N

• Anatomic lobectomy or

pneumonectomy

• Muscle flap for bronchial

stump

CBDCA AUC=6 Paclitaxel 225 mg/m2 x 2 cycles Tissue: MALDI-TOF Specimens for proteomic analysis & other correlative studies Resection: MALDI-TOF & other specimens

Molecular Targeting with Trimodality Therapy RTOG OG 08 0839 39

Molecular Targeting: Future Plans

PI: Martin Edelman, MD

RTOG OG 0617 0617

A Randomized Phase III Comparison of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab (IND #103444) In Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer

Schema

S T R A T I F Y RT Technique 1.3D-CRT 2.IMRT Zubrod 1.0 2.1 PET Staging 1.No 2.Yes Histology 1.Squamous 2.Non- Squamous R A N D O M I Z E Concurrent Treatment Consolidation Treatment Arm A Concurrent chemotherapy* RT to 60 Gy, 5 x per wk for 6 wks Arm A Consolidation chemotherapy* Arm B Concurrent chemotherapy* RT to 74 Gy, 5 x per wk for 7.5 wks Arm B Consolidation chemotherapy* Arm C Concurrent chemotherapy* and Cetuximab RT to 60 Gy, 5 x per wk for 6 wks Arm C Consolidation chemotherapy* and Cetuximab Arm D Concurrent chemotherapy* and Cetuximab RT to 74 Gy, 5 x per wk for 7.5 wks Arm D Consolidation chemotherapy* and Cetuximab

*Carboplatin and paclitaxel

Primary Objective

• To compare the overall survival of patients

treated with high-dose versus standard-dose conformal radiation therapy in the setting of concurrent chemotherapy.

• To compare the overall survival of patients

treated with cetuximab versus without cetuximab in the setting of concurrent chemotherapy.

RTOG 0617

Date opened November 2007 Targeted accrual 500 Projected monthly accrual 9 Total entered through 04/10/11 426 Monthly accrual 10.5 Projected completion November 2011 Monthly accrual (last 6 months) 15.0 Projected completion September 2011

RTOG 0617

Through 04/10/2011

Projected 324 20% Projected 65 Actual 423

RTOG 0617 Planned Interim Analysis

No difference in toxicity between arms No patient safety concerns

RTOG 0617 Planned Interim Analysis

Efficacy analysis reveals that we have crossed a futility threshold for the high dose question High-dose radiation (74 Gy) will not result in an

• verall survival benefit

The question of whether or not cetuximab confers a survival benefit remains important

RTOG 0617

Definitely, Probably, or Possibly Related to Treatment (Using CTCAE Version 3.0)

Arm A: 60 Gy Arm B: 74 Gy June 2011 (n=91) Grade (n=82) Grade 1 2 3 4 5 1 2 3 4 5

Worst non-hematologic 12 (13%) 37 (41%) 32 (35%) 7 (8%) 1 (1%) 8 (10%) 30 (37%) 31 (38%) 8 (10%) 1 (1%) Worst overall 3 (3%) 23 (25%) 40 (44%) 22 (24%) 1 (1%) 5 (6%) 23 (28%) 30 (37%) 19 (23%) 1 (1%)

Arm A: 60 Gy Arm B: 74 Gy January 2011 (n=71) Grade (n=71) Grade 1 2 3 4 5 1 2 3 4 5

Worst non-hematologic 6 (9%) 29 (41%) 27 (38%) 7 (10%) 1 (1%) 9 (13%) 27 (38%) 24 (34%) 7 (10%) (0%) Worst overall 2 (3%) 19 (27%) 29 (41%) 19 (27%) 1 (1%) 6 (9%) 20 (28%) 26 (37%) 15 (21%) (0%)

RTOG 0617

Definitely, Probably, or Possibly Related to Treatment (Using CTCAE Version 3.0)

Arm C: 60 Gy + Cetuximab Arm D: 74 Gy + Cetuximab June 2011 (n=75) Grade (n=67) Grade 1 2 3 4 5 1 2 3 4 5

Worst non-hematologic 1 (1%) 24 (32%) 38 (51%) 5 (7%) 2 (3%) 1 (2%) 17 (25%) 34 (51%) 5 (8%) 6 (9%) Worst overall 1 (1%) 12 (16%) 38 (51%) 17 (23%) 2 (3%) 1 (2%) 6 (9%) 31 (46%) 19 (28%) 6 (9%)

Arm C: 60 Gy + Cetuximab Arm D: 74 Gy + Cetuximab January 2011 (n=57) Grade (n=60) Grade 1 2 3 4 5 1 2 3 4 5

Worst non-hematologic 1 (2%) 19 (33%) 30 (53%) 3 (5%) 2 (4%) 1 (2%) 19 (32%) 27 (45%) 3 (5%) 6 (10%) Worst overall 1 (2%) 11 (19%) 28 (49%) 13 (23%) 2 (4%) 1 (2%) 9 (15%) 28 (47%) 12 (20%) 6 (10%)

RTOG 0617 Next plans

Two 74 Gy arms are closed to accrual 60 Gy arms +/- Cetuximab are still open to accrual Analysis ongoing

Thinking newer strategies

• Mid-treatment FDG-PET based target

volumes adapted radiation therapy

• Isoeffect radiation dose prescriptions
• Why?

▫ PET tumor volumes shrink during XRT ▫ May incorporate all Stage III patients, not just those selected to get 74 Gy based on NTCP

RTOG 1106-Multicenter Study

RTOG1106 is going to test the feasibility and efficacy of during-RT PET-MTV based individualized radiation dose escalation in a multicenter setting.

RTOG 0617 high dose arm: Uniform dose prescription

1: Conc. chem- RT 50 Gy/25fx (ED2^=50 Gy) 2: During-RT FDG- PET/CT adaptive chem- RT to MLD 20 Gy $ in 2.4-3.5 Gy/fx for 9-13 fxs to a total of 86 Gy (100 Gy ED2 lung ) /30 fxs R A N D O M I Z E * FDG PET/ CT based RT plan to 74 Gy ED2 Inoperable

• r

unresectable Stage III NSCLC (FDG- PET/CT staged) 1: Continue conc. chem-RT to a total of 74 Gy ED2 /37 fxs

• r MLD of 20 Gy

2: Concurrent chem-RT to ED2^=50 Gy in 17-21 fxs FDG- PET/CT at 40- 50 Gy ED2^ for all pts

F-Miso-PET for Selected Institutions

Experimental arm: Individualized adaptive RT

Tumor Volume Reduced During-RT (UMCC 2003-76, UMCC 2006-040)

Change in PET-MTV 40 80 120 160 200 240 280 320 360 400 Pre-RT During-RT Post-RT PET-MTV (cc) Change in CT-GTV 50 100 150 200 250 300 350 400 450 500 Pre-RT During-RT Post-RT CT-GTV (cc)

20 40 60 80 100 120 140 160 180 200 PET-MTV (%) Pre-RT During-RT Post-RT Change in PET-MTV based on Pre-RT Change in CT-GTV based on Pre-RT 25 50 75 100 125 150 175 200 225 250 Pre-RT During-RT Post-RT CT-GTV (%)

Preliminary Results Arm B

RT Dose >70 Gy NID2 RT Dose <70 Gy NID2

(n=9) (n=9)

• Kong. University of Michigan

During-RT PET-CT adapted composite plan: 17.2% lung NTCP~ 86 Gy to during-RT PET-PTV (102 ED2 lung, ~92 Gy ED2 tumor, ~120 Gy BED for a/b=10). Pre-RT PET-CT based plan: 17.2% lung NTCP~ 70 Gy 9.8% NTCP ~ 50 Gy

Pre-RT

During-RT

During-RT PET-CT based plan: 17.2% NTCP- 86 Gy tumor

Pre-RT PET-CT based plan: 17.2% NTCP, 70 Gy tumor

Pre-RT PET-CT individualized plan: 17.2% NTCP~ 70 Gy to tumor. During-RT PET-CT adapted plan: 17.2% NTCP~ 86 Gy to residual PET-tumor.

B4 tx

RTOG Lung Cancer Strategy

• To further define the role of radiation therapy in small

cell lung cancer

• To further define SBRT in Stage I NSCLC
• To optimize radiation delivery for lung cancer
• To further clarify the role of biological therapy in

combination with radiation therapy

• To establish a rich biomarker database for correlation

with outcome/ toxicity