RTOG Lung Committee RTOG Lung Cancer …e-syllabus.gotoper.com/_media/files/lcc2011/31 Bradley LCC...

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

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Slide 2 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)

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Slide 3 Monthly RTOG Lung Accrual

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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

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Slide 5

CDDPVP-16

CDDPVP-16

CDDPVP-16

CDDPVP-16

70 Gy Gy, 2.0 Gy QD

61.2 Gy, 1.8 Gy QD FB Con bst

CDDPVP-16

CDDPVP-16

CDDPVP-16

CDDPVP-16

PCI

45 Gy 1.5 Gy BID

CDDPVP-16

CDDPVP-16

CDDPVP-16

CDDPVP-16

R

A

N

D

O

M

I

Z

E

RTOG 0538 / CALGB 30610

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Slide 6 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

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Study Design

PCI

20-30 Gy in

5-12 fractions

No PCI

RandomAny response

Stratification: Performance score and Institute

< 5 weeks

4-6 weeks

No responseChemotherapy

(4-6 cycles)

Prophylactic cranial irradiation in

extensive disease small cell lung cancer

(EORTC 08993-22993)Slotman et al. NEJM 2007

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Slide 8

(months)

0 4 8 12 16 20 24 28 32 36

0

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

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Slide 9

Study Design

PCI

25 Gy in 10 fx

IF RT

Chest and

Other Sites

RandomAny responseChemotherapy

(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

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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

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Slide 11 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

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Slide 12

Stereotactic

Body

Radiation

Therapy

(SBRT)

Pulmonary VeinBronchus

Esophagus

Cord Skin

Chestwall

Lung

Physical Targeting

Early Stage NSCLC

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• 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

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Slide 14 RTOG 0236: Local Control

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

Timmerman et al. : JAMA 2010

1 failure within PTV, 1 within same lobe

Local C

ontr

ol (%

)

0

25

50

75

100

Months after Start of SBRT0 6 12 18 24 30 36

0

25

50

75

100

0 6 12 18 24 30 36

Patientsat Risk 55 54 47 46 39 34 23

Fail: 1Total: 55

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

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Slide 15 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

Dis

sem

inate

d R

ecurr

ence (

%)

0

25

50

75

100

Months after Start of SBRT0 6 12 18 24 30 36

0

25

50

75

100

0 6 12 18 24 30 36

Patientsat Risk 55 51 44 43 38 33 21

Fail: 11Total: 55

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

/ // //

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Ove

rall S

urv

iva

l (%

)

0

25

50

75

100

Months after Start of SBRT

0 6 12 18 24 30 360

25

50

75

100

0 6 12 18 24 30 36

Patientsat Risk 55 54 47 46 40 35 24

Dead: 26Total: 55

MST: 48.1(95% CI): (29.6, not reached)

/// / / //

Overall Survival

36 monthoverall survival = 56% (CI: 42-68%)

• Median survival is 48.1 months

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Slide 17 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

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Slide 18

Treatment Patient Category

Local Control

3-year OverallSurvival

Lobectomy/Pneumonectomy Standard riskoperable

95+% 75-90%

Sublobar resection Standard riskoperable

75-95% 61-90%

Sublobar resection High riskoperable

75-95% 60-80%

Sublobar+brachytherapy High riskoperable

90-95% 65-80%

SBRT High riskoperable

90-95%* ?? but likely at least 55%

SBRT Medicallyinoperable

90-95%* 55%

Rough Comparisons

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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

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Slide 20 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

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Slide 21

0813 - SBRT Dose Levels

Level 5 10 Gy x 5 50 GyLevel 6 10.5 Gy x 5 52.5 GyLevel 7 11 Gy x 5 55 GyLevel 8 11.5 Gy x 5 57.5 GyLevel 9 12 Gy x 5 60 Gy

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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 ToxicityRespiratory

Soft tissue/chest wall

Skin

Secondary Endpoints

LC/OS/DFS

PET response

PFTs

Biomarkers

R

a

n

d

o

m

i

z

e

VS.

PI: Videtic

12 Gy X 4

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Slide 23

• 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

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Slide 24 ROSEL: Radiosurgery or Surgery for

operable stage I NSCLC

Netherlands Trial

PI: Suresh Senan, MD

CLOSED!!! Failed to accrue

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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

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Slide 26

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

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Slide 27 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

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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

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Slide 29 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

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Slide 30 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

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NSCLC IIIA CBDCA AUC =2.0

Paclitaxel 50 mg/m2

XRT 61.2 Gy (1.8 Gy/d)

ResectableY 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.

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Slide 32 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

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Slide 33 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%)

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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

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Slide 35 RTOG 0229 Survival

Time (Months)

Overall Survival

% Alive (95% Cl) # at Risk

Progression-Free Survival

%Alive (95% Cl) # at Risk

0

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)

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Slide 36 Overall Survival by Mediastinal Nodal

Clearance Status (RTOG 0229)

Time (Months)

No Mediastinal Nodal

Clearance


Mediastinal Nodal

Clearance


0

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

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NSCLC IIIA CBDCA AUC =2.0

Paclitaxel 50 mg/m2

XRT 61.2 Gy (1.8 Gy/d)

Panitumumab

ResectableY 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 0839

Molecular Targeting: Future Plans

PI: Martin Edelman, MD

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Slide 38 RTOG 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

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Slide 39 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


Arm C

Concurrent chemotherapy* and

Cetuximab

RT to 60 Gy, 5 x per wk for 6 wks

Arm C


and Cetuximab

Arm D

Concurrent chemotherapy* and

Cetuximab

RT to 74 Gy, 5 x per wk for 7.5 wks

Arm D


and Cetuximab

*Carboplatin and paclitaxel

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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.

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Slide 41 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

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Slide 42 RTOG 0617

Through 04/10/2011

Projected 32420% Projected 65Actual 423

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RTOG 0617

Planned Interim Analysis

No difference in toxicity between arms

No patient safety concerns

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Slide 44 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 overall survival benefit

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

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Slide 45 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-hematologic12

(13%)

37

(41%)

32

(35%)

7

(8%)

1

(1%)

8

(10%)

30

(37%)

31

(38%)

8

(10%)

1

(1%)

Worst overall3

(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


(9%)

29

(41%)

27

(38%)

7

(10%)

1

(1%)

9

(13%)

27

(38%)

24

(34%)

7

(10%)

0

(0%)

Worst overall2

(3%)

19

(27%)

29

(41%)

19

(27%)

1

(1%)

6

(9%)

20

(28%)

26

(37%)

15

(21%)

0

(0%)

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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


(1%)

24

(32%)

38

(51%)

5

(7%)

2

(3%)

1

(2%)

17

(25%)

34

(51%)

5

(8%)

6

(9%)

Worst overall1

(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


(2%)

19

(33%)

30

(53%)

3

(5%)

2

(4%)

1

(2%)

19

(32%)

27

(45%)

3

(5%)

6

(10%)

Worst overall1

(2%)

11

(19%)

28

(49%)

13

(23%)

2

(4%)

1

(2%)

9

(15%)

28

(47%)

12

(20%)

6

(10%)

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Slide 47 RTOG 0617

Next plans

Two 74 Gy arms are closed to accrual

60 Gy arms +/- Cetuximab are still open to accrual

Analysis ongoing

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Slide 48 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

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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

or

unresectable

Stage III

NSCLC

(FDG-

PET/CT

staged)

1: Continue conc.

chem-RT to a total of

74 Gy ED2 /37 fxs

or 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

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Slide 50 Tumor Volume Reduced During-RT

(UMCC 2003-76, UMCC 2006-040)Change in PET-MTV

04080

120160200240280320360400

Pre-RT During-RT Post-RT

PE

T-M

TV

(cc)

Change in CT-GTV

0

50

100

150

200

250

300

350

400

450

500


CT

-GT

V (

cc)

020406080

100120140160180200

PE

T-M

TV

(%

)


Change in PET-MTV based on Pre-RT Change in CT-GTV based on Pre-RT

0

25

50

75

100

125

150

175

200

225

250


CT

-GT

V (

%)

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Slide 51 Preliminary Results Arm B

RT Dose >70 Gy NID2

RT Dose <70 Gy NID2

(n=9)

(n=9)

Kong. University of Michigan

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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

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Slide 53

During-RT PET-CT based plan:

17.2% NTCP- 86 Gy tumor

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

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Slide 54

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

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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

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RTOG Lung Committee RTOG Lung Cancer …e-syllabus.gotoper.com/_media/files/lcc2011/31 Bradley LCC...

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Transcript of RTOG Lung Committee RTOG Lung Cancer …e-syllabus.gotoper.com/_media/files/lcc2011/31 Bradley LCC...