Slide 1
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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Slide 4
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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Slide 7
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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Slide 10 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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Slide 13
• 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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Slide 16
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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Slide 19 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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Slide 22 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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Slide 25 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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Slide 28 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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Slide 31
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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Slide 34 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
% Alive (95% Cl) # at Risk
Mediastinal Nodal
Clearance
% Alive (95% Cl) # at Risk
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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Slide 37
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
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
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Slide 40 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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Slide 43
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
Worst non-hematologic6
(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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Slide 46 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-hematologic1
(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
Worst non-hematologic1
(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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Slide 49 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
Pre-RT During-RT Post-RT
CT
-GT
V (
cc)
020406080
100120140160180200
PE
T-M
TV
(%
)
Pre-RT During-RT Post-RT
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
Pre-RT During-RT Post-RT
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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Slide 52
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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Slide 55 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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