RTOG1106: Randomized Phase IIR Trial
of Personalized Adaptive Radiotherapy
Based on Mid-treatment FDG-PET in
Locally Advanced NSCLC
P.I.: Feng-Ming (Spring) Kong, M.D., Ph.D.
Study Team
Mitchell Machtay, M.D.
Jeffrey D. Bradley, M.D.
Jean Moran, Ph.D.
Vera Hirsh, M.D.
Barry Siegel, M.D.
RTOG 1106/ACRINxxxx
Inoperable
Stage II/III
NSCLC
(FDGPET/CT
staged)
FDG
PET/
CT
based
RT
plan
to 74
Gy
ED2
R
A
N
D
O
M
I
Z
E
*
A: Chemo-RT
50 Gy/25fx
(ED2^=50 Gy)
A: Continue Chemo-RT
to 74 Gy ED2 /37 fxs
or MLD of 20 Gy
RTOG
0617
arm:
Standard
dose
script
B: Use FDG-PET for
adaptive Chemo-RT:
To MLD 20 Gy in 2.43.5 Gy/fx for 10 fxs to a
maximum of 100 Gy
ED2 /30 fxs
Study
arm:
Individual
adaptive
RT
FDG- PET/CT at
40-50 Gy for all pts
B: Chemo-RT
48 Gy/20fx
(ED2^=50 Gy)
F-Miso or FLT PET for Selected Institutions
Estimated Sample size: ~120 patients
(85% power to detect 20% difference in 2-yr. local PFS)
Background - 1
The Traditional Approach
CT
1-3 months
PET
Treatment including
Radiation Therapy
Weeks to months
post-treatment
outcome
Months to years
ACRIN 6668/RTOG 0235: FDG-PET
2-3 months after XRT
R
Eligibility E
G
Stage III
I
NSCLC plan
S
for conc.
T
chemo-RT
E
PS 0-1
R
FDGPET with
SUV
Sample Size: 250
Chemo-RT +/‘adjuvant’
chemo
FDGPET with
SUV
Primary Endpoint: Survival as a
function of post-RT SUV
ACRIN 6668/RTOG 0235 Update
Activation Date: 3/1/2005.
Closed to Accrual: 5/15/2009.
Total Accrual: 251 pts.
 236 verified eligible (94%).
Total # Participating Sites: 37.
Central Review in Process.
 Qualitative, SUVpeak, MTV
Primary Outcome Analysis in Early/mid 2011.
RTOG 0515 Results
Exploratory trial of pre-Tx FDG-PET for XRT planning
N=47
Variable
CT Only
PET/CT Difference
p
Mean GTV (cc)
98.7
86.2
-12.5%
<0.0001
Mean # involved
nodes
2.1
2.4
14%
0.41
Mean Lung dose
(Gy)
19 Gy
17.8 Gy
-6%
0.06
Mean esophageal
dose (Gy)
28.7 Gy
27.1 Gy
-6%
0.30
Bradley et al. ASTRO 2009
Hypotheses
Use of mid-treatment FDG-PET is as useful or
more useful than pre-RT FDG-PET and/or 3month post-RT PET.
Mid treatment PET can be used to
individualize (and escalate) XRT dose will
result in improved outcomes (2-yr. LPFS)
compared with standard XRT.
When should PET be done?
The Traditional Approach
CT
1-3 months
PET
•Post-RT PET response is highly
correlated with
pathologic
Treatment
including
post-treatment
response.
Radiation Therapy
outcome
•Post-RT PET is predictive of long
term survival and pattern of failure
(Mac Manus et al, 2003)
RTOG235/Acrin688 results awaited.
However, post-RT
Weeks
PETtotumor
months
response
Months
doestonot
years
provide
an opportunity to change the treatment plan.
PET during RT?
PET scan can be performed during-RT




University of Michigan study, ASTRO 2005
MAASTRO study, ASTRO 2005
Stanford study, ASTRO 2007
Princess Margaret Hospital, ASTRO 2008
UM has demonstrated that PET response at 45 Gy
during-RT was highly correlated with post-RT response
in a small pilot study.
The above finding has been recently validated in
another 50+ patients from Michigan.
Kong et al, JCO, 2007
Individualized RT Escalation Is Feasible
Michigan trial usees PET-MTV guided isotoxicity
adaptive plan to escalate tumor dose:
 30 daily treatments, 2.2-3.8 Gy per fraction, 66 Gy~85.5 Gy
 To NTCP of 17% (mean lung dose 20 Gy), with concurrent and
adjuvant carbo and taxol, maximum at102 Gy in 2 Gy
equivalent dose for lung (=ED2) (92 Gy ED2 for tumor).
14 patients completed treatments per study, all patients
treated >74 Gy ED2 (median=92 Gy for tumor),
majority of them received the maximum dose.
6 patients followed up for 1.5 years, no local failure thus
far, 2 brain mets, only 1 death thus far from GI
bleeding (gastric and esophageal ulcers).
Tumor Response During-RT
Pre- RT
Tumor
Tumor
Heart
During-RT at 45 Gy Tumor
Heart
Example-1
Tumor
CT-lunGwindow
CT-mediastinum window
FDGPET
UM002
Pre-RT
GTV: 468 cm3
MTV: 353 cm3
During-RT
GTV: 402 cm3
MTV: 268 cm3
3 mo post
GTV: 174 cm3
Patient-2
MTV: 12 cm3
This 48 YO male
received 85.5 Gy
(120 Gy BED) had
grade 0 clinical
toxicity thus far.
He works full time
now with heavy duty.
9 mo post
16 mo post
FDG Activity & PET-MTV Reduction
PET results during RT correlates well with post-RT results
Change in PET-MTV
22
20
18
16
14
12
10
8
6
4
2
0
PET-MTV (cc)
NMTA
NMTA-max Change
400
360
320
280
240
200
160
120
80
40
0
Pre-RT
Pre-RT
During-RT
Post-RT
During-RT
Post-RT
PET-MTV Decreased More than CT-GTV
CT
PET
50 pts 88 tumors
During-RT
Pre-RT
During-RT
Mid-course FDG-PET and PFS
1 Year Progression-Free Survival
(Kong et al, ASTRO 2009)
Mid-course FDG-PET and Survival
Local Progression Free Survival
Overall Survival
NSUV During-RT < 3.0
NSUV During-RT < 3.0
NSUV During-RT > 3.0
NSUV During-RT > 3.0
NSUV=tumor SUVmax/Aorta SUVmean.
(Kong et al, ASTRO 2009)
Proposed RTOG/ACRIN Trial
Followup to ACRIN 6668/RTOG 0235.
FDG-PET during RT
Validate UM results
Study adaptive RT/dose escalation
Randomization to assess the efficacy of
mid-treatment FDG-PET
Opportunity to study a novel tracer (e.g.
F-Miso) in limited institution sub-study.
RTOG 1106/ACRINxxxx
Inoperable
Stage II/III
NSCLC
(FDGPET/CT
staged)
FDG
PET/
CT
based
RT
plan
to 74
Gy
ED2
R
A
N
D
O
M
I
Z
E
*
A: Chemo-RT
50 Gy/25fx
(ED2=50 Gy)
A: Continue Chemo-RT
to 74 Gy ED2 /37 fxs
or MLD of 20 Gy
RTOG
0617
arm:
Standard
dose
script
B: Use FDG-PET for
adaptive Chemo-RT:
To MLD 20 Gy in 2.43.5 Gy/fx for 10 fxs to a
maximum of 100 Gy
ED2 /30 fxs
Study
arm:
Individual
adaptive
RT
FDG- PET/CT at
40-50 Gy for all pts
B: Chemo-RT
48 Gy/20fx
(ED2=50 Gy)
F-Miso or FLT PET for Selected Institutions
Estimated Sample size: ~120 patients
(85% power to detect 20% difference in 2-yr. local PFS)
Secondary Aims
To compare toxicity between such a PET image-guided
adaptive dose escalation and conventional RT.
To validate recent findings from a single institution that a
tumor metabolic response during-RT predicts long term
local tumor control, LPFS and overall survival.
To perform a pilot study to assess whether a novel PET
tracer (F-Miso) is more predictive than FDG-PET.
To obtain blood and tissue samples to explore
relationships between imaging findings, biomarkers and
outcomes (both anti-tumor efficacy and toxicity).
FLT versus F-Miso
Which is the ‘better’ exploratory agent?
FLT
Ease of use
√
F-Miso
√
Sensitivity relative to FDG
Specificity relative to FDG
Relevance to Radioresistance
√
√
Other Issues Still to be Resolved
ACRIN Co-PI TBA.
Radiotherapy Fractionation issues.
Randomization, stratification issues.
Sample size for FLT/FMISO sub-study.
Insurance company reimbursement for
mid course PET.
Backup