8/2/2012
Physiological Adaptive Radiotherapy
James Balter
Yue Cao
University of Michigan
No conflicts exist
Background
• While geometric and biological adaptation have
some benefit, individual patients have tumors
and normal tissues that respond differentially to
the same therapy
• Probes that more directly predict the response
of individual patients to treatment may enhance
the benefit of therapy individualization
Examples of physiological probes
• Blood tests
– ICG, TGFB
• Imaging surrogates
–
–
–
–
–
–
Metabolism (FDG)
Perfusion (DCE, MAA)
Ventilation
Diffusion
Diffusion Tensor
Spectroscopy
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8/2/2012
Dose “painting”
• Theory: Tumors have differential responses that can be
spatially mapped
• Adjusting the dose distribution to provide heterogeneity
that relates to the (imaged) distribution of mapped
surrogate markers can improve local control, and
potentially survival
• Challenges:
–
–
–
–
–
Spatial resolution
Signal reproducibility
Sensitivity
Mapping to physical patient
Achieving sufficient differentiation to be biologically relevant
Duprez et al – dose painting by the numbers
• Direct formula relating SUV
to local dose increase
• PET—directed dose
painting performed twice
over the treatment course
• Remaining dose via
“standard” IMRT
Duprez et al (IJROBP 80(4):1045-55,
2011
Duprez et al – dose versus PET intensity
Ihigh – 95% of max on PET
Ilow – 25% of Ihigh
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8/2/2012
Adaptive dose painting - toxicity
• Dose was escalated within GTV safely
• FDG-aided dose painting did not significantly increase toxicity beyond
conventional doses
• No improvement realized on tumor control
Duprez et al (IJROBP 80(4):1045-55, 2011
FDG PET-based dose painting has been
demonstrated, in clinical trials to be:
21%
1. Safer than conventional IMRT
21%
2. More effective than conventional IMRT
20%
19%
19%
3. Practical to deliver, but without published
evidence of improved local control
4. Practical to deliver, but without published
evidence of safety
5. Impractical due to increased toxicity with no
evidence of benefit
Answer: 3.
• Source: Duprez et al. Adaptive Dose Painting By
the Numbers for Head and Neck Cancer. IJROBP
80(4):1045-55, 2011
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8/2/2012
Limited sensitivity of PET
Christian et. al – Simulated PET images from Autoradiographs
- included effects of blurring, voxel sampling
- showed decreased sensitivity of PET image relative to
underlying signals
N Christian et al (Radiother Oncol 81(1):101-6, 2008
Factors that limit PET as a Primary tool
for dose painting include:
18%
19%
21%
22%
20%
1.
2.
3.
4.
5.
Excess radiation dose from imaging
Limited sensitivity
Lack of availability of PET scanners
Cost of imaging
Spatial distortion
Answer: 2.
• Source: N Christian et al. The limitation of PET
imaging for biological adaptive-IMRT assessed in
animal models. Radiother Oncol 91(1):101-6,
2009.
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8/2/2012
Biomarker-based early assessment
• Deliver enough dose to manifest patient-specific
early effects
• Alter decisions for remaining treatment based
on observations:
– Rearrange dose to:
• Lower toxicity risk
• Locally boost non-responding tumor
– Lower/Raise overall dose based on likelihood of
overall response/risk
RTOG 1106
• Based on the observation that FDG-avid regions
of lung tumors shrink
• Initial PTV receives intended dose (up to lung
dose tolerance)
• Boost volume based on FDG-avid volume during
treatment (dose based on screening plan bin)
Spring Kong, UM
Pre-RT
B4 tx
During-RT
Spring Kong, UM
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8/2/2012
RTOG 1106 Schema
PRE-TX FDG-PET/CT (FMISO-PET/CT) IMAGING
SCREENING PLAN
to determine Mean Lung Dose & Tx Dose Bin (74 Gy to 95% PTV)
STRATIFIED RANDOMIZATION (MEAN LUNG DOSE & TUMOR VOLUME)
ARM 1: CONCURRENT CHEMO-RT
RT to 50 Gy (2 Gy/Fx)
Carboplatin/Paclitaxel Weekly
ARM 2: CONCURRENT CHEMO-RT
RT to 47.5-49.5 Gy (variable Gy/Fx)
Carboplatin/Paclitaxel Weekly
DURING-TX FDG-PET/CT IMAGING
ARM 1: CONTINUE RT
Same RT plan to 60 Gy total (30 Fx)
ARM 2: ADAPTIVE RT
Based on during-tx FDG-PET
RT up to 85.5 Gy individualized by MLD
CONSOLIDATIVE CHEMOTHERAPY
Spring Kong, UM
Individualized Dose Prescription
Mean
Lung
Initial
# Fractions
Physical
Adaptive
Phase
Adaptive
Phase
# Fraction
Total
Dose for
Dose
for ~50 Gy
Dose
Max Dose
Physical
for ART
Physical
74 Gy
per fx
EQD2
at this point
per fx
Max Dose
PTV dose
(Gy)
Tumor Dose
(Gy)
(Gy)
(Gy)
(Gy)
(Gy)
<13.5
2.85
17
48.45
2.85
37.05
13
85.5
13.5
2.85
17
48.45
2.85
37.05
13
85.5
13.9
2.80
17
47.6
37.7
13
85.3
14.3
2.75
18
49.5
3
36
12
85.5
14.7
2.70
18
48.6
3.05
36.6
12
85.2
15.1
2.65
18
47.7
3.15
37.8
12
85.5
15.5
2.60
19
49.4
3.25
35.75
11
85.2
16.0
2.55
19
48.45
3.3
36.3
11
84.8
47.5
3.4
37.4
11
84.9
49
3.55
35.5
10
This
is the Rx
for Arm
2–
16.5
2.50
19
Initial
17.0
2.45 Plan 20
2.9
Max Dose
84.5
17.6
2.40
20
48
3.65
36.5
10
84.5
18.1
2.35
21
49.35
3.85
34.65
9
84.0
18.7
2.30
21
48.3
3.9
35.1
9
19.3
2.25
22
49.5
4.15
33.2
8
82.7
20.0
2.20
22
48.4
4.25
34
8
82.4
Spring Kong,
>20 UM 2.20
22
48.4
4.25
34
8
82.4
83.4
Individualized Dose Prescription
Mean
Lung
Initial
# Fractions
Physical
Adaptive
Phase
Adaptive
Phase
# Fraction
Total
Dose for
Dose
for ~50 Gy
Dose
Max Dose
Physical
for ART
Physical
74 Gy
per fx
EQD2
at this point
per fx
Max Dose
PTV dose
(Gy)
Tumor Dose
(Gy)
(Gy)
(Gy)
(Gy)
(Gy)
<13.5
2.85
17
48.45
2.85
37.05
13
85.5
13.5
2.85
17
48.45
2.85
37.05
13
85.5
13.9
2.80
17
47.6
14.3
2.75
18
49.5
14.7
2.70
18
48.6
15.1
2.65
18
15.5
2.60
19
49.4
16.0
2.55
19
48.45
This
is the Rx
for Arm
2–
16.5
2.50
19
Initial
17.0
2.45 Plan 20
47.7
Max Dose
This
Max Dose
2.9 is the37.7
13 Rx for
85.3Arm 2 –
3
36
12 Plan 85.5
Adaptive
3.05
36.6
12
85.2
Dose/Fx
should
be reduced
3.15
37.8
12
85.5
until
objectives
are accepable
3.25 OAR
35.75
11
85.2
3.3
36.3
11
84.8
47.5
3.4
37.4
11
84.9
49
3.55
35.5
10
84.5
17.6
2.40
20
48
3.65
36.5
10
84.5
18.1
2.35
21
49.35
3.85
34.65
9
84.0
18.7
2.30
21
48.3
3.9
35.1
9
19.3
2.25
22
49.5
4.15
33.2
8
82.7
20.0
2.20
22
48.4
4.25
34
8
82.4
Spring Kong,
>20 UM 2.20
22
48.4
4.25
34
8
82.4
83.4
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8/2/2012
Treatment Targets for Arm 2
30 daily fractions, 2.2-4.25 Gy daily fractions
CT1GTV
EX1GTV
CT2PTV
CT1CTV
CT2GTV
CT1PTV
PET2MTV
IN1GTV
PET2PTV
PET1MTV
2.2-2.85 Gy/Fx
Targets for the 1st plan
CT1GTV = EX1GTV + IN1GTV + PET1MTV
CT1CTV = CT1GTV + 0.5 cm
CT1CTV = CT1GTV + at least 0.5 cm
2.4-4.25 Gy/Fx
Targets for adaptive plan
PET2PTV = PET2MTV + 0.5 cm
Spring Kong, UM
Adaptive Plan Targets
CT2PTV (>70 Gy Composite)
Spring Kong, UM
DurPTV (Adaptive Rx)
Persistent Low Blood Volume as a boost volume for HNC?
•Prognostic Values of Pre Tx tumor BV and perfusion
•Outcome from RT (Hermans 1997 & 2003)
•Response to induction chemotherapy (Zima 2007)
•Better perfused HNC better response to CT & RT
17mL/100g
Regions of persistent
low blood volume
within initial PTV may
present a target for
integrated boost
Primary
TV
Pre RT
2 weeks after the start
of RT
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8/2/2012
High Cerebral Blood Volume (CBV) in High-Grade
Gliomas – local boost volume?
fTV w High-CBV <0.07
P=0.002
fTV w High-CBV >0.07
(month)
Cao, IJROPB, 2006
Early CBV Changes During RT
Pt A
Decrease
Better OS
Pt B
Little Change
Worse OS
Pre RT
Week 3
Y Cao, UM
TBV change predictive of LF
Cao et al IJROBP 72(5):1287-90, 2008
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8/2/2012
Normal tissue sparing
• Ventilation/perfusion for assessing normal lung
function distribution for treatment
planning/adaptation
• Perfusion for liver toxicity prediction/dose
modification
Pre-treatment:
RT planning with functional lung sparing
based on perfusion SPECT
SM McGuire et al IJROBP 66(5):1543-52, 2006
Liver adaptive radiotherapy
• RILD (liver toxicity) includes venous occlusion as
a noted symptom
• Dynamic contrast-enhanced (DCE) imaging and
analysis of venous perfusion has been
hypothesized as a mechanism for customizing
treatment to limit toxicity while maximizing
tumor dose
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8/2/2012
DCE MRI and CT - Early Assessment of Venous perfusion
changes as a predictor of local damage
170 ml/100g/min
40Gy
30Gy
20Gy
10Gy
0 ml/100g/min
Prior to RT
Cao Y et al , Medical Physics 2007
After 45 Gy
30 fx of 1.5 Gy/fx twice daily
DCE CT study - Methods
• Eleven patients with unresectable intrahepatic cancer
– 1 with hepatocellular carcinoma, 5 with cholangiocarcinoma, and 5
with colorectal carcinoma metastatic to the liver
• 3D conformal RT
– 1.5 Gy/fraction b.i.d.
– Median dose 67.5 Gy (range 48–78 Gy)
– Concurrent continuous infusion hepatic artery floxuridine (FUdR) as a
radiation sensitizer for the first 4 weeks of RT
• CT Liver perfusion protocol
– Pre RT, after 15 and 30 Fx, and 1 month after RT
• Overall liver function assessment
– indocyanine extraction
– Pre RT, after 15 and 30 Fx, and 1 month after RT
Results: Individual Perfusion Dose
Response
160
y = -0.0276x + 163.5
R2 = 0.91
140
120
100
80
60
40
20
Fp 1 month after RT
Fp 1 month after RT
160
140
120
100
80
60
40
y = -0.0423x + 229.7
R2 = 0.85
20
0
0
0
1000
2000
3000
4000
5000
6000
dos e at the e nd of RT (cGy)
7000
0
1000
2000
3000
4000
5000
6000
dose at the end of RT (cGy)
Slope: reduction in perfusion caused by every Gy
Intercept with x axis: critical dose resulting in undetectable venous
perfusion
Cao, Int J Rad Onc Biol Phys, 2007
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8/2/2012
Evaluation of Overall Liver Function
Indocyanine green: Independent measure of overall liver function
r = 0.7
p <0.001
31
160
140
y = -21.3x + 233.9
R2 = 0.89
120
100
P<0.001
80
60
40
20
0
mean D at the end of RT
m e an F p p os t R T (F p>20)
Results: Correlation of venous perfusion
with Overall Liver Function
5000
y = -88.7x + 4291.4
R2 = 0.10
4500
4000
3500
3000
2500
2000
2
2
4
6
8
T1/2 ICG post RT
10
12
4
6
8
10
12
T1/2 ICG post RT
The mean perfusion in the functional liver volume, but not
the mean liver dose, correlates with the half life time of ICG clearance.
Normal liver sparing based on DCE
perfusion is based on the premise that
23%
1. Venous occlusion is a symptom of RILD
21%
2. DCE imaging is easy to perform in the liver
18%
21%
18%
3. Hypervascularity is a symptom of radiation
injury
4. No other imaging seems to work
5. The biological model of radiation dose versus
perfusion damage has been thoroughly tested
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8/2/2012
Answer: 1.
• Source: Y Cao et al. The prediction of radiationinduced liver dysfunction using a local dose and
regional venous perfusion model. Med Phys
34(2):604-12, 2007.
Functional Bone Marrow Sparing (UCSD)
• LK Mell et al(UCSD). (JCO 28(15)suppl, 2010:
e13570)
• MRI mapping of functional bone marrow
supported dose re-organization for sparing
blood formation in pelvic RT
Serial IDEAL Fat Fraction Maps in a Cervical Cancer
Patient Undergoing Chemoradiation
Pre-Treatment
Mid-Treatment
Post-Treatment
0
Loren Mell, UCSD
12
8/2/2012
FDG-PET / MRI-IDEAL -Guided IMRT Plan
in a Patient with Cervical Cancer
Fused PET/CT, FFMRI.
SUV>1.1; FF < 50%
Active Bone Marrow-Sparing
IMRT Plan
Acknowledgment: Velocity AI, Velocity Medical
Solutions, Atlanta, GA
Loren Mell, UCSD
Evidence to date
• Some individualized therapy trials are underway
• Little direct clinical evidence to date
– Ghent –HN dose painting – evidence to date is that
dose can be modified safely
– Kong – lung dose adaptation – evidence to date is that
local boosting can be achieved safely respecting
normal tissue limits
– No substantial statistical evidence to date of:
• Improved local control
• Improved normal tissue sparing at same local control
Current evidence clearly shows that
physiological adaptation improves:
19%
21%
21%
19%
20%
1.
2.
3.
4.
5.
Local control for gliomas
Survival for head and neck cancer
Toxicity for intrahepatic radiotherapy
Toxicity for intrathoracic tumors
None of the above
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8/2/2012
Answer: 5.
• Source: J Balter et al. Metabolic and functional
imaging in Radiation Oncology. Seminars in
Radiation Oncology 21(2). 2011
Technical challenges
• Image-based maps need to be applied to the
physical patient
• Dose accumulation further requires accurate
mapping
• Shrinking tumors require assumptions about
dose addition
Current solutions for dose accumulation
• Duprez – local rigid
image registration
• RTOG 1106 – Rigid
alignment biased
towards local skeletal
alignment in vicinity of
PTV
Martha Matuszak UM
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8/2/2012
Summary
• Physiological adaptation is emerging as a tool in
clinical trials
• Preliminary evidence indicates a potential role
for such adaptation
• Evidence to date has indicated the potential for
dose modification, but has not yet proven
improvement in local control, nor equivalent
control at reduced toxicity
Acknowledgements
•
•
•
•
Fengming Kong
Randall Ten Haken
Martha Matuszak
Lauren Mell (UCSD)
15