2011 Joint AAPM/COMP Meeting
“NMR
Assessment of
Tumor Hypoxia and
Oxygen Dynamics”
Ralph P. Mason
Director Cancer Imaging Program,
Dept. Radiology & Simmons Cancer Center
UT Southwestern, Dallas TX
Considerations
•
•
•
•
•
•
Oxygen tension
Hypoxia
Dynamics
Spatial resolution
Dynamic range
Precision
Joint Imaging-Therapy Symposium
Focus of presentation:
1.
19F NMR
of PFCsquantitative mapping of oxygen dynamics
pO2 and hypoxic fractions
Pre-clinical
2. BOLD and TOLD
semi-quantitative
immediately feasible in human
Strengths of a 19F MRI approach
•
•
•
•
•
High sensitivity (g close to 1H)
Large chemical shift range
Negligible background signal
Stable compounds
Depth of penetration
Tumor oxygenation using PFCs
Strengths of a 19F MRI approach
•
•
•
•
•
High sensitivity (g close to 1H)
Large chemical shift range
Negligible background signal
Stable compounds
Depth of penetration
F
F
F
F
F
F
Br(CF2)7CF3
High sensitivity to changes in pO2
R1 (s-1) = a+b*pO2 (torr)
Zhao Methods Enzymol 386 2004
Sensitivity to oxygen
R1 (1/T1) = R1a + R1p.X
Acute changes in pO2 with intervention
pO2 = kX (Henry‟s law)
R1a = R1a + R1p/k.pO2
Solubility oxygen in water ~ 2 vol.%
in PFC ~40 vol.% PFC
Air
High sensitivity to changes in pO2
Molecular Amplifier
Zhao, Methods Enzymol 2004
PFOB, Bellemann et al. Biomedizin. Tech. (2002)
Oxygen
PFC emulsion sequestration
Long term changes in tumor pO2
Yu, Curr. Med. Chem 2005
pO2 from 19F NMRS
Dunning prostate R3327-AT1 tumor;
Oxypherol IV with vascular clearance
Mason, et al.. Int. J. Radiat. Oncol. Biol. Phys. 29 (1994)
“FREDOM”
(Fluorine Relaxometry using Echo planar imaging for
Dynamic Oxygen Mapping)
>100
85
70
55
40
25
10
-5
F
F
F
F
F
FREDOM
120
`
Amplitude
>700k
l
3rd
1st
l
l
7th
9th l
80
ARDVARC
Alternated R1 Delays with
Variable Acquisitions to
Reduce Clearance Effects
l
60
l
400k
40
l
20
<100k
F
5th
100
0
yi = A*( 1 - (1+W) exp(-R1*t) )
l
l
l
l
l
l
Tau (s)
2nd
-20
0
0 .4 5
10
20 30
40
50 60
70
80
90
0 .4 0
0 .3 5
R1
0 .3 0
1/R1 map
0 .2 5
0 .2 0
(1/R1) error
18.0 s
2.5 s
11.0
1.4
<3.0
0.35
0 .1 5
0 .1 0
0 .0 5
-2 0
20
60
100
140
180
p O 2 (to rr)
“Nanodroplets”
Kodibagkar and Zhao
pO2 (torr) = (R1 – 0.0835)/0.001876
pO2 map
>100 torr
80
60
40
20
<0
l
Dunning prostate R3327-AT1
0.8
0.8
FREDOM
Eppendorf
Oxygen Dynamics in response to respiratory challenge
0.6
0.6
< 2 cm3
< 2 cm3
0.4
0.4
m
0.2
0.0
0.8 5
x
0.2
x
15 25 35 45 55 65 75 85
mx
>100
0.6
0.0
0.8
Dunning prostate R3327-AT1 rat tumor
m
5
m
15 25 35 45 55 65 75 85
>100
0.6
> 3.5 cm3
0.4
> 3.5 cm3
0.4
x
0.2
0.2
0.0
0.0
5
15 25 35 45 55 65 75 85
>100
pO2 torr
5
15 25 35 45 55 65 75 85
>100
pO2 torr
Jiang, Zhao 2004
Mason et al, Radiat. Res. 1999
Differential Oxygen Dynamics in R3327 tumors
a)
21% O2
b)
100% O2
c) 95% O2/5% CO2
Variation in mean baseline pO2 for 7 HI tumors
with respect to growth
> 100
80
60
40
20
0
torr
HI
Mean baseline pO2 (torr)
50
AT1
40
30
20
10
0
0
Zhao et al
Zhao et al, Radiat. Res. „01
1
2
3
4
Tumor size (cm3)
5
6
Irradiation study in small Dunning prostate HI tumors (< 2 cm3)
Small tumors
Modulating response to irradiation
1
Dunning prostate R3327-HI tumor
Pedicle site
Small (< 2 cc) or large tumors (> 3.5 cc)
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Cum. survival
.8
.6
Irradiation
.4
O2
Control
.2
Air
0
0
10
20
30
40
50
60
70
Days after irradiation
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Irradiation study in small Dunning prostate HI tumors (< 2 cm3)
Cum. survival
.8
.6
Irradiation
.4
O2
Control
Air
0
10
20
30
40
50
60
70
.8
100% O2
.6
m
x
.4
Irradiation
O2
Air
.2 Control
m x
21% O2
0
0
<10 20 40
20
40
80
21% O2
pO2 ( torr)
Zhao et al. Radiat. Res. 2003
60
100
120
140
Days after irradiation
60 80 100 120 140 >160
Days after irradiation
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Relative frequency
.7
.6
.5
.4
.3
.2
.1
0
.7
.6
.5
.4
.3
.2
.1
0
1
0
Irradiation study in large HI tumors
1
Small tumors
.2
Zhao et al. Radiat. Res. 2003
Zhao et al. Radiat. Res. 2003
100% O2
.7
.6
.5
.4
.3
.2
.1
0 mx
.7
.6
.5
.4
.3
.2
.1
0
<10 20
100% O2
m
x
21% O2
40
60
80 100 120 140 >160 pO2 (torr)
CD31-FITC
Hoescht 33342
Influence of oxygen breathing on IR for large AT1 tumors
AT1 response to IR
50
40
30
20
10
80
60
Normalized Volume
0 .5
100
40
torr
100% O
Breathing
O2
2
0 .4
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0 .3
m
0 .2
x
0 .1
0
0
0 .5
50 m
40
30 x
20
10
0 <2.5 5 10
21% O2
Breathing air
0 .4
0 .3
0
3
6
9
Days Post Irradiation
12
0 .2
15
0 .1
0
20
21% O2
20
40
60
80
100% O2
Pimo
CD31
Hoechst
0
-10
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Bussink, van der Kogel
Bourke et al, IJROBP 2007
Mean pO2 (torr)
80
60
CA4P (30 mg/kg)
Oxygen
*
Air
Air
Oxygen
•Irradiation (5 Gy) + CA4P (30 mg/kg) on 13762NF rat breast tumors
Importance of timing and sequence because
hypoxia affects tumor response to radiation.
CA4P 24 h
Air
Oxygen
*
+
*
+
5
40
20
* *
*
*
**
*
*
* * *
*
0
*‡ *‡
‡
‡
10
16
10 11
30 12
6013
90 14
12015min
-20
*
Time course
‡
‡
23
>100
85
70
55
40
25
10
-5
torr
13762NF rat breast tumor
Normalized tumor volume
Baseline
Air
Bourke et al, IJROBP 2007
Experimental combination treatment
Combined therapy IR+ VTA CA4P
100
100 120 140 >150
IR + O2
4
CA4P
3
CA4P + 24h IR
2
(IR + O2) + 1h CA4P
1
CA4P + 24h (IR + O2)
0
02
33
74
5
10
Post treatment (days)
Zhao et al., IJROBP 2005
IR
IR + 1h CA4P
Ctrl
6
14
Zhao, IJROBP 2011
Prognostic Radiology
FREDOM
Hexamethyldisiloxane –Proton MR oximetry
1. 6
1. 4
H3C
• Interrogate heterogeneity
• Reveal differential response
H3 C
CH3
Si
O
1. 2
1
Si
CH3
R1
• Measure baseline tumor oxygenation (map)
• Assess dynamic response to intervention
H3 C
R1 0. 8
s-1 0. 6
CH3
0. 4
0. 2
0
0
10
800
HMDSO
H2O
Minimally invasive
Spatial and temporal resolution
Non-toxic, readily available
200
400
600
oxygen t ensi on ( t or r )
8
6
4
2
-0
-2
-4
-6
-8
-10
ppm
ISMRM 2004- DOD CaP
PISTOL
Proton Imaging of Siloxanes for Tissue Oxygen Mapping
Accessible tumors
Head & neck
breast
cervix
prostate
Rat thigh muscle
200
180
Air
Oxygen
Air
160
140
Mean
120
pO2
(torr) 100
80
60
40
20
0
0
10
20
30
40
50
60
70
Potential Applications
80
90
Time
Rat prostate R3327-AT1 tumor
Kodibagkar, et al. NMR Biomed 2008
Current Restrictions
Accessible tumors
Head & neck
breast
cervix
prostate
Endogenous indicators
• Lactate
• Water relaxation T1, T2
Relaxation rate (
S -1 )
300
250
200
150
100
50
0
0
20 40 60 80 100 120 140 160
pO2
Need IND
Lack of clinical 19F MRI
Mason, Kidney Int. 2006
GA Wright SMA
Whole bovine blood
R1 (■), R2 (▲) and R2* (●)
BOLD in rat breast tumor 13762NF
BOLD MRI
(Blood Oxygenation Level Dependent)
Hb + O  HbO
2
2
dHb: paramagnetic property
Hb: non-paramagnetic property
Oxygen 50s
100s
150s
260s
>80
TOLD
(Tissue Oxygen Level Dependent)
60
40
20
0
-20
<-40
250
 SI (%)
200
150
F ig. 2B
100
10
50
8
A ir
0
0
20 40 60 80 100 120 140 160
pO2
• BOLD signal enhancement is related to change of tumor
vascular oxygenation and blood flow (microcirculation)
• TOLD signal enhancement is related to change of tumor
tissue oxygenation
Matsumoto, Krishna et al. MRM
)
S I (%
(%)
ΔSI
Relaxation rate (
S -1 )
300
O xygen
6
4
2
0
25
75
T im e (s)
125
175
225
275
ISMRM 2008
BOLD Oximetry
FREDOM in 13762NF BrCa
Fig. 4
A
40
dHb: paramagnetic
Hb: non-paramagnetic
35
>100
85
70
55
40
25
10
-5
HF 10 (%)
30
25
20
15
10
5
torr
0
Oxygen (100% O22)
-5
15
15%
0
80
pO22 (torr
(torr))
pO
Air
Oxygen
60
**
40
2
4
6
8
10
12
14
SI (% )
SI
**
**
**
*
20
**
*
12
12%
BOLD (%)
Air (21% O22)
*
99%
66%
33%
00%
0
15
30
45
1
7
0
2
14
3
21
4
28
5
35
6
42
60
75
90 105 120 135 150
 pO2 (torr)
0
7
49
Time (min)
13762 NF rat breast tumors
Zhao et al. Magn. Reson. Med. 62, 357-364 (2009)
DOCENT- Dynamic Oxygen Challenge Evaluated by NMR T 1 and T 2*
T2*-weighted BOLD dynamics
Air
Carbogen
Air Carbogen
0.25
0.3
30
Air
1.0
0.2
0.8
0.15
0.6
0.1
55
00
AT1
0.05
0.2
0
-0.05
0.4
0
5
0
10
2
0
2
4
15
Time (min)
4
6
20
6
Time (min)
8
825
Carbogen
0.25
25
0.2
20
0.15
15
0.1
10
0.05
5
00
0
0
5
-0.05
2 100
0
Large
42
15
4
6 20
6
8
825
Time (min)
- 0.2
smallsmall
AT1 AT1
smallsmall
HI HI
largelarge
AT1AT
largelarge
HI HI
- 0.4
Dunning prostate R3327
HI
T1- weighted TOLD dynamics
- 0.6
ΔSI related to tumor
growth delay with IR
AT1
Air
10%
100
80
Carbogen
8%
T 1 -weighted ΔSI (%)
SI (%)
Delta
(%)
Δ SI
0.3
Delta
Δ SI (%)
3030
2525
2020
1515
1010
T2*-weighted BOLD dynamics
T2*-weighted BOLD
dynamics
Small
HI
T2*-weighted BOLD dynamics
Zhao et al., Magn. Reson. Med. 2009
60
6%
40
4%
20
2%
0
-20
0%
-2
-2%
0
1
2
3
4
5
Time (mins)
6
7
8
9
10
-40
-60
%SI
18
16
14
12
10
8
6
4
2
0
HI
AT1
0
10
20 30 40 50
BOLD (%ΔSI)
60 70
Why measure pO2/hypoxia?
Tumor aggressivenessangiogenesis/metastasis
Correlation between BOLD and TOLD responses
in Dunning prostate rat tumors
Δ R1 (s-1; CB-air)
TOLD (%ΔSI)
Correlation between BOLD and TOLD responses
in Dunning prostate rat tumors
0.08
HI
0.04
AT1
0.00
-0.04
-0.08
-25 -20 -15 -10 -5 0
ΔR2* (s-1; CB-air)
5
10
Clinical Translation
MR Mammography
Therapeutic resistance
Radiation
Photo dynamic therapy
Patient stratificationIMRT
hypoxia selective cytotoxin TPZ
Prognosis
+ Gd-DTPA
Amersham
Locally advanced breast canceradjuvant chemotherapy (AC)
Pre-
Locally advanced breast canceradjuvant chemotherapy: BOLD analysis
Hb + O  HbO
2
2
post-chemotherapy
Air
25%
300%
250%
200%
150%
Patient 1
100%
50%
0%
0
2.1
4.2
6.3
8.4
10.5
Time (min.)
DCE
good response
Relative signal intensity
Relative signal intensity
350%
Oxygen
Pre-
post-chemotherapy
Air
20%
15%
10%
good response
5%
0%
poor response
-5%
0
36 72 108 144 180 216 252 288 324 360 396 432 468 504
Time (s)
Patient 2
Jiang, Tripathy, Weatherall, DOD EOH 2005
10 patients: 30% good responders
BOLD
good response
poor response
Jiang, Tripathy, Weatherall
Disease free survival vs. cervical tumor oxygen tension
Relative BOLD response
20%
poor responders
good responders
16%
12%
8%
4%
0%
a.
Entire Tumor
Hypovascular area Hypervascular area
Research supported by Susan G. Komen Foundation IMG-0402967,
DOD Predoctoral Traineeship award DAMD17-02-1-0592 (LJ),
F y les et a l. R a d io th er. O n co l. 4 8 : 1 4 9 -5 6 , 1 9 9 8 .
Cervical Cancer
Lung Cancer
U
T
a
45
b
120
30
40
25
R2*=21.76 s-1
100
SI (au)
35
45
80
60
c
Oxygen
40
R2* (sec-1)
Tumor
R2* = -0.22 s-
T2* Values vs Time
1
Air
-1
R *=21.98s
Stanford, Le
CLIN. CANCER RES. 2006
40
2
35
20
30
40
0
140
15
30
45
10
0.01
0.02
0.03
0.04
TE (sec)
d
T2* (ms)
Air
25
Oxygen
R *=18.06s-1
120
40
2
30
15
25
20
SI (au)
35 20
Uterus
R2* = -1.42 s-1
100
80
20
10
Air
-1
R *=19.48s
2
10
O2
60
0
15
Oxygen
10
40
0
0.01
0.02
TE (sec)
0.03
0.04
-4
e
-2
0
2
4
6
Time (min)
8
Feasibility of BOLD Magnetic
Resonance Imaging of Lung
Tumors at 3T
Q. Yuan, Y. Ding, R. M. Hallac,
P. T. Weatherall, R. D. Sims,
T. Boike, R. Timmerman,
R. P. Mason ISMRM 2010
Advanced PCa:T2* Maps
Lung cancer pre-SBRT
Air
T
Oxygen (8 mins)
L
ΔSI (%)
4-point moving average
Air
Oxygen
T2*(secs)
Movsas et al. Urology 2002
Raj, Ding, Yuan, Hallac, Sims, Weatherall DOD PrCA
38 patients H&N Ca
Kaanders et al 2004
Oxic- ARCON
Oxic –normal
Hypoxic ARCON
Hypoxic normal
Joint Imaging-Therapy Symposium
•
•
•
•
Non Invasive
Spatial discrimination- heterogeneity
3- dimensional
Dynamic capabilities
Tumor Characteristics
Traditional
•Location
•Size
•Stage
Goals
•Detection
•Prognosis
•Response
Potential
• Gene expression (Genomics)
• Receptor expression (Proteomics)
• Physiology (pO2, pH, TBF, TBV)
•Non-invasive
•Spatial, temporal resolution
•Cost, ease, robustness
Acknowledgements
Oximetry-FREDOM; PISTOL
Dawen Zhao, MD, Ph.D.
Vikram Kodibagkar, Ph.D.
Lan Jiang, Ph.D.
Yulin Song, Ph.D.
Jesús Pacheco-Torres
Radiation Oncology
Joe Gilio, Ph.D.
Kenneth Gall, Ph.D.
Karen Chang, Ph.D.
Debu Saha, Ph.D.
Tim Solberg, Ph.D.
Peter Peschke, Ph.D. DKFZ
• 19F pre-clinical
• BOLD-TOLD-human patients
DOCENT
Paul Weatherall, MD
Doug Sims, MD
Jayanthi Lea, MD
Debu Tripathy, MD
Yao Ding
Qing Yuan, PhD
Roddy McColl, PhD
Rami Hallac, MS
Baran Sumer, MD
Robert Timmerman, MD
Ganesh Raj, MD
Eric Hahn, Ph.D.
• NIH NCI; DOD BrCa and CaP
Initiatives; The American Cancer
Society, The Whitaker Foundation;
NIH BRTP P41-RR02584
• NCI SAIRP U24 CA126608
Cancer Imaging Program
• Susan G. Komen Foundation
• Mary Kay Ash Foundation
• P30 CA142543