2011 Joint AAPM/COMP Meeting

Ralph P. Mason

Director Cancer Imaging Program,

Dept. Radiology & Simmons Cancer Center

UT Southwestern, Dallas TX

“NMR Assessment of Tumor Hypoxia and Oxygen Dynamics”

Joint Imaging-Therapy Symposium

Considerations

• Oxygen tension

• Hypoxia

• Dynamics

• Spatial resolution

• Dynamic range

• Precision

Focus of presentation:

1. 19F NMR of PFCs-

quantitative 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

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

R1 (s-1) = a+b*pO2 (torr)

High sensitivity to changes in pO2

Zhao Methods Enzymol 386 2004

Br(CF2)7CF3

F

F

F

F

F

F

Sensitivity to oxygen

R1 (1/T1) = R1a + R1p.X

pO2 = kX (Henry‟s law)

R1a = R1a + R1p/k.pO2

Solubility oxygen in water ~ 2 vol.%

in PFC ~40 vol.% PFC

Molecular Amplifier

High sensitivity to changes in pO2

Zhao, Methods Enzymol 2004

Acute changes in pO2 with intervention

PFOB, Bellemann et al. Biomedizin. Tech. (2002)

Air Oxygen

Yu, Curr. Med. Chem 2005

PFC emulsion sequestrationLong term changes in tumor pO2

Mason, et al.. Int. J. Radiat. Oncol. Biol. Phys. 29 (1994)

Dunning prostate R3327-AT1 tumor;

Oxypherol IV with vascular clearance

pO2 from 19F NMRS

Kodibagkar and Zhao“Nanodroplets”

-5

10

25

40

55

70

85

>100

F

F

F

F

F

F

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

R1

-20 20 60 100 140 180

pO2 (torr)

“FREDOM”(Fluorine Relaxometry using Echo planar imaging for

Dynamic Oxygen Mapping)

>700k

400k

<100k

Amplitude

pO2 map

l

>100 torr

80

60

40

20

<0

1/R1 map

<3.0

18.0 s

11.0

2.5 s

1.4

0.35

(1/R1) error

yi = A*( 1 - (1+W) exp(-R1*t) )

pO2 (torr) = (R1 – 0.0835)/0.001876

FREDOM

ARDVARCAlternated R1 Delays with Variable Acquisitions to Reduce Clearance Effects

Tau (s)

l

l

l

l

l

l

l

l

l

l

l

l

l

l

-20

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80 90

1st

2nd

3rd5th

7th

9th

`

5 15 25 35 45 55 65 75 85 1000.0

0.2

0.4

0.6

0.8

5 15 25 35 45 55 65 75 85 1000.0

0.2

0.4

0.6

0.8

pO2 torr

>

>

5 15 25 35 45 55 65 75 85 1000.0

0.2

0.4

0.6

0.8

pO2 torr

>

5 15 25 35 45 55 65 75 85 1000.0

0.2

0.4

0.6

0.8

>

m x

x

m

x

m x

m

FREDOM Eppendorf

< 2 cm3 < 2 cm3

> 3.5 cm3 > 3.5 cm3

Dunning prostate R3327-AT1

Mason et al, Radiat. Res. 1999

Dunning prostate R3327-AT1 rat tumor

Oxygen Dynamics in response to respiratory challenge

Jiang, Zhao 2004

a) 21% O2 b) 100% O2 c) 95% O2/5% CO2

torr

0

> 100

60

40

20

80

AT1

HI

Zhao et al

Differential Oxygen Dynamics in R3327 tumors

0

10

20

30

40

50

0 1 2 3 4 5 6

Tumor size (cm3)

Mea

n b

asel

ine

pO

2 (

torr

)

Variation in mean baseline pO2 for 7 HI tumors

with respect to growth

Zhao et al, Radiat. Res. „01

Modulating response to irradiation

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

. su

rviv

al

Days after irradiation

Small tumors

0

.2

.4

.6

.8

1

0 10 20 30 40 50 60 70

Control

Irradiation

O2 Air

Irradiation study in small Dunning prostate HI tumors (< 2 cm3)

Zhao et al. Radiat. Res. 2003

Single dose 30 Gy; 6 MeV

TCD50 60 Gy

Cum

. su

rviv

al

Days after irradiation

Small tumors

0

.2

.4

.6

.8

1

0 10 20 30 40 50 60 70

Control

Irradiation

O2 Air

0.1.2.3.4.5.6.7

xm

<10 20 40 60 80 100 120 140 >160

pO2 ( torr)

0

.1

.2

.3

.4

.5

.6

.7

mx

100% O2

21% O2

Irradiation study in small Dunning prostate HI tumors (< 2 cm3)

Zhao et al. Radiat. Res. 2003

Single dose 30 Gy; 6 MeV

TCD50 60 Gy

<10 20 40 60 80 100 120 140 >1600.1

.2

.3

.4

.5

.6

.7

mx

pO2 (torr)

0.1

.2

.3

.4

.5

.6

.7

xm

Rel

ativ

e fr

equen

cy

100% O2

21% O2

Irradiation study in large HI tumors

Days after irradiation

0 20 40 60 80 100 120 140

0

.2

.4

.6

.8

1

O2Air

Irradiation

Control

Zhao et al. Radiat. Res. 2003

21% O2 100% O2CD31-FITC Hoescht 33342

100 80 60 40 torr 20 0

-10

AT1 response to IR

Single dose 30 Gy; 6 MeV

TCD50 60 GyBourke et al, IJROBP 2007

Influence of oxygen breathing on IR for large AT1 tumors

21% O2 100% O2

Pimo

CD31

Hoechst

0

0.1

0.2

0.3

0.4

0.5

100% O2

x

m

0

0.1

0.2

0.3

0.4

0.5

100% O2

0

0.1

0.2

0.3

0.4

0.5

100% O2

xx

mm

0

0.1

0 .2

0 .3

0 .4

0 .5

21% O2

<2.5 5 10 20 40 60 80 100 120 140 >150

x

m

0

0.1

0 .2

0 .3

0 .4

0 .5

21% O2

0

0.1

0 .2

0 .3

0 .4

0 .5

21% O2

<2.5 5 10 20 40 60 80 100 120 140 >150

xx

m

50

40

30

20

100

50

40

30

20

10

0

Breathing air

Breathing O2

Bussink, van der Kogel

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 3 6 9 12 15

Days Post Irradiation

Norm

aliz

ed V

olu

me

Bourke et al, IJROBP 2007

-20

0

20

40

60

80

100

10 11 12 13 14 15 16 23

Air Oxygen Air

CA4P (30 mg/kg)OxygenOxygenAir Air

Baseline CA4P 24 h

10 30 60 90 120 min

Time course

Mean

pO

2(t

orr) *

*

*

*

*

*

* *

*

+

+

**

*

*‡*

*

*

**‡

‡‡‡

‡

Zhao et al., IJROBP 2005

Combined therapy IR+ VTA CA4P

-5

10

25

40

55

70

85

>100

torr

13762NF rat breast tumor

0

1

2

3

4

5

2 3 4 5 6

Ctrl

CA4P

IR

IR + 1h CA4P

CA4P + 24h (IR + O2)

Post treatment (days)

Norm

ali

zed

tu

mor

volu

me

CA4P + 24h IR

IR + O2

(IR + O2) + 1h CA4P

0 3 7 10 14

Experimental combination treatment

•Irradiation (5 Gy) + CA4P (30 mg/kg) on 13762NF rat breast tumors

Importance of timing and sequence because

hypoxia affects tumor response to radiation.

Zhao, IJROBP 2011

FREDOM

• Measure baseline tumor oxygenation (map)

• Assess dynamic response to intervention

• Interrogate heterogeneity

• Reveal differential responseMinimally invasive

Spatial and temporal resolution

Non-toxic, readily available

Prognostic Radiology Hexamethyldisiloxane –Proton MR oximetry

Si

H3C

H3C

H3C

O Si

CH3

CH3

CH3

0

0. 2

0. 4

0. 6

0. 8

1

1. 2

1. 4

1. 6

0 200 400 600 800

oxygen t ensi on ( t or r )

R1

ISMRM 2004- DOD CaP

ppm-10-8-6-4-2-0246810

H2OHMDSO

R1

s-1

Kodibagkar, et al. NMR Biomed 2008Rat prostate R3327-AT1 tumor

PISTOLProton Imaging of Siloxanes for Tissue Oxygen Mapping

0 10 20 30 40 50 60 70 80 900

20

40

60

80

100

120

140

160

180

200

OxygenAirAirAirAir Air

pO2

(torr)

Time

Mean

0 10 20 30 40 50 60 70 80 900

20

40

60

80

100

120

140

160

180

200

OxygenAirAirAirAir Air

pO2

(torr)

Time

Mean

Rat thigh muscle

Potential Applications

Accessible tumors

Head & neck

breast

cervix

prostate

Current Restrictions

Accessible tumors

Head & neck

breast

cervix

prostate

Need IND

Lack of clinical 19F MRI

Endogenous indicators

• Lactate

• Water relaxation T1, T2

Re

lax

ati

on

ra

te (

S-1

)

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

Re

lax

ati

on

ra

te (

S-1

)

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

Whole bovine blood

R1 (■), R2 (▲) and R2* (●)

Mason, Kidney Int. 2006

GA Wright SMA

BOLD MRI (Blood Oxygenation Level Dependent)

dHb: paramagnetic property

Hb: non-paramagnetic property

• 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

22HbOOHb + TOLD

(Tissue Oxygen Level Dependent)

Matsumoto, Krishna et al. MRM

Re

lax

ati

on

ra

te (

S-1

)

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

Re

lax

ati

on

ra

te (

S-1

)

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

0

50

100

150

200

250

300

0 20 40 60 80 100 120 140 160

pO2

<-40

>80

-20

0

20

40

60

SI (%)

SI (

%)

T im e (s)

0

2

4

6

8

10

25 75 125 175 225 275

A ir O xygen

Fig. 2B

SI (

%)

T im e (s)

0

2

4

6

8

10

25 75 125 175 225 275

A ir O xygen

Fig. 2B

ΔS

I (%

)

Oxygen 50s 100s 150s 260s

BOLD in rat breast tumor 13762NF

ISMRM 2008

FREDOM in 13762NF BrCa

Zhao et al. Magn. Reson. Med. 62, 357-364 (2009)

0

20

40

60

80

0 1 2 3 4 5 6 77 14 21 28 35 42 49

Time (min)

pO

2(t

orr

)

Air Oxygen

-5

10

25

40

55

70

85

>100

Air (21% O2 ) Oxygen (100% O2 )

Fig. 4 A

**

**

*

****

**

* *

0

20

40

60

80

0 1 2 3 4 5 6 77 14 21 28 35 42 497 14 21 28 35 42 49

Time (min)

pO

2( torr

)

Air Oxygen

-5

10

25

40

55

70

85

>100

-5

10

25

40

55

70

85

>100

Air (21% O2 ) Oxygen (100% O2 )Air (21% O2) Oxygen (100% O2)

Fig. 4 A

**

**

*

****

**

* *

torr

BOLD Oximetry

-5

0

5

10

15

20

25

30

35

40

HF

10 (

%)

0 2 4 6 8 10 12 14

SI (% )

-5

0

5

10

15

20

25

30

35

40

HF

10 (

%)

0 2 4 6 8 10 12 14

SI (% )

-5

0

5

10

15

20

25

30

35

40

HF

10 (

%)

0 2 4 6 8 10 12 14

SI (% )

-5

0

5

10

15

20

25

30

35

40

HF

10 (

%)

0 2 4 6 8 10 12 14

SI (% )

Zhao et al., Magn. Reson. Med. 200913762 NF rat breast tumors

pO2 (torr)

0%

3%

6%

9%

12%

15%

0 15 30 45 60 75 90 105 120 135 150

15

12

9

6

3

0

BO

LD

(%)

dHb: paramagnetic

Hb: non-paramagnetic

T2*-weighted BOLD dynamicsT2*-weighted BOLD dynamics

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 5 10 15 20 25

Time (min)

Delt

a S

I (%

)

Air Carbogen

0 2 4 6 8

30

25

20

15

10

5

0

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 5 10 15 20 25

Time (min)

ΔS

I (%

)

Air Carbogen

0 2 4 6 8

30

25

20

15

10

5

0

Small

HI

AT1

Large

HI

AT1

1.0

0.8

0.6

0.4

0.2

0

- 0.2

- 0.4

- 0.6

Dunning prostate R3327

T2*-weighted BOLD dynamics

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 5 10 15 20 25

Time (min)

Delta

SI (%

)

small AT1 small HI large AT large HI

Air Carbogen

0 2 4 6 8

30

25

20

15

10

5

0

T2*-weighted BOLD dynamics

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0 5 10 15 20 25

Time (min)

ΔS

I (%

)

small AT1 small HI large AT1 large HI

Air Carbogen30

25

20

15

10

5

0

ΔSI related to tumor

growth delay with IR

DOCENT- Dynamic Oxygen Challenge Evaluated by NMR T1 and T2*

0 2 4 6 8

-2%

0%

2%

4%

6%

8%

10%

-2 0 1 2 3 4 5 6 7 8 9 10

Time (mins)

T1-w

eig

hte

d Δ

SI (%

)

CarbogenAir 100

80

60

40

20

0

-20

-40

-60%SI

T1- weighted TOLD dynamics

02468

1012141618

TO

LD

(%

ΔS

I)

BOLD (%ΔSI)

0 10 20 30 40 50 60 70

Correlation between BOLD and TOLD responses

in Dunning prostate rat tumors

HI

AT1

-0.08

-0.04

0.00

0.04

0.08

Δ R

1(s

-1;

CB

-air

)

-25 -20 -15 -10 -5 0 5 10

ΔR2* (s-1; CB-air)

Correlation between BOLD and TOLD responses

in Dunning prostate rat tumors

HI

AT1

Why measure pO2/hypoxia?

Tumor aggressiveness-

angiogenesis/metastasis

Therapeutic resistance

Radiation

Photo dynamic therapy

Patient stratification-

IMRT

hypoxia selective cytotoxin TPZ

Prognosis

Clinical Translation

MR Mammography

+ Gd-DTPAAmersham

Locally advanced breast cancer-adjuvant chemotherapy (AC)

Pre- post-chemotherapy

0%

50%

100%

150%

200%

250%

300%

350%

0 2.1 4.2 6.3 8.4 10.5

Time (min.)

Re

lati

ve

sig

na

l in

ten

sit

y

good response poor responseDCE

Pre- post-chemotherapyPre- post-chemotherapy

0%

50%

100%

150%

200%

250%

300%

350%

0 2.1 4.2 6.3 8.4 10.5

Time (min.)

Re

lati

ve

sig

na

l in

ten

sit

y

good response poor responseDCE

Patient 1

Patient 2

Jiang, Tripathy, Weatherall, DOD EOH 2005

Locally advanced breast cancer-adjuvant chemotherapy: BOLD analysis

Jiang, Tripathy, Weatherall

-5%

0%

5%

10%

15%

20%

25%

0 36 72 108 144 180 216 252 288 324 360 396 432 468 504

Time (s)

Rela

tiv

e s

ign

al in

ten

sit

y

good response poor response

Air Oxygen Air

BOLD

Pre- post-chemotherapy

good response

-5%

0%

5%

10%

15%

20%

25%

0 36 72 108 144 180 216 252 288 324 360 396 432 468 504

Time (s)

Rela

tiv

e s

ign

al in

ten

sit

y

good response poor response

Air Oxygen Air

BOLD

Pre- post-chemotherapy

good response

Pre-Pre- post-chemotherapy

good response

22HbOOHb +

10 patients: 30% good responders

0%

4%

8%

12%

16%

20%

Entire Tumor Hypovascular area Hypervascular area

Rela

tive

BO

LD

re

sp

onse

poor respondersgood responders

a.

0%

4%

8%

12%

16%

20%

Entire Tumor Hypovascular area Hypervascular area

Rela

tive

BO

LD

re

sp

onse

poor respondersgood responders

a.

Research supported by Susan G. Komen Foundation IMG-0402967,

DOD Predoctoral Traineeship award DAMD17-02-1-0592 (LJ),

Disease free survival vs. cervical tumor oxygen tension

Fyles et al. Radiother. O ncol. 48: 149-56, 1998.

0 0.01 0.02 0.03 0.0440

60

80

100

120

140

TE (sec)

SI (a

u)

OxygenR

2*=18.06s

-1

AirR

2*=19.48s

-1

0 0.01 0.02 0.03 0.0440

60

80

100

120

TE (sec)

SI (a

u)

Oxygen

R2*=21.76 s

-1

Air

R2*=21.98s

-1

10

15

20

25

30

35

40

45

10

15

20

25

30

35

40

45

Uterus

R2* = -1.42 s-1

Tumor

R2* = -0.22 s-

1

a b c

d

e

T

Air

Oxygen

10

15

20

25

30

35

40

45

R2* (sec-1)

U

Cervical Cancer Lung Cancer

T2* Values vs Time

0

10

20

30

40

-4 -2 0 2 4 6 8

Time (min)

T2

* (m

s)

O2

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

Stanford, Le

CLIN. CANCER RES. 2006

L

T

ΔSI (%)

Air Oxygen

T2*(secs)

Lung cancer pre-SBRT Advanced PCa:T2* Maps

Air Oxygen (8 mins)

4-point moving average

Movsas et al. Urology 2002 Raj, Ding, Yuan, Hallac, Sims, Weatherall DOD PrCA

38 patients H&N CaKaanders et al 2004

Oxic- ARCON

Oxic –normal

Hypoxic ARCON

Hypoxic normal

Tumor Characteristics

Traditional

•Location

•Size

•Stage

Potential

• Gene expression (Genomics)

• Receptor expression (Proteomics)

• Physiology (pO2, pH, TBF, TBV)

Goals

•Detection

•Prognosis

•Response

•Non-invasive

•Spatial, temporal resolution

•Cost, ease, robustness

• Non Invasive

• Spatial discrimination- heterogeneity

• 3- dimensional

• Dynamic capabilities

• 19F pre-clinical

• BOLD-TOLD-human patients

Joint Imaging-Therapy SymposiumOximetry-FREDOM; PISTOL

Dawen Zhao, MD, Ph.D.

Vikram Kodibagkar, Ph.D.

Lan Jiang, Ph.D.

Yulin Song, Ph.D.

Jesús Pacheco-Torres

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

AcknowledgementsRadiation OncologyJoe Gilio, Ph.D.

Kenneth Gall, Ph.D.Karen Chang, Ph.D.Debu Saha, Ph.D.Tim Solberg, Ph.D.

Peter Peschke, Ph.D. DKFZ

Eric Hahn, Ph.D.

• NIH NCI; DOD BrCa and CaPInitiatives; 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