Functional/Molecular Imaging:
MRI for Planning/Assessment of RT
Advanced MRI Techniques:
Current & Future Applications in RT
Andrea Pirzkall, M.D.
Associate Adjunct Professor
Departments of Radiation Oncology, Radiology, and
Neurological Surgery
Center for Molecular and Functional Imaging
Imaging in RT ?
Issues of Interest..
1. Subregions, -volumes?
(GTV, BTV)
• Target definition
2. Margins? (CTV)
3. Lymph nodal involvement;
distant spread?
• Treatment Response
• Predictors of outcome
1. Treatment effect or
tumor recurrence?
2. Surrogate for
therapeutic
effectiveness?
aMRI for RT at UCSF
• 2 major disease sites
– Brain gliomas
– Prostate cancer
Brain Gliomas - Glioblastoma Multiforme (GBM)
- Background • Most malignant type of brain tumor in adults
• Standard of care: surgery, radiation therapy, concurrent
chemotherapy (Temozolomide)
– Median survival 15 mos *
– RT: 3D-CRT, 60 Gy/30 Fx (2 Gy/day); >80% local failure
• Newer, molecularly targeted and/or antiangiogenic, agents
increasingly added to standard therapy and tested in clinical
trials
• Early assessment of therapy response is critical but often
hindered by questionable changes in morphological
appearance
* Stupp R, NEJM 2005
Brain Gliomas – Characteristics & Challenges
T1w post Gad SPGR
T2w FSE
T1w SPGR
pre-surgery, at initial diagnosis
•
•
Infiltrative
Spatially heterogeneous
→ difficulty to define
treatment margins and/or
plan focal therapy
•
DSC
Tumor vessels are
structurally and
functionally abnormal
SWI at 7T
→ impairs delivery of therapeutic
agents
→ creates abnormal microenvironment
(e.g. hypoxia) that reduces
effectiveness of RT and CHT
Brain Gliomas - Challenges
• Monitoring/assessing response to therapy
Initial scan
Treatment effect or
Tumor recurrence?
→ Pseudo-progression
Follow-up
Contrast enhancement represents an
area of BBB breakdown, and may not
be synonymous with tumor progression
or angiogenesis.
Brain Gliomas - Challenges
• Patient selection
Predictive
measures?
Survival 15.1 months
Survival 32.3 months
Can non-invasive MR measurements provide surrogate markers for
biologic behavior and patient outcome (survival, time-to-progression) ?
MR Imaging Tools & Modalities
• Advanced MRI techniques prove valuable to
assess the metabolic and physiologic aspects of
brain and tumor tissue:
– 3D Proton Magnetic Resonance Spectroscopy
Imaging (MRSI)
– Perfusion weighted Imaging (PWI)
– Diffusion weighted Imaging (DWI)
• @ UCSF: Brain tumor SPORE imaging protocol 2002 – 2007,
renewed 2007-2012
3D 1H Magnetic Resonance Spectroscopy
Imaging (MRSI)
Parameters:
1. Metabolites:
1Cho, 2Cr,
3NAA, 4Lip,
5Lac
2. Metabolic
Indices:
Assesses metabolic status of brain and
tumor tissue based on measurements of
cellular metabolites that reflect the biological
behavior of each respective volume
compartment
CNI, CrNI,
CCrI
MRSI: Metabolic Indices, i.e. CNI
Cho
Cr
NAA
normal
Cho
tumor
CNI measures the
increase in Cho,
decrease in NAA
relative to normal
Perfusion Weighted Imaging (PWI)
Signal Intensity
Assesses overall cerebral
blood volume, tissue
micro-vasculature and
angiogenesis as well as
vessel permeability
injection
Peak Height
→ Angiogenesis
Recovery
→ Vessel leakiness
time (sec)
time (sec)
CBV
Perfusion Weighted Imaging (PWI)
Perfusion Imaging with DSC (T2*) and DCE
T1W Post-Gd
T1W fBV
* Zierhut M, et al, ISMRM 2006
T2*W rCBV
T1W KPS
T2*W %Rec
Diffusion Weighted Imaging (DWI)
T1w post Gad
T2w EP
ADC
FA
Assesses water diffusivity in brain tissue which has been used to
- infer changes in cellularity, cell membrane permeability, and
extra-cellular space ⇒ Apparent Diffusion Coefficient (nADC)
- and structural integrity ⇒ Fractional Anisotropy (nFA)
(normalized to normal appearing white matter, NAWM)
Diffusion Tensor Imaging (DTI)
• DTI sensitive to anisotropic or directionally dependent diffusion,
describes 3D diffusivity of water
⇒ to measure and tract fiber orientation (esp in large WM tracts)
Photo of cadaver
brain from
Visible Human
Project, NLM
DTI color map of
axonal fiber
orientation
Vector plot of primary eigenvector
→ describes orientation of axonal bundles
Diffusion Tensor Imaging (DTI):
Structure Avoidance
• DTI Fiber tracks match cortical mapping
• Motor pathways tracked from cortex to midbrain
Tumor
Red: shoulder motor
Blue: wrist motor
Yellow: overlap
* Berman JI, et. al., Journal of Neurosurgery. 2004.
aMRI in RT: Results so far..
1.
Target definition
•
Spatial extent
•
Spatial heterogeneity
•
Pattern of recurrence
2.
Treatment response
•
Treatment effect or tumor recurrence
•
Surrogate for therapeutic effectiveness
•
Radiation changes in normal tissue
3.
Prediction of outcome
•
Survival
•
Time-to-progression
•
Focal failure
Target Definition
Spatial Extent
Discordance according to MRI/MRSI
T2h
MRI:
48 cc
8 mm
MRSI:
T2 hyperintensity
CNI 2
Contrast Enhancement
CNI 3
CNI 4
CNI 2 : T2
8 cc
12 cc
5 cc
CE
* Pirzkall A, et al. IJROBP 2001
10 mm
14 mm
18 mm
29 cc
CNI 2 : CE
15 cc
15 cc
CNI 3 : CE
10 cc
CNI 4 : CE
Treatment margins?
Pattern of Recurrence post 3D-CRT relative to pre-RT MRI/MRSI
•
•
•
Clinical example: Increasing CE during FU residing within pre-RT MRI/S and 60 Gy
pre-RT
7 mos post RT
Increased CE during FU occurred within the combined MRI/MRSI volume as
defined at pre-RT in 8/9 patient
Normal tissue exposure to 60 Gy nearly double that of the MRI/MRSI volume
(median 78.5 cc vs 38.8 cc, respectively)
* Park I, et al. IJROBP 2007
Treatment margins?
- Early Delayed RT Changes • Radiation changes in normal appearing brain tissue
Cho / NAA (median)
0.75
0.70
(a) < 25 Gy
25-50 Gy
> 50 Gy
Also, vessels in
NAWM become
leaky and have
decreased rCBV
2 months after
XRT
0.65
0.60
0.55
Pre-RT
Post-RT
2 mo.
4 mo.
6 mo.
→ Dose dependent increase in Cho/NAA ratio & vessel permeability
* Lee M. J Magn Reson Imag 2004
Treatment margins?
- Late Delayed RT Changes• Radiation changes assessed at high field strength MRI (7T)
– Astrocytoma ° III, 5 yrs post therapy (60 Gy CRT + 6 cycles BCNU)
Tumor site
Surrounding & “Normal” tissue
Spatial heterogeneity
MRSI
CNI
CCrI
13
CrNI
LLI
0
Spatial heterogeneity
MRI vs MRSI vs PWI
MRSI
Tumor with high Cho & high Cr
Tumor with high Cho & low Cr
Necrosis
PWI
rCBV < NAWM
Increased vasculature
Difference between the spatial distribution of regions with increased
metabolism (high Cho) and those with increased rCBV
Target Definition?
Guiding RT Delivery: IMRT
CNI 2
CTV
(FLAIR
+ CNI2)
CNI 3
CNI 4
GTV
(CNI3,4
+ CE)
72 Gy
60 Gy
30 Fx
MRI T1w post Gad + MRSI
IMRT treatment plan
Predictors of outcome
&
Treatment Response
Predictors of worse survival
@ pre-surgery
pre-surgery
MRI
PWI
DWI
MRSI
(56 pts)
Volume
none
Parameter
↑ vol% CEL/T2all
↑ vol% Nec/T2all
↓ 25% ADC/T2all
↑ Lac & Lip/T2all
* Crawford F, et al. ISMRM 2006
Predictors of worse survival
@ pre-Tx
pre-Tx (70 pts)
MRI
PWI
DWI
MRSI
Volume
CEL, NEL, T2all
rCBV>3
ADC<1.5
CNI>2
Lac>0.25
Parameter
↑ rCBV (75, 90%)/NEL
↑ Lac (max, 75, 90%)/NEL
* Saraswathy S, et al. ISMRM 2007
Predictors of worse survival
@ prior to surgery & prior to adjuvant therapy
pre-surgery
MRI
PWI
DWI
MRSI
(56 pts)
pre-Tx (70 pts)
Amount
residual
functional
tumor left
behind is
critical !!
Volume
none
CEL, NEL, T2all
rCBV>3
⇐
ADC<1.5
CNI>2
Lac>0.25
Parameter
↑ vol% CEL/T2all
↑ vol% Nec/T2all
↓ 25% ADC/T2all
↑ Lac & Lip/T2all
↑ rCBV (75, 90%)/NEL
↑ Lac (max, 75, 90%)/NEL
⇑
⇑
More malignant phenotype?
Suggestive of poor
response to RT and CHT
(high cell density, regions of
hypoxia & necrosis)
Predictors of shorter Time-to-progression
following surgery and adjuvant cytotoxic therapy
• Temporal changes ∆ pre-/post-RT
– %Recovery [within NEL]
• ↑ vascular leakiness correlates with shorter TTP
• @ pre-Tx
– Higher peak heights of Cho and Cr as well as related
indices (CNI, CCrI, CrNI) [within NEL > CEL]
• suggest heightened proliferation and predict shorter TTP
– Higher CBV and PH [within NEL]
• Suggest increased angiogenesis and predict shorter TTP
* Pirzkall A, et al. ISMRM 2007
Predictors of shorter Time-to-progression
following surgery and adjuvant cytotoxic therapy
High Cho and Lac
prior to RT
Pre-RT
Post-RT
Customized image-guided therapy
Resection Cavity (RC)
Contrast enhancement (CE)
T2 hyperintensity (T2 h)
60 Gy CRT
m/p low-risk volume (LRV)
m/p high-risk volume (HRV)
“New” target definition:
LRV: rCBV>3
CTV: RC+T2h+CE+LRV
ADC<1.5
BED
→ 2 Gy/day
CNI>2
→ 60 Gy
→ 60 Gy
Lac>0.25
GTV: HRV
HRV: ↑ Lac
→ 2.5 - 3 Gy/day
↑ CBV/PH
→ 72 - 90 Gy
→ 84-120 Gy
OR: → focal therapy (RS, CED, else)
Focal therapy: Image guided CED
• Clinical phase I study for newly diagnosed GBM s/p GTR
in preparation
– CED of liposomal CPT-11
– Adjuvant RT + Temozolomide
Prognostic Value of MRSI
- Radiosurgery in recurrent GBM Time to further treatment
Survival
100
100
(p < 0.01)
80
(p < 0.01)
80
60
A: No abnormal voxels
outside treated
volume (18 pts)
B: Abnormal voxels
outside treated
volume (18 pts)
60
A
40
20
A
40
20
B
0
B
0
0
10
20
30
40
50
0
10
20
30
40
50
Patients with MRSI abnormal regions that were beyond the conventional
radiosurgical target volume do worse compared to others in whom MRSI
abnormality was confined to the volume treated with RS.
* Graves et al. Neurosurg 2000,46(2):319-226
Guiding RT Delivery: Radiosurgery
Conventional RS Target
CNI > 2
Guiding RT Delivery: Radiosurgery
Conventional RS Target
CNI > 2
PIDL based on MRSI
Treatment Effect or Tumor Recurrence?
Pre-treatment
5 mos. post-GK
MRI ⇒ progression,
MRSI ⇒ radiation response
Histology ⇒NECROSIS
Chan et al, 2003
Pre-treatment
5 mos. post-GK
MRI ⇒ progression,
MRSI ⇒ progression
Histology ⇒TUMOR
Treatment Response
following surgery + adjuvant cytotoxic AND cytostatic therapy
• Antiangiogenic Tx
– Avastin + CPT-11
• Recurrent GBM
• Molecularly targeted Tx
– Enzastaurin +
Temozolomide + RT
• Newly dx GBM
→ Data acquisition/evaluation ongoing
– Avastin + Temozolomide
+/- Tarceva
(in patients stable post
XRT+Temozolomide, EGRF
status dependent?)
• Newly dx GBM
→ To be launched (~6 mos)
Treatment Response
following surgery + adjuvant cytotoxic AND cytostatic therapy
Historic
•
•
6 mos PFS 15%
Med PFS
9 wks
Avastin/
Irinotecan
30%
20 wks
Q:
• Anti-VEGF effect only?
• Improved drug delivery?
• Synergistic effects?
Pre-Tx
* Vredenburgh JJ, et al, Clin Cancer Res 2007
After 4 cycles of
Avastin/Irinotecan
aMRI in Prostate Cancer
MRI/MRSI Assessment prior to Therapy
Cancer
Citrate
Cancer vs. Healthy
•
•
MRI: Reduced signal
intensity on T2w
Healthy
Polyamines
Choline
Creatine
Polyamines
Creatine
Choline
Citrate
MRSI: Increased choline
and decreased citrate and
polyamines on MRSI
PPM 3.0
2.5
2.0
PPM 3.0
2.5
2.0
MRSI Scoring System for Prostate
Peripheral Zone Abnormalities
Step-section histopathological tumor maps were used to identify MRSI voxels of
unequivocally benign (n = 306) or malignant (n = 81) peripheral zone tissue in 22
patients with MRI/MRSI studies prior to radical prostatectomy.
1
2
definitely healthy probably healthy
PPM 3.0 2.5 2.0
•
•
PPM 3.0 2.5 2.0
3
equivocal
PPM 3.0 2.5 2.0
4
5
probably cancer definitely cancer
PPM 3.0 2.5 2.0
PPM 3.0 2.5 2.0
The score is based on primarily on the choline+creatine/citrate ratio
Secondarily on choline/creatine ratio, levels of citrate, polyamines and
spectral S/N
Jung JA, Radiology 2004; 233:701-708
Use of MRSI for Radiation Planning
•
•
•
•
(1)
(2)
(3)
(4)
IMRT
RS
PPI (seeds)
HDR
Int. J. Radiat. Oncol. Biol. Phys. 1999; 44:921-929;
Int. J. Radiat. Oncol. Biol. Phys. 2000; 47:1085-1096;
Int. J. Radiat. Oncol. Biol. Phys. 2002; 52:429-438;
Int. J. Radiat. Oncol. Biol. Phys. 2004; 59:1196-1207.
Use of MRSI for Radiation Planning
- HDR -
An average of 2 DIL’s
were contoured on CT
images based on
concordant MRI/MRSI
findings
MRI planning scan with the HDR
catheters in place, manually aligned
with a MRI/MRSI staging exam
Pouliot, Int J Radiat Oncol Biol Phys 2004; 59:1196-1207.
Dose to DIL >120%, while
simultaneously treating the
entire prostate (100%) w/o
increasing the dose to
surrounding normal tissues
MRSI Assessment following Therapy
After therapy,
difficult to detect
cancer based on
MRI alone
Atrophy
Healthy
polyamine
Cho Cr
PPM 3.0 2.5
2.0
Citrate
PPM 3.0 2.5
2.0
Cancer
Cho
Cr
Citrate
PPM 3.0 2.5
2.0
Biomarker of Therapeutic Failure
- Elevated Choline Cancer
Radiation atypia
Choline
Creatine
The presence of three or more abnormal voxels with choline/
creatine >1.5 demonstrated a sensitivity and specificity of 87%
and 72%, respectively, and an overall accuracy of 81% for the
diagnosis of local recurrent/residual disease.
Coakley, Radiology 2004; 233:441-448.
Biomarker of Effective Therapy
- Metabolic Atrophy -
•
•
Increasing metabolic atrophy paralleled decreasing serum PSA with time after
Brachytherapy and EBRT, but occurred significantly earlier.
The presence of residual abnormal metabolism did not correlate with PSA in individual
patients after radiation.
Pickett B et al, IJROBP 59(3):665-73, 2004. Pickett B et al, IJROBP 60(4):1047-55, 2004.
Time Course of Metabolic Atrophy
% of voxels 100
w/ metabolic
atrophy
Brachytherapy: 144 Gy (N = 39)
EBRT: 74 - 81 Gy (N = 29)
80
Brachytherapy was
associated with an
earlier more dramatic
decrease in prostate
metabolism than
EBRT resulting in an
significantly larger %
of the prostate
demonstrating
metabolic atrophy at
the 6-12 and 13-24
month time points
60
* p < 0.05
*
*
40
20
0
Pre-Therapy
Pickett B et al, IJROBP 65(1):65-72, 2006
6 -12
13 -24
25 - 48
Time after Radiation Therapy (months)
> 48
(mean -53)
Time to Resolution of Metabolic Abnormality
Proportion of Patients
1
.75
.5
.25
0
•
•
Brachytherapy (N = 39)
EBRT (N = 29)
0
12
24
36
Months from Treatment
48
60
The median time to resolution of abnormalities for Brachytherapy patients was 24.8 mos,
7.4 mos sooner than for EBRT patients (32.2 months).
All patients receiving Brachytherapy had resolution of metabolic abnormalities by 60 mos,
while 10% of patients receiving EBRT still had metabolic abnormalities at 60 mos.
Pickett, B., Int J Radiat Oncol Biol Phys, 2006
Summary
• There are many new MR methods that are likely to impact
the diagnosis and management of patients with cancer.
• These methods give information about changes in tissue
structure and function rather than merely anatomy.
• They can be acquired as an add-on to a conventional
anatomic MR exam being used for treatment planning or
follow-up.
• Quantitative analysis and integration of the results from
multiple parameters are critical aspects of this technology.
• Validation of the biological significance of these
parameters requires correlations with histology and
outcome.
Acknowledgements
- UCSF Prostate Imaging Program MR Scientists
Radiology
John Kurhanewicz, Ph.D.
Dan Vigneron, Ph.D.
Mark Swanson, Ph.D.
Sarah J. Nelson, Ph.D.
Susan Noworolski, Ph.D.
Albert Chen, BS
Samson Jarso, BS
Mark Alpers, B.S.
Akpene, BS
Penny Wood, BS
Kristin Wright, BS
Beverly Fein, RN
Saying Li, MD
Tuan-Khanh Tran, Ph.D.
Josh Star-Lack, Ph.D.
Lucas Carjaval, BS
Niles Bruce, R.T.
Evelyn Proctor, R.T.
Fergus Coakley, MD
Aliya Qayyum, MD
Jeff Hom, Bs
Ullrich Muller-Lisse, MD
Kyle Yu, MD
Juergen Scheidler, MD
Urology
Peter R. Carroll, MD
Katsuto Shinohara, MD
Eric Small, MD
Biostatistics
Vivian Weinberg, Ph.D.
Ying Lu, Ph.D.
Cancer Center
Chris Haqq
Robert Bok, Ph.D. M.D.
Mark Schuman, Ph.D.
Radiation Oncology
Stanford
Mack Roach, MD
Jean Pouliet, Ph.D.
Barbie Pickett, Ph.D.
Joe Hsu, MD
Randy Ten-Haken, MD
Youngbok Kim, Ph.D.
John Pauly, Ph.D
Chuck Cunningham, Ph.D
Pathology
Jeff Simko, MD
Lars Schmitt
Laura Tabatabai, MD
GE Health
Ralph Hurd, Ph.D
Doug, Kelley
Pom Sailasuta,Ph.D.
Susan Kohler, Ph.D.
NIH Funding
R01 CA079980-06
Acknowledgements
- UCSF Brain Imaging Program Surbeck Laboratory
Neurosurgery
Radiation Oncology
Sarah J. Nelson, PhD
Tracy R. McKnight, PhD
Esin Ozturk, PhD
Michael Lee, PhD
Janine Lupo, MS
Forrest Crawford, MS
Il Woo Park, MS
Colleen McGue, BS
Suja Saraswathy, MS
Mitchel Berger, MD
Michael McDermott, MD
Michael D. Prados, MD
Susan Chang, MD
Kathleen Lamborn, PhD
Krystof Bankiewicz, PhD
Lynn J. Verhey, PhD
David Larson, MD, PhD
Penny Sneed, MD
William Wara, MD
Jean Nakamura, MD
Radiology
William P. Dillon, MD
Soonmee Cha, MD
Grant support
P50 CA97297
RO1 CA-59-880
R21 CA110171
UC Discovery Grants LSIT01-10107 and
ITL-BIO04-10148 funded in conjunction
with
GE Healthcare