8/2/2012
Towards personalized
medicine – integration of
imaging into therapy
Robert Jeraj
Associate Professor of Medical Physics, Human Oncology,
Radiology and Biomedical Engineering
Translational Imaging Research (TIR) Program
University of Wisconsin Carbone Cancer Center, Madison, WI
rjeraj@wisc.edu
Imaging and therapy
Wilhelm Röntgen examines a
patient with X-rays, 1896
Georges Chicotot treats a
patient with X-Rays,1907
100 years later…
Image Guided Radiation Therapy
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100 years later…
Image Guided Surgery
100 years later…
What did medical physics contribute?
Imaging advances
– New imaging modalities: MRI, PET, combined
modalities
– Improved imaging technologies: contrast,
resolution, noise, speed, accuracy
Treatment advances
– New RT technologies: Co-60, linacs, IMRT
– Surgery: Minimally invasive procedures
We can be very PROUD of these achievements!
Disease progression
100 years later…
Where is medical physics in Tx chain?
?
Medical physics space
Shore et al 2012, Br J Urol Intl, 6: 22
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100 years later…
Where is the medicine going?
”4 P’s of medicine”: Individuals respond differently to
environmental conditions, according to their genetic
endowment and their own behavior. In the future, research
will allow us to predict how, when, and in whom a disease
will develop. We can envision a time when we will be able to
precisely target treatment on a personalized basis to those
who need it, avoiding treatment to those who do not.
Ultimately, this individualized approach will allow us to
preempt disease before it occurs, utilizing the participation
of individuals, communities, and healthcare providers in a
proactive fashion, as early as possible, and throughout the
natural cycle of a disease process.
Elias A. Zerhouni, M.D.
Director, National Institutes of Health (NIH), 2008
100 years later…
Where is the medicine going?
”4 P’s of medicine”: Individuals respond differently to
environmental conditions, according to their genetic
endowment and their own behavior. In the future, research
will allow us to predict how, when, and in whom a disease
will develop. We can envision a time when we will be able to
precisely target treatment on a personalized basis to those
who need it, avoiding treatment to those who do not.
Ultimately, this individualized approach will allow us to
preempt disease before it occurs, utilizing the participation
of individuals, communities, and healthcare providers in a
proactive fashion, as early as possible, and throughout the
natural cycle of a disease process.
Elias A. Zerhouni, M.D.
Director, National Institutes of Health (NIH), 2008
Imaging in treatment process
PRE Tx
TREATMENT
POST Tx
| | | …. |
TREATMENT
| | | …. |
DIAGNOSIS
STAGING
TREATMENT
SELECTION
TREATMENT
SELECTION
TREATMENT ASSESSMENT
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TREATMENT SELECTION
PRE Tx
TREATMENT
POST Tx
TREATMENT
| | | …. |
| | | …. |
DIAGNOSIS
STAGING
TREATMENT
SELECTION
TREATMENT
SELECTION
TREATMENT ASSESSMENT
FMISO PET in HN
FMISO PET + (hypoxia) + TPZ boost
FMISO PET – (no hypoxia)
FMISO PET focal uptake
mildly larger than bgrd
FMISO PET + (hypoxia) + chemo boost
Rischin et al 2006, J Clin Oncol, 24: 2098.
FES PET in Breast
LABC or Metastatic Br CA
Recurrent or Metastatic Br CA
Primary Tamoxifen Rx
Aromatase Inhibitor Rx
HER2 Neg
HER2 Pos
10
FES SUV
FES SUV
8
6
4
2
0
Responders
Non-Responders
Mortimer et al 2001,
J Clin Oncol, 19: 2797
Responders
FES PET SUV=1.5
Non-Responders
Linden et al 2006,
J Clin Oncol, 24: 2793
(P < 0.01 for both)
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DCE/DSc MRI in GBM
Radiation Therapy
FTV = 0.07
Yao et al. 2011, Sem Rad Oncol, 21:147
Can we image everything - lung?
Sequist et al. 2011, Ann Oncol, 22:2616
Riley et al. 2009, Proc Am Thorac Soc, 6:201
Maemondo et al 2010, N Engl J Med, 362:2380
© The Author 2011. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email:
journals.permissions@oup.com
MICAD: Molecular Imaging and
Contrast Agent Database
1260 agents listed
(July 2012)
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But can we really use them all?
1
1. Credentialing
2. Modality creation
3. Supporting tools
4. Development
5. Clinical trials
3
2
100%
Regulatory approval
(eIND, RDRC)
4
10%
Regulatory approval (full IND)
Multicenter trial infrastructure
(NCI CIP, ACRIN)
1%
5
Role for medical physics?
Highly interdisciplinary
Cell/molecular biology
Chemistry/radiochemistry
Radiology
Medical physics
Pharmacology
Medicine
Engineering
Mathematics
Material science
Computer science
Courtesy of W. Cai, UW
Is imaging just an expensive tool?
NO, this makes
imaging essential,
and complementary
…branched evolutionary tumor growth,
with 63 to 69% of all somatic mutations
not detectable across every tumor region…
Gerlinger et al 2012, N Engl J Med 366: 883.
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TREATMENT ASSESSMENT
PRE Tx
TREATMENT
POST Tx
TREATMENT
| | | …. |
| | | …. |
DIAGNOSIS
STAGING
TREATMENT
SELECTION
TREATMENT
SELECTION
TREATMENT ASSESSMENT
Treatment response assessment
WHO (1979, 1981)1,2
– anatomic
RECIST (2000, 2009)3,4
– Response Evaluation Criteria
In Solid Tumors
– anatomic, CT/MR based
– unidimensional
– 4 response categories (CR, PR, SD, PD)
complete
response
|
-100%
1WHO
partial
response
|
-60%
stable
disease
|
|
-30%
0%
|
+30%
progressive
disease
|
|
+60%
+100%
1979, 2Miller et al. 1981, 3Therasse et al. 2000, 4Eisenhauer et al. 2009
Power of molecular imaging
Pre-treatment
1 month post treatment
• FDG PET response correctly predicts response to Gleevec in majority of patients
• FDG PET response correctly predicts SD and PD, while CT does not
• FDG PET response precedes the CT response (shrinkage) by several weeks
• FDG PET response is strongly associated with a longer progression free
survival (92% vs. 12% after 1 year) and closely correlated with subjective
symptom control
Stroobants et al 2003, Eur J Cancer 39, 2012
Van der Abbelle 2008, The Oncologist 13(suppl 2), 8
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Acute myeloid leukemia
Day 14 BMBx
17.4 mo
Specificity = 43%
NPV = 64%
Day 28 BMBx
6.9 mo
Hussein et al 2008, Am J Hemat, 83(6): 446
How early can imaging predict future?
Post-therapy
(2 wks)
Pre-therapy
CLINICAL
OUTCOME
(6 mo)
Complete
remission
Chemo
FLT PET
SUV
10
Resistant
disease
Chemo
5
0
Vanderhoek et al 2011, Leuk Res 35: 310
SUV
10
5
Post-therapy
Day 6
Resistant Disease
(6 mo)
Complete Remission
(6 mo)
Early treatment response assessment
Day 5
Day 4
Day 2
0
SUVmax
Coefficient
of Variation
Complete
0.81 ± 0.03
Remission
3.6 ± 0.4
0.33 ± 0.02
Resistant
Disease
11.4 ± 0.8 0.71 ± 0.04
SUVmean
Post-therapy
Day 2
6.1 σ 6.5 σ 6.3 σ
1.6 ± 0.1
Better
than
t-test: p<0.001
for SUV Higgs!!!
, SUV , CV
mean
max
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Heterogeneity of the response
Post
CT#
Pre
CT#
Post FLT PET/Pre FLT PET
SUV
SUV
Ratio
SUV
Pre-treatment FLT PET
Post-treatment FLT PET
Imaging vs biopsies
Percentage of Bone Marrow
20
Complete Remission
Resistant Disease
15
10
NPV = 64%
5
0
1
2
3
4
5
SUV
Role for medical physics?
ADVANCED IMAGE ANALYSIS
X
FLT PET
CT Mask
FLT PET
Bone Marrow
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FDG PET in NSCLC
HR = 2.27
(1.70-3.02 95% CI)
N=1474
SUVmax
Weight
Best cut-off 5-20
SUVmean
LBM
Median
5-10
Unspecified Unspecified Arbitrary
2.5
Berghmans et al 2008, J Thorac Oncol, 3: 6.
PET-based response assessment
EORTC, NCI Recommendations (1999, 2005) 1,2
– SUV-based approach
– SUVmean and SUVmax
– Response categories with thresholds (CR, PR, SD, PD)
PET Response Criteria in Solid Tumors (PERCIST)
(2009) 3
– SUV-based approach
– SUVpeak
– Response categories with thresholds (CR, PR, SD, PD)
1Young
et al 1999, 2Shankar et al 2006, 3Wahl et al 2009
Images are more than just one number!
Size measures
– Volume
– 1D size (axial)
SUVpeak
SUVmax SUVmean
Standardized Uptake
Value (SUV) measures:
– SUVmean
– SUVtotal
– SUVmax
– SUVpeak
1D Size (axial)
250
Volume
Number of Voxels
Uptake Non-uniformity
measure:
– SUVsd
…
SUVtotal
SUVsd
200
150
100
50
0
0
5
10
15
20
Standardized Uptake Value
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Different measures tell different stories
SUVmax
SUVmean
GOOD RESPONSE
SUVtotal
POOR RESPONSE
Volume
NEW LESIONS
Role for medical physics?
SCANNER
HARMONIZATION
UW GE DVST S2N2 vs Dis/cc
measured for different
reconstruction settings
NCI Gemini TF S2N2 vs Dis/cc
measured for one reconstruction
setting
Phantom measurements to
characterize the scanners
Comparative patient data from
UW and NCI studied
Patient S2N2 data presented
using phantom data for reference
NCI
TREATMENT SELECTION - AGAIN
PRE Tx
TREATMENT
POST Tx
| | | …. |
TREATMENT
| | | …. |
DIAGNOSIS
STAGING
TREATMENT
SELECTION
TREATMENT
SELECTION
TREATMENT ASSESSMENT
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EGFR resistance mechanisms
Published by AAAS
Sequist et al. 2011, Sci Transl Med, 3:75
Origins of treatment resistance
...several lines of evidence support the
hypothesis that resistant tumors are a
mixture of sensitive and resistant cells…
Pao and Chimielcki 2010, Nature Rev Cancer, 760.
Role for medical physics?
NEXT TALK
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Summary
Medical physics has been extremely successful, but it has
“captured” only a small part of the interface between
imaging and therapy – ENORMOUS POTENTIAL!!!
Future of medicine – personalized therapy - is complex, but
extremely exciting, don’t wait - EXPAND HORIZONS!!!
MANY ESSENTIAL ROLES we should play beyond
radiotherapy and diagnostic imaging:
– Clinical trial design!
– Molecular imaging chain
– Advanced image analysis
– Quantitative imaging
– Modeling
–…
CJ’s FUTURE
Pondering her future…
... Easy decision…
Courtesy of Stephanie Harmon and her niece CJ, March 2012
Thanks to:
Image-guided therapy group
– Vikram Adhikarla
– Tyler Bradshaw
– Enrique Cuna
– Ngoneh Jallow
– Matt La Fontaine
– Paulina Galavis
– Stephanie Harmon
– Courtney Morrison
– Surendra Prajapati
– Urban Simoncic
– Peter Scully
– Benny Titz
– Natalie Weisse
– Koala Yip
– Stephen Yip
– Former students…
Medical Oncology/Hematology
– Glenn Liu
– George Wilding
– Mark Juckett
– Brad Kahl
– Anne Traynor
Human Oncology
– Søren Bentzen
– Paul Harari
– Mark Ritter
Radiology
– Scott Perlman
– Chris Jaskowiak
Veterinary School
– Lisa Forrest
– David Vail
Funding
– NIH, PCF, UWCCC, Pfizer,
AstraZeneca, Amgen, EntreMed
Medical Physics
– Rock Mackie
– Jerry Nickles
– Onofre DeJesus
Phase I Office
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Medical physics and ART
Courtesy of Koala Yip and her mom, January 2012
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