Role of imaging in oncology
Positron Emission Tomography
for Treatment Assessment
ANATOMICAL
IGRT
MOLECULAR
Robert Jeraj
Department of Medical Physics
University of Wisconsin – Madison, WI
BEFORE
THERAPY
AFTER
| | | | | …... | |
rjeraj@wisc.edu
DIAGNOSIS
STAGING
TARGET DEF.
RESPONSE EVALUATION
RT PLANNING
TUMOR RESP., EARLY TOX
LOCAL FAILURE, LATE TOXICITY
days, weeks
Why treatment assessment?
Based on early treatment assessment one could modify
treatment:
– If likely not successful:
• Escalate therapy
• Change therapy
• Selectively add dose (RT)
months, years
Treatment assessment now
Histopathological evaluation:
– Typically by regression score (viable tumor vs. fibrosis),
e.g., Salzer-Kuntschik for osteosarcomas
– Limitations: need complete resection, problem with point
biopsies because of tumor heterogeneities
– If likely successful:
• Deescalate therapy
• Stop therapy early
Enormous benefits for the patient - improved tumor
control, reduced side effects, and costs
Radiological evaluation:
– Defined by the therapy-induced reduction of tumor size:
WHO, RECIST
– Limitations: numerous
1
Anatomic response criteria
WHO (Miller, Cancer, 207, 1981):
– the size of a tumor should be estimated based on two
perpendicular diameters
– positive tumor response to therapy should be defined as
a reduction of at least 50% in the product of these two
diameters
RECIST (Response Evaluation In Solid Tumors)
(Therasse, JNCI, 205, 2000):
– The size of a tumor is estimated based on
unidimensional measurement
– Positive tumor response to therapy is at least 30%
decrease in the largest dimension of the tumor
Ideal…
RECIST
Complete Response (CR): Disappearance of all disease compared
with the baseline examination, whether it be measurable or not
Partial Response (PR): A reduction in the sum of the greatest lengths
of individual tumors by at least 30% compared with the baseline
measurement
Progressive Disease (PD): An increase in the total length of all
measurable lesions of more than 20% compared with the smallest sum
of lesion sizes (not the baseline values), or the appearance of
unequivocal new disease
Stable Disease (SD): This lies between the definitions for PR and PD
… and reality
Inherent inconsistencies in
expert observers: 15-40%
Jaffe, J Clin Oncol, 24, 3245 (2006)
Jaffe, J Clin Oncol, 24, 3245 (2006)
2
Other issues…
Tumor shrinkage is only the final step in a complex
cascade of cellular and subcellular changes after treatment
Visual example
Pre-treatment
3 months post treatment
Several cycles of therapy (radiotherapy fractions,
chemotherapy) are needed before treatment response can
be assessed by anatomic imaging
Residual mass is often present after treatment – it is hard
to differentiate between viable tumor posttreatment
changes, such as scarring and fibrosis.
CT scan and comparable FDG-PET scan in a patient with gastro intestinal
stromal tumor (GIST) with hepatic metastatic lesions
Gwyther, Eur J Nucl Med Mol Imaging, 33, S11 (2006)
FDG PET response criteria
Typical behavior of FDG uptake
EORTC FDG PET response criteria
(Young et al, Eur J Cancer 35(13), 1773, 1999):
– Patient preparation – overnight (6h) fasting)
– Timing of scans – within 2 weeks of Tx
– Attenuation corrections – no recommendation
– Uptake measurements – SUVBSA recommended
– Tumor sampling – SUVmax and SUVmean
– Response – complicated
3
Prognostic relevance of FDG-PET
AFTER therapy
EORTC response criteria
Complete Metabolic Response (CMR): Complete
resolution of FDG uptake within the tumor volume
Partial Metabolic Response (PR): A reduction of a
minimum of 15-25% in tumor FDG SUV after one cycle of
chemotherapy, and greater than 25% after more than one
treatment cycle. No recommendation for radiotherapy!
Tumor
Ref
No
pat
Head neck
Kunkel 2003
35
>60
18
0.002
Esophagus
Flamen 2002
36
>34
7
Stable Metabolic Disease (SMD): Increase of less than
25% or a decrease of less than 15% in tumor FDG SUV and
no visible increase in extent (20% in the longest dimension)
Prognostic relevance of FDG-PET
DURING therapy
Survival
non-resp (mo)
0.005
Post-treatment metabolic response is
MacManus 2003
73
>36
<12
highly
predictive
of overall
survival
P
0.01
Swisher 2004
70
>24
14
Hellwig 2004
47
56
19
<0.001
Cervix
Grigsby 2004
152
>45
<20
<0.001
Lymphoma
Several 2001-04
>200
(>30,>60)
3-30
Lung
Progressive Metabolic Disease (PMD): Increase in FDG
tumor SUV of greater than 25% within the tumor region, or
increase of extend of FDG uptake (20% in the longest
direction) or appearance of new lesions
Survival
respond (mo)
0.001
All chemoradiotherapy except lymphoma (chemo only)
FDG-PET and radiation therapy
16
Tumor
Ref
No
pat
Crit
Survival
respond (mo)
Survival
non-resp (mo)
Head neck
Brun 2002
47
50%
>120
40
0.004
Weber 2001
37
35%
>48
20
0.04
14
P
12
Lung
Mid-treatment
metabolic
response
is
Wieder 2004
20 30%
>38
18
highly
predictive
of
overall
survival
Weber 2003
57 20%
9
5
0.01
0.005
Stomach
Ott 2003
35
35%
>48
17
<0.001
Lymphoma
Kostakoglu 2002
30
Vis
>24
5
<0.001
SUVmax
10
Esophagus
Average
8
6
4
2
RT
0
All chemotherapy
0
10
20
30
40
50
60
70
Time [days]
Baardwijk, Radiother Oncol, 82, 145 (2007)
4
FDG-PET and radiation therapy
Molecular imaging targets in oncology
FLT
16
Rapid cellular proliferation
14
12
FRGD
Metabolic non-responders
Increased cellular metabolism:
metabolism:
-Increased glycolysis
-Increased aminoamino-acid
metabolism
SUVmax
10
Average
8
Subverted cellular regulation:
regulation:
-Intracellular signaling
-CellCell-toto-cell signaling
-Extracellular matrix
signaling
6
Metabolic responders
4
2
RT
Evading cellular death
0
0
10
FDG
20
30
40
50
60
70
Altered tumor microenvironment:
-Hypoxia
-Changes in perfusion
-Changes in diffusion
Time [days]
Baardwijk, Radiother Oncol, 82, 145 (2007)
FAnnexin V
CuATSM
Response to targeted therapy in SCC
Response to chemotherapy in NHL
Avastin (bevacizumab) therapy
Guanine nucleotide analogue prodrug (GS-9219)
280 mm 3
Pre-treatment
T/M=2.7
T/M
2.5
0
FLT-PET/CT
SUV
15
330 mm 3
Post-treatment
T/M=1.1
0
FLT-PET/CT
Pre-treatment
… 1 week later
Reiser et al, Clin Cancer Res, 14(9), 2824, (2008)
5
Response to chemotherapy in AML
Response to molecular targeted therapy
Antracycline, cytarabine and/or etoposide
Sunitinib melate (Sutent)
Responders
Non-responders
Sunitinib treatment
Pre-treatment
Week 4
withdrawal
Week 6
Responder
SUV
4
day 5
day 3
day 1
post-therapy
Mean
SUV
Max
SUV
Coefficient
of Variation
Responders
0.79 ± 0.04
3.4 ± 0.2
0.30 ± 0.01
Nonresponders
1.60 ± 0.14
11.4 ± 0.8
0.71 ± 0.04
Partialresponder
0.88
5.1
0.41
SUV
10
0
FLT-PET/CT
0
day 1
Partial–responder
Non-responder
post-therapy
SUV
5
0
FLT-PET/CT
Response to molecular targeted therapy
Response to combination therapy
Sunitinib melate (Sutent)
Bevacizumab + Bevacizumab/Cisplatin/RT
Pre-therapy
k1 (perfusion)
VB (vasculature)
Pre-Avastin:Week 1
k1
VB
0.3
0.6
0
0
SUV
7
0
CuATSM-PET/CT
Post-therapy
Pre-Avastin:Week 1
k1 (perfusion)
VB (vasculature)
SUV
20
Pre-RT: Week 3
SUV
7
Mid-RT: Week 5
SUV
7
0
CuATSM-PET/CT
Pre-RT: Week 3
SUV
4
0
CuATSM-PET/CT
Mid-RT: Week 5
SUV
4
VB
k1
0.3
0.6
0
FDG-PET/CT
0
0
FLT-PET/CT
0
FLT-PET/CT
0
6
Pre-treatment
Mid-treatment
(1 wk of XRT)
Adaptative radiotherapy
Pre-treatment
Response to radiation therapy
Adaptative radiotherapy
Mid-treatment
(1 wk of XRT)
Response to radiation therapy
Response to radiation therapy
Response to radiation therapy
Temporal development
Dose painting
Pre-treatment
Pre
Day 3
Mid-treatment
Treatment response
Day 6
Dose painting plan
Dose prescription
Prescription function
FLT-PET/CT
7
Response to radiation therapy
Response to radiation therapy
Normal tissue response
Normal tissue response
Pre-RT
Post-RT
Conclusions
Treatment assessment has enormous potential to
change patient care
Anatomical imaging used for treatment
assessment has many limitations
Functional/molecular imaging is more powerful
and versatile in assessment of treatment response
Response criteria are more complex, tumor and
tracer dependent
Need for clinical trials with extensive
functional/molecular imaging component
Pre-RT
Post-RT
Thanks to:
Image-guided therapy group
– Vikram Adhikarla
– Dave Barbee
– Steve Bowen
– Joseph Grudzinski
– Michael Daveau
– Matt LaFontaine
– Keisha McCall
– Matt Nyflott
– Peter Scully
– Urban Simoncic
– Chihwa Song
– Benny Titz
– Matt Vanderhoek
– Stephen Yip
Medical Physics
– Jerry Nickles
– Onofre DeJesus
– Dhanabalan Murali
– Rock Mackie
– Sean Fain
Radiology
– Scott Perlman
– Jamey Weichert
– Chris Jaskowiak
– Mark McNall
Human Oncology
– Søren Bentzen
– Paul Harari
– Mark Ritter
– Minesh Mehta
– Wolfgang Tome
– Wendy Walker
Medicine/UWCCC
– George Wilding
– Glenn Liu
– Phase I office
Hematology
– Mark Juckett
– Nancy Turman
Veterinary School
– Lisa Forrest
– David Vail
NIH, NSF, Susan Komen Foundation,
UWCCC
8