PET in SarcomaImaging Treatment Response

CTOS 2004 MontrealJ.F. Eary, M.D.University of Washington

Defining Tumor ResponseDefining Tumor Response

Conventional ImagingConventional Imaging Tumor shrinkage, disappearanceTumor shrinkage, disappearance Tumor qualitative changeTumor qualitative change

Clinical ExamClinical Exam

Defining Tumor ResponseDefining Tumor Response

Clinical QuestionsClinical Questions1. How early can response be detected?1. How early can response be detected?

2. Which is the best treatment agent?2. Which is the best treatment agent?

3. Is an image response a surrogate for effectiveness of 3. Is an image response a surrogate for effectiveness of therapy?therapy?

4. Can patient outcome be inferred?4. Can patient outcome be inferred?

5. Does image response predict for patient outcome?5. Does image response predict for patient outcome?

Tumor ResponseTumor Response

1. Slowed growth1. Slowed growth

2. Stasis2. Stasis

3. Necrosis - coagulative, liquefactive3. Necrosis - coagulative, liquefactive

4. Hemorrhage4. Hemorrhage

5. Serious fluid accumulations5. Serious fluid accumulations

6. Granulation tissue formation6. Granulation tissue formation

7. Scar formation7. Scar formation

8. Loss of vascularity8. Loss of vascularity

9. Loss of malignant elements9. Loss of malignant elements

Re-Defining Tumor ResponseRe-Defining Tumor Response

Quantitative tumor biological parametersQuantitative tumor biological parameters1. Metabolism1. Metabolism

2. Receptor quantity2. Receptor quantity

3. Proliferation3. Proliferation

4. Uptake of thymidine agents4. Uptake of thymidine agents

PET Contributions to Tumor PET Contributions to Tumor Response AssessmentResponse Assessment

1. Quantitative1. Quantitative

2. High spatial resolution2. High spatial resolution

3. Biologically relevant imaging agents3. Biologically relevant imaging agents

Using PET to answer important questions in oncology–

What are the critical differences between normal, malignant, and treated tissue?

How can this information be used to understand the biochemical processes by which therapy kills or fails to kill cells?

From all of the available options, what will be the best treatment for an individual patient?

PET Measurement as a Surrogate Endpoint for

Patient Outcome Tumor staging and grading, including

heterogeneity

Following response to treatment

Identifying the cause of resistance in the individual patient

Prediction / detection of normal tissue damage

Assessing metastases / metastatic potential

Factors in Response and Factors in Response and ResistanceResistance

Surface Surface ReceptorsReceptors

OctreotideOctreotide

Proliferative Proliferative RateRate

Thymidine & Thymidine & AnalogsAnalogs

Glycolytic Glycolytic RateRate

FDGFDG

HypoxiaHypoxia

FMISO, EF1, FMISO, EF1, ATSMATSM

Efflux PumpsEfflux Pumps

MIBI, MIBI, Verapamil, Verapamil, ColchicineColchicine

Nuclear Nuclear ReceptorsReceptors

FES, FES, FDHTFDHT

18FDG is the most important PET procedure

18FDG is the most important PET procedure

*

OHO

HOHO

F OH*

OHO

HOHO

F OH

2-fluoro-2-deoxy-D-glucose2-fluoro-2-deoxy-D-glucose

• FDG reflects altered tissue metabolism• FDG reflects altered tissue metabolism

More than just “grading” images.More than just “grading” images.

High Grade Sarcoma: Near Complete High Grade Sarcoma: Near Complete Response to ChemotherapyResponse to Chemotherapy

Pre-rx

Post-rx

(SUV images, same scale)

ESFT: Response assessed by ESFT: Response assessed by PETPET

Before chemotherapy After chemotherapy

High Grade Sarcoma: High Grade Sarcoma: Tumor Progression during Tumor Progression during

ChemotherapyChemotherapy

Pre-rx

Post-rx

Survival Based on Initial SUV

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Time (months)

Pre SUV<7

Pre SUV>7Su

rviv

al P

rob

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Survival Based onPost-Chemotherapy SUV

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Post SUV<4.2

Post SUV>4.2

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rviv

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Surviving

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a b

c d

SUV Grade

Diameter SUV + Grade

p = 0.026 p = 0.004

p = 0.171 p = 0.0009

SUV > 4

SUV ≤ 4 Grade I

Grade II/III

Diameter ≤ 9 cm

Diameter > 9 cm

FDG PET in Chondrosarcoma

STS Survival Based on Change in Tumor SUV after Neoadjuvant Chemotherapy

STS Survival based on 40% change in SUV after Neoadjuvant ChemoRx

Can We Predict Response Can We Predict Response to Treatment?to Treatment?

Quantitative FDG imaging Quantitative FDG imaging FMISOFMISO C-11 ThymidineC-11 Thymidine C-11 VerapamilC-11 Verapamil

Quantitative FDG imaging Quantitative FDG imaging FMISOFMISO C-11 ThymidineC-11 Thymidine C-11 VerapamilC-11 Verapamil

High Grade Sarcoma: High Grade Sarcoma: Heterogeneous Response to Heterogeneous Response to

ChemotherapyChemotherapy

Pre-rx

Post-rx

3-D Ellipsoidal Model for 3-D Ellipsoidal Model for Homogeneous TumorsHomogeneous Tumors

Utilization U(x) as a Utilization U(x) as a function of position function of position ((xx) is given by) is given by

x1

x2

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0.60.7

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1

U(U(xx) = ) = gg[ [ (x-m)’A(x-m)(x-m)’A(x-m) ] ]

mm is the relative location is the relative location

AA is a shape matrix is a shape matrix

g g is a monotone level functionis a monotone level function

Multivariate Survival AnalysisMultivariate Survival Analysis

Variable Variable (Standardized)(Standardized)

%Change in Risk%Change in Risk 95% C.I.95% C.I. P-valueP-value

SUVSUV 32.232.2 (13,54)(13,54) 0.00050.0005

HeterogeneityHeterogeneity(Elliptical)(Elliptical)

36.236.2 (11,68)(11,68) 0.00380.0038

HeterogeneityHeterogeneity(Boundary-(Boundary-Elliptical)Elliptical)

71.771.7 (-54,542)(-54,542) 0.420.42

N=179 (71 deaths)

Volume, RD, Boundary Morphology, Age: All not significant

Liposarcoma PET StudiesLiposarcoma PET Studies

FDGFDG Blood VolumeBlood Volume ThymidineThymidine

PET Imaging of Factors that PET Imaging of Factors that Limit Response to TherapyLimit Response to Therapy HypoxiaHypoxia

Direct effects: resistance to rads, chemoDirect effects: resistance to rads, chemo Indirect: genetic instabilityIndirect: genetic instability

VEGF, mutant p53VEGF, mutant p53

Multi Drug ResistanceMulti Drug Resistance viavia P-glycoprotein P-glycoprotein high energy requirementhigh energy requirement

PET IMAGING

HIGH GRADE LEIOMYOSARCOMA

18F-FMISO

SUVMAX=3.2 SUVMAX=13.6

FDG

FMISO : identify treatment resistant tumorsFMISO : identify response/re-oxygenationFMISO : select patients for Tirpazamine therapy

PET and Pharmacokinetics:[11C]-verapamil as a marker for the transport of

anti-HIV drugs

Hypothesis: Blocking P-gp will increase the delivery of anti-HIV

nucleosides to the brain

(Sagittal images of a macaque)

No inhibitor

After Cyclosporine (P-pg inhibitor)Brain Uptake

[18F]-FBA-annexin V [18F]-FBA-annexin V ImagesImages

Rats were injected with 0.5 mCi and imaged for 10 min beginning at 60 min after injection. Apoptosis of liver was induced by injection of cycloheximide (5 mg/kg, 4 hr).

Normal Apoptosis

Molecular Imaging AnswersMolecular Imaging Answers

Early indicators of the Early indicators of the effectiveness of therapy will effectiveness of therapy will

improve care--improve care--Reduce ineffective medication useReduce ineffective medication use

Reduce unhelpful proceduresReduce unhelpful proceduresReduce costReduce cost

Improve survival and quality of lifeImprove survival and quality of life

DNA

Microarrays

DNA

Microarrays