multiple pet tracers in sts treatment response

CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service

MULTIPLE PET TRACERS IN STSMULTIPLE PET TRACERS IN STSTREATMENT RESPONSETREATMENT RESPONSE

MULTIPLE PET TRACERS IN STSMULTIPLE PET TRACERS IN STSTREATMENT RESPONSETREATMENT RESPONSE

UNIVERSITY OF UNIVERSITY OF WASHINGYONWASHINGYON

SEATTLE CANCER CARE SEATTLE CANCER CARE ALLIANCEALLIANCE

CHILDRENS HOSPITALCHILDRENS HOSPITALSEATTLE, WASHINGTONSEATTLE, WASHINGTON

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E.U. CONRAD MD, J.F. EARY MD, J.E. BUTRYNSKI MD,J.M. LINK PhD, A. M. CIZIK MPH, M MUZI MS, and K.A. KROHN PhD supported by NIH NCI CA 42045, S10 RR017229-01


SARCOMA GRADING & SUBTYPESSARCOMA GRADING & SUBTYPESFrench Protocol 1997French Protocol 1997

SARCOMA GRADING & SUBTYPESSARCOMA GRADING & SUBTYPESFrench Protocol 1997French Protocol 1997

MitosesMitosesDifferentiationDifferentiationNecrosisNecrosisGrade Discrepancies = Grade Discrepancies = 34.6%34.6% ““IntermediateIntermediate” Malignancies Were ” Malignancies Were OmittedOmitted!!

Guillou L, Coindre JM, Bonichon F, et al: Comparative Study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group Grading Systems in a Population of 410 Adult Patients with Soft-Tissue Sarcoma, J Clin Oncol, 15(1): 350–62, 1997.

Deyrup AT and Weiss SW. Grading of Soft Tissue Sarcomas: the challenge of providing precise information in an imprecise world. Histopathology 48: 43-50, 2006.

NCI vs FRENCH SARCOMA PATH GRADE


Sarcoma Patient SurvivalSarcoma Patient SurvivalPET “GRADE”PET “GRADE”

Sarcoma Patient SurvivalSarcoma Patient SurvivalPET “GRADE”PET “GRADE”

Eary JF, O’Sullivan, F, Powitan Y, Kingshuk RC, Vernon C, Bruckner JD, and Conrad III EU: Sarcoma tumor FDG uptake Eary JF, O’Sullivan, F, Powitan Y, Kingshuk RC, Vernon C, Bruckner JD, and Conrad III EU: Sarcoma tumor FDG uptake measured by PET and patient outcome: a retrospective analysis. European Journal of Nuclear Medicine, 29(9): 1149–1154, measured by PET and patient outcome: a retrospective analysis. European Journal of Nuclear Medicine, 29(9): 1149–1154, 2002.2002.

Overall SurvivalOverall Survival Disease-free SurvivalDisease-free Survival

p<0.003p<0.003 p<0.001p<0.001

SUV < 6.0 ?


Biopsy - Sampling Error in Biopsy - Sampling Error in Large TumorsLarge Tumors

Biopsy - Sampling Error in Biopsy - Sampling Error in Large TumorsLarge Tumors

High-grade Bx: Myxoid & round-cell liposarcoma; no necrosis.

Interm’-grade Bx: Myxoid liposarcoma; no round-cell areas, no necrosis.

Necrotic Bx: No viable tumor identified.

GRADING “VARIANCE”?


UW NEOADJUVANT CHEMOTHERAPY UW NEOADJUVANT CHEMOTHERAPY

UW NEOADJUVANT CHEMOTHERAPY UW NEOADJUVANT CHEMOTHERAPY

PET PRIOR TO BIOPSY & RESECTIONPET PRIOR TO BIOPSY & RESECTION

FDG PETFDG PET BiopsyBiopsy Chemo 1Chemo 1 Chemo 2Chemo 2

FDG PETFDG PET Chemo 3Chemo 3 Chemo 4Chemo 4

FDG PETFDG PET ResectionResection Postop Postop ChemoChemo


FDG PET SURVIVAL:FDG PET SURVIVAL:SOFT TISSUE vs BONE vs CARTILAGESOFT TISSUE vs BONE vs CARTILAGE

FDG PET SURVIVAL:FDG PET SURVIVAL:SOFT TISSUE vs BONE vs CARTILAGESOFT TISSUE vs BONE vs CARTILAGE

Eary JF, O’Sullivan, F, Powitan Y, Kingshuk RC, Vernon C, Bruckner JD, and Conrad III EU: Sarcoma tumor FDG uptake Eary JF, O’Sullivan, F, Powitan Y, Kingshuk RC, Vernon C, Bruckner JD, and Conrad III EU: Sarcoma tumor FDG uptake measured by PET and patient outcome: a retrospective analysis. European Journal of Nuclear Medicine, 29(9): 1149–1154, measured by PET and patient outcome: a retrospective analysis. European Journal of Nuclear Medicine, 29(9): 1149–1154, 2002.2002.

Tumor TypeTumor Type MeanMean++SDSD MeanMean++95%CI95%CI MedianMedian Log-rankLog-rank(Months)(Months) (Months)(Months) SUVSUVmaxmax (p value)(p value)

Evaluating Overall SurvivalEvaluating Overall SurvivalCartilageCartilage 23.923.9 ++16.316.3 23.923.9 ++ 7.417.41 3.93.9 0.0080.008BoneBone 17.617.6 ++16.416.4 17.617.6 ++ 4.564.56 10.010.0 0.5050.505Soft TissueSoft Tissue 18.718.7 ++15.715.7 18.718.7 ++ 2.682.68 5.65.6 0.0020.002OverallOverall 18.918.9 ++16.016.0 18.918.9 ++ 2.182.18 6.06.0 0.0030.003

Evaluating Disease-free SurvivalEvaluating Disease-free SurvivalCartilageCartilage 17.717.7 ++15.815.8 17.717.7 ++ 7.007.00 3.93.9 0.1030.103BoneBone 11.211.2 ++13.813.8 11.211.2 ++ 3.853.85 10.010.0 0.4830.483Soft TissueSoft Tissue 14.514.5 ++14.814.8 14.514.5 ++ 2.522.52 5.65.6 0.0050.005OverallOverall 14.014.0 ++14.714.7 14.014.0 ++ 2.002.00 6.06.0 0.0010.001


Prognostic Factors for DFSPrognostic Factors for DFSPrognostic Factors for DFSPrognostic Factors for DFS

VariableVariable Exp Exp (Coef)(Coef)

95% C.I.95% C.I. P-P-ValueValue

SUVSUVmaxmax response (>40%) response (>40%) 0.2860.286 0.104–0.7900.104–0.790 0.0090.009

Tumor size (<10 cm)Tumor size (<10 cm) 0.6030.603 0.250–1.4570.250–1.457 0.2610.261

Tumor grade (Gr 3)Tumor grade (Gr 3) 0.6580.658 0.253–1.7110.253–1.711 0.3780.378

Residual viable tumor (Residual viable tumor (<<5%) 5%) 0.6280.628 0.184–2.1410.184–2.141 0.4330.433

Location (extremity)Location (extremity) 0.8860.886 0.366–2.1420.366–2.142 0.7890.789

Schuetze SM, Rubin BP, Vernon C, Hawkins DS, Bruckner JD, Conrad EU, Eary JF. Use of PET in Localized Extremity Soft Tissue Sarcoma Treated with Neoadjuvant Chemotherapy. CANCER 103: 329-348. 2004.

> 40%

< 40%


PET vs”RECIST”PET vs”RECIST”PET vs”RECIST”PET vs”RECIST”

ASCO 2005 Schuetze Eary,Conrad et alASCO 2005 Schuetze Eary,Conrad et al

Prospective series ( n= 33)Prospective series ( n= 33) 2 cycles(poor resp) vs 4 cycles(good resp)2 cycles(poor resp) vs 4 cycles(good resp) MRI vs PET(40%) vs Histologic ResponseMRI vs PET(40%) vs Histologic Response FDG PET vs Path p=0.092FDG PET vs Path p=0.092 RECIST did not predict Path p=0.002RECIST did not predict Path p=0.002


Factors in Response and ResistanceFactors in Response and ResistanceFactors in Response and ResistanceFactors in Response and Resistance

Proliferative RateProliferative Rate

Thymidine & Thymidine & AnalogsAnalogs

Glycolytic RateGlycolytic Rate

FDGFDG

HypoxiaHypoxia

FMISO, EF1, FMISO, EF1, ATSMATSM

Efflux PumpsEfflux Pumps

MIBI, Verapamil, MIBI, Verapamil, ColchicineColchicine


MULTIPLE IMAGING MULTIPLE IMAGING FDG—Water—ThymidineFDG—Water—ThymidineMULTIPLE IMAGING MULTIPLE IMAGING

FDG—Water—ThymidineFDG—Water—Thymidine

FDG PERFUSION (H2O)

THYMIDINE

PRECHEMO

POST CHEMOPREOP

Pre-Chemo PET

Post-Chemo PET


Verapamil ModelVerapamil ModelVerapamil ModelVerapamil Model

• P-glycoprotein Substrate (similar to Adriamycin)P-glycoprotein Substrate (similar to Adriamycin) Quantify Serial Scans vs. Patient BaselineQuantify Serial Scans vs. Patient Baseline• P-glycoprotein Inactivated by Cyclosporin,etc.P-glycoprotein Inactivated by Cyclosporin,etc.• Does Chemo Induce P-gp Activity ? Does Chemo Induce P-gp Activity ?

• Hendrikse NH, de Vries EGE, Franssen EJF, Vaalburg Hendrikse NH, de Vries EGE, Franssen EJF, Vaalburg

W, van der Graaf WTA.W, van der Graaf WTA. C-11 Verapamil kinetics in C-11 Verapamil kinetics in human tissue. human tissue. EJCPEJCP 2001. 2001.


UW Verapamil UW Verapamil (Preliminary Studies )(Preliminary Studies )

UW Verapamil UW Verapamil (Preliminary Studies )(Preliminary Studies )

0

0.05

0.1

0.15

0.2

0 10 20 30 40 50 60

With P-gp

P-gp inhibited

% ID

/cc

Time Post Injection (Min)

Primate Human (Brain)

Brain

P-gp Blocked

P-gP Active

CYCLOSPORIN


Specific AimsSpecific AimsSpecific AimsSpecific Aims

• Specific Aim 1:Specific Aim 1: Correlate [C-11]thymidine uptake in Correlate [C-11]thymidine uptake in sarcoma patients with histologic, immunohistochemical, and sarcoma patients with histologic, immunohistochemical, and gene expression profiles.gene expression profiles.

• Specific Aim 2:Specific Aim 2: Perform pre-and post-chemotherapy Perform pre-and post-chemotherapy hypoxia imaging with [F-18] fluoromisonidazole (FMISO) hypoxia imaging with [F-18] fluoromisonidazole (FMISO) and correlate imaging results with tissue hypoxia markers. and correlate imaging results with tissue hypoxia markers.

• Specific Aim 3:Specific Aim 3: Quantitate the efflux of [C-11] verapamil in Quantitate the efflux of [C-11] verapamil in sarcoma tumors sarcoma tumors in vivoin vivo and correlate with tissue molecular and correlate with tissue molecular markers for p-glycoprotein pump and drug-resistance markers for p-glycoprotein pump and drug-resistance markers.markers.


METHODOLOGY:METHODOLOGY:METHODOLOGY:METHODOLOGY:

Chemo 1ABiopsy 3X Chemo

Thymidine 2

Thymidine 3

FMISO 2FMISO 3

Water 1 Water 2

ResectionFollowed by

XRT

Then follow-up

Imaging

Study

1

Imaging

Study

2

Imaging

Study

3

FMISO 1Chemo +/-

Thymidine 1

Verapamil 1 Verapamil 2

METHODS:SYNTHESIS AGENTS& IMAGINGDATA COLLECTION &ANALYSISMODELING BLOOD FLOW


RESULTS-MULTIPLE TRACERSRESULTS-MULTIPLE TRACERSRESULTS-MULTIPLE TRACERSRESULTS-MULTIPLE TRACERS

Patient Patient ID #ID #

GenderGender AgeAge DiagnosisDiagnosis GradeGrade Location Location SizeSize Metastatic Metastatic Disease at Disease at presentationpresentation

501501 FF 4848 Pleomorphic Pleomorphic liposarcomaliposarcoma 33

L proximal L proximal medial thighmedial thigh

8 cm 8 cm NoNo

502502 FF 5555 Myfibroblastic Myfibroblastic fibrosarcomafibrosarcoma 22 R forearmR forearm 7 cm7 cm IndeterminateIndeterminate

503503 MM 5454 Myofibroblastic Myofibroblastic sarcomasarcoma 22

L pelvis to L pelvis to proximal thighproximal thigh

10 cm10 cm LN+LN+

504504 FF 1818 Alveolar Alveolar rhabdomyosarcomrhabdomyosarcom 33 R forearmR forearm 15 cm15 cm LN+, Lung, SpineLN+, Lung, Spine


Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on

MRIMRI


MRIMRI

Status Post-2Status Post-2Cycles Neoadjuvant Cycles Neoadjuvant Chemotherapy on Chemotherapy on

MRIMRI

Status Post-2Status Post-2Cycles Neoadjuvant Cycles Neoadjuvant Chemotherapy on Chemotherapy on

MRIMRI

501501501501



MRIMRI


MRIMRI

Status Post-2 Cycles Status Post-2 Cycles Neoadjuvant Neoadjuvant

Chemotherapy on Chemotherapy on MRIMRI



502502502502



MRIMRI


MRIMRI





503503503503


Pre-Neoadjuvant Chemotherapy on MRIPre-Neoadjuvant Chemotherapy on MRIPre-Neoadjuvant Chemotherapy on MRIPre-Neoadjuvant Chemotherapy on MRI Status Post-2 Cycles Neoadjuvant Chemotherapy Status Post-2 Cycles Neoadjuvant Chemotherapy on MRIon MRI

Status Post-2 Cycles Neoadjuvant Chemotherapy Status Post-2 Cycles Neoadjuvant Chemotherapy on MRIon MRI

504504504504


Results: SUVResults: SUVmaxmaxResults: SUVResults: SUVmaxmax

SUVmaxHistologic Necrosis Status

Water TdR Ver Miso FDG

501a 5.0 3.0 3.4 2.4 9.2501b 2.2 2.5501c 5.3 2.0 2.4 2.3 4.8

7% -32% -27% -5% -45% 70% NED

502a 4.4 4.0 4.0 3.0 3.7502b 2.5 2.9 4.6

-37% -2% 24% 75% AWD

503a 12.2 6.3 5.8 2.8 35.0503b 6.1 7.5 >90.0 70% AWD

-3% 164% 1.6504a 4.1 4.7 3.2 2.3 8.1504b 1.8 2.3504c 4.3 2.9 2.7 2.5 3.8

6% -38% -18% -24% -53% * AWD


FDG -48%

Blood Flow -7%

Thymidine -32%

Verapamil-27%

FMISO -5%

PRE THERAPY POST THERAPY

Lip

osar

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a



MRIMRI


MRIMRI

Status Post-2 Weeks Status Post-2 Weeks Neoadjuvant Neoadjuvant


Status Post-2 Weeks Status Post-2 Weeks Neoadjuvant Neoadjuvant


503503503503

FDG +257%

TdR -3%

FMISO +164%

Poor Responder - MFH


Gene ArrayGene ArrayData Results – PendingData Results – Pending

Gene ArrayGene ArrayData Results – PendingData Results – Pending

Nielsen TO, West RB…, and van de Rijn M, et al: Molecular characterisation of soft tissue tumors: a gene expression study. The Lancet, 359: 1301–1307, 2002.

• Gene Array Correlation with F-MISO, Verapmil and Thymidine

• Tumor Heterogenity Mapping


Water(20-80s)

Verapamil(5-25m)

Pre

-The

rapy

Pre

-The

rapy

Pos

t-T

hera

pyP

ost-

The

rapy

T2 coronal MRI

MULTIPLE PET TRACERS:MULTIPLE PET TRACERS:MULTIPLE PET TRACERS:MULTIPLE PET TRACERS:


SARCOMA CHALLENGES- SARCOMA CHALLENGES- ASSESSING GRADE :ASSESSING GRADE :

SARCOMA CHALLENGES- SARCOMA CHALLENGES- ASSESSING GRADE :ASSESSING GRADE :

1. CLINICAL “GRADE”:1. CLINICAL “GRADE”: Soft Tissue Density, Depth, SizeSoft Tissue Density, Depth, Size

2. MRI2. MRI “GRADE”: “GRADE”: Size. T2(fluid), inflam zone,Size. T2(fluid), inflam zone, “ “Heterogeneity”(density/necrosis)Heterogeneity”(density/necrosis) 3. PET “SUV” GRADE:3. PET “SUV” GRADE: INITIAL/PRE-CHEMO vs POST- INITIAL/PRE-CHEMO vs POST- CHEMOCHEMO

““FINAL GRADE” ?FINAL GRADE” ?


CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !

multiple pet tracers in sts treatment response

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