Multiple pet tracers in sts treatment response
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MULTIPLE PET TRACERS IN STS TREATMENT RESPONSE. 1 University of Washington Medical Center and 2 Children’s Hospital and Regional Medical Center, Seattle, Washington, USA. UNIVERSITY OF WASHINGYON SEATTLE CANCER CARE ALLIANCE CHILDRENS HOSPITAL SEATTLE, WASHINGTON.

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MULTIPLE PET TRACERS IN STS TREATMENT RESPONSE

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Multiple pet tracers in sts treatment response

MULTIPLE PET TRACERS IN STSTREATMENT RESPONSE

1University of Washington Medical Center and

2Children’s Hospital and Regional Medical Center, Seattle, Washington, USA

UNIVERSITY OF WASHINGYON

SEATTLE CANCER CARE ALLIANCE

CHILDRENS HOSPITAL

SEATTLE, WASHINGTON

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 subtypes french protocol 1997

SARCOMA GRADING & SUBTYPESFrench Protocol 1997

  • Mitoses

  • Differentiation

  • Necrosis

  • Grade Discrepancies = 34.6%

  • “Intermediate” Malignancies Were Omitted!

NCI vs FRENCH

SARCOMA PATH GRADE

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.


Sarcoma patient survival pet grade

Overall Survival

Disease-free Survival

p<0.003

p<0.001

Sarcoma Patient SurvivalPET “GRADE”

SUV < 6.0 ?

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, 2002.


Biopsy sampling error in large 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.

Biopsy - Sampling Error in Large Tumors

GRADING “VARIANCE”?


Uw neoadjuvant chemotherapy

UW NEOADJUVANT CHEMOTHERAPY

FDG PETBiopsyChemo 1Chemo 2

FDG PETChemo 3Chemo 4

FDG PETResectionPostop

Chemo

PET PRIOR TO BIOPSY & RESECTION


Fdg pet survival soft tissue vs bone vs cartilage

FDG PET SURVIVAL:SOFT TISSUE vs BONE vs CARTILAGE

Tumor TypeMean+SDMean+95%CIMedianLog-rank

(Months)(Months)SUVmax(p value)

Evaluating Overall Survival

Cartilage23.9+16.323.9+7.413.90.008

Bone17.6+16.417.6+4.5610.00.505

Soft Tissue18.7+15.718.7+2.685.60.002

Overall18.9+16.018.9+2.186.00.003

Evaluating Disease-free Survival

Cartilage17.7+15.817.7+7.003.90.103

Bone11.2+13.811.2+3.8510.00.483

Soft Tissue14.5+14.814.5+2.525.60.005

Overall14.0+14.714.0+2.006.00.001

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, 2002.


Prognostic factors for dfs

Prognostic Factors for DFS

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”

  • ASCO 2005 Schuetze Eary,Conrad et al

  • Prospective series ( n= 33)

  • 2 cycles(poor resp) vs 4 cycles(good resp)

  • MRI vs PET(40%) vs Histologic Response

  • FDG PET vs Path p=0.092

  • RECIST did not predict Path p=0.002


Factors in response and resistance

Proliferative Rate

Thymidine & Analogs

Glycolytic Rate

FDG

Hypoxia

FMISO, EF1, ATSM

Efflux Pumps

MIBI, Verapamil, Colchicine

Factors in Response and Resistance


Multiple imaging fdg water thymidine

MULTIPLE IMAGING FDG—Water—Thymidine

PRE

CHEMO

Pre-Chemo PET

Post-Chemo PET

POST CHEMO

PREOP

FDG

PERFUSION

(H2O)

THYMIDINE


Verapamil model

Verapamil Model

  • P-glycoprotein Substrate (similar to Adriamycin)

  • Quantify Serial Scans vs. Patient Baseline

  • P-glycoprotein Inactivated by Cyclosporin,etc.

  • Does Chemo Induce P-gp Activity ?

  • Hendrikse NH, de Vries EGE, Franssen EJF, Vaalburg W, van der Graaf WTA. C-11 Verapamil kinetics in human tissue. EJCP 2001.


Uw verapamil preliminary studies

Primate

Human (Brain)

P-gP Active

Brain

P-gp Blocked

UW Verapamil (Preliminary Studies )

CYCLOSPORIN


Specific aims

Specific Aims

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

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

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


Methodology

METHODOLOGY:

METHODS:

SYNTHESIS AGENTS& IMAGING

DATA COLLECTION &ANALYSIS

MODELING BLOOD FLOW

Resection

Thymidine

2

Verapamil 1

Verapamil 2

Followed by

FMISO 2

Chemo +/-

A

Biopsy

FMISO 1

Chemo 1

3X Chemo

FMISO 3

XRT

Then follow-

Thymidine 1

Thymidine 3

up

Water 1

Water 2

Imaging

Imaging

Imaging

Study

Study

Study

1

2

3


Results multiple tracers

RESULTS-MULTIPLE TRACERS


Pre neoadjuvant chemotherapy on mri

Pre-Neoadjuvant Chemotherapy on MRI

501

Status Post-2Cycles Neoadjuvant Chemotherapy on MRI


Multiple pet tracers in sts treatment response

Pre-Neoadjuvant Chemotherapy on MRI

502

Status Post-2 Cycles Neoadjuvant Chemotherapy on MRI


Multiple pet tracers in sts treatment response

Pre-Neoadjuvant Chemotherapy on MRI

503

Status Post-2 Cycles Neoadjuvant Chemotherapy on MRI


Multiple pet tracers in sts treatment response

504

Pre-Neoadjuvant Chemotherapy on MRI

Status Post-2 Cycles Neoadjuvant Chemotherapy on MRI


Results suv max

Results: SUVmax


Multiple pet tracers in sts treatment response

PRE THERAPY

POST THERAPY

FDG -48%

Blood Flow -7%

Liposarcoma

Thymidine

-32%

Verapamil

-27%

FMISO

-5%


Multiple pet tracers in sts treatment response

Pre-Neoadjuvant Chemotherapy on MRI

503

Poor Responder - MFH

Status Post-2 Weeks Neoadjuvant Chemotherapy on MRI

FDG +257%

TdR -3%

FMISO +164%


Gene array data results pending

Gene ArrayData Results – Pending

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

  • Tumor Heterogenity Mapping

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.


Multiple pet tracers

MULTIPLE PET TRACERS:

T2 coronal MRI

Post-Therapy

Pre-Therapy

Water

(20-80s)

Verapamil

(5-25m)


Sarcoma challenges assessing grade

SARCOMA CHALLENGES- ASSESSING GRADE :

  • 1. CLINICAL “GRADE”:

  • Soft Tissue Density, Depth, Size

  • 2. MRI “GRADE”:

  • Size. T2(fluid), inflam zone,

  • “Heterogeneity”(density/necrosis)

  • 3. PET “SUV” GRADE:

  • INITIAL/PRE-CHEMO vs POST-

  • CHEMO

  • “FINAL GRADE” ?


Ctos in seattle 2007

CTOS IN SEATTLE 2007 !


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