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
11 Uni
vers
ity
of W
ashi
ngto
n M
edic
al C
ente
r an
dU
nive
rsit
y of
Was
hing
ton
Med
ical
Cen
ter
and
22 Chi
ldre
n’s
Hos
pita
l and
Reg
iona
l Med
ical
Cen
ter,
Sea
ttle
, Was
hing
ton,
USA
Chi
ldre
n’s
Hos
pita
l and
Reg
iona
l Med
ical
Cen
ter,
Sea
ttle
, Was
hing
ton,
USA
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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 ?
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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”?
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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%
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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.
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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.
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Status Post-2 Cycles Status Post-2 Cycles Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
Status Post-2 Cycles Status Post-2 Cycles Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
502502502502
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Status Post-2 Cycles Status Post-2 Cycles Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
Status Post-2 Cycles Status Post-2 Cycles Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
503503503503
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
FDG -48%
Blood Flow -7%
Thymidine -32%
Verapamil-27%
FMISO -5%
PRE THERAPY POST THERAPY
Lip
osar
com
a
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Pre-Neoadjuvant Pre-Neoadjuvant Chemotherapy on Chemotherapy on
MRIMRI
Status Post-2 Weeks Status Post-2 Weeks Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
Status Post-2 Weeks Status Post-2 Weeks Neoadjuvant Neoadjuvant
Chemotherapy on Chemotherapy on MRIMRI
503503503503
FDG +257%
TdR -3%
FMISO +164%
Poor Responder - MFH
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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:
CTOS-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
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-VENICE NOVEMBER 2006 University of Washington Sarcoma Service
CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !CTOS IN SEATTLE 2007 !