755

Document Sample
755 Powered By Docstoc
					                                                                 MULTIPLE PET TRACERS IN STS
Hospital and Regional Medical Center, Seattle, Washington, USA
                                                                   TREATMENT RESPONSE
                                                                                                 UNIVERSITY OF
                                                                                                 WASHINGYON
                                                                                             SEATTLE CANCER CARE
                                                                                                   ALLIANCE
of Washington Medical Center and




                                                                                              CHILDRENS HOSPITAL
                                                                                             SEATTLE, WASHINGTON


                                                                 E.U. CONRAD MD, J.F. EARY MD, J.E. BUTRYNSKI MD,
1University
                                2Children’s




                                                                 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 & SUBTYPES
                  French Protocol 1997

Mitoses
Differentiation          NCI vs FRENCH
Necrosis                 SARCOMA PATH GRADE

Grade Discrepancies = 34.6%
“Intermediate” Malignancies Were Omitted!

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.



CTOS-VENICE NOVEMBER 2006                                            University of Washington Sarcoma Service
                       Sarcoma Patient Survival
                           PET “GRADE”
                  Overall Survival                                            Disease-free Survival




                    SUV < 6.0 ?


 p<0.003                                                          p<0.001

 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.
CTOS-VENICE NOVEMBER 2006                                                  University of Washington Sarcoma Service
                  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.

GRADING “VARIANCE”?
     CTOS-VENICE NOVEMBER 2006    University of Washington Sarcoma Service
     UW NEOADJUVANT CHEMOTHERAPY


     FDG PET                Biopsy   Chemo 1                   Chemo 2


                        FDG PET      Chemo 3                   Chemo 4


                        FDG PET      Resection                  Postop
                                                                Chemo


           PET PRIOR TO BIOPSY & RESECTION


CTOS-VENICE NOVEMBER 2006                University of Washington Sarcoma Service
                 FDG PET SURVIVAL:
          SOFT TISSUE vs BONE vs CARTILAGE

 Tumor Type              Mean+SD                            Mean+95%CI                   Median                Log-rank
                         (Months)                            (Months)                    SUVmax                (p value)
 Evaluating Overall Survival
 Cartilage              23.9 +16.3                            23.9 +     7.41               3.9                   0.008
 Bone                   17.6 +16.4                            17.6 +     4.56              10.0                   0.505
 Soft Tissue            18.7 +15.7                            18.7 +     2.68               5.6                   0.002
 Overall                18.9 +16.0                            18.9 +     2.18               6.0                   0.003

 Evaluating Disease-free Survival
 Cartilage              17.7 +15.8                            17.7 +     7.00               3.9                   0.103
 Bone                    11.2 +13.8                           11.2 +     3.85              10.0                   0.483
 Soft Tissue            14.5 +14.8                            14.5 +     2.52               5.6                   0.005
 Overall                14.0 +14.7                            14.0 +     2.00               6.0                   0.001


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.
CTOS-VENICE NOVEMBER 2006                                                   University of Washington Sarcoma Service
           Prognostic Factors for DFS
Variable                                   Exp         95% C.I.         P-Value
                                         (Coef)
SUVmax response (>40%)                     0.286     0.104–0.790           0.009
Tumor size (<10 cm)                        0.603     0.250–1.457           0.261
Tumor grade (Gr 3)                         0.658      0.253–1.711          0.378
Residual viable tumor (<5%)                0.628     0.184–2.141           0.433
Location (extremity)                       0.886     0.366–2.142           0.789


                       > 40%   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
                < 40%          Chemotherapy. CANCER 103: 329-348.
                               2004.

CTOS-VENICE NOVEMBER 2006              University of Washington Sarcoma Service
                      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


CTOS-VENICE NOVEMBER 2006       University of Washington Sarcoma Service
        Factors in Response and Resistance
       Proliferative Rate
                            Glycolytic Rate
          Thymidine &
            Analogs              FDG


                                                Hypoxia
                                            FMISO, EF1,
                                              ATSM


                                           Efflux Pumps
                                        MIBI, Verapamil,
                                          Colchicine
CTOS-VENICE NOVEMBER 2006         University of Washington Sarcoma Service
                  MULTIPLE IMAGING
                 FDG—Water—Thymidine
             PRE
             CHEMO                Pre-Chemo PET




 POST                             Post-Chemo PET
CHEMO
PREOP

                            FDG      PERFUSION THYMIDINE
                                      (H2O)
CTOS-VENICE NOVEMBER 2006            University of Washington Sarcoma Service
                      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.

CTOS-VENICE NOVEMBER 2006       University of Washington Sarcoma Service
                                    UW Verapamil
                             (Preliminary Studies )

                 Primate                                 Human (Brain)
                     P-gP Active                    0.2
                                                                                    With P-g p

                                                                                    P-gp inh ibited
                                                0.15

Brain




                                          % ID/cc
                                                    0.1


                   P-gp Blocked
                                                0.05




                                                     0
                                                      0    10     20    30      40     50        60
                                                                 Time Post Injection (Min)
        CYCLOSPORIN

        CTOS-VENICE NOVEMBER 2006                         University of Washington Sarcoma Service
                                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.
    CTOS-VENICE NOVEMBER 2006            University of Washington Sarcoma Service
                            METHODOLOGY:
         METHODS:
         SYNTHESIS AGENTS& IMAGING
         DATA COLLECTION &ANALYSIS
         MODELING BLOOD FLOW
                                                                                      Resection
              Verapamil 1             Thymidine 2                  Verapamil 2       Followed by
                                      FMISO 2                                        Chemo +/-
Biopsy   A    FMISO 1       Chemo 1                 3X Chemo        FMISO 3
                                                                                        XRT

             Thymidine 1                                           Thymidine 3       Then follow-
              Water 1                                                Water 2              up

             Imaging                  Imaging                      Imaging
              Study                     Study                        Study
                 1                        2                            3




 CTOS-VENICE NOVEMBER 2006                              University of Washington Sarcoma Service
          RESULTS-MULTIPLE TRACERS

Patient   Gender       Age    Diagnosis         Grade Location           Size      Metastatic
ID #                                                                               Disease at
                                                                                   presentation
                              Pleomorphic             L proximal
   501         F        48    liposarcoma         3   medial thigh
                                                                         8 cm               No


                              Myfibroblastic
   502         F        55    fibrosarcoma        2   R forearm          7 cm          Indeterminate



                              Myofibroblastic         L pelvis to
   503        M         54    sarcoma             2   proximal thigh
                                                                         10 cm             LN+



                              Alveolar
   504         F        18    rhabdomyosarcom     3   R forearm          15 cm       LN+, Lung, Spine




          CTOS-VENICE NOVEMBER 2006                        University of Washington Sarcoma Service
                                                          Pre-Neoadjuvant
                                                          Chemotherapy on
                                                               MRI


501



                                                           Status Post-2
                                                        Cycles Neoadjuvant
                                                         Chemotherapy on
                                                               MRI




      CTOS-VENICE NOVEMBER 2006   University of Washington Sarcoma Service
                                                          Pre-Neoadjuvant
                                                          Chemotherapy on
                                                               MRI


502




                                                        Status Post-2 Cycles
                                                            Neoadjuvant
                                                         Chemotherapy on
                                                                MRI




      CTOS-VENICE NOVEMBER 2006   University of Washington Sarcoma Service
                                                          Pre-Neoadjuvant
                                                          Chemotherapy on
                                                               MRI


503




                                                        Status Post-2 Cycles
                                                            Neoadjuvant
                                                         Chemotherapy on
                                                                MRI




      CTOS-VENICE NOVEMBER 2006   University of Washington Sarcoma Service
          504




                                      Status Post-2 Cycles Neoadjuvant Chemotherapy
Pre-Neoadjuvant Chemotherapy on MRI
                                                          on MRI
      CTOS-VENICE NOVEMBER 2006                 University of Washington Sarcoma Service
                              Results: SUVmax
                                                              Histologic
                               SUVmax                         Necrosis         Status
            Water      TdR       Ver    Miso      FDG


   501a      5.0        3.0      3.4      2.4      9.2
   501b                 2.2               2.5
   501c     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      3.7
   502b                 2.5               2.9      4.6
                      -37%               -2%      24%            75%           AWD
   503a     12.2        6.3      5.8      2.8     35.0
   503b                 6.1               7.5    >90.0           70%           AWD
                       -3%              164%       1.6
   504a      4.1        4.7      3.2      2.3      8.1
   504b                 1.8               2.3
   504c      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
                              PRE THERAPY              POST THERAPY




FDG -48%

Blood Flow
-7%
             Liposarcoma




Thymidine
-32%



Verapamil
-27%


FMISO
-5%

             CTOS-VENICE NOVEMBER 2006      University of Washington Sarcoma Service
                                                          Pre-Neoadjuvant
                                                          Chemotherapy on
                                                               MRI


503                                                    Poor
                                                       Responder -
                                                       MFH


                                                        Status Post-2 Weeks
                                                            Neoadjuvant
                                                         Chemotherapy on
                                                                MRI

                                                       FDG +257%
                                                       TdR -3%
                                                       FMISO +164%


      CTOS-VENICE NOVEMBER 2006   University of Washington Sarcoma Service
                       Gene Array
                  Data 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.




CTOS-VENICE NOVEMBER 2006       University of Washington Sarcoma Service
                           MULTIPLE PET TRACERS:




                                         Post-Therapy
T2 coronal   Pre-Therapy
   MRI




  Water
 (20-80s)



Verapamil
 (5-25m)


             CTOS-VENICE NOVEMBER 2006                  University of Washington Sarcoma Service
      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-VENICE NOVEMBER 2006              University of Washington Sarcoma Service
         CTOS IN SEATTLE 2007 !




CTOS-VENICE NOVEMBER 2006   University of Washington Sarcoma Service

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:0
posted:8/15/2012
language:
pages:26