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					       PET
      in Oncology.

              Walid Omar, MD
        Nuclear Medicine Dept. NCI
NCI
Presentation outline:

      • What is Positron Emission Tomography (PET)
      •   History of PET development.
      •   PET tracers and future developments.
      •   Clinical Applications in oncology.
      •   Evaluation of treatment response.
      •   New developments in PET scanners.


NCI
             COINCIDENCE IMAGING

      Positron Decay     Positron Annihilation
                       • Two 511 keV photons
                       • Emitted simultaneously
       18F
                       • 180° apart
               e+
                        e+ + e- =       180°



NCI
PET

                                                   solution


 PET tracers annihilate with emission of two 511
 Kev gamma rays emitted at 180 degree apart.             12 %
                                                         energy
                                                         resolution



                    2D      3D




NCI
History :
      • 1975 PHILIPS & Hoffman (PET)
         24 (5cm) NaI TL detectors in hexagonal array
         pattern FBP
      • 1978 (PET II)
           48 (3.75 cm) NaI TL detectors in hexagonal array
           pattern First clinical PET
      • 1981 (Derenzon & Budinger)
           developed the circular geometry
      • Bismuth Germanate Crystal (BGO)/(LGO)
      • Cooling system.

NCI
NCI
NCI
      Requirements for a PET facility?

      •   Cyclotron.
      •   Radiochemistry lab.
      •   PET scanner or PET/CT.
      •   Data processing
      •   Staff
      •   Distribution of PET tracers.



NCI
NCI
      Discovery       LS16
                                    Gemini




                             PET
                               CT




      REVEAL-RT                      REVEA
         function +                    L-XL
           anatomy

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                                      The changing focus of PET ...

                  PET applications worldwide
              mid 80’s                                2004

                                                    5%5%
                         neurology
        10%
      15%
                         cardiology               90%
            75%
                         oncology
         < 10.000                              > 300.000
      procedures p.a.                        procedures p.a.

NCI
  Tx.
             neurology                    oncology
             Em. FDG




  • homogenous organ            • Inhomogeneous body
  • limited variety             • wide variety
  • high activity conc.         • lower activity conc.
  • Uniform attenuation         • high non uniform attn.
  • single organ - single FOV   • WB - multiple FOV

NCI
      PET RADIOPHARMACEUTICALS
PET tracers in Oncology.


      Fluodeoxyglucose F-18
      Water O-15
      Sodium acetate C-11
      Carbon monoxide C-11
      Fluoride F-18
      Methionine C-11
      Thymidine C-11
      Ammonia N13

NCI
FLUORINE-18 FLUORODEOXYGLUCOSE
             (F-18 FDG)
      Extracellular                               Intracellular

                                               Hexokinase

        Glucose                  Glucose                Glucose-6-P


                                               Hexokinase

         FDG                       FDG                      FDG-6-P   X
                                             G-6-Phosphatase

                  Metabolic pathway of glucose and 18F FDG
NCI
           Oncological PET
  HCFA / CMS Approved
  Lung                 Melanoma
  Malignant Lymphoma   Pancreas
  Colorectal           Bone & Soft Tissue
  Malignant Melanoma   Ovarian Cancer.
  Esophagus            Thyroid Ca.
  Head & Neck Cancer
  Breast
  Brain
NCI
                  Normal PET Scan
      • AC / WB image.
      • No bladder Artifacts.
      • Heart and kidneys
        are normally seen.




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NSCLC




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       SUMMARY OF EVIDENCE FOR
        FDG PET IN LUNG CANCER

              For Staging:
              • An estimated 37% change was noted
                 in management effect, based on 1,565
                 patient studies


      Gambhir S.S., et al. “A Tabulated Summary of the FDG PET Literature”
                        J Nucl Med; Vol. 42(5):1S-93S, 2001
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             COLON CANCER




      Metastatic Colon Cancer




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      Ga-67 H D.




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      Hodgkin Disease




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      H D.




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       Advantages of Nuclear Medicine?
      • Metabolic imaging
      • Quantitation is possible especially with PET
      • PET provides ideal solution to quantitate
       tumor biological parameters such
        as metabolism, receptor quantity, cell
        proliferation and uptake of therapeutic agents.



NCI
      EVALUATING TREATMENT RESPONSE
       • Tumor response to chemotherapy:
         • Biologic and metabolic decrease in metabolic
           function and trapping of radiopharmaceuticals
           occurs:
            • Very early after initiation of treatment
            • Precedes clinical decrease in tumor size
            • Precedes decrease in size detected by X-ray,
              CT or MRI.
       • Important to be evaluated early in the course
        of treatment in order to either continue on
        same chemotherapy or change to a different
        regimen before bone marrow depression.
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      NHL Pre-chemotheray




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      NHL Post-chemotheray




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    FDG-PET PREDICTION OF RESPONSE TO
 NEOADJUVANT CHEMOTHERAPY IN CARCINOMA
           OF THE GE JUNCTION




                     N=22                   N=15




NCI        Weber, et al., J Clin Oncol 19:3058, 2001
    FDG-PET PREDICTION OF RESPONSE TO
 NEOADJUVANT CHEMOTHERAPY IN CARCINOMA
           OF THE GE JUNCTION
      Baseline              Day 14

                                              Responder




                                             Non-
                                             responder




NCI              Weber, et al., J Clin Oncol 19:3058, 2001
             METABOLIC RESPONSE TO
                GLEEVEC IN GIST
         DANA-FARBER CANCER INSTITUTE




  Baseline     24 hours   7 days   2 months                  5.5
 months

                                                 AVDA-2001
                                         Dana-Farber Cancer Institute

NCI
 OTHER PET APPROACHES FOR ASSESSING
        RESPONSE TO THERAPY
         • Monitoring
           •   Blood flow
           •   Amino acid metabolism
           •   DNA synthesis (proliferation)
           •   Apoptosis
         • Predicting
           •   Chemotherapeutic agents
           •   MDR substrates
           •   Hypoxia tracers
           •   Receptor ligands



NCI
      PET RADIOPHARMACEUTICALS


      • Labeled chemo-theraputicagents
          F-18 flurodioxy uridine

      • Hypoxia imaging agents
          F-18 Fluro-misonidazole.

      • Tumor receptor status imaging agents.
          F-18-17B-estradiol.


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                 C-11 THYMIDINE

      • DNA precursor, incorporated into DNA
      • Direct assessment of tumor proliferation




NCI
                    C-11 THYMIDINE
      • Uptake in vitro correlates with tumor proliferative
        rate (Higashi et al., 1993)
      • Uptake in animal tumor model correlated with viable
        tumor cells better than FDG uptake cells after
        fractionated radiotherapy (Reinhardt et al., 1997)
      • Uptake correlated with grade in NHL (Martiat et al.,
        1988)
      • More rapid decline in C-11 thymidine uptake than in
        FDG uptake in NSCLC responding to chemotherapy
        (Shields et al., 1998)

NCI
                NON-SMALL CELL CANCER:
                 RESPONSE TO THERAPY
                        FDG   Thymidine

      3/14/96


      4/09/96                             coronal
                                           slices


      5/22/96

                                                    UW
                                                    MC
NCI   UWMC PET Center
 3´-Deoxy-3´-[18F]fluorothymidine (FLT)
                              )




           Shields et al., Nature Med 1998; 11:1334
NCI
             FLT-PET




      Buck et al., Cancer Res 2002; 62:3331
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               FLT-PET IN BREAST CANCER



        Pre-Treatment




       Post-Treatment


  Courtesy of A. Shields,
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  M
                  TUMOR HYPOXIA

      • Hypoxic components in most solid animal tumors
        and presumably most human tumors
      • Increases local tumor aggressiveness and metastatic
        potential
      • Results in resistance to radiotherapy and
        chemotherapy
      • Radioresistance potentially overcome by use of
        high-LET radiation, hyperbaric oxygenation,
        hyperthermia, or hypoxic-cell radiosensitizers



NCI
      MEASUREMENT OF TUMOR HYPOXIA

       • Oxygen electrodes
         • Direct measurement of extracellular O2 levels
         • Pre-therapy O2 levels correlated with outcome of
           radiotherapy in cervical and head & neck cancers
         • Invasive, technically demanding technique
         • Requires accessible tumors
         • Subject to sampling errors




NCI
      MEASUREMENT OF TUMOR HYPOXIA

       • Imaging by PET
         • Traditionally analogs of the radiosensitizer
           misonidazole
         • Noninvasive
         • Entire tumor sampled
         • Repeated measurements possible
         • Resolution limited by PET scanner




NCI
         PREDICTING RESPONSE OF
       ADVANCED BREAST CANCER TO
           HORMONAL THERAPY
      • Hormonal therapy
         • Low morbidity alternative to chemotherapy
         • Only 50-60% of patients with ER+ breast cancer
           respond to hormonal therapy
         • Suggests that receptors not always functional
      • Hypothesis: FDG-PET can be used to define
        functional estrogen receptors by detecting
        metabolic response to receptor agonist



NCI
                           PREDICTING RESPONSE TO
                             HORMONAL THERAPY
                               “Metabolic Flare”
                     100


                     80                                  •   FDG-PET before and after
                                                             7-10 days tamoxifen in 40
  % Change FDG-SUV




                     60
                                                             pts. with advanced ER+
                     40                                      cancers
                     20
                                                         •   With change ≥ 10%:
                                                                  PPV 91%
                      0
                                                                  NPV 94%
                     -20
                                                             for predicting response
                     -40


                     -60

                           Responders   Non-responders
                                                         Mortimer, et al. JCO 2001; 19:2797
                           N = 21         N = 19
NCI
BREAST CARCINOMA: THERAPY FDG-
        PET PREDICTING OF RESPONSE TO
                       HORMONAL
            Before Hormonal Therapy After Hormonal Therapy


      Responder


                     SUV=4.7              SUV=7.5




           Non-
      responder
                     SUV=5.7               SUV=5.5
NCI
      Limitations of PET
      General Limitations:
        High cost.
        Require large space.
        High training for the operating staff is a must.
      Specific Limitations:
        FDG-is a non-specific agent.
        False positive uptake in granulomas.
        Difficult to interpret in areas of normal uptake.
        Depend on glucose transport, that’s why not sensitive
        in mucine & mucinous secreting tumors.


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              CT/PET Image Fusion


      • Guide surgery or biopsy
      • Oncology
         – fibrosis vs. active tumor
         – evaluation of therapy response
         – uptake of FDG vs. size on CT
      • Radiotherapy Applications
         – Tailor field size to viable tumor
         – Assessment of residual mass on CT post therapy




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      Image Fusion: CT & FDG Coincidence Imaging




        Epitheliod Sarcoma after resection

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      Image Fusion: CT & FDG Coincidence Imaging




      Lung Cancer: Poorly differentiated sq. C Ca Rt UC. CT & FDG concordant
      findings for pleural based mass. Patient to be treated by chemotherapy.

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      Glioblastoma: Tumor recurrence

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      LYMPHOMA




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       CT/PET Dependable Image Quality
         7 minute exam                12 minute exam                17 minute exam




      120 lbs – 1 min/bed           160 lbs - 2 min/bed            250 lbs - 3 min/bed
NCI                         Images courtesy of UCLA, Dr. Czernin
                           CT/PET




      3 min/bed, five beds, 1 min CT: 16 min total

NCI              Images courtesy of UCLA, Dr. Czernin
      Ready to use synergies

                        “The use of PET
                        information in the
                        RT planning
                        process significantly
                        improves outcome
                        and patient
                        management.”
                         R. Thompson, M.D.
                         Cedars Sinai Medical Center,
                         Los Angeles, USA




NCI
      Selection of radiation therapy targets by means of 18F-FDG
      imaging (delineated by red lines) resulted in much more
      accurate targeting than did CT alone (delineated by yellow
      lines). The latter would have left untreated cancerous areas
      in the mediastinum
      Wagner H.N., “Highlights 2001 Lecture: Against All Odds, Nuclear Medicine
NCI                 Has Thrived” J Nucl Med; Vol 42(8);12N-30N.
       Gated FDG study showed that a much smaller area need be
       irradiated than the larger area delineated by the green line, thu
       sparing unnecessary irradiation of the spinal cord

      Wagner H.N., “Highlights 2001 Lecture: Against All Odds, Nuclear Medicine
                    Has Thrived” J Nucl Med; Vol 42(8);12N-30N.
NCI
      Clinical Integration




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                     Therapy Connectivity
  • Therapy Connectivity
      – PET and CT DICOM
      – Established connectivity with:
         • Varian, Nomos, Nucletron…etc




NCI
                           Therapy Positioning

• Therapy
  Positioning with
  Open-Port™
  design
      – Patient
        positioning
        accessories
         •   BreastBoard
         •   HipFix
         •   Headholder




NCI
           CHALLENGES:

      • Higher cost
      • Re-designing of installation sites
      • Patient through put
      • Budgeting




NCI
      Thank you



         “
NCI

				
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