PET Imaging of Hypoxia

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1 PET Imaging of Hypoxia John Humm, PhD Dept. of Medical Physics MSKCC AAPM Session: Introduction to Cancer Biology Tuesday 20 th July

2 Many strong hypoxia radiotracer imaging programs University of Washington Seattle have been studying 18 F-FMISO since Washington University in St. Louis developed Cu-ATSM. The group at Edmonton developed a family of hypoxia compounds including IAZA, FAZA and IAZGP UPENN developed 18 F-EF5

3 What do PET images of hypoxia look like? 60 Cu-ATSM Chao et al., IJROBP 49;1171, F-FMISO Lee et al., IJROBP 40;2, 2008

4 What can be gained from hypoxia imaging? (i) Is this tumor hypoxic? Identification of tumor hypoxia as a prognostic indicator of treatment outcome (Höckel et al. Can Res 56: 4509, 1996) (ii) Where is it hypoxic? Determination of the spatial distribution of hypoxia for the purpose of radiobiologically driven dose painting (Ling et al Int.J.Radiat.Oncol.Biol.Phys.47: 551, 2000)

5 Methods to measure hypoxia I po 2 probes Eppendorf & OxyLite mm FSa-II Tumors Frequency % Total 175 Readings in 5 Tumors po 2 probe 10 MicroPET images of hypoxia tracers po 2 in mmhg 2

6 Methods to measure hypoxia II Resect Tumor, Freeze & Section MicroPET images of hypoxia tracers Immunohistochemistry & Autoradiography 2

7 Methods to measure hypoxia III Compare to other Imaging Modalities MRI Gd-DTPA blood flow c MicroPET images of hypoxia tracers Figure 8 : 131 I - Electron Spin Parametric Resonance Courtesy Howard Halpern University of Chicago 2

8 Methods to measure hypoxia IV EcoRI RX/HIF1α TG Hypoxia Responsive Element (HRE) Transfect tumor cell lines with a plasmid containing a reporter gene under the regulation of HIF in this case with a TkGFP reporter construct Autoradiograph of the Hypoxia Tracer 18 F-FMISO Autoradiograph of the reporter construct 124 I-FIAU

9 18 F-FMISO Scans of H&N Patients

10 The concept of a GTV h CT FDG FMISO Lee et al, Fluorine-18-Labeled Fluoro-Misonidazole Positron Emission and Computed Tomography Guided Intensity-Modulated Radiation Therapy in the Treatment of Head and Neck Cancer. IJROBP 2008;70(1):2-13.

11 How do we define the hypoxic volume on an 18 F-FMISO PET image? What criterion do we use to segment the hypoxic tumor sub-volume? How reproducible is an 18 F-FMISO scan?

12 Effect of segmentation threshold FDG-FMISO T/B > 1.0 FDG-FMISO T/B > 1.2 FDG-FMISO T/B > 1.4

13 PET VOXELS Hoechst BLUE Pimonidazole - GREEN Why are the 18 F-FMISO uptake ratios so low

14 Comparison of 2 pre-treatment 18 F-FMISO scans FMISO1 vs. FMISO2 Day0 FMISO image Day3 FMISO image Plot registered voxel intensities from 1 st FMISO image with the 2nd

15 Analysis of 18 F-FMISO Dynamic PET A(t) [Bq/cc] Hypoxia criterion Tumor- Blood Ratio(T:B) 1.3 not reliable t [min] Kinetic analysis of Time-Activity Curves (TAC) is necessary Thorwarth et al, BMC Cancer Dec 1;5:152.

16 A compartmental model to mimic FMISO metabolism. Plasma k Free/NS Bound 1 k Bound 3 Cp k 2 C 1 C 2 [O2]

17 H&N Patient Dynamic PET Images Carotid artery 1 min 2 min 3 min 4 min 5 min 10 min 15 min 20 min 25 min 30 min tumor 90 min 95 min 180 min 185 min CT 17

18 Parametric Images of 18 F-FMISO k 1 k 3 C p (t) C 1 (t) C 2 (t) k 2 Concordance 46 voxels CT 3hr FMISO k3 map k1 map

19 Parametric Images of 18 F-FMISO Discordance CT 3hr FMISO k3 map k1 map 51 voxels

20 Validation of Parametric Images

21 Image Guided po 2 Measurements

22 po 2 tracks overlaid on the late and parametric image maps Track 1 Track 2 Track 3 T:B Late Image Track 1 Track 2 Track 3 k 3 Hypoxia Image

23 Correlation of parametric rate constants to po 2 track values k 3 [min -1 ] k 3 k 1 k 1 [ml/min/g] k 3 [min -1 ] k K 1 [ml/min/g] po 2 [mmhg] po 2 [mmhg]

24 Conclusions Radiobiological dose painting may be a possibility but there are many obstacles. Validation steps is still ongoing, but appear promising in spite of the difficulties. Ideally we would like to be able to image the patient at one single time point and obtain a map of the hypoxia distribution, but kinetic analysis may be a necessary. At a minimum. hopefully we will be able to strategy patients by hypoxic volume.

25 Acknowledgements Dept of Medical Physics C. Clifton Ling Ph.D. Pat Zanzonico, Ph.D. Joseph O'Donoghue, Ph.D. Sean Carlin, Ph.D. James Russell, Ph.D. Sadek Nehmeh, Ph.D. Andrei Pugachev Ph.D. Wenli Wang, Ph.D. Rachel Bartlett, Ph.D. Nuclear Medicine Service Steven M Larson, MD Heiko Schöder, MD Cyclotron / Radiochemistry Jason Lewis, Ph.D. Shangde Cai, Ph.D. Howard Sheh, M.S. Peter Smith-Jones Ph.D. Radiation Oncology Nancy Lee, MD Gloria Li, Ph.D.