1. Prospects for imaging prostate cancer with PET/CT and PET/MR Maurizio Conti Siemens Healthcare Molecular Imaging, Knoxville, Tennessee, USA Mediterranean Thematic Workshops in Advanced Molecular Imaging Alghero, September 2-7, 2014

2. index motivation & introduction PET tracers for prostate cancer advances in PET technology and new opportunities for PET improved detectability for prostate cancer lesions PET/MR for prostate cancer imaging new directions: a discussion on PET scanner architectures new directions: guided biopsy

3. Motivation Prostate cancer is the leading cancer for men in the US (and second for death): one out of six men will be diagnosed with prostate cancer in his life; Accurate localization/staging is the key to success in treatment; The techniques available for detection and localization are very poor, compared to all other major cancers. Typical prostate cancer path: High PSA “blind” biopsy (false negative 30% !) if positive, prostatectomy + bone scan for metastasis future of PET in prostate cancer: Develop high specificity tracers Develop high performance PET instrumentation

4. Prostate cancer imaging The holy grail(s) of prostate cancer imaging today:  Specific tracers, high sensitivity and high specificity of the imaging scan  Improve early detection and localization of small lesion inside prostate and in lymph nodes (support for diagnosis and biopsy and treatment)  assess aggressiveness of disease via non-invasive techniques (treatment or active surveillance)

5. Tracers

6. PET tracers for prostate cancer TracerMechanismSpecificityUptake [ 18 F]FDGGlucose metabolismNon specificLow uptake [ 11 C/ 18 F]choline Lipid metabolism Non specificHigh uptake [ 11 C/ 18 F]acetateNon specificHigh uptake [ 18 F]NaFCalcium analogNon specificHigh uptake [ 11 C]methionine Amino acid transport Non specificHigh uptake [ 18 F]FACBCNon specificHigh uptake [ 18 F]FLT Cell proliferation Non specificLow uptake [ 18 F]FMAUNon specificHigh uptake [ 18 F]FDHTAndrogen receptorSpecificHigh uptake [ 18 F]DCFBC, [ 18 F]DCFPyL, [ 68 Ga]PSMA PSMA inhibitorSpecificHigh uptake [ 64 Cu/ 89 Zr]J591, [ 89 Zr]5A10, others Free PSA and PSMA antibodies SpecificHigh uptake

7. PSMA tracers Compound is inhibitor of a specific site in PSMA (high affinity): It bounds strongly and only to PSMA Low molecular weight (fast uptake) * Banerjee et al.: “Synthesis and Evaluation of Technetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen (PSMA)”J Med Chem 51, 4504-4517, 2008 ** Courtesy of Martin Pomper

8. A.Afshar-Oromieh et al.: “Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer”, EJNMMI 41: 11-20 (2014) * Figure from journal article R.C.Mease et al.: “N-[N-[(S)-1,3-Dicarboxypropyl]Carbamoyl]-4- [18F]Fluorobenzyl-LCysteine, [18F]DCFBC: A New Imaging Probe for Prostate Cancer”, Clin. Cancer Res. 14: 3036-3043 (2008) * Courtesy of Martin Pomper, private communication PSMA tracers Ga68-PSMA F18-PSMA F18-choline Ga68-PSMA F18-PSMA

9. New prospects for PET

10. “High sensitivity, high resolution PET with high specificity tracers, for early and spatially accurate detection of tumors inside the prostate.” Objectives: Better diagnosis and staging: providing a tool for guided biopsy and more accurate assessment of the grade of the disease; Reduce the need for radical prostatectomy; Guide the radical prostatectomy, obtaining less positive margins and sparing healthy tissue; Safer diagnosis and staging: reducing the need of "blind" surgical removal of pelvic lymph nodes; Provide more accurate tumor localization information for any localized therapy, in order to achieve more effective and safer therapy. Vision

11. Typical patient path high PSA US-guided blind biopsy false positivetrue positivetrue negativefalse negative no treatmentunder treatmentover treatment treatment active surveillance prostatectomylocalized therapy: BrachyTP, RadioTP, Hadrons, HIFU monitoring adjust therapy PET PET-guided biopsy X X PET PET-aided choice of treatment PET positive Impact of Hi Res PET with highly specific tracer PET guidance for surgery accurate monitoring with PET true negative no treatment PET negative X X diagnosis/staging: high resolution localization inside prostate detection of early metastasis in lymph nodes biopsy: high resolution localization inside prostate

12. High resolution, high sensitivity with new PET scanners Improvements in PET technology in recent years: scintillation material: LSO (LYSO) -> higher sensitivity small crystal detectors -> higher resolution long axial coverage (>20cm)-> higher sensitivity PSF reconstruction-> lower noise, higher contrast TOF reconstruction-> lower noise, faster convergence, better localization accuracy new modality:-> PET/MR PST+TOF: lower noise -> smaller pixel-size and better spatial resolution. osem 4mm psf 2mm psf+tof 2mm osem 2mm osem+tof 2mm

13. High resolution, high sensitivity with new PET scanners : a simulation

14. Original image Resample (2mm pixel) Deconvolve (pixel size & filter) Add lesions Forward project into sinogram Apply normalization -1 & attenuation Add scatterAdd randoms Add Poisson noise reconstruct New image Scale to set counts High resolution, high sensitivity with new PET scanners : a simulation

15. Lesions Start from clinical 11 C-choline images Add lesions Lesion intensity: SUV = 4, 6, 8 Lesion size: 4 mm, 6 mm, 10 mm Forward project, add simulated Scatter, Randoms, Poisson noise Total number of netTrues (Trues+Scatter) = 30x10 6 Random Fraction=50% 100 or 50 realizations Reconstruction Method analog to original image for comparison (typically OSEM, 4mm pixel, 21 subsets, 2 iterations, 6mm filter) OSEM+PSF+TOF (2mm pixel, 21 subsets, 2 iterations, <4mm filter) Lesions Create lesions in two positions: inside the prostate (to differentiate extra capsule and intra capsule tumors) outside the prostate in the pelvic area (simulate metastasis on lymph nodes) High resolution, high sensitivity with new PET scanners : a simulation

16. 11 C-choline patient with simulated small lesions: 6mm lesion, 6:1 contrast (a)the original PET/CT image, with no simulated lesion; (b)the simulation with lesions, reconstruction with low resolution OSEM; (c)the simulation with lesions, PSF+TOF reconstruction with 2mm voxel size Original reconstruction: OSEM, 5.5x5.5x3.3 mm 3 voxels, 20 subsets, 2 iterations, 6mm filter Proposed reconstruction: OSEM+PSF+TOF, 2x2x2 mm 3, 21 subsets, 2 iterations, no filter (a) (b) (c) High resolution, high sensitivity with new PET scanners : a simulation

17. LROC curve for all data (all patients, all lesions) Higher detectability with high resolution imaging 4mm lesion 6mm lesion 10mm lesion Numerical observer’s analysis High resolution, high sensitivity with new PET scanners : a simulation

18. PET + MR: multi parametric MRI

19. PET + Multi parametric MR: T2w MRI (anatomy) Dynamic Contrast Enhanced (DCE) MRI (vascularity) Diffusion Weighted Imaging (DWI) MRI (water diffusion, cell density) Magnetic Resonance Spectroscopy Imaging (MRSI) (choline/citrate ratio, 13 C pyruvate/lactate ratio) synergic contribution to diagnosis !

20. DCE (Dynamic contrast enhanced MRI): Gd-chelate as contrast agent for angiogenesis S.Verna et al., “Overview of Dynamic Contrast-Enhanced MRI in Prostate Cancer Diagnosis and Management”, AJR 198,1277–1288, 2012 fused DCE T2w PET + MR: multi parametric MRI

21. DWI (Diffusion weighted MRI): restricted water diffusion in tumor B. Turbey et al., “Multiparametric 3T Prostate Magnetic Resonance Imaging to Detect Cancer: Histopathological Correlation Using Prostatectomy Specimens Processed in Customized Magnetic Resonance Imaging Based Molds”, Journal of Urology 186, 1818-1824, 2011 T2w DWI PET + MR: multi parametric MRI

22. MRSI: (choline+creatine)/citrate ratio as a marker of cancer K.L.Zachian et al.,“1H magnetic resonance spectroscopy of prostate cancer: Biomarkers for tumorcharacterization”, Cancer Biomarkers 4, 263-276, 2008

23. MRSI: hyperpolarized 13 C ( 13 C-pyruvate contrast agent), tracks a dramatic increase in lactate/pyruvate ratio in tumor cells Simon Hu et al.,“13C-Pyruvate Imaging Reveals Alterations in Glycolysis that Precede c-Myc- Induced Tumor Formation and Regression”, Cell Metabolism 14, 131–142, 2011 Before therapy After therapy PET + MR: multi parametric MRI

24. PET+Multi parametric MR to guide the biopsy Takei et al., “A Case of Multimodality Multiparametric 11C-Choline PET/MR for Biopsy Targeting in Prior Biopsy-Negative Primary Prostate Cancer”, Clinical Nuclear Medicine 37, 918, 2012 PET/CT PET/MR MultiPar-MR 11 C-choline PET/CT & PET/MR T2w MRI + DWI MRI + DCE MRI *Munich, on Siemens mMR DWI DCE T2w PET + MR: multi parametric MRI

25. New directions: PET scanner architectures for imaging of prostate cancer

26. Question: which approach is most interesting or effective or realistic ? New directions: PET scanner architectures for imaging of prostate cancer a high performance whole body PET scanner, with classic ring architecture, with top of the line reconstruction: high resolution, high sensitivity, PSF, TOF, optimized protocol for prostate cancer Pros: available now, general purpose scanner Cons: limited resolution (  4mm), limited sensitivity the same high performance whole body PET scanner with a high resolution insert, with a local magnification; Pros: high res (≤2mm), can use present scanners Cons: technical issues, complex reconstruction a dedicated high performance small diameter PET camera with small scintillating crystals, with increased sensitivity and resolution. Pros: high res (≤2mm), lower cost than full scanner Cons: engineering development, all cost is for urologist

27. New directions: instrumentation for biopsy TASKS: Detection and diagnosis Staging and characterization Surgery and biopsy

28. Today, ultrasound, no information on the location of the tumor, only anatomical information of the shape of prostate Future, PET+CT/MR, high resolution information about the location of the tumor, fused with the anatomical map*. * Even choline could be used: low specificity but high sensitivity. New directions: instrumentation for biopsy

29. “on-line” MR guided biopsy

30. “off-line” MR-US guided biopsy Registration method: MR image is acquired previously; MR volume is identified; MR-US are registered real time during US-guided biopsy. Rastinehad et al., “Improving Detection of Clinically Significant Prostate Cancer: Magnetic Resonance Imaging/Transrectal Ultrasound Fusion Guided Prostate Biopsy”, The Journal of Urology 191, 1749–1754, 2014 Commercial products: Koelis, UroNav, and Artemis

31. Question: which approach is best to guide a prostate cancer biopsy? New directions: more on biopsy Method performance: sensitivity&localization technical complexitycost USPoor: blind biopsynoneLow on-line MRHigh: can locate some tumorslow Moderate+: requires to perform biopsy in MR scanner MR+US (MR off-line, registered) Adequate: can locate some tumors but possible registration issues low-moderateModerate: requires MR scan PET+US (PET off-line, registered) Adequate+: can locate active tumors but possible registration issues low-moderateModerate: requires PET scan MR+US (simultaneous)High: can locate some tumorsmoderate Moderate+: requires to perform biopsy in MR scanner PET+US (simultaneous)High+: can locate active tumorsvery high High: requires to perform biopsy in PET scanner MR+PET+US (simultaneous) Very high: can locate active tumors + multimodality synergy very high Very high: requires to perform biopsy in PET/MR scanner

32. “on-line” PET guided biopsy using magnification probes ? PET ring from S. Majewski Simultaneous acquisition method:  biopsy probe in PET/MR or PET/CT scanner;  US and/or PET and/or MR images are acquired simultaneously;  the biopsy can be guided by US-PET-MR *H. Wu, Y.C. Tai et al.: “Micro Insert: A Prototype Full-Ring PET Device for Improving the Image Resolution of a Small-Animal PET Scanner”, J Nucl Med 49, p. 1668, 2008 *J. Zhou, J. Qi, “Theoretical analysis and simulation study of a high-resolution zoom-in PET system”, Phys Med Biol 54, p. 5193, 2009 F. Garibaldi et al.: “TOPEM: A multimodality probe (PET TOF, MRI, and MRS) for diagnosis and follow up of prostate cancer” IEEE Nucl Sci Symp Conf Rec 2010, p. 2442, 2010 S. Majewski et al., “Dedicated mobile PET prostate imager”, J Nucl Med 52 (Suppl. 1), p.1945, 2011 Needs:  High resolution, high sensitivity probe: Small crystals, TOF, magnification effect*  Complex reconstruction algorithm: Localization of the probe Attenuation correction Anisotropic resolution (artifacts?)  How to do an acceptable PET image in a few seconds? High sensitivity and TOF? Better reconstruction algorithms?

33. Thanks! And thanks to: Harshali Bal Lars Eriksson Hossein Jadvar Peter Choyke Stefano Fanti Martin Pomper Stan Majewski H. Bal et al.,“Improving PET spatial resolution and detectability for prostate cancer imaging”, Phys. Med. Biol. 59, 4411-4426 (2014). M. Conti,“New prospects for PET in prostate cancer imaging: a physicist’s viewpoint”, Eur.J.Nucl.Med.Mol.Imag.Phys.,in press (2014) It is a time of great opportunities for PET imaging of prostate cancer! Put on your pink glasses!