Prospects for imaging prostate cancer with PETCT and

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

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

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

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)

Tracers

PET tracers for prostate cancer Tracer Mechanism Specificity Uptake Glucose metabolism Non specific Low uptake Non specific High uptake Non specific High uptake Non specific Low uptake Non specific High uptake Androgen receptor Specific High uptake [18 F]DCFBC, [18 F]DCFPy. L, [68 Ga]PSMA inhibitor Specific High uptake [64 Cu/89 Zr]J 591, [89 Zr]5 A 10, others Free PSA and PSMA antibodies Specific High uptake [18 F]FDG [11 C/18 F]choline [11 C/18 F]acetate [18 F]Na. F [11 C]methionine [18 F]FACBC [18 F]FLT [18 F]FMAU [18 F]FDHT Lipid metabolism Calcium analog Amino acid transport Cell proliferation

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

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

New prospects for PET

Vision “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.

Typical patient path Impact of Hi Res PET with highly specific tracer diagnosis/staging: • high resolution localization inside prostate • detection of early metastasis in lymph nodes high PSA biopsy: high resolution localization inside prostate PET-guided US-guided biopsy blind biopsy X false positive X over treatment prostatectomy PET negative PET positive true positive PET-aided treatment choice of treatment active surveillance true negative no treatment X true negative false negative no treatment under treatment X localized therapy: Brachy. TP, Radio. TP, Hadrons, HIFU PET monitoring PET guidance for surgery accurate monitoring with PET adjust therapy

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

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

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

High resolution, high sensitivity with new PET scanners : a simulation Lesions Create lesions in two positions: • inside the prostate (to differentiate extra capsule and intra capsule tumors) • outside the prostate in the pelvic area Lesions (simulate metastasis on lymph nodes) • 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 net. Trues (Trues+Scatter) = 30 x 106 • Random Fraction=50% • 100 or 50 realizations Reconstruction • Method analog to original image for comparison (typically OSEM, 4 mm pixel, 21 subsets, 2 iterations, 6 mm filter) • OSEM+PSF+TOF (2 mm pixel, 21 subsets, 2 iterations, <4 mm filter)

High resolution, high sensitivity with new PET scanners : a simulation 11 C-choline patient with simulated small lesions: 6 mm lesion, 6: 1 contrast (a) (b) (c) (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 2 mm voxel size Original reconstruction: OSEM, 5. 5 x 3. 3 mm 3 voxels, 20 subsets, 2 iterations, 6 mm filter Proposed reconstruction: OSEM+PSF+TOF, 2 x 2 x 2 mm 3, 21 subsets, 2 iterations, no filter

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

PET + MR: multi parametric MRI

PET + MR: multi parametric MRI PET + Multi parametric MR: • T 2 w MRI (anatomy) • Dynamic Contrast Enhanced (DCE) MRI • Diffusion Weighted Imaging (DWI) MRI (vascularity) (water diffusion, cell density) • Magnetic Resonance Spectroscopy Imaging (MRSI) (choline/citrate ratio, 13 C pyruvate/lactate ratio) synergic contribution to diagnosis !

PET + MR: multi parametric MRI 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 T 2 w fused DCE

PET + MR: multi parametric MRI DWI (Diffusion weighted MRI): restricted water diffusion in tumor B. Turbey et al. , “Multiparametric 3 T 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 T 2 w DWI

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

PET + MR: multi parametric MRI MRSI: hyperpolarized 13 C (13 C-pyruvate contrast agent), tracks a dramatic increase in lactate/pyruvate ratio in tumor cells Simon Hu et al. , “ 13 C-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 PET+Multi parametric MR to guide the biopsy 11 C-choline PET/CT Takei et al. , “A Case of Multimodality Multiparametric 11 C-Choline PET/MR for Biopsy Targeting in Prior Biopsy-Negative Primary Prostate Cancer”, Clinical Nuclear Medicine 37, 918, 2012 PET/CT & PET/MR T 2 w MRI + DWI MRI + DCE MRI DWI *Munich, on Siemens m. MR DCE Multi. Par-MR PET/MR T 2 w

New directions: PET scanner architectures for imaging of prostate cancer

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

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

New directions: instrumentation for biopsy 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.

“on-line” MR guided biopsy

“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, Uro. Nav, and Artemis

New directions: more on biopsy Question: which approach is best to guide a prostate cancer biopsy? Method performance: sensitivity&localization US Poor: blind biopsy on-line MR High: can locate some tumors MR+US (MR off-line, registered) PET+US (PET off-line, registered) Adequate: can locate some tumors but possible registration issues Adequate+: can locate active tumors but possible registration issues technical complexity none low cost Low Moderate+: requires to perform biopsy in MR scanner low-moderate Moderate: requires MR scan low-moderate Moderate: requires PET scan MR+US (simultaneous) High: can locate some tumors moderate Moderate+: requires to perform biopsy in MR scanner PET+US (simultaneous) High+: can locate active tumors very 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

“on-line” PET guided biopsy using magnification probes ? Simultaneous acquisition method: q biopsy probe in PET/MR or PET/CT scanner; q US and/or PET and/or MR images are acquired simultaneously; q the biopsy can be guided by US-PET-MR Needs: q High resolution, high sensitivity probe: • Small crystals, TOF, magnification effect* q Complex reconstruction algorithm: • Localization of the probe • Attenuation correction • Anisotropic resolution (artifacts? ) q How to do an acceptable PET image in a few seconds? • High sensitivity and TOF? • Better reconstruction algorithms? PET ring from S. Majewski *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

Thanks! Put on your pink glasses! And thanks to: Harshali Bal Lars Eriksson Hossein Jadvar Peter Choyke Stefano Fanti Martin Pomper Stan Majewski It is a time of great opportunities for PET imaging of prostate cancer! 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)