F-18 and Ga-68: Potentially «Deadly Poisons» for Conventional Nuclear Medicine?

Transcription

1 F-18 and Ga-68: Potentially «Deadly Poisons» for Conventional Nuclear Medicine? Gustav K. von Schulthess, MD, PhD, MD hon Anass Johayem, PhD Nuclear Medicine and Radiopharmacy University Hospital Zurich, Switzerland Acknowledgements Philipp A. Kaufmann; MD, Anass Johayem, PhD; Irene Burger, MD; Martin Huellner, MD; Erik Stromqvist, MS* *GE Healthcare Uppsala, SE Slide 1 Conflict of interest declaration 1. Consultant to GE Healthcare 2. Grant recipient Bayer, GE Healthcare, Guerbet, Lilly, Sirtex mostly in the function of: 3. Course Co-Director International Diagnostic Course Davos (IDKD) Swiss Non-Profit Organisation, providing world-wide organ based education in imaging in workshops - IDKD Rio de Janeiro, Brazil:, November 4-6, IDKD Davos, Switzerland: Musculoskeletal, March 26-30, IDKD Asia (Hong Kong and Beijing): Chest, Heart, Vessels, Hong Kong, May 28-30, Beijing, June 4-6, IDKD Athens, Greece: Neuro, September 29-October 1, Slide 2 1

2 Table of contents 1. Why does the world like PET? 2. USZ PET-Radiopharmacy 3. Examinations available in Nuclear Medicine and PET 4. Examinations available in PET only 5. Can PET-exams replace all NM exams? Slide 3 Why does the world like (FDG-)PET(-CT)? 1. Spatial resolution down to 2 mm, axial FOV up to 25 cm 2. Electronic collimation (dual photon effect) 3. Attenuation correction - easy with CT (more difficult with MR) - potential emission only by TOF-PET 4. Wonderful tracers like FDG, not available in conventional Nuclear Medicine 5. Short half lives of PET radioisotopes - easy biomolecule label: F, C, N, O - minimize nuclear waste => Only problem: tracer logistics Slide 4 2

3 Table of contents 1. Why does the world like PET? 2. Presentation of USZ PET-Radiopharmacy 3. Tracers used in Nuclear Medicine and PET 4. Can PET-exams replace all NM exams? 5. Ga-68 logistics 6. Conclusions Slide 5 USZ and PET Radiopharmacy PET installed (now 3 PET/CT and 1 PET/MR) PET-Radiopharmacy productive (FDG, NH3, H2O) - PET-Trace based RPh production - business analysis: need to sell => GMP lab from the outset FDG PET reimbursed => growth of PET market => USZ forcibly becomes tracer provider 4. Current: USZ provides 2/3 of PET tracers in Switzerland Population > 8 Mio = > of doses / year nd production facility opened Slide 6 3

4 PET examinations USZ Total PET: N = * these tracers use Ga Slide 7 USZ numbers 1. Currently > PET examinations 2. Currently > doses of PET-tracers / year produced - F-18-FDG - F-18-Choline - F-18-Tyrosine - F-18-Na-F - N-13-NH3 - O-15-H2O - Ga-68 PSMA - Ga-68 DOTATATE - F-18-Flutemetamol -C-11-PIB - other research tracers Slide 8 4

5 Table of contents 1. Why does the world like PET? 2. Presentation of USZ PET-Radiopharmacy 3. Tracers used in Nuclear Medicine and PET 4. Can PET-exams replace all NM exams? 5. Ga-68 logistics 6. Conclusions Slide 9 PET examinations USZ Total PET: N = Replacement of conventional Nuclear Medicine by PET has started a decade ago Ga-DOTA-peptides vs In-Octreotide (USZ 10 -> 150/year, partly reimbursed) NH3 PET is clearly better than Nuc perfusion studies (reimbursed) FE-Tyrosine use is increasing (reimbursed) Slide 10 5

6 MRI vs FDG- vs FET-PET vs DCMR Ian Law: Mol-Anat Imaging, G. v. Schulthess ed 2015 A T1 MRI + C FDG PET FET PET CBV DSC MRI B T1 MRI + C FDG PET FET PET FET PET & MRI Slide 11 F-18 Ethyl Tyrosine (FET) Brain Tumor Imaging replaces old brain scans for brain tumor imaging 1. F-18-FET and other Amino Acids like C-11-Methionine are best for evaluating malignancy of brain tumors 2. F-18-FET is easy to produce and is readily shipped 3. F-18-FET is not sensitive enough to evaluate malignant body tumors 4. F-18-FET is accepted by the Swiss «FDA» and reimbursed for brain tumors by the Swiss Health Authorities Slide 12 6

7 F-18-NaF-PET/CT degenerative and metastatic changes degenerative disease vertebral arch metastasis vertebral body metastasis Slide 13 F-18-NaF-PET/CT Bone Scanning Replaces bone scans with Tc-99m-MDP/DPD agents 1. F-18-NaF is a much better bone scanning agent than the Tc-99m labeled bone scanning agents 2. F-18-NaF is easy to produce and is readily shipped 3. Use of F-18-NaF-PET for bone mets limited, as specific FDG, F- Choline, Ga-DOTA-peptide and -PSMA-11 available 4. Use of F-18-NaF-PET for benign bone disease largely unexplored (literature survey) 5. F-18-NaF-PET approved by «Swiss FDA», but not reimbursed by the Swiss Authorities (cost compared to bone scan) Slide 14 7

8 O-15 Water brain perfusion in Moya-Moya disease Baseline cerebral perfusion scan with Acetazolamide stress Diamox Baseline Difference 0.6 ml/mltiss/min ml/mltiss/min ml/mltiss/min Slide 15 O-15 Water PET Brain Perfusion Scanning Replaces brain perfusion scans 1. O-15-H2O PET is a better procedure than conventional NUC brain perfusion scans 2. O-15-H2O PET is quantitative 3. O-15-H2O PET needs a cyclotron in-house near the scanners 4. O-15-H2O PET can be produced according to a pharmacopea (in-house use only), but is not reimbursed by the Swiss Health Authorities Slide 16 8

9 PET myocardial perf. Imaging with NH3 or Rb Slide 17 PET vs SPECT in myocardial perf. imaging N = 2 159, Merhige E. et al, JNMMI 2007 Use of perfusion (Rb) PET vs myocardial perfusion SPECT Coronary Angiography procedures reduced from 30 to 15% Cost reduced by 20% Slide 18 9

10 NH 3 or Rb Myocardial Perfusion Scanning Replaces myocardial perfusion scans with Mibi/Myoview 1. N-13-NH 3 and Rb-82 are much better myocardial perfusion agents thantc-99m-mibi/myoview 2. N-13-NH 3 requires an in-house cyclotron Rb-82 is generator produced, unfortunately very expensive! 3. N-13-NH 3 requires production according to pharmacopea (in-house use only), Rb-82 needs an approved generator 4. Procedure reimbursed by the Swiss Authorities => explicit wish that there is a shift from conventional NUC to PET Slide 19 PET vs. SPECT in myocardial perf. imaging Flurpiridaz, a new F-18 based PET tracer Flurpiridaz F-18 based alternative to NH3 and Rb Advantage: centralized production Disadvantage: half life of 109 min with clearance characteristics like with MPI SPECT tracers Slide 20 10

11 In-11-Octreo-SPECT vs Ga-68 DOTATOC PET Dramatic difference SPECT Buchmann et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. EJNM Slide 21 Ga-68-DOTA-peptides Replace tumor scanning by In-111-Octreotide 1. Ga-68-DOTA-peptides are much better tumor scanning agents than In-111-Octreotide 2. In ZRH usage from 15 yearly scans to >150 yearly scans 3. Ga-68 logistics? 4. Ga-68 based «orphan» tracer (< 100 scans needed per 1 Mio/y) 5. Ga-68-DOTA-peptides are partly reimbursed in Switzerland Slide 22 11

12 PET examinations USZ Total PET: N = Slide 23 MIP PET/CT vs PET/MR FDG is THE PET tracer PET/CT 2 min/bed PET/MR 1 min/bed PET/MR 3 min/bed Slide 24 12

13 FDG-PET for inflammatory processes Spondylodiscitis Synovitis Slide 25 F-18-FDG Tumor (no replacement) and inflammation imaging 1. F-18-FDG is THE PET tracer which has made PET big 2. While FDG is well established in tumor imaging, its use in inflammation imaging is lagging behind 3. F-18-FDG is easy to produce and is readily shipped 4. F-18-FDG is accepted by the Swiss «FDA» and reimbursed for virtually all tumors by the Swiss Health Authorities Slide 26 13

14 Dual phase Choline-PET/CT recurrence (PSA 13,1) late phase late phase late phase FCH-PET/CT FCH-PET/CT FCH-PET/CT early phase early phase early phase FCH-PET/CT FCH-PET/CT Initial tumor stage: pt3a cn cm0, Slide Gleason 27 6 FCH-PET/CT Dual phase Choline-PET/CT recurrence (PSA 0.3) early phase late phase late phase 5.1 FCH-PET/CT early phase 8.5 FCH-PET MIP FCH-PET MIP FCH-PET/CT Slide 28 14

15 F-18-Choline Prostate cancer imaging 1. Choline PET tracers second most widely used PET tracers in Switzerland 2. Choline PET tracers are easily produced and shipped 3. Estimated market potential 10-20% of FDG market 4. Sensitivity gap: > 50% scans + for PSA > 2.0 ng/ml 5. Approved by «Swiss FDA» and reimbursed by Swiss Health Authorities Slide 29 Amyloid Scanning: C-11 PIB Biogen and Neuroimmune/Univ. Zurich Slide 30 15

16 Amyloid Scanning: C-11 PIB - Alzheimer? Nature Abstract Slide 31 Amyloid tracers Dementia imaging 1. Not yet widely used due to lack of clinical impact 2. The 3 patented F-18 based compounds are easily produced by synthesis modules and shipped 3. Estimated market potential huge, if amyloid removal trials successful (we will know in 5 years or so) 4. Amyvid approved by «Swiss FDA» 5. Not reimbursed by Swiss Health Authorities Slide 32 16

17 NUC examinations USZ Total NUC: N = (< PET N = 5 800) Slide 33 I-124 or thyroid carcinoma thyroid remnants in pat prior to radioiodine Rx A B C D Bockisch et al: Molecular-Anatomic Imaging, G. von Schulthess ed. 3rd edition Slide 34 17

18 I-124 Iodine Thyroid (cancer) imaging 1. Very useful in thyroid disease 2. Not widely available, but due to 4.2 days T ½ shippable 3. Relatively expensive compared to I-123 and particularly I Slide 35 F-Choline PET/MR Parathyroid disease 61 year old female. Primary hyperparathyroidism * Disclaimer: Off-label use PET/MR 61 yo female. Primary hyperparathyroidism. Orevi M et al. Localization of parathyroid adenoma by (1)(1)C-choline PET/CT: preliminary results. Clin Nucl Med 2014;39: Lezaic L et al. (1)(8)F-Fluorocholine PET/CT for localization of hyperfunctioning parathyroid tissue in primary hyperparathyroidism: a pilot study. Eur J Nucl Med Mol Imaging 2014;41: Slide 36 18

19 F-Choline PET/MR Parathyroid disease 35 year old male with secondary hyperparathyroidism * Disclaimer: Off-label use PET/MR 35 yo male. Secondary hyperparathyroidism. Huellner MW et al. Visualization of Parathyroid Hyperplasia using 18F- Fluorocholine-PET/MR in a Patient with Secondary Hyperparathyroidism. Clin Nucl Med 2015 Oct 12 [ahead of print] Slide 37 Table of contents 1. Why does the world like PET? 2. Presentation of USZ PET-Radiopharmacy 3. Tracers used in Nuclear Medicine and PET 4. Can PET-exams replace all NM exams? 5. Ga-68 logistics 6. Conclusions Slide 38 19

20 NUC examinations USZ Total NUC: N = (< PET N = 5 800) Slide 39 Useful isotopes in PET imaging Positron range varies from mm 43 Sc Slide 40 20

21 Table of contents 1. Why does the world like PET? 2. Presentation of USZ PET-Radiopharmacy 3. Tracers used in Nuclear Medicine and PET 4. Can PET-exams replace all NM exams? 5. Ga-68 logistics 6. Conclusions Slide 41 Ga-68: Analogue of Tc-99m for PET Tc-99m chemistry can be translated into Ga-68 chemistry 1. Ga-68 is a metal ion 2. Ga-68 can be bound via chelator => Chelator-biomolecule complex synthesized at leasure. Ga-68 snapped on => Advantage when labeling peptides and proteins 3. Ga-68 is suitable for kit production 4. Ga-68 can be produced by a generator 5. Chelator-based tracers = useful theragnostic compounds Ga-68 seems the perfect PET equivalent to Tc-99m Some issues have to be looked at though! Slide 42 21

22 Issues warranting discussion with Ga /2-life = 68 min: distribution or decentral production to be discussed 2. Positron range is around 5 times larger than for F-18 => somewhat inferior spatial resolution compared to F Generator yield: 2 3 doses only need high volume application to change this 4. ½ life of 270 days => creates some waste disposial/activity recovery issues Slide 43 Distribution radius F-18 / Ga-68 compounds F-18 =110 min / Ga-68 = 70 min. radius for delivery 2 T 1/2 F-18 = 10 Mio 2 T 1/2 Ga-68 = 6 Mio Strassburg/Karlsruhe Munich h 10 1h 30 1h h 20 2h 15 Lyon 2h 50 Milano 2h 20 2h 10 F-18 will distribute throughout Switzerland in 2 half lives (8 Mio) Ga-68 will distribute to many Swiss Slide sites 44 in 2 half lives (5 Mio) 22

23 Problems with current Ga-68 production The «batch cost» vs. «dose price» gap 1. Most costs reside with batch production - personnel - chemicals / pharmaceuticals / equipment - sterility / toxicity tests - regulatory affairs 2. Revenue is mostly dose based, except for - portioning - transport of substance => Dose production cost ~ batch cost / # doses Slide 45 The «batch cost» vs. «dose price» gap General batch cost PET tracers CHF / US$ / # doses dose price US$ / / CHF without transportation cost! Slide 46 23

24 Production yield F-18 based compounds Half life F-18 = 110 minutes Radiotracer GBq mci T 1/2 FDG F-Choline F-Ethyltyrosine Can we achieve this also with Ga-68 compounds? Can we offset any investment into this? Slide 47 Ga-68-PSMA-11 in recurrent Pca Ga-68-PSMA-11 is a Killer Application F-Choline Ga-PSMA-11 A I B I II II III III Slide 48 24

25 Ga-68-PSMA-11 PET/MR for restaging 75 y.o. man with PCA after prostatectomy 2005: : PSA 0.2 -> 0.5 ng/ml PSMA MIP PSMA Ax T2 axial T2 & PSMA Ax DWI axial DCE axial Slide 49 Ga-68-PSMA-11 as a Killer Application? Recurrent Prostate Cancer Urologist worries when PSA rises above 0.2 ng/ml Choline tracers detect > 50% of recurrences above 2.0 ng/ml Ga-68 PSMA-11 > 50% of recurrences above ng/ml Slide 50 25

26 What are Killer Applications? A technology can be introduced successfully only, if there is a clinical blockbuster application 1. CT started with brain and body imaging as a killer app 2. MR started with brain as killer app 3. PET started with FDG and oncology as killer app and PET/CT followed suit 4. New tracers: Choline satisfying an important clinical need Ga-68-PSMA-11: estimated use 10-20% of FDG Slide 51 Production yield Ga-68 based compounds Half life F-18 = 68 minutes Tracer origin GBq mci doses doses at T 1/2 - generator based liquid target solid target This will solve the Ga-68 generator issues - low yield / radioactive waste disposal and recovery Only high yield Ga-68 production will allow distribution of labeled tracer or Ga-68-Chloride to distant sites Slide 52 26

27 Issues with cyclotron Ga Solid targetry more complex than liquid target technology - get target into beam and out again by mechanical gimmick - dissolve solid target and purify - synthesize tracer 2. Radiolysis ok at 2 doses, how about 20 doses? Slide 53 Ga-68 can be used in kit labeling ready to use applications under development Radiotracer 1. DOTA-peptides (NOC, TOC, TATE) (FDA-approved) 2. PSMA (available for research) 3. Pentixafor (CXCR4 receptor ligand) 4. Others (no extensive literature review done) Distribute Ga-68 as ionic solution for kit labeling Depending on Ga-68 labeling infrastructure needed, some sites may want Ga-68 ion, others Ga-68 tracer Kit technology not accessible to F Slide 54 27

28 [ 68 Ga]Pentixafor /[ 177 Lu]Pentixather [ 68 Ga]Pentixafor PET in lymphoproliferative diseases Mantle cell lymphoma Multiple Myeloma Wester HJ, Schottelius M et al Further optimization and characterization of ligands o emitters, low energy ß emitters o Fluorescent CXCR4 ligands o Hybrid Probes o CXCR7 ligands CXCR4 affinity Peptide Ga Pentixafor Lu Pentixather Y Pentixather Bi Pentixather AlF NOTA Pentixather Cu NOTA Pentixather IC 50 [nm] 24.8 ± ± ± ± ± ± Slide 55 Development CXCR4 PET tracer Pentixafor Pentixafor PET-CT (xenografts) PET (patient) Daudi SU-DHL-8 Kidney 68 Ga-Pentixafor (~50pmol) 68 Ga-Pentixafor (~50pmol) + Plerixafor (~100nmol) Wester, Keller et al. Theranostics 2015 Gourni, Demmer et al. J Nucl Med 2011 Patient imaging: 10/14 MM positive 7/7 aggr. NHL positive Slide 56 28

29 Ga-68 EDTA PET/CT Dynamic Renal Imaging Hofman MS and Hicks RJ. Seminars in Nuclear Medicine 2016; 46: Slide 57 PET vs. SPECT V/Q Slide 58 29

30 Sentinel Node Imaging with Ga-68 nanocoll. PET/CT Courtesy Rodney Hicks, Melburne, Au Slide 59 NUC examinations USZ Total NUC: N = (< PET N = 5 800) Slide 60 30

31 Summary: Ga-68 pipeline for distribution 1. We have all the tools to replace conventional NM with PET Ga-68 can be produced in Curie quantities from solid targets 2. Ga-68 is better for peptide and protein labelling than F Ga-68 is a better partner in a theranostic pair than F Ga-68 distribution radius is 68/110 = 62% of that of F-18 e. g. can also be distributed regionally 5. Ga-68 can be used to label kits, which has many advantages Slide 61 31