(Theranostics) Νεώτερες εξελίξεις. στη Μοριακή Διάγνωση / Θεραπεία του ευνουχοάντοχου καρκίνου του προστάτη

Transcription

1 Νεώτερες εξελίξεις στη Μοριακή Διάγνωση / Θεραπεία του ευνουχοάντοχου καρκίνου του προστάτη (Theranostics) Γ. Αρσος Γ Εργ. Πυρηνικής Ιατρικής ΑΠΘ, ΓΝ Παπαγεωργίου

2 .no conflict of interest

3 NUCLEAR MEDICINE open radiation sources Prostate cancer diagnosis (imaging) therapy

4 Radioactivity Particles for therpy : Efficacy : Energy (MeV) Half Life Time (days) Toxicity : Tissue range (μm -> mm)

5 Particles = tissue damage = therapy radio pharmaceuticals = specific tissue uptake γ photons = imaging Cancer in general Prostate cancer

6 PSA (ng/ml) Predicting radionuclide bone scan findings in pts with newly diagnosed, untreated prostate cancer : PSA is superior to all other clinical parameters 521 pts with newly diagnosed, untreated Ca Pro age 70 (44 92) yrs pts PSA 20 ng/ml ONLY 1 Bone Scan (+) 11,3 NPV (PSA<20) for BS 99.7% Chybowski FM et al, J Urol 1991

7 DIAGNOSIS & STAGING.. 3 Skeletal metastasis (M staging) is best assessed by bone scan. This may NOT be indicated in :.. - asymptomatic patients - If the serum PSA level is <20 ng/ml - in the presence of well or moderately differentiated tumors Heidenreich A et al Eur Urol 2014

8 PΕΤ/CT Positron emission tomography/ Computerized tomography Hybrid : 2 modalities (PET + CT) Main field : Oncology One stop - shop

9 GE Discovery 710 LSO κρύσταλλοι Τime of Flight (TOF) Γ Εργαστήριο Πυρηνικής Ιατρικής ΑΠΘ ΓΝ Παπαγεωργίου Δεκέμβριος 2016 Ευρώπη Μ. Ανατολή : 99 PET/CT scaners Σε Ακαδημαϊκά, Δημόσια και ιδιωτικά κέντρα University College London

10 PET radionuclides Production t ½ (min) 11 C Cyclotron N Cyclotron O Cyclotron F Cyclotron Ga Generator 68

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12 analogues PET radio-pharmaceuticals Carbohydrate Aminoacids 18F-FDG 18F-Fluciclovine Positron emitter + Fatty acids Peptide 11C/18F-Choline Nucleotide Surface Molecules 68Ga-PSMA 18F-PSMA Molecular imaging!

13 The all-purpose PET radio-pharmaceutical : 18F-FDG But not for ProCa!

14 FDG tumor model Glycolysis Normal cell FDG6P Glucose 6-phosphatase G6P Hexo kinase Glucose 6-phosphatase FDG G GluT FDG G Tumour cell Glucose 6-phosphatase FDG Hexo kinase G FDG6P G6P Glucose 6-phosphatase Glycol. G, Glucose; FDG, Fluoro-deoxy-glucose; P, phosphate

15 Is this patient diabetic? NO, it is just trouble for uro-oncologic imaging!

16 PET in diabetic patients Glu 200 mg% Glu 79 mg%

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18 The important contribution of CT PET tomography CT tomography PET/CT

19 challenges for radionuclide imaging diagnosis staging follow up recurrence CRPC! treatment assessment Pro Ca : Theranostics

20 Bone Scan T N M Molecular Imaging

21 PET : The danger Of False Positive! PET : the power of True Negative! Alas! Not in Urology! (at least for FDG in ProCa)

22 PET/CT in urological oncology Challenging : urinary excretion of most tracers (bladder cath, diuretics) TRACER TUMOUR FDG SGCT post-chemo residual masses RENAL BLADDER URETER PENIS metastatic disease CHOLINE Ca Pro recurrence -? PSMA Ca Pro Revolution! Theranostics! Girentuximab RCC

23 86 y Op 1996, RTx 2001 PSA 88 ng/ml under ADT SUVmax 2,4

24 70 y ProCa GS (4+4) under ADT PSA 5,5 -> 7,5 ng/ml SUVmax 3,6 CT : Enlarged R/P + Iliac LNs -> SUVmax 2,2

25 DIAGNOSIS & STAGING.. 3 Skeletal metastasis (M staging) is best assessed by bone scan.... In equivocal cases, 18F-fluorodeoxyglucose-PET or PET/CT could be of value, especially to differentiate active metastases and healing bones. Heidenreich A et al Eur Urol 2014

26 CHOLINE DATA Essential component of phospholipids and cell membrane metabolism Phosphorylated by choline kinase & trapped in the cell Incorporated into cell membrane phospholipids through phosphadidylcholine synthesis Increase in malignant tumours : Cell membrane metabolism Choline use Choline Kinase expression

27 Beheshti M, J Nucl Med yrs pt3a, N0, R0, GS 7 primary PSA 1.34 ng/ml PSA 4.7 ng/ml 3 mo after RT

28 18F-FCH PET/CT Beheshti M, Semin Nucl Med 2009

29 primary Krause BJ et al Urol Oncol 2013

30 recurrence Krause BJ et al Urol Oncol 2013

31 11C-Choline PET/CT DW-MRI Butiharto T et al, Eur Urol 2011

32 70-yr-old, GS 8, T1 N1 26 months after RP PSA 2 to 7 ng/ml / 9 mo lesion 1.5 cm intense CE MRI 3.0 T : Suggestive of meningioma Schillaci O et al, NMC 2010 FP : Infections Benign Prostate Hypertrophy Other malignancies CVI : : FN : ADT

33 Current status of choline-pet and prostate cancer Dif. benign / malignant intraprostatic T-staging of primary disease N-staging prior to primary treatment : Good specificity Low sensitivity / FN rate : PSA/PSA-kinetics Clinically : equivocal nodes / very high risk patients Positive scan > negative scan At biochemical recurrence : Promise in restaging Identifying localised dis./ excluding distant spread Treatment response assessment Radiotherapy planning no evidence increasing evidence accepted practice in UK no evidence under investigation no evidence under investigation Taylor BP et al, Trends Urol 2014

34 PET/CT ROLE IN PROSTATE CANCER PET/CT with choline tracers may identify sites of metastatic disease in pts with biochemical recurrence after primary treatment failure Further study is needed to determine the best use of choline PET/CT imaging in pts with prostate cancer Data of the utility of 18F-FDG-PET/CT in pts with prostate cancer is limited Routine use of 18F-FDG PET/CT is not recommended at this time

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36 Glutamate carboxypeptidase II (GCPII) N-acetyl-L-aspartyl-L-glutamate peptidase I AAG peptidase prostate-specific membrane antigen (PSMA) 750 aminoacids, 84 kda Expression : prostate, kidney, small intestine, CNS Prostate : X100 of most other tissues Pro Ca : upregulation X 8-12 over noncancer prostate Higher expression : time to progression relapse Target : therapy and imaging in human prostate cancer Approved imaging agent : capromabpentide (PROSTASCINT) 2 nd -generation Abs / Low-MW ligands for imaging and therapy

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38 MoAb to the cell membrane of prostate cancer cell line LNCaP 7E11C5.3 MoAb : recognizes PSMA ProstaScint : radiolabeling of the 7E11C5.3 MoAb with indium-111 Rising PSA after brachytherapy 7 years earlier / current PSA = 1.8 ng/ml ProstaScint / CT : uptake within a small lymph node in the interaortocaval groove (arrow) Taneja SS, Rev Urol 2004

39 Afshar-Oromieh A et al, EJNMMI 2013

40 Eiber M et al. JNM 2015 Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Pts with Biochemical Recurrence After Radical Prostatectomy Patients : 248 biochemical recurrence after RP retrospective Median PSA : 1.99 ng/ml ( ) Imaging : CE-PET/CT Ligand : 68Ga-PSMA 68Ga-PSMA PET/CT (+) Exclusively identified additional involved regions : 222 (89.5%) pts : 61 (24.6%) pts No significant difference in detection efficacy with ADT : P =

41 Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Pts with Biochemical Recurrence After Radical Prostatectomy > > <1 PSA (ng/ml) PSA velocity (ng/ml/yr) Eiber M et al. JNM 2015

42 18 F-Choline 68 Ga-PSMA

43 Choline PSMA Detection rate in PC with low biochemical relapse of PSA < 1.0 ng/ml scanned either by 18F/11C choline or 68Ga-PSMA ligand Virgolini I. et al, EJNMMI 2018

44 PSMA ligands used in patients - status October 2017 Virgolini I. et al, EJNMMI 2018

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46 THERANOSTICS Acronym of Therapeutics & Diagnostics epitomizes the inseparability of diagnosis and therapy Takes into account personalized management of disease for a specific patient Molecular phenotypes of neoplasms are determined by molecular imaging with specific probes using : - positron emission tomography (PET) - single photon emission computed tomography (SPECT) - magnetic resonance imaging (MRI) - or optical methods The treatment is specifically targeted against the tumor Baum RP et al, Theranostics 2012

47 Molecular Theranostics : A Primer for the Imaging Professional Lee DY et al, AJR 2011

48 DISEASE PROBE RTx AGENT TARGET TIME HyperThyro 131I (low dose) 131I Thyroid cell NIS NBL 123I-MIBG 131I-MIBG Symp.Neuron Uptake 1 NETs 111In-Octreotide 68Ga-DOTATOC/TATE 177Lu-DOTATOC/TATE 90Y-DOTATOC/TATE Dif. NET cell SSR 40 s 80 s 00 s DISEASE PROBE RTx AGENT TARGET TIME Pro Ca 68Ga-PSMA-L 177Lu-PSMA-L PSMA expression 68Ga-PSMA-L 227Ac-PSMA-L PSMA expression 10 s 17

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50 Abi-Ghanem AS et al SNM 2015

51 Bone scan : indirect evidense of metastasis a lot of false positives Osseus metastasis Osteoblastic bone healing 89Sr 223Ra 177Lu-PSMA 225Ac-PSMA 15 y normal Ant 85 y ProCa pathologic # R femur PSA 600 ng/ml Post BM metastasis normal 12 year boy

52 NEJM 2013

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55 Radium-223 within the metastatic castration-resistant prostate cancer treatment paradigm * Symptomatic bone metastases Solid bars, overall survival benefit Striped bar, no overall survival benefit EBRT, external beam radiation therapy mcrpc, metastatic castration-resistant prostate cancer Shore ND. Urology 2015

56 Ahmadzadefhar H et al. JNM pts, median age of 73 y, 307 cycles 223RaCl2 Before treatment : 31 pts bone scanning + radiologic imaging 32 pts, bone scanning + PSMA PET Conclusion: When PSMA PET is used as the gatekeeper in addition to bone scanning, radionuclide therapy with 223Ra may be more effective and have more success regarding changes in the PSA. An increase in PSA during therapy cycles occurs because of disease progression.

57 Ahmadzadefhar H et al. JNM 2017

58 Concordant Bone Scan 68Ga-PSMA : 223Ra therapy Ahmadzadefhar H et al. JNM 2017

59 Discordant Bone Scan 68Ga-PSMA : 177Lu-PSMA therapy Ahmadzadefhar H et al. JNM 2017

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61 Information for healthcare professionals Xofigo must not be used with the anti-androgen Zytiga (abiraterone acetate) and prednisone/prednisolone because of possible increased risk of fractures and mortality. The safety and efficacy of Xofigo in combination with second generation androgen receptor antagonists such as Xtandi (enzalutamide) have not been established. Both medicines can continue to be used separately, in line with the recommendations in their product information. Further information will be made available once an ongoing review of the evidence is complete.

62 225 Actinium T1/2 = 10 days a-particle range : μ order < cell!

63 Kratochwil C et al JNM 2016

64 Kratochwil C et al JNM 2016

65 Kratochwil C et al JNM 2016

66 Targeted Alpha Therapy of mcrpc with 225Actinium- PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control 40 pts mcrpc 3 cycles of 100 kbq/kg BW 225Ac-PSMA-617 in 2 months intervals. Kratochwil C et al JNM 2018

67 Targeted Alpha Therapy of mcrpc with 225Actinium- PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control Kratochwil C et al JNM 2018

68 Targeted Alpha Therapy of mcrpc with 225Actinium- PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control Kratochwil C et al JNM 2018

69 Targeted Alpha Therapy of mcrpc with 225Actinium- PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control 31 / 40 pts treated per protocol Discontinuation : 5 non-response / xerostomia most common preceding therapies Abiraterone, docetaxel, enzalutamide, cabazitaxel PSA decline >50% : 63% any PSA response : 87% Median duration of tumor-control : 9.0 mo 5 pts enduring responses of > 2 years Kratochwil C et al JNM 2018

70 PSA 237 -> 43 μg/l Sathegke M. et al, EJNMMI 2017

71 CONCLUSIONS 1. Choline : low sensitivity inappropriate for decision making lack of theranostics Ra : tricky patients selection important incobatibilities 3. PSMA : key to diagnosis and theranostics for CRPC Ac : as 225Ac-PSMA targets ALL types of CRCP secondaries 5. 68Ga / 18F PSMA-L PET/CT soon available in Greece!

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