Prostate cancer Screening - Human Health Campus

Prostate cancer Screening - Human Health Campus

Nuclear Medicine University Hospital Zürich SWITZERLAND Prostate Cancer: new Diagnostic and Therapeutic Approaches with Molecular Imaging Irene A. Bu...

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Nuclear Medicine University Hospital Zürich SWITZERLAND

Prostate Cancer: new Diagnostic and Therapeutic Approaches with Molecular Imaging Irene A. Burger, MD Pärnu (Estonia), October 6 – 10, 2014 Radiology and Nuclear Medicine Department University Hospital Zurich Switzerland

Topics 1. PET imaging for prostate cancer: Tracers 2. Choline-PET/CT imaging protocols & indications 3. Choline-PET/MR – outlook

4. Prostate cancer therapy

Nuclear Medicine, University Hospital Zurich, Switzerland

1. PET imaging for prostate cancer: Tracers

Alphabet-soup: 11C-Cholin

11C-Acetate 18F-FCH

18F-FECH

18F-FDG 18F-FB-[Lys3]BBN 18F-FDHT 64Cu-labeled

mAb 3/A12

18F-Fluoride 18F-DCFPyL

Nuclear Medicine, University Hospital Zurich, Switzerland

68Ga-PSMA

Targets: Metabolism: 18F-FDG

11C-Acetate

Bone reaction:

Membrane proliferation: 11C-Cholin 18F-FECH 18F-FCH

18F-Fluoride

Androgen receptor: 18F-FDHT

PSMA targeting: 64Cu-labeled mAb 3/A12 89Zr-J591

GRP receptor: 18F-FB-[Lys3]BBN

111IN-7E11

18F-DCFPyL 68Ga-PSMA

Overview:

Nuclear Medicine, University Hospital Zurich, Switzerland

Cell Metabolism: FDG: is limited!

Schoder H et al. Semin Nucl Med 2004, 34:274-292 Nuclear Medicine, University Hospital Zurich, Switzerland

11C-Acetate:  Acetate participates in cytoplasmic lipid synthesis, which is believed to be increased in tumors.  Prostate cells undergo metabolic transformation from citrate producing cells to citrate-oxidizing malignant cells(1)

 This leads to an increased acetate turnover in malignant cells(1)  Similar sensitivity to Cholin (2)

1) Costello et al. Urol 1997 2) Buchegger F. et al. EJNMMI, 2014 (41:68-78)

FDG Nuclear Medicine, University Hospital Zurich, Switzerland

AC

Amino acids: 18F-FACBC (Leucine)  Leucine is essential for the mTOR pathway regulating cell growth (controlling mRNA translation)  Membrane transporters of L-leucine are overexpressed in prostate cancer.

A

B

(A) MRI axial T2 weighted image showing indeterimined 5 mm lymphnode within the mesorectal fascie. (B) FACBC PET/CT confirmed the suspicion for lymphnode metastasis with very high 18F-FACBC uptake. (Images Courtesy: Dr. Frode Willoch, MD PhD, Aleris, Norway) Nuclear Medicine, University Hospital Zurich, Switzerland

18F-Fluoride

– a better bone scan?

+ Very high sensitivity for bone metastasis - Expensive & radiation (5-8 mSv) - No lymphnode or local recurrence detection Nuclear Medicine, University Hospital Zurich, Switzerland

18F-Fluoride

– a better bone scan: YES  A) Planar bone scan negative  C) Degenerative change (Osteophyt)

 B&D) solitary bone metastasis

Sens

Spec

PPV

NPV

BS

39

79

52

64

SPECT

71

85

73

83

18F

100

100

100

100

PET

1) Even-Sapir et al. JNM 2006 Nuclear Medicine, University Hospital Zurich, Switzerland

But: 18F-Fluoride vs Choline A

B

18F-FCH

C

18F-Fluoride

 Metastasis in the left acetabulum is Fluoride and Choline positive  Degenerative lesion in the pubic bone only pos on Fluoride scan.

 Metastasis in the thoracic spine only Choline positive

1) Beheshti et al. EJNM 2008 35:1766-1774 Nuclear Medicine, University Hospital Zurich, Switzerland

But: 18F-Fluoride vs Choline CT

18F-FCH

 Initial not sclerotic but Choline positive metastasis

 Under hormone therapy no FCH uptake is visible

 However an increase in bone density

1) Beheshti et al. EJNM 2008 35:1766-1774 Nuclear Medicine, University Hospital Zurich, Switzerland

18F-FDHT

 16ß-18F-fluoro-5 – dihydrotestosterone targeting the androgen receptor  Sensitivity of 78 % (1)

 Usefull for multiparametric analysis (2)

1) Larson S et al. JNM 2004 2) Fox JJ et al. JNM 2011

Nuclear Medicine, University Hospital Zurich, Switzerland

PSMA Trans membranous protein with high specificity for prostate tissue  Intra – or extracellular domains targeted  Several antibodies or small antibodies have been tested  High specificity but delayed washout for AB or small AB  small molecule inhibitors of the enzymatic domain: GaPSMA Improved biodistribution, faster BP clearence, less radiation

Nuclear Medicine, University Hospital Zurich, Switzerland

PSMA – Antibody Tracers 70 years old prostate cancer patient after def. RT 3 years agao. Now increase in PSA. A) CT negative B) FDG negative C) Zr-89 J591 shows increased activity in T 11 and D) L 3 (black arrow) Apart from the faint osetoblastic reaction in L1 (arrow head) lesions have no CT correlation. No evidence of lymph node lesions or local residue. Images Courtesy: Dr. H. Vargas, MSKCC, NY, USA

Nuclear Medicine, University Hospital Zurich, Switzerland

PSMA – Antibody Tracers

77 years old PCA, ED 01/2013, PSA to 4.14 ng/ml. A)Ga-68 PSMA MIP image. With bone metastases in Th3, L1 and proximal femur (arrows). Apart from the faint osteoblastic reaction in L1 (arrow head) lesions have no CT correlation. No evidence of lymph node lesions or local residue. Images Courtesy: Dr. Vikas Prasad, Charité, Berlin, Germany

PSMA – Antibody Tracers

PET images in the same patient: (a) MIP 68Ga-labelled PSMA (b) MIP 18Ffluoroethylcholine The scan with the PSMA ligand shows significantly more lesions than the fluoroethylcholine

EDITORIAL: Eder et al. Eur J Nucl Med Mol Imaging (2013) 40:819–823 Nuclear Medicine, University Hospital Zurich, Switzerland

Gastrin-Releasing Peptide Receptor 

18F-Bombesin

– high uptake in Xenografts

Bombesin

Cholin

In house experience:

Nuclear Medicine, University Hospital Zurich, Switzerland

Gastrin-Releasing Peptide Receptor 

68Ga-Bombesin

– however:

Region based in 14 patients: Sens / Spec / Acc of 89% / 81% / 83%

Kaehkoenen et al. Clinical Cancer Research (2013) 19:5434-5443 Nuclear Medicine, University Hospital Zurich, Switzerland

II. Choline-PET/CT imaging protocols & indications

Choline Tracers 11C-choline

18F-Fluoromethylcholine

18F-Fluoroethylcholine

11C-labeled

18F-labeled

18F-labeled

FCH

FECH

short half-life time

Less lipophilic than FECH

More lipophilic than FCH

difficult to do dual-phase studies

probably slightly better tumor to background ratios compared to FECH

probably slightly lower tumor to background ratios compared to FCH

Little urinary secretion

Nuclear Medicine, University Hospital Zurich, Switzerland

Fluorocholine PET: Mechanism of uptake

Up regulated in malignant tumors

Linked with fatty acids – part of the cell membrane

Nuclear Medicine, University Hospital Zurich, Switzerland

Fluorocholine (FCH)-PET vs FDG-PET

18FCH Nuclear Medicine, University Hospital Zurich, Switzerland

18FDG

FCH-PET/CT Imaging Protocol  Patient positioning on the PET/CT scanner  CT acquisition  i.v.-injection of FCH (aprox. 200 MBq)  PET-imaging  wait for 3 minutes after injection  always start at the pelvic floor  1.5 – 3 minutes per cradle position  early and late phase imaging recommended

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH: Typical Time Activity Curves PET SCAN 2

Tumor Bladder Inflammatory

Δ-

Time [minutes] Nuclear Medicine, University Hospital Zurich, Switzerland

30

28

26

24

22

20

18

16

14

12

10

8

6

4

Δ+

2

0

Activity

PET SCAN 1

Arterial

Imaging goals  Initial staging  (Primary tumor?)  Lymph node metastasis?

 Distant metastasis?

 Recurrent disease  Local recurrence?  Lymph node metastasis?  Distant metastasis?

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/CT Initial experience

19 patients:

10 newly diagnosed PC 9 suspected recurrence Results: Differentiation of benign hyperplasia from PC is not possible. In recurrent prostate cancer, FCH PET/CT promising imaging modality for local recurrence and lymph node metastases.

Nuclear Medicine, University Hospital Zurich, Switzerland

Tumor related Fluorocholine Uptake

Schmid DT et al; Radiology 2005. Nuclear Medicine, University Hospital Zurich, Switzerland

FCH: Benign Prostate Hyperplasia

10 patients: 1 FCH = extent of tumor 9 FCH = regions with BPH * Schmid DT et al; Radiology 2005. Schmid DT et al; Radiology 2005. Nuclear Medicine, University Hospital Zurich, Switzerland

Staging: 59y, GS 9, (PSA 24): high risk

18F-Fluorocholine-PET/CT

99mTc-DPD

Staging: 63y, cT3, (PSA 20): high risk

Histology:

CT

1mm FCH-PET

FCH-PET MIP

FCH-PET/CT

Cytokeratin stain

FCH-PET/CT Indications: PC Recurrence  Biochemical recurrence with a PSA > 2.0 ng/ml or with a high PSA velocity (PSAdt < 7.2 months)  Local recurrence only?  Lymph node metastases?

 PSA elevation during anti-hormonal treatment  Documentation and localization of tumor progression

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/CT: biochmical PC Recurrence  Biochemical recurrence detection correlates well with the PSA values: N = 2124 patients

N = 63 patients

Giampiero et al, EJNM 2010 Krause et al, EJNM 2008

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/CT: biochmical PC Recurrence  But also PSA velocity has an impact on the detection rate of PC recurrence:

PSA_dt Cut off: 7.2 m

N = 102 patients, PSA < 1.5 Nuclear Medicine, University Hospital Zurich, Switzerland

Castellucci et al, EJNM 2010

FCH-PET/CT: recurrence (PSA 13,1) late phase

late phase

late phase

5.5 6.6

early phase

5.9

early phase

early phase

4.8 5.6

Initial tumor stage: pT3a cN0 cM0, Gleason 6

5.2

FCH-PET/CT: Impact on recurrence therapy



156 questionnaires answered after Choline PET/CT in recurrent PC:

Conclusion: CH-PET/CT has an important impact on the therapeutic strategy in patients with rPCA and can help to determine an appropriate treatment.

Soyka et al; Eur J Nucl Med Mol Imaging 2012; 39:936-43. Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/CT: Clinical implications

Conclusion: Our results strengthen the current evidence of the usefulness of PET and PET/CT using 11C-choline or 18F-FCH as tracers in PCa workup, whereby the diagnostic evidence is stronger in restaging than in staging settings. In general, proper patient selection, by considering predictive clinical parameters like PSA level, PSA doubling time, and initial tumor stage, is the key to avoiding FN results up front. The current evidence, although promising, has crucial limitations in terms of its applicability in common clinical scenarios.

Umbehr MH, et al; Eur Urol 2013; Published online ahead of print on April 19, 2013

Nuclear Medicine, University Hospital Zurich, Switzerland

III. Choline-PET/MR outlook

FCH-PET/MR Imaging Protocol  Whole body MRI:  WB Dixon T1: dual-echo gradient echo pulse sequences decomposed into water-only and fat-only contrasts – for AC  Coronal T2 non fs  Optional diffusion weighted images (DWI)

 Pelvic MRI:  T2 fast spin echo sequences: in 3 planes with a small FOV  DWI and/or DCE / spectroscopy (not routinely)

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/MR Imaging:

WB MR (15 min)

PET (21 min)

PET/MR image fusion

FCH-PET/MR: WB MRI and Choline PET/CT  7 men with untreated Primary CAP  25 men with PSA Relapse after curative therapy  WB MRI: Sensitivity 78.4%, Specificity 94.1%  C-11 Ch: Sensitivity 96.6%, Specificity 76.5%  Complementary role of MRI and C-11 Choline PET-CT

Eschmann SM et al. Nuklearmedizin 2007

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/MR: BPH versus tumor T2 axial

T2 axial

T2 axial

T2 axial & Choline

T2 axial & Choline

T2 axial & Choline

BPH – nodules

Biopsy: Prostate Ca Gleason 9 (5+4)

Nuclear Medicine, University Hospital Zurich, Switzerland

FCH-PET/MR: BPH versus tumor

• Information about the exact location of FCH activity (peripheral vs central / transitional zone) can increase the specificity of FCH PET from 73 % to 92% • AUC for MRI(T2)/FCH > than multiparametric MRI

Perrot et al. EJNMMI 2014; 41:1744-1755 Nuclear Medicine, University Hospital Zurich, Switzerland

FCH/ADC: for T-staging?

Park et al. JNM 2012; 53:546-551 Nuclear Medicine, University Hospital Zurich, Switzerland

FCH/ADC: for T-staging? Choline

ADC

Choline/ADC

Parametric PET/MRI using PCHOL/ADC improves lesion-to-background contrast (TBRs) of Gleason ≥ 3 + 4 disease, compared with 11C-choline PET/CT or diffusion-weighted MRI.

Park et al. JNM 2012; 53:546-551 Nuclear Medicine, University Hospital Zurich, Switzerland

Staging: 59y, GS 9, (PSA 24): high risk T2 axial

T2 axial & DWI

T2 axial & Choline

T2 axial

T2 axial & DWI

T2 axial & Choline

Staging Prostate Cancer: PET/CT-MRI T2 axial

T2 axial & Choline

T2 axial & DWI

 Accurate local T-staging with PET/MRI  Choline information might could replace DWI or DCE for local staging but this will nee further investigation.

Nuclear Medicine, University Hospital Zurich, Switzerland

Staging Prostate Cancer: PET/CT-MRI

&

Pathology: pT3b, pN0(0/12)

Nuclear Medicine, University Hospital Zurich, Switzerland

Staging Prostate Cancer: PET/CT-MRI  One stop shop: Local tumor extent with N & M staging  The additional MRI has to be performed as a dedicated MRI, high resolution T2 (pelvis), DWI and DCE.

 Pelvic MRI might increase specificity of Choline PET  Choline/ADC might separate low risk from Gleason 7 disease  Promising one step tool for patients with high risk prostate cancer:  Gleason score > 8 / PSA over 20 / extracapsular extension

Nuclear Medicine, University Hospital Zurich, Switzerland

IV. Prostate cancer therapy

Alpharadin (223Radium-Chloride) • Is now commercially available (Xofigo®)

Nuclear Medicine, University Hospital Zurich, Switzerland

Alpharadin (223Radium-Chloride)

Nuclear Medicine, University Hospital Zurich, Switzerland

Alpharadin (223Radium-Chloride)

Nuclear Medicine, University Hospital Zurich, Switzerland

Nuclear Medicine University Hospital Zürich SWITZERLAND

Thank you!