remarks concerning the finnish prostate radioligand ......68ga -psma 11 pet/ct in primary staging of...
TRANSCRIPT
Kalevi Kairemo, MD, PhD, MSc(Eng),
Professor,Chief Physician, Molecular Radiotherapy & Nuclear Medicine
Docrates Cancer Center
Saukonpaadenranta 2, FI-00180 Helsinki, Finland
www.docrates.com
Visiting professor
Department of Nuclear Medicine
The University of Texas MD Anderson Cancer Center
1400 Pressler, FCT 16.6005, Unit 1483
Houston, TX 77030
Remarks concerning the Finnish prostate radioligand therapy (PRLT) experience
Jadvar
Center MM et al. Eur Urol 2012.
Incidence
Rate
Mortality
Rate
Prostate Cancer Management Options
• Newly diagnosed local disease - “primary staging”
– Active surveillance and watchful waiting (low risk patients)
– Surgery, radical prostatectomy
– Radiation therapy
– Multimodality for high-risk disease
– Radiation plus androgen deprivation therapy, ADT
• Recurrent disease – “secondary staging”
– Radiation, surgery, cryotherapy, HIFU for local recurrence
– Androgen deprivation therapy for metastatic disease
– Radionuclide therapy of bone metastases (153Sm-EDTMP, 223Ra (®Xofigo/Alpharadin), 177Lu-labeled bisphosphonates)
– PSMA radioligand therapy (PRLT) based on PSMA-targeting
Methods needed:
TLC
HPLC
MS
NMR
Molecular imaging (MAP/Docrates environment, own pictures)
Radiochemical synthesis Radionuclide production
Quality control
PET imaging
PETtrace10 16.5 MeV(p) 8.4 MeV (d)
Radiopharmaceuticals for PET/CT of prostate cancer?
Maximum intensity
projection (MIP) images
obtained in different
patients demonstrating
the differences in
normal biodistribution of 18F-FDG (A), 11C-
choline (B), 18F-choline
(C), 18F-fluciclovine (D), 68Ga-PSMA-11 (E), and 18F-NaF (F).
Ravizzini & Kairemo et al., in press
Theranostics of Prostate Cancer (“Prostagnostics”):
December 2018 Status in Diagnosis and Therapy
Virgolini et al. EJNMMI 2018
• A cell surface enzyme that is continually internalized - synonym: glutamate carboxypeptidase II (GCP-II)
• Folate hydrolase (FOLH1) activity
• cell surface protein with overexpression in prostate
cancer (750 AA, 84 kDa)
• PSMA expression increases progressively in:
• Higher grade tumors
• Under androgen deprivation
• Metastastic disease
• Hormone-refractory prostate cancer mCRPC
• also in tumor neovasculature
• promising target for prostate cancer specific
imaging and therapy - “thera(g)nostics”
• variety of tracers for PET/SPECT-imaging
Maurer T et al, Nat Rev Urol, 2016
FDG – the molecule of the century (Henry N. Wagner)
PSMA – the theragnostic target of our decade
PSMA for Targeting Prostate Cancer
Schematic representation of the overall
pathway involving PSMA and induction of
tumor-supporting signaling based on our
data. Free glutamate released from PSMA
after processing of glutamate-containing
substrates activates mGluR I receptors found
on the plasma membrane of prostate cancer
cells. Activation of the glutamatergic system
induces downstream calcium signaling and
activation of the PI3K cascade, positively
regulating tumor growth.
PSMA LIGANDS USED IN PATIENTS
Virgolini et al. EJNMMI 2018
68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict
the intensity of tracer accumulation in the primary tumour
Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, Scarpa L, di Santo G, Geraldo Roig L, Maffey-Steffan J, Horninger W, Virgolini IJ.
Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):941-949. doi: 10.1007/s00259-017-3631-6. Epub 2017 Jan 31.
median SUVmax: 12.5 vs. 3.9
tumour to normal prostate
68G-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer
accumulation in the primary tumour
Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, Scarpa L, di Santo G, Geraldo Roig L, Maffey-Steffan
J, Horninger W, Virgolini IJ.
Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):941-949. doi: 10.1007/s00259-017-3631-6. Epub 2017 Jan 31.
Compound Radionuclide Ref
PSMA-11
(PSMA-HBED-CC)
Ga-68 Eder, Afshar-
Oromieh 2012
PSMA-617 Lu-177, Ac-225
(Ga-68, In-111)
Afshar-Oromieh,
Benesova 2015
PSMA I&T Ga-68, Lu-177,
In-111
Weineisen 2015
PSMA I&S Tc-99m Robu 2017
MIP 1404/ 1405/ 1427 Tc-99m Hiller 2013
MIP 1095 I-131 (I-124) Barret 2013
DCFPyL F-18 Chen 2011
DCFBC F-18 Cho 2012
PSMA-1007 F-18 Cardinale, Giesel
2017
PSMA Ligands used in Patients
PSMA I&T
PSMA I&S
case A M 85, GS 6 (IX/04), Gr 2,
Initial S-PSA 9.8,
HT, f/u, docetaxel, S-PSA 200->9
Pain between shoulder blades?
X-15
Ga68PSMA
10 min 60 min
Right prostate lobe
Retroperitoneal, supraclavicular
lnn
Skeletal metastases: skull, spine,
ribs, sternum, scapulae, pelvis,
femori
Ga68PSMA
0
2
4
6
8
10
12
14
0:00 0:28 0:57 1:26 1:55
Prost
L5
Ln
Acetab
case A
Ga68PSMA-11: Docrates 2015
case E X-15
Ga68PSMA
Ga68PSMA
10 min
60 min 60 min
M 72, GS6 (03), Gr2,
pEBRT, Casodex ad
II/15, S-PSA 4.4
X-15
FCH
FCH: bilateral apical, 5 p, 11p
SUVmax 3.3
SUVmax 4.5
PSMA: unilateral apical, 5 p
Histology (9):
5p: high grade PIN
11p: normal
M 62, GS 8 (I/13), iS-PSA 65, T4N1M1, EBRT, TAB, S-
PSA 0.6 (X-13) Casodex, Docetaxel, Zytiga, S-PSA
6.9 (III-15), Ra-223 x 6, IX-15 NaF response (-67%),
XII-15 relapse, liver metastases
IV-15 FCH Ga-PSMA XII-15
case F
Ga-PSMA XII-15
M 67, GS 8 (I/09), iS-PSA 38, LHRH, TURP, EBRT,
bicalutamide, mediastinal lnn mts (IX-13) Docetaxel, Zytiga,
S-PSA 3.1 (XII-15), perineum metastasis (histology)
case G
Ga-PSMA
III-16
M/69, GS 8, T3N1M0, EBRT IV-10, Zoladex, Zometa until 2013. Now S-PSA 1.56->2.05.
FCH: negative; NaF: negative;PSMA-PET-CT: tiny retroperitoneal lymph nodes ->EBRT
case I
III-16
FCH
50/m, GS6, X-17, apex,
2pzl, PI-RADS 3/5
PI-RADS 4/5
SUVmax 4.2 & 5.3
Maximum intensity
projection (MIP)
image shows
distribution of F-
18-PSMA-1007,
and two small
apical primary
cancers (GS6) are
shown better in
Transaxial PET
and PET/CT fusion
images (arrows)
18F-PSMA-1007: Docrates 2017
Lu-177-PSMA Therapy
In CRPC
NUCLIDE: 177Lu
• T1/2= 6,71 d = 161 h
• E (Σ 83%)
• Emax = 497 keV (max range ≈1,9 mm in water)
• Eave = 149 keV (range ≈0,25 mm in water)
• E (17%)
• 113 keV (6 %)
• 208 keV (11 %)
• Short range!
DOSE
Cum Act (MBq h)
Dose (Gy)
Dose kernel (mGy s-1 MBq-1)
Dose and anatomy
A D C B
E
F
1st 177Lu-PSMA-617 at 24 hr 2nd 177Lu-PSMA-617 at 24 hr Kuva 3. Esimerkki 177Lu-PSMA-617-hoitoannoskuvauksesta gammakameralla. Tällä potilaalla on verraten laaja imusolmuketastasointi lantiossa, retroperitoneumissa
ja mediastinumissa sekä luustometastasointi lantion alueella. Kokokehokuvat AP-( kuva A) ja PA-suunnista (kuva B) ensimmäisellä 177Lu-PSMA-hoitoannoksella (6.8
GBq) vrk:n kuluttua sekä toiset samanlaiset kokokehokuvat AP-(kuva C) ja PA-suunnista (kuva D) toisella 177Lu-PSMA-hoitoannoksella (6.7 GBq) kuukautta
myöhemmin. Ensimmäisen 177Lu-PSMA-hoitoannoksen jälkeisissä SPECT/TT-kuvissa näkyy tarkemmin retroperitoneaalisen imusolmukemetastaasin kertymä (kuva
E) ja ristiluun luumetastaasin kertymä (kuva F). Poikkileikekuvien tasot on merkitty kokokehokuviin sinisellä (E) ja punaisella viivalla (F). Parhaiten vertaamalla kuvia B
ja D ilmenee myös, että kohdekudoksen määrä (aktiivisuus) on pienentynyt 1. hoidosta 2. hoitoon. Tätä ei voi kuitenkaan käyttää vastearvioon, mutta kertoo
epäsuorasti samasta ilmiöstä.
Kairemo K. BestPractice Onkologia ja hematologia 2017;7:20-24.
68Ga-PSMA-11 at 1 hr (BL) 68Ga-PSMA-11 at 1 hr (after 2nd Tx)
Kairemo K. BestPractice Onkologia ja hematologia 2017;7:20-24.
German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients.
Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schäfers M, Essler M, Baum RP, Kulkarni HR, Schmidt M, Drzezga A, Bartenstein P, Pfestroff A, Luster
M, Lützen U, Marx M, Prasad V, Brenner W, Heinzel A, Mottaghy FM, Ruf J, Meyer PT, Heuschkel M, Eveslage M, Bögemann M, Fendler WP, Krause BJ.
J Nucl Med. 2017 Jan;58(1):85-90. doi: 10.2967/jnumed.116.183194. Epub 2016 Oct 20.
Remarks of the pilot study Web-based follow-up of
Lutetium-177-PSMA treatments
Kalevi Kairemo, MD, PhD
Professor, Chief Physician, Molecular Radiotherapy & Nuclear Medicine
Docrates Cancer Center
Saukonpaadenranta 2, FI-00180 Helsinki, Finland
www.docrates.com
Median Overall Survival in the follow-up of lung cancer patients (traditional follow-up vs. web-based follow-up)
Source: Denis et. al (2017), Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients
Web-based follow-up of 177Lu-PSMA treatment • Dynamic symptom questionnaire addressing common
symptoms related to 177Lu-PSMA treatments: • general condition, diarrhea, dry mouth, fatigue, frost injuries,
nausea, pain, vomiting and possible other symptoms
• Follow-up protocol (automatic reminders by Kaiku Health): • Symptom questionnaire: weekly • Quality of life questionnaire (EORTC QLQ-C30): Every 3
months
• Kaiku Health can be used on any device: computer, tablet or smartphone. The only requirement is Internet connection.
Algorithms assess the severity of symptoms related to Lu-177-PSMA treatment
Kairemo K. WFNMB, Melbourne, Apr 20-24, 2018.
Patient-reported Kaiku Health symptom profile
Patient-reported general well-being (green = improved; yellow = stayed the same; red = worsened)
Jul 15 Jul 17 Jul 25 Aug 2 Aug 10 Aug 18 Aug 27 Sep 4
Development in general well-being
Kairemo K. WFNMB, Melbourne, Apr 20-24, 2018.
Kairemo K. WFNMB, Melbourne, Apr 20-24, 2018.
1 6
m/67, PCa -16, GS9 Lnn, lung & skeletal disease degarelix, docetaxel, denosumab, cabazitaxel, enzalutamide Before 6 cycles of Lu-177-PSMA S-PSA 1990 (IV-16) -> 2.6 (IX-17) Indirect response on Lu-177-imagings
Lu-177-PSMA-617 SPECT/CT at 1 d
1st 2nd 3rd
5th 6th
4th
BL
After 3 cycles
After 6 cycles
010203040506070
6/1
5/2
01
6
7/1
5/2
01
6
8/1
5/2
01
6
9/1
5/2
01
6
10/15/20…
11/15/20…
12/15/20…
1/1
5/2
01
7
2/1
5/2
01
7
3/1
5/2
01
7
4/1
5/2
01
7
5/1
5/2
01
7
6/1
5/2
01
7
7/1
5/2
01
7
8/1
5/2
01
7
9/1
5/2
01
7
m/67, PCa -16, GS9 Lnn, lung & skeletal disease degarelix, docetaxel, denosumab, cabazitaxel, enzalutamide Before 6 cycles of Lu-177-PSMA In Ga-68-PSMA-PET -55 % and -79 % ”metabolic response”
Ga-68-PSMA-11 PET/CT at 1 h
Ga-68-PSMA-11 PET/CT at 1 h
Ga-68-PSMA-11 PET/CT at 1 h
-55 %
-79 %
In April 2016 study an extensive left side
lymph node disease (obturatory, para-aortal,
retrocrural, left mediastinum and
supraclavicular (red rectangle) can be seen in
the MIP-image (2nd from left ). Normal organs,
i.e. salivary and lacrimal glands, liver, spleen
visualize in the MIP-images (all panels).
In March 2017 study all the pathologic lymph
nodes disappeared including the left
mediastinum and supraclavicular regions (red
rectangle) (most right).
The serum PSA (ng/ml) curve of the patient who
received three 177Lu-PSMA-treatments for his 1st
relapse (upper panel).
Two 68Ga-PSMA-PET/CT-studies performed
before (most left) and 6 weeks after all 177Lu-
PSMA-treatments (most right) (lower panel).
In the lower panel also 177Lu-PSMA-SPECT/CT
studies are shown after 1st and 3rd cycle (lower
panel).
In the first Ga-68-PSMA-PET/CT study, i.e. before 177Lu-PSMA-therapies multiple lung and skeletal
metastases were visible (lower panel, left). Normal
organs, i.e. salivary and lacrimal glands, liver,
spleen visualize in the MIP-images (all panels). In
the 177Lu-PSMA-SPECT/CT after 1st cycle (lower
panel, 2nd from the left) lung metastases are seen,
which all disappear after the 3rd cycle of 177Lu-
PSMA-treatments, only the bone metastasis in Th
7 vertebra is weakly visualized (lower panel, 2nd
from the right). The second 68Ga-PSMA-PET/CT
study demonstrates activity only in the Th 7
vertebra (lower panel, right).
The serum PSA decreased from 7.6 to 0.36 ng/ml.
Ga-68-PSMA-11 PET/CT V-17 F-18-PSMA-1007 PET/CT V-18 Lu-177-PSMA-617 SPECT/CT VII-18 Ga-68-PSMA-11 PET/CT V-17
Liver metastases and PSMA-derivatives
Ga-68-PSMA-11-PET VIII-17
Active prostate disease in the left lung,
because of diffuse and weak uptake with
PSMA expression. Additionally, there is a
marginal skeletal uptake in the right lower
ramus of the pubic bone which just meets
the criteria. No other active distant
metastases.
Active and large PSMA-positive skeletal metastases, in the skull, thorax,
spine, pelvis and extremities. They are predominantly located in the LS-spine
and pelvis. Classification 2/3. Lymph node disease in lung hili and
mediastinum. Liver disease in in the left lobe. Lung infiltration is possible. All
these major lesions express PSMA.
F-18-PSMA-1007-PET II-18
22 %
44 %
225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer
Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A.
J Nucl Med. 2016 Dec;57(12):1941-1944. Epub 2016 Jul 7.
225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer
Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A.
J Nucl Med. 2016 Dec;57(12):1941-1944. Epub 2016 Jul 7.
213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer.
Sathekge M, Knoesen O, Meckel M, Modiselle M, Vorster M, Marx S.
Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):1099-1100. doi: 10.1007/s00259-017-3657-9. Epub 2017 Mar 2.
CONCLUSIONS for Peptide Radionuclide Ligand Therapy (PRLT)
Theragnostic concept – proof of principle:
(Selection and follow-up of mCRPC patients for PRLT by 68Ga/18F-PSMA
PET/CT)
Effective in advanced mCRPC (tumor shrinkage and symptom
reduction) – even at low doses
Excellent tolerability
- no relevant hematological or renal toxicity in most patients
- salivary gland toxicity - xerostomia: mostly transient
Normal organ/ tumor dosimetry vs. kinetics
New Insights in Theragnostics
Thank you