177Lu-PSMA targeted Radionuclide Therapy€¦ · Gaertner et al. Uptake of PSMA-ligands in normal...
Transcript of 177Lu-PSMA targeted Radionuclide Therapy€¦ · Gaertner et al. Uptake of PSMA-ligands in normal...
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177Lu-PSMA targeted Radionuclide Therapy Hojjat Ahmadzadehfar
Seite 2 Siegel R et al. CA Cancer J Clin 2013; 63:11-30
Prostate cancer Estimated new cases
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Prostate cancer Estimated deaths
Siegel R et al. CA Cancer J Clin 2013; 63:11-30
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Prostate cancer Five-year relative survival rate
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Prostate cancer PSMA
Prostate-specific membrane antigen
(PSMA) is highly expressed on prostate
epithelial cells and strongly upregulated in
prostate cancer.
Kahn et al. 111In-labeled 7E11 mAb (ProstaScint). Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection of occult prostate
cancer recurrence. J Urol. 1994;152:1490–1495
111In-labeled 7E11 mAb (ProstaScint)
Radiolabeled 7E11 antibody does not bind to
viable cells but only to intracellular part
of PSMA, which may be accessible only in dead
, dying,or apoptotic cells within tumor sites.
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Prostate cancer PSMA therapy using mAb
Charles B. Simone II and Stephen M. Hahn . Clin Cancer Res; 19(18) September 15, 2013
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177Lu-PSMA mAb Toxicity
Tagawa et al. Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant
prostate cancer. Clin Cancer Res. 2013 Sep 15;19(18):5182-91.
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PSMA therapy mAb vs peptide
mAb Peptide
elephant hummingbird
-poor permeability in solid tumours -slow clearance from the circulation
suboptimal tumour targeting and an increased absorbed dose to red marrow, narrowing the therapeutic window
177Lu-J591
7 Tage p.i.
177Lu-PSMA-617 7 Tage p.i.
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» Operation
» Hormone therapy
» Chemotherapy
» Radiation
» Radionuclides
mCRPC Therapy of mCRPC
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mCRPC Approved therapies
Drug Trial Disease state N Comparator Median OS (m) HR
Docetaxel TAX-321 1 Chemonaive 1006 Mitoxantron 18.9 vs. 16.5(p=0.009) 0.76
Carbazitaxel TROPIC 2 Post-Docetaxel 755 Mitoxantron 15.1 vs. 12.7 (p<0.0001) 0.70
Abiraterone COU-AA-3013 Post-Docetaxel
1195 Placebo+ Presnisone
14.8 vs. 10.9 (p<0.0001) 0.65
Abiraterone
COU-AA-302 4 Chemonaive 1088 Placebo+ Presnisone
27.2 vs. NR (p=0.01)
Ra-223 ALSYMPCA 5 Bone-metastaric mCRPC
922 Placebo + BSC
14.9 vs. 11.3 (p<0.001) 0.70
Enzalutamide AFFIRM 6 Post-Docetaxel
1199 Placebo 18.4 vs. 13.6 (p<0.001) 0.631
Enzalutamide
PREVAIL 7 Chemonaive
1717 Placebo 32.4 vs. 30.2 (p<0.0001) 0.706
1Tannock IF et al. NEJM 2004;35(15):1502-12, 2 deBono JS et al. Lancet 2010;376:1147-54; 3 deBono JS et al. NEJM 2011;364:1995-2005; 4 Ryan CJ et al.
NEJM 2013; 368:138-48; 5 Parker C et al. N Engl J Med 2013; 369:213-223; 6 Scher HI et al. NEJM 2012;367: 1187-97;7 Beer TM et al. ADCO GU 2014,
abstract LBA1; 8 Kantoff PW et al. NEJM 2010; 363: 411-22
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PSMA therapy As the last therapeutic option
Theranostics
Tx with 6.1 GBq 177Lu-PSMA
68Ga-PSMA PET
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Radioligand Therapy using 177Lu-PSMA-617
Inclusion criteria
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• WBC > 2 Tsd./µl.
• Hb > 8 g/dl, in the case of symptomatic anaemia a red-blood-cell transfusion should be preceded the therapy.
• Platelets > 75 x 109/l
• Creatinine < 2 mg/dl
• Rule out an obstructive renal disease by using Tc-MAG3 or Tc-DTPA
• ECOG <= 2
Radioligand Therapy Inclusion criteria
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Radioligand Therapy using 177Lu-PSMA-617
Response
Ahmadzadehfar H & Rahbar K et al. EJNMMI Res. 2015 Dec;5(1):114
Die erste Studie: 10 Patienten
70 %: PSA-decline
50 %: PSA-decline>50%
Radioligand Therapy using 177Lu-PSMA-617
Response
Rahbar K……Ahmadzadehfar H. J Nucl Med. 2016 Apr 7. pii: jnumed.116.173757
The first multicentre study: 82 patients, 1 cycle
64 %: PSA-decline 31 %: PSA-decline>50%
Ga-PSMA-PET Lu-PSMA-GK
Radioligand Therapy using 177Lu-PSMA-617
Response
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Rahbar & Ahmadzadehfar et al. J Nucl Med. 2017 Jan;58(1):85-90
45 % > 50 %-PSA-decline
145 patients :248 cycles
Radioligand Therapy using 177Lu-PSMA-617
Response
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40 patients, one cycle
Radioligand Therapy using 177Lu-PSMA-617
Predictive factors of response
Seite 19 Ferdinandus J, …….. Ahmadzadehfar H.,
parameters p-value
p-value
multivariate analysis
Activity (MBq)/weight (kg) 0.62
Abiretarone 0.69
Enzalutamide 0.87
Chemotherapy 0.57
Ra-223 0.27
Bisphosphonate or denosumab 0.80
Number of bone metastases 0.75
Extent of lymph node
metastases
0.38
Existence of liver metastases 0.90
ECOG performance status 0.19
AST 0.23
ALT 0.21
GGT (> 100) 0.008 ns
ALP 0.15
LDH 0.04 ns
Creatinine 0.19
parameters p-value
p-value
multivariate analysis
Total bilirubin 0.18
Hb 0.04 ns
RBC 0.17
WBS 0.21
PSA level 0.15
SUV max (bone) 0.26
SUV max (lymph node) 0.30
SUV max bone/liver 0.09
SUV max bone/spleen 0.06
SUV max lymph node/liver 0.16
SUV max lymph node/spleen 0.22
Plt (>300) 0.02 0.01
CRP (>20) 0.009 ns
Age (< 65) 0.01 ns
Gleason score (=10) 0.01 ns
Regular need for pain medication 0.005 0.0018
Radioligand Therapy using 177Lu-PSMA-617
Predictive factors of response
40 patients, one cycle
Seite 20 Ferdinandus J, …….. Ahmadzadehfar H.,
Radioligand Therapy using 177Lu-PSMA-617
Predictive factors of response
» Regarding a PSA decline >
50%, only a Gleason score of 10 and
regular need for pain medication
had a negative impact on the
therapeutic response in the
univariate analysis
in the multivariate analysis, only the
regular need for pain medication
was significant.
PSA-decline > 50 %
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
Rahbar & Ahmadzadehfar et al. J Nucl Med. 2017 Jan;58(1):85-90
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Rahbar & Ahmadzadehfar et al. J Nucl Med. 2017 Jan;58(1):85-90
Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
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49 hormone refractory mPC patients with distant metastases and progressive
disease
Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
Ahmadzadehfar et al. Oncotarget 2017
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
Ahmadzadehfar et al. Oncotarget 2017
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
49 patients Hematotoxicity according to common toxicity criteria (version 4.0) in all patients prior to and after 3 cycles of RLT
Ahmadzadehfar et al. Oncotarget 2017
low hematotoxicity
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Radioligand Therapy using 177Lu-PSMA-617
Hematotoxicity
Group 1 (Hx of Ra-223) Group 2
CTC 0°
(%)
CTC 1°
(%)
CTC 2°
(%)
CTC 3°
(%)
CTC 0°
(%)
CTC 1°
(%)
CTC 2°
(%)
CTC 3°
(%)
p-value
WBC 15 (75) 3 (15) 2 (10) 0 (0)
27
(93.1) 2 (6.9) 0 (0) 0 (0)
0.12
Hb 8 (40) 1 (05) 10 (50) 1 (05)
22
(75.8) 2 (6.9) 2 (6.9) 3 (10.4)
0.008
Plt 16 (93.8) 2 (10) 1 (5.0) 1 (5.0)*
21
(72.4) 5 (17.2) 1 (3.4) 2 (7.0)+
0.88
Ahmadzadehfar et al. Oncotarget 2017
Lu-PSMA Tx after therapy with Ra-223 is
feasible and safe
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Radioligand Therapy using 177Lu-PSMA-617
Nephrototoxicity
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Radioligand Therapy using 177Lu-PSMA-617
Nephrototoxicity
Rahbar & Ahmadzadehfar et al. J Nucl Med. 2017 Jan;58(1):85-90
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Radioligand Therapy using 177Lu-PSMA-617
Renal toxicity
Yordanova ………. Ahmadzadehfar. EJNMMI 2017
55 patients
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Radioligand Therapy using 177Lu-PSMA-617
Renal toxicity
Yordanova ………. Ahmadzadehfar. EJNMMI 2017
» Twenty patients were treated with
more than 3 cycles 177Lu-PSMA-
therapy. Eleven, six and three
patients with 4, 5 and 6 cycles,
respectively. Again, there was no
significant radiation induced
impairment of the renal function (CTC
3° or 4°)
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Radioligand Therapy using 177Lu-PSMA-617
Renal toxicity
Yordanova ………. Ahmadzadehfar. EJNMMI 2017
low nephrototoxicity
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Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
» a mean of 192.6±11.0 MBq.
» 2-cc blood samples were withdrawn in short variable
times (3, 15, 30, 60, and 180 min and 24, 48,and 120
h) after injection.
» Whole-body images were obtained at 4, 24, 48, and
120 h post-injection (p.i.).
» The geometric mean of anterior and posterior counts
was determined through region of interest (ROI)
analysis.
» The OLINDA/EXM dosimetry program was used for
curve fitting, residence time calculation, and absorbed
dose calculations.
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Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
Kabasakal et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA)
inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015 Dec;42(13):1976-83
Seite 36 Kabasakal et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA)
inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015 Dec;42(13):1976-83
Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
» Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients
(mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after
administration of 3.6 GBq (range 3.4 to 3.9 GBq) 177Lu-DKFZ-PSMA-617
Seite 37 Delker et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol
Imaging. 2016 Jan;43(1):42-51
Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
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Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
Delker et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol
Imaging. 2016 Jan;43(1):42-51
» 135 patients
» SUV was measured in the lacrimal and salivary glands, brain, heart,
liver, spleen, kidneys, muscle and bone
» SUV was correlated with visual tumor load, total tracer retention and
PSA
Seite 39 Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:
55094-55103
Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
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Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:
55094-55103
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Radioligand Therapy using 177Lu-PSMA-617
Dosimetry
Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:
55094-55103
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Radioligand Therapy using 177Lu-PSMA-617
Amount of the activity
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• Accoriding to retrospective studies 6-7.4 GBq activity is safe
Radioligand Therapy Amount of activity
Rathke et al. Repeated Lu-177-PSMA-617 radioligand therapy using treatment activities up to 9.3 GBq. JNM 2017
10 pat 10 pat 10 pat 10 pat
4 GBq 6 GBq 7.4 GBq 9.3 GBq
Initial PSA response presented no correlation to treatment activity 21 patients completed 3 cycles of PSMA therapies
2/10, 4/10, 4/10 and 7/10 patients with doses of 4, 6, 7.4 and 9.3 GBq were in partial remission 8 weeks after completing all 3 cycles
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Radioligand Therapy Amount of activity
Rathke et al. Repeated Lu-177-PSMA-617 radioligand therapy using treatment activities up to 9.3 GBq. JNM 2017
WBC (/nl)
platelet count
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Radioligand Therapy using 177Lu-PSMA-617
Overall Survival
Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097
PSMA-patients
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097
Historical collective
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Seite 48 Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
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Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Ahmadzadehfar et al. EJNMMI 2017
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Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Ahmadzadehfar et al. EJNMMI 2017
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Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Median OS: 60 weeks
Ahmadzadehfar et al. EJNMMI 2017
Seite 52 Bräuer et al. EJNMMI 2017
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Median OS: 32 weeks
48 % of patients had an ECOG 2/3
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Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
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Inclusion criteria •patients with mCRPC •patients with a history of therapy with either abiraterone or enzalutamide or both •patients treated with at least 3 cycles of RLT, or patients with 1 – 2 cycles of RLT who died before the third cycle, did not receive the third cycle because of significant worsening of their general condition or because of an excellent response to the first or second cycle •patient follow-up of at least two months after the last cycle or the patient died •complete documentation.
150 patients were evaluated
100 patients were eligible
Ahmadzadehfar et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand
therapy. Oncotarget 2017
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
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100 patients (347 cylces; median: 3 cycles; 1-8 cycles)
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Ahmadzadehfar et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand
therapy. Oncotarget 2017
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Median OS
All patients: 60 weeks
Responder to the first cycle: 71 weeks
Non-responder to the first cycle: 29 weeks
P<0.0001
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Ahmadzadehfar et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand
therapy. Oncotarget 2017
Seite 57
Median OS
noe CTx: 63 weeks (49.1-76.9)
Hx of CTx: 57 weeks (40.2-73.8)
P=0.40
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Ahmadzadehfar et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand
therapy. Oncotarget 2017
Seite 58 Ahmadzadehfar et al.
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Parameters p-value
Median OS
reported in
weeks (95 % CI)
Multivariate
analysis
p-value
Number of bone
metastases
29 patients ≤ 20 met
45 patients > 20 met
24 patients : super scan
or
diffuse bone/bone
marrow met
0.02
94 (60.7–127.3)
55 (38.8–71.2)
37 (12.7–61.3)
ns
Existence of liver
metastases
13 patients: yes
87 patients: no
0.04
28 (18.6–37.4)
60 (47.3–72.7)
0.02
HR: 3.2 (95% CI:
1.5 - 7.1)
ECOG performance status
(0/1 vs 2/3)
77patients: 0–1
23 patients: 2–3
<0.000
1
71 (43.7–98.3)
33 (24.7–41.3)
ns
Blood transfusion prior to
the first cycle
16 patients: yes
84 patients: no
0.04
36 (28.3–43.7)
63 (49.5–76.5)
ns
Albumin (cut-off: 38.6 g/l)
49 patients ≤ 38.6
51 patients > 38.6
0.0003
38 (26.0–50.0)
95 (47.3–142.7)
0.01
HR: 0.9 (95% CI:
0.8 - 0.95)
AST (cut-off: 24 U/l))
56 patients ≤ 24
44 patients > 24
0.0002
88 (61.1–114.9)
36 (16.8–55.2)
0.04
HR: 2.5 (95% CI:
1.3 - 4.8)
GGT (cut-off: 31 U/l)
42 patients ≤ 31
58 patients > 31
0.0001
88 (63.4–112.6)
47 (31.5–62.5)
ns
ALP (cut-off: 140 U/l)
52 patients ≤ 140
48 patients > 140
0.0003
71 (45.9–96.0)
42 (24.0–60.0)
ns
ALP (cut-off: 220 U/l)
65 patients ≤ 220
35 patients > 220
0.019
70 (56.9–83.1)
37 (17.7–56.2)
ns
LDH (cut-off: 225 U/l)
36 patients < 225
64 patients ≥ 225
<0.000
1
not reached
46 (29.6–62.4)
ns
Hb (cut-off: 10.4 g/dl)
33 patients <10.4
67 patients ≥10.4
0.0001
36 (24.5–47.5)
88 (60.7–115.3)
<0.0001
HR: 0.5 (95% CI:
0.2 - 0.9)
CRP (cut-off: 16 mg/l)
65 patients ≤ 16
35 patients > 16
0.0001
71 (46.8–95.2)
33 (25.2–40.8)
ns
Regular need for analgesics
39 patients: yes
61 patients: no
0.007
36 (24.7–47.3)
70 (56.1–83.9)
ns
Regular need for opioids
35 patients: yes
65 patients: no
0.0002
33 ( 24.9–41.1)
88 (48.0–127.9)
ns
PSA percent change (cut-off: -
14%)
62 patients: decline > 14 %
38: no PSA decline or decline
≤14%
<0.0001
88 (58.3–117.7)
29 (20.1–37.8)
<0.0001
HR: 6.9 (95% CI:
3.6 - 13.3)
PSA any decline
69 patients: yes
31 patients: no
<0.0001
71 (45.4–96.6)
29 (20.5–37.5)
ns
PSA decline ≥ 50%
38 patients: yes
62 patients: no
0.009
70 (39.5–100.5)
49 (30.2–67.8)
ns
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Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Rahbar et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A
retrospective analysis of overall survival in the “real life”. EJNMMI 2017
Seite 60
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Rahbar et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A
retrospective analysis of overall survival in the “real life”. EJNMMI 2017
Seite 61
N = 104 Estimated Median OS 56 Weeks [95%CI: 50.5 – 61.5]
N = 104 log rank P = 0.004 Hazard ratio: 0.38 [95%CI: 0.19 – 0.75] P = 0.005
any initial PSA decline N = 70 Estimated: 62.9 weeks [95%CI: 51.4 – 74.2]
no PSA decline N = 34 estimated: 47 weeks [95%CI: 39.4 – 54.5]
Rahbar et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A
retrospective analysis of overall survival in the “real life”. EJNMMI 2017
Seite 62
Radioligand Therapy using 177Lu-PSMA-617
Overall-Survival
Rahbar et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A
retrospective analysis of overall survival in the “real life”. EJNMMI 2017
Seite 63
Case Reports
3. Tx
4.8 GBq
08.2015
PSA: 9
ALP: 69
LDH: 208
ECOG:0
Seite 64
Case Reports
• 81 y patient, Gleason Score:7,
• Known bone & Ln met
• Under GNRH
• Hx of abiraterone and enzalutamide
• ECOG : 0
Seite 65
Case Reports
Wie X, …….. Ahmadzadehfar H., CNM 2016
PSA: 1030 ng/ml PSA: 5.5 ng/ml
Seite 66
Case Reports
Seite 66 Prior to the 1. cycle Prior to the 3. cylce After the 4. cycle
PSA:195 PSA:2.4
About 70-80 % of patients with mCRPC show a good response to RLT
Patients with a positive response (any PSA-decline) have a longer OS
PSMA therapy has low toxicity profile
Performing repeated cycles of Lu-PSMA-617 after 223Ra seems to
be safe, with a very small probability of hematotoxicity
Time for prospective studies
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Conclusion
Hojjat Ahmadzadehfar, MD, MSc
Associate Professor
Head of the therapy section
Department of Nuclear Medicine
University Hospital Bonn