lu-177 octreotaat en lu-177 psma behandelingen

LU-177 OCTREOTAAT EN LU-177 PSMA BEHANDELINGEN: EEN
NIEUWE KANS VOOR PATIËNTEN MET NET EN PROSTAATCA
MARCEL P.M. STOKKEL
NUCLEAR MEDICINE PHYSICIAN
DISCLOSURE
Nothing to declare
Veilig gebruik van isotopen
SOORTEN RADIOACTIEVE STRALING
ISOTOPEN IN DE NUCLEAIRE GENEESKUNDE
Ɣ- straling
ß-straling (+Ɣ)
• Gamma camera;
• Sr89
• Tc99m
• In111
• Sm153 (+Ɣ)
• I123
• I131 (+Ɣ)
• PET scanners
• F18
• Ga68
• I124
• Zr89
• Y90
• Lu177 (+Ɣ)
• Gammacamera: SPECT/CT
• PET scanner: PET/CT
N1, N2, N3 ?
HOE KRIJG JE ISOTOOP BIJ TUMOR?
CARRIERS: OM ROUTE TE BEPALEN
Algemene carriers:
• Aminozuren
• Eiwitten
• Suikers: FDG
1. Niet alle auto’s hebben een trekhaak!
2. Niet alle auto’s kunnen alle isotopen trekken!
• Vetten
• Bloedcellen
Specifieke carriers
• Antilichamen
• Medicijnen
• Hormonen
3. Wat wil je bereiken: welke “aanhanger” nodig?
THERANOSTICS
•
Therapeuticum
•
Herceptin
•
Erlotinib
•
Rituximab
•
Cetuximab
•
Somatostatines
•
Anti-PD1
•
Anti-PD-L1
•
……………………..
•
MIBG
•
PSMA
•
DOTATAAT/DOTATOC/DOTANOC
•
Radioactief Jodium
Door middel van een scan
vaststellen of het middel
wordt opgenomen:
WERKT HET OF NIET?
NUCLEAIRE GENEESKUNDE EN NET: WELKE AUTO?
BEELDVORMING NET: GAMMA STRALING
111In-pentetreotide
P-NET
68Ga-DOTA-peptides
18F-DOPA
P-NET
AVL: GA68-DOTATAAT
SI-NET
11C-HTP
P-NET
SSTR2
Normal
• Dispersed neuro-endocrine cells
• Endocrine organs or tissues:
– (Pituitary, thyroid, breast, lung, prostate,
kidney, liver)
• Lymphocytes
The spleen shows the highest tracer uptake
Pathological
• Primary neuroendocrine tumors and their
metastases
NUCLEAIRE GENEESKUNDE EN PCA: WELKE AUTO?
Ga68-PSMA
PHYSIOLOGICAL UPTAKE
Lacrimal gland
Parotid gland
Submandibular gland
Liver
Spleen
Kidney
Small intestine, colon
Bladder
PROSTATE CANCER: TYPICAL LOCALIZATION
Van diagnostiek naar therapie = van Ɣ naar ß
NET:
Ga68-Dotataat
Lu177-Dotataat
Prostaatca:
Ga68-PSMA
Lu177-PSMA
PRRT: van D/x naar R/x (aanhanger)
1972
• Somatostatin first isolated
1987
• Octreotide synthesis
1991
• Octreoscan first employed
1992
• Five somatostatin receptors
(sst1–5) identified
1994
• Octreoscan registered
1994
• First PRRT with high-dose 111Inoctreotide
1996
•
2000
• First 177Lu-octreotate PRRT
2010
• First 68Ga-PSMA PET/CT
2015
• Phase III study (result: 2017)
2015
• First Lu177-PSMA therapy
First 90Y-octreotide PRRT
Klinisch probleem NET: Symptomatisch (SSA)
SPECT
PET
Vinik AI et al. Pancreas 2009
•
NETs are generally slow growing tumors
•
The diagnosis is usually made when they are metastatic
•
Functioning tumors may be discovered at earlier stage
Cure
RADIOLABELLED SOMATOSTATIN ANALOGS FOR PRRT
Peptide
Nuclide
Chelator
90Y
Energy 2.3 MeV
Range
11 mm
Half-life 64 hrs
177Lu
-b-D-NaI-Cys-Tyr-D-Trp-Lys-Val-Cys-ThrNH2
D. Storch et al. J Nucl Med 2005
Energy
Range
Gamma
Gamma
Half-life
0.5 MeV
2 mm
113 KeV (6%)
208 KeV (11%)
6.7 days
INDICATIONS FOR PRRT
• Indications:
• Patients with positive expression of sstr2, or metastatic or
inoperable NET
• The ideal candidates are those with well-differentiated
and moderately differentiated NET grade 1 or 2
• Negative FDG PET/CT scans
DISCORDANT LOCALIZATION OF 18FDG IN 18F-DA- AND
123I-MIBG-NEGATIVE SITES
DEDIFFERENTIATION
18FDG
shows larger lesions and additional tumors
Mamede M et al. Nucl Med Comm 2006
CONTRAINDICATIONS
• Absolute
• Pregnancy
• Severe acute concomitant illnesses
• Severe unmanageable psychiatric disorder
• Relative:
• Breast feeding (if not discontinued).
• Severely compromised renal function:
• For PRRNT with a 90Y-labelled peptide age-adjusted normal renal
function is essential.
• Patients with compromised renal function may still be considered for
177Lu-labelled peptide treatment.
SCREENING PROGRAM
• The availability of the following information is mandatory when considering a
patient for PRRNT:
• NET proven by histopathology (immunohistochemistry)
• High sstr expression determined by functional wholebody imaging with 111Inpentetreotide (OctreoScan) or 68 Ga-DOTA-peptide PET/CT or
immunohistochemistry
• FDG PET/CT
• Kidney function
• Bone marrow status
CLINICAL PRACTICE:
PROPOSED AMINO ACID PROTECTIVE SCHEME
Single-day 50-g protection protocol:
• A solution containing a 50-g cocktail of lysine
and arginine (25 g of lysine and 25 g of
arginine) diluted in 2 l of normal saline infused
over 4 h, starting 30–60 min before PRRNT.
TREATMENT REGIMENS FOR THE NON-COMPROMISED
PATIENT: STANDARD ACTIVITY
• 90Y-DOTATATE / 90Y-DOTATOC
• Administered activity: 3.7 GBq (100 mCi)/m2 body surface
• Number of cycles: two
• Time interval between cycles: 6–12 weeks
• 177Lu-DOTATATE / 177Lu-DOTATOC
• Administered activity: 5.55–7.4 GBq (150–200 mCi)
• Number of cycles: three to five
• Time interval between cycles: 6–12 weeks
COMBINATION 90Y/177LU PEPTIDES
• Sequential administration:
• 90Y administered activity: 2.5–5.0 GBq (68–135 mCi)
• 177Lu administered activity: 5.55–7.4 GBq (150–200 mCi)
• Number of cycles: two to six
• Time interval between cycles: 6–16 weeks
SIDE-EFFECTS
Acute effects:
• Side-effects, such as nausea, headache and rarely vomiting
• metabolic acidosis induced by the amino acid co-administration
• PRRT may exacerbate the hormone related syndromes
• sudden massive release of the hormones and receptor stimulation: RR!
• In-patient treatment (24 hrs)
DELAYED SIDE EFFECTS
• Renal toxicity
• loss of kidney function can occur after PRRT, with a creatinine clearance loss
• 3.8 % per year for 177Lu-DOTATATE
• 7.3 % per year for 90Y-DOTATOC
• Bone marrow toxicity
• Severe (grade 3 and 4), mostly reversible, acute bone marrow toxicity:
• less than 10–13 % of treatment cycles with 90Y-DOTATOC,
• 2–3 % of cycles with 177Lu-DOTATATE
• Endocrine systems: no significant alterations have been reported
Relief of symptoms: 80%
PRRT
Author
Number
of
patients
Number
of cycles
CR (%)
PR (%)
SD (%)
PD (%)
CR+PR (%)
Y-90-DOTATOC
Otte, 1999 [64]
Paganelli, 1999 [65]
Paganelli, 2001 [66]
Walherr, 2001 [67]
Valkema, 2001 [68]
Pagnanelli, 2002 [69]
Chinol, 2002 [70]
Waldherr, 2002 [71]
Bodei, 2003 [72]
Bodei, 2004 [73]
Valkema, 2006 [74]
Forrer, 2006 [75]
Frilling, 2006 [76]
29
20
30
41
32
87
111
39
40
141
58
116
14
4
4
4
3
4
4
4
5
2
2-16
4
2
4 (20)
7 (23)
1 (2)
4 (13)
4 (5)
6 (5)
2 (5)
1 (2.5)
6 (4)
7 (12)
5 (4)
0 (0)
2 (7)
0 (0)
(0)
9 (22)
3 (9)
20 (23)
24 (22)
7 (18)
7 (17.5)
31 (22)
5 (9)
26 (23)
3 (21.4)
20 (69)
11 (55)
19 (64)
25 (61)
17 (53)
43 (49)
54 (49)
27 (69)
18 (45)
78 (55)
29 (50)
72 (62)
8 (57)
3 (10)
5 (25)
4 (13)
6 (15)
8 (25)
17 (20)
22 (20)
3 (8)
13 (32.5)
25 (18)
17 (29)
13 (11)
3 (21.4)
4 (20)
7 (23)
10 (24)
7 (22)
24 (28)
30 (27)
9 (23)
8 (20)
37 (26)
12 (21)
31 (27)
3 (21.4)
Lu-177-DOTATATE
Kwekkeboom, 2003 [77]
Kwekkeboom, 2003 [78]
Kwekkeboom, 2008 [79]
Garkavij, 2010 [80]
Bodei, 2011 [81]
Kunikowska, 2011 [82]
34
76
310
12
51
25
4
4
4
3-4
1-4
3-5
1 (3)
1 (1)
5 (2)
0 (0)
1 (2)
0 (0)
12 (35)
22 (29)
86 (28)
2 (16.6)
14 (27)
5 (25)
14 (41)
30 (40)
107 (35)
3 (25)
13 (26)
13 (52)
7 (21)
14 (18)
61 (20)
5 (41.6)
9 (18)
3 (12)
13 (38)
23 (30)
91 (30)
2 (17)
15 (29)
5 (25)
Survival in GEP NETs
& bronchopulmonary NET
Phase III studies were missing
van der Zwan WA et al. EJE 2015
NETTER-1 STUDY: PHASE III STUDY
• Statistically significant increase in progression-free survival (PFS)
with 4 administrations Lutathera 7.4 GBq every 8 weeks in
patients with advanced neuroendocrine tumors of the midgut (p
<0.0001, hazard ratio = 0.21; 95% CI: .13-.34).
• The median PFS in the Lutathera arm has not been reached while
the median was 8.4 months in arm Octreotide LAR (60mg).
AVL CASUS
WHAT ABOUT LU177-PSMA THERAPY
• Common practice in Duitsland
• Indicatie: prostaatca, maar wanneer?
• Dosis – Activiteit?
• Interval?
• DFS – OS?
Daar gaan we weer!
WAT BEHANDELEN EN WAT ZIJN DE ALTERNATIEVEN
Klachten:
PSA stijging?
Botpijnen
Bloed bij plassen
Pijn algemeen
PSA CHANGES ON 177LU-PSMA-I&T RLT AFTER 1
CYCLE
A, maximum change. B, change 8 weeks after cycle 1. Asterisks indicate more than 100%
increase in PSA response.
The proportion of patients who achieved a PSA decrease of at least 30%, 50% and 90% was
29% (5 of 17), 24% (4 of 17) and 6% (1 of 17), respectively.
RESULTS
Hematological toxicity:
• N=1: (grade 3 or 4) occurred 7 wks p.i.
• N=2: disturbance of only 1 hematologic cell line
• N=1: reduction of grades 1 and 2 in leucocytes and
thrombocytes,
• N=6: no hematotoxicity
Nephrotoxicity: not observed
PHASE II AND III STUDIES.......
Purpose: To assess the efficacy of a single infusion of radiolabeled anti-prostatespecific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177;
177Lu) by prostate-specific antigen (PSA) decline, measurable disease response,
and survival.
RESPONSES OF PSA
46.9% versus 13.3% with >30% PSA decline (P =0.048) for cohort 2 and 3 vs 1
PROBABILITY OF SURVIVAL BY DOSE RECEIVED
Imaging. Left, 99mTc-MDP bone scan
of pretreatment bony metastases. Right,
177Lu-J591 scan: 7 days after 177LuJ591administration.
ISSUES TO BE CLARIFIED IN 68GA-PSMA PET/CT
• Clearly better than other techniques in re-staging Pca.
•
What about staging?
•
Does it change treatment plan
•
Does it improve survival
•
Is there a clear correlation with 177Lu-PSMA: what does it tell us?
•
Is there a role in therapy monitoring?
•
Chemotherapy, radiotherapy, PRRT: correlation between uptake and response?
• Small lesions can be missed: what else do we have?
76-y-old patient after external-beam radiation therapy to bone metastases and hormone therapy. Richard
P. Baum et al. J Nucl Med 2016;57:1006-1013
(c) Copyright 2014 SNMMI; all rights reserved
A) 68Ga-PSMA PET/CT revealed progressive bone and lymph node metastases.
B)177Lu-PSMA scintigraphy after first (1), second (2), and third (3) RLT cycles.
C) 68Ga-PSMA PET/CT showed excellent molecular response
RNT: BOOMING BUSINESS