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

• Gamma camera; • Tc99m • In111 • I123

• PET scanners • F18 • Ga68 • I124 • Zr89

ß-straling (+Ɣ)

• Sr89

• Sm153 (+Ɣ)

• I131 (+Ɣ)

• 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

• Vetten

• Bloedcellen

Specifieke carriers

• Antilichamen

• Medicijnen

• Hormonen

1. Niet alle auto’s hebben een trekhaak!

2. Niet alle auto’s kunnen alle isotopen trekken!

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

68Ga-DOTA-peptides P-NET

111In-pentetreotide P-NET

18F-DOPA SI-NET

11C-HTP P-NET

AVL: GA68-DOTATAAT

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

Spleen Liver

Kidney Small intestine, colon

Parotid gland Submandibular gland

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 111In-

octreotide

1996 • First 90Y-octreotide PRRT

2000 • First 177Lu-octreotate PRRT

2015 • Phase III study (result: 2017)

2010 • First 68Ga-PSMA PET/CT

2015 • First Lu177-PSMA therapy

Cure • NETs are generally slow growing tumors • The diagnosis is usually made when they are metastatic • Functioning tumors may be discovered at earlier stage

Klinisch probleem NET: Symptomatisch (SSA)

Vinik AI et al. Pancreas 2009

SPECT

PET

RADIOLABELLED SOMATOSTATIN ANALOGS FOR PRRT

Peptide Chelator Nuclide

D. Storch et al. J Nucl Med 2005

90Y

Energy 2.3 MeV Range 11 mm Half-life 64 hrs

177Lu Energy 0.5 MeV Range 2 mm Gamma 113 KeV (6%) Gamma 208 KeV (11%) Half-life 6.7 days

-b-D-NaI-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2

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 111In-

pentetreotide (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

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)

Relief of symptoms: 80%

Survival in GEP NETs

& bronchopulmonary NET

van der Zwan WA et al. EJE 2015

Phase III studies were missing

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-prostate-specific 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 177Lu-J591administration.

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

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