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Elif Hindié

Service de Médecine Nucléaire - CHU de Bordeaux

Approche Théranostique en Médecine Nucléaire

57ème Journées Scientifiques de la Société Française de Physique Médicale

13-15 Juin 2018 ; Toulouse

• Pas de conflit d’intérêt

Théranostique(ou Théragnostique)

• Contraction de « Thérapie et Diagnostic » ; approche importante de médecine personnalisée.

• En médecine Nucléaire elle se symbolise par la possibilité d’administrer un traitement radiopharmaceutique« radiothérapie interne vectorisée » sur la base d’une imagerie moléculaire préalable

Radiothérapie Interne Vectorisée« Targeted Radionuclide Therapy »

• Administration of radiolabelled molecules to irradiate tumors

• The main requirement: A high uptake and tumor-to-background tissue ratio of the targeting molecule (to maximize efficacy and limit toxicity)

• Different from external beam radiotherapy:

– Systemic tretment can target all metastases, including occult metastases

– Delivers a low dose rate irradiation over a prolonged period of time

– Heterogeneous distribution in tumors can limit efficacy (loss of target expression, fibrosis, necrosis)

• A similar ligand can be used for imaging before therapy: “image and treat”

The Theranostic approach in Nuclear Medicine

• Radioiodine Imaging & Therapy of Thyroid Cancer

• MIBG Imaging & Therapy of Neurobalstoma

• CD20-targeted radionuclide therapy of Lymphoma

• Somatostatin receptors Imaging & Therapy of Neuroendocrine Tumors

• PSMA-targetd Imaging & Therapy of Prostate Cancer

• …..

Cloning and characterization of the thyroid iodide transporter.Dai G, Levy O, Carrasco N.

Nature. 1996 Feb 1; 379:458-60.

The Na+/I- symporter (NIS) is the plasma membrane protein that catalyzes active I- transport in the thyroid, the first step in thyroid hormone biogenesis.

It is essential for the treatment of thyroid cancer by radioiodine.

The expression of NIS can be variable in thyroid carcinoma tissues.

• Burch HB, Cooper DS, JAMA. 2015; 314: 2544-54.

Radioiodine Imaging & Therapy of Hyperthyroidism and Thyroid CancerThe 1st Theranostic Application

Targeting the Norepinephrine Transporter

123I / 131I-MIBG

123I-MIBG imaging is a mainstay in the evaluation of neuroblastoma.

131I-MIBG has been used for treatment of relapsed high-risk neuroblastoma; the outcome remains suboptimal.

131I-MIBG has also been used in metastatic paraganglioma / pheochromocytoma patients.

Norepinephrine Transporter as a Target for Imaging and Therapy.Pandit-Taskar N, Modak S.

J Nucl Med. 2017; 58(Suppl 2):39S-53S.

Two radiolabelled anti-CD20 antibodies have been developped: • One labelled with iodine-131• One labelled with Yttrium-90

90Y-Ibritumomab tiuxetan (ZEVALIN):

• No requirement for thyroid protection

• Can be used as outpatient (no need for overnight stay)

AMM 2004 : Lymphome folliculaire en rechuteExtension AMM Zevalin en 2008 au traitement de consolidation

du lymphome folliculaire

Targeting of CD20 in Non-Hodgkin LymphomaRadio-immunotherapy (RIT)

AN OVERVIEW ON PET RADIOCHEMISTRY: PART 2 - RADIOMETALS.Brandt M, Cardinale J, Aulsebrook M, Gasser G, Mindt T.

J Nucl Med. 2018 May 10.

Some useful Radionuclides

For Imaging

-emitters• 123I• 111In

Positron emitters (PET)• 18F

• 68Ga• 64Cu• 44Sc et 43Sc• 89Zr• …..

For Treatment

-emitters• 131I• 90Y

• 177Lu• …

α-emitters• 225Ac• 213Bi• 211At• …

Rösch F, Herzog H, Qaim SM. Pharmaceuticals (Basel). 2017; 10(2).

• Schematic illustration of the class of tumor targeting vectors (e.g., peptides) conjugated to a chelator, which is able to coordinate a diagnostic and a therapeutic

radiometal (e.g., 68Ga and 177Lu). • The typical chelator is DOTA, and for several tracers, there exists a sophisticated linker and spacer chemistry.

Imaging and Targeted Radionuclide Therapy of Neuroendocrine Tumors

Imagerie et Radiothérapie Interne Vectorisée des

Tumeurs Neuro-Endocrines Gastro-Entéro-Pancréatiques « TNE-GEP » par ciblage des Récepteurs de la Somatostatine

Distribution des sites primitifs des TNE

Recommendations for management of patients with neuroendocrine liver metastases.

Frilling A, et al; Working Group on Neuroendocrine Liver Metastases.Lancet Oncol. 2014 ;15:e8-21.

TNE - GEP : Probabilité de métastases hépatiques selon le site

La plupart des TNE-GEP sont bien différenciées, de grade G1 ou G2 (Ki67 ≤ 20%)

TNE-GEP ~ 1000 nouveaux cas/an en France

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions.

Deroose CM, Hindié E, Kebebew E, Goichot B, Pacak K, Taïeb D, Imperiale A.

J Nucl Med. 2016; 57:1949-1956

• Imaging with Radiolabelled Somatostain Analogs:111In-Octreotide (Octreoscan)

68Ga-DOTA-PEPTIDES (TATE, TOC or NOC)

Plate-forme de radiomarquage au 68GaGénérateur 68Ge (T1/2: 271 J) / 68Ga (T1/2: 68min)

Conformité Pharmacopée Européenne

15

Chlorure de 68Ga

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions.

Deroose CM, Hindié E, Kebebew E, Goichot B, Pacak K, Taïeb D, Imperiale A.

J Nucl Med. 2016; 57:1949-1956

TNE métastatique

111In-OctreoscanScintigraphie

68Ga-DOTATATETEP-TDM

Imagerie des TNE-GEP par ciblage des Récepteurs de la Somatostatine« Surexpression des récepteurs au niveau de la membrane des cellules tumorales »

Analogue de la somatostatine + Chélate + Radionucléide

111In-OctreoscanSPECT/CT

68Ga-DOTATATEPET/CT

CE/CT

Duodenal NET

Peptides used for Therapy

Somatostatin analogue + Chelator + Radionuclide

90Y-DOTA-Tyr3-Octreotide

177Lu-DOTA-Octreotate

Energy (keV) Half-life

90Y βmoy = 933 2.7 days

177Lu moy = 133 6.7 days+ rays allowing post-therapy imaging

Octreoscan111In-Pentétréotide

177Lu-DOTATATE (Lutathera)(Images à 24h; émission γ 208 keV)

Mr R. TNE pancréas ; 1ère cycle thérapeutique

(CHU Bordeaux)

• Non-randomized study: 1109 patients

• GEP-NET and other neuroendocrine tumors

• Hepatic metastases 82%, bone metastases 19%

• 90Y-DOTA-TOC: (3.7GBq)/m2; median 2 cycles (1-10)

• Morphological response: 34%

• Transient grades 3-4 hematological toxicity: 12.8%• Long-term severe renal toxicity: 9.2%

– Previous chemotherapy treatments in many patients

90Y-DOTATOCHôpital Universitaire de Bâle

• Single Centre series of 504 patients, non randomized

• 4 cycles of 7.4GBq of 177Lu-DOTA-Octreotate; 8 weeks interval– Perfusion of amino acids for kidney protection (1L: 25g lysine + 25g arginine over 4h)

• Morphological response: 30% (SWOG criteria)

• Median time to progression : 40 months

• Nausea: 25% ; vomiting 10% (due to amino acids perfusion)

• Transient hematological toxicity grades 3-4 : 3.6% per cycle ; 9.5% of patients overall

• Myelodysplasie : 4 patients

• Hepatic toxicity: 3 patients

• Severe renal failure: only 2 patients

177Lu-DOTA-OctreotateErasmus Medical Centre, Rotterdam

Radiothérapie Interne Vectorisée (RIV) par ciblage des récepteurs de la somatostatine

• Elle concerne les patients avec métastases, ou localement avancés, inopérables.

• Uniquement les TNE-GEP bien différenciées (Ki67 ≤ 20%)

• Après vérification en scintigraphie que les lésions captent (approche théranostique)

• LUTATHERA (lutécium-oxodotréotide ; 177Lu-DOTATATE, 177Lu-DOTA-Octreotate)

• Elimination urinaire : ~ 60% éliminés dans les 24h, sous forme non métabolisée (rapport du CHMP du 20 juillet 2017)

• 177Lu : émetteur - ; demi-vie = 6,7 jours ; énergie moy = 133 keV+ petit pourcentage d’émission permettant l’imagerie post-traitement

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours.Teunissen JJ, Kwekkeboom DJ, Valkema R, Krenning EP.Endocr Relat Cancer. 2011 Oct 17;18 Suppl 1:S27-51.

Métastases hépatiques d’une TNE

A) Scintigraphie 177Lu-DOTA-Octreotate après chacune des 4 administrations.

B) TDM abdominale avant traitement (Pre-PRRT)

et 3 mois après le dernier cycle (Post-PRRT).

177Lu-DOTA-OctreotateErasmus Medical Centre, Rotterdam

Schéma d’administration établi depuis les années 2000

« Erasmus Medical Centre »

• 4 traitements par 200mCi (7,4 GBq) de 177Lu-DOTA-Octreotate, espacés ~8 semaines

• perfusion concomitante (dans l’autre bras) d’acides aminés pour protection rénale

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Objectif

Design Essai international, multicentrique, randomisé, controllé

Evaluer l’efficacité et la tolérance du 177Lu-Dotatate (Lutathera®) plus octreotide30mg comparé à l’octreotide 60mg chez des patients atteint d’une tumeurneuroendocrine non résécable, de l’intestin moyen, positive aux récepteurs de la somatostatine, et qui progressait sous octreotide 30mg

Baseline &

Randomisation

n = 115

Dose 1

n = 115

Traitements et Critères d’EvaluationSurvie sans progression (Critères RECIST)

Suivi de 5 ans

Dose 2 Dose 3 Dose 4

NETTER -1 Objectif & Design de l’Etude

4 administrations de 7.4 GBq de LUTATHERA toutes les 8 semaines + SSA (oct LAR 30mg - contr. sympt)

SSA à haute dose (oct LAR 60 mg) toutes les 4 semaines

From Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors.Strosberg J, et al; NETTER-1 Trial Investigators.

N Engl J Med. 2017 Jan 12;376(2):125-135.

• At the time of the data cutoff for the primary analysis (July 24, 2015), the medianprogression-free survival had not yet been reached in the 177Lu-Dotatate group and was 8.4 months in the control group.

• Hazard ratio for disease progression or death with 177Lu-Dotatate vs. control, 0.21 (95% CI, 0.13 to 0.33; P<0.001)

16 centres déjà actifs en mai 2017

En France actuellement en attente de la décision de la

Commission de la Transparence de la Haute Autorité de Santé

Principal investigator: Dr Eric Baudin - IGR

The French OCCLURANDOM study

Inclusions as of Sep 2017

LUTARTERIAL = Imagerie par 68Ga-DOTA-peptides

et RIV par 177Lu-DOTA-peptides des tumeurs neuroendocrines GEP :

évaluation de l’intérêt d’une administration par voie intra-artérielle

hépatique chez les patients avec métastases hépatiques dominantes

Objectif principal : Comparer en TEP le niveau de captation tumorale hépatique

de 68Ga-DOTA-peptides administrés par voie IAH à la captation obtenue par voie IV

conventionnelle, chez des patients TNE GEP avec métastases H prédominantes.

Etude pilote, interventionnelle, non randomisée, tricentrique, prospective

CHU Bordeaux, CLCC Bergonié Bordeaux, Toulouse Oncopôle

• 20 patients seront inclus pour imagerie TEP par 68Ga-DOTA-peptides

• les 10 premiers patients présentant un rapport ≥ 3 (TEP IAH/IV) recevront

un 5ème traitement par 177Lu-DOTA peptides (LUTATHERA®) par voie IAH.

Theranostic in Prostate Cancer

• Many molecular probes are useful only for imaging:

• 11C-Choline

• 18F-Fluoromethylcholine

• 18F-FACBC (fluciclovine)

• Some are helpful both for imaging and treatment

• Radiolabelled PSMA ligands• Bombesin ligands targeting GRP-R

• PSMA is a peptidase (enzyme), belonging to the type II transmembrane protein family (also named glutamate carboxypeptidase II ).

• Overexpressed in the majority of prostate cancers.

• The expression levels of PSMA correlate with progression of the disease, with increased amounts in high grade, metastatic, and hormone-refractory tumors.

• Physiological expression is seen in salivary glands, kidneys, small intestine and brain.

• It can be targeted with antibodies or small molecule inhibitors

• A Glu-urea-Lys motif has been found to bind with high affinity to the catalytic domain of PSMA.

• It internalizes upon binding to a specific ligand up to threefold in comparison to the basal internalization level.

Targeting of the Prostate-Specific Membrane Antigen« PSMA »

Current status of theranostics in prostate cancer.Virgolini I, et al.

Eur J Nucl Med Mol Imaging. 2018

Mar; 45:471-495.

Radiolabelled PSMA ligands used in patients - status October 2017

glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA

Physiological distribution

• Lacrymal and salivary glands• Small intestine• Kidneys• Liver, spleen• urinary tract and bladder

Afshar-Oromieh A, et al. PET imaging with a [(68)Ga]gallium-labelled PSMA ligand for the

diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.

Eur J Nucl Med Mol Imaging 2013;40:486–95

PSMA-HBED-CC-68Ga(PSMA-11)

The Utility of PET/CT in the Planning of External Radiation Therapy for

Prostate Cancer.Calais J. J Nucl Med. 2018 Apr;

59:557-567.

• A 77-y-old man with newly diagnosed prostate cancer (PSA level, 7.1; Gleason score, 4 + 5 = 9). • MRI showed right prostate lesion with extracapsular extension and right seminal vesicle invasion. • Bone scan was negative.

• 68Ga-PSMA PET/CT showed:- intense 68Ga-PSMA uptake in prostate with seminal vesicle invasion (yellow arrows), - 68Ga-PSMA–positive subcentimeter external iliac lymph nodes (blue arrows), and - focal 68Ga-PSMA uptake in 2 bone lesions (red arrows).

• Patient was staged as hormone-sensitive oligometastatic M1b and offered SBRT to 2 bone metastases in addition to radiotherapy to prostate and pelvic nodes with concurrent androgen deprivation therapy.

Example of PSMA-PET/CT at staging high-risk prostate cancer

Diagnostic value of PSMA-PET in biochemical recurrence of prostate cancer

• Récidive biologique : - PSA > 0,2 ng/ml si prostatectomie totale

- PSA > Nadir PSA + 2 ng/ml si radiothérapie externe

- Fréquente ++ (20-50% selon traitement initial)

• Prise en charge thérapeutique précoce de la récidive => meilleur pronostic

Current status of theranostics in prostate cancer.Virgolini I, et al. Eur J Nucl Med Mol Imaging. 2018 Mar; 45:471-495.

• Detection rate in PC patients with low biochemical relapse of PSA < 1.0 ng/ml scanned either by 18F/11C–choline (orange bars) or 68Ga-PSMA-ligand (green bars)

68Ga-PSMA PET/CT mapping of prostate cancer biochemical recurrence following radical prostatectomyin 270 patients with PSA < 1.0ng/ml: Impact on Salvage Radiotherapy Planning.

Calais J, et al. J Nucl Med. 2018 Feb; 59:230-237.

• Examples of PSMA-positive lesions which are localized outside of consensus CTV : perirectal LN (A), inguinal LN (B), lumbo-aortic LN (C), bone (D), lung (E).

Preclinical Evaluation of a Tailor-Made DOTA-ConjugatedPSMA Inhibitor with Optimized Linker Moiety for Imaging

and Endoradiotherapy of Prostate Cancer.Benešová M, et al.

J Nucl Med. 2015; 56:914-20.

68Ga-PSMA-617 PET/CT (1 h after injection) demonstrating a first patient with multiple

lymph node metastases.

Organ distribution of 177Lu-PSMA-617at 1h (B) and 24 h after injection (C).

PSMA-617

From 68Ga-PSMA Imaging to 177Lu-PSMA Therapy

[¹⁷⁷Lu]Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer.Kratochwil C, et al.

Eur J Nucl Med Mol Imaging. 2015 May; 42:987-8.

Patient with metastatic PCa.

• PSMA PET/CT (a) demonstrates a tumour phenotype with strong PSMA expression.

• The patient was treated with a cumulative activity of 7.4 GBq 177Lu-DKFZ-617 (b, c).

• Restaging with PSMA PET/CT (d) reveals a striking radiological response.

• PSA level decreased from 38.0 to 4.6 ng/ml.

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistantprostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study.

Hofman MS, et al.Lancet Oncol. 2018 May 7. pii: S1470-2045(18)30198-0.

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients.

Rahbar K, et al.J Nucl Med. 2017; 58:85-90.

• Retrospective multicenter data analysis to evaluate efficacy and safety of 177Lu-PSMA-617

• 145 patients: 1-4 therapy cycles ; activity of 2-8 GBq per cycle.

• Grade 3-4 hematotoxicity occurred in 18 patients (anemia 10%, thrombocytopenia 4%, leukopenia 3%)

• Xerostomia occurred in 8%.

• The overall biochemical response rate (PSA decline ≥ 50% from baseline) was 45% after all therapy cycles (40% of patients already responded after a single cycle).

CONCLUSIONS: • 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of

other third-line systemic therapies in mCRPC patients. • Future phase II/III studies are warranted to elucidate the survival benefit.

Evaluation of radiation safety in (177)Lu-PSMA therapy and development of outpatienttreatment protocol.

Demir M, et al.J Radiol Prot. 2016 Jun;36(2):269-78.

• This work analyzed the dose rate of 23 patients treated with 7400 MBq177Lu-PSMA at variable time marks (0, 1, 2, 4, 18, 24, 48 and 120 h) after the termination of infusion.

• The mean dose rate at 1 m after 6 h was 15 ±  4 μSv h(-1).

• The radiation dose of the nurse and radiopharmacist was 6 and 4 μSv per patient, whereas the dose of the physicist and physician was 2 μSv.

• Seven patients excreted a mean of 45% from the initial activity in 6 h.

• Our findings demonstrate that (177)Lu-PSMA is a safe treatment modality to be applied as an outpatient protocol.

α radiation

• α-emitters produce densely ionizing high-LET radiation, causing complex DNA damage leading to prominent cell killing due to unrepaired damage.

• They are less influenced by cell cycle or oxygenation state and can counteract previous resistance to conventional radiotherapy and chemotherapy

• 225Ac emits 4 α-particles and has a half-life of 10 days that fits with the long retention time of PSMA ligands in tumor tissue

• However side-effects are more frequent and appreciation needs longer follow-up.

68Ga-PSMA-11 PET/CT scans.

• Pretherapeutic tumor spread (A),

• Restaging 2 mo after third cycle of 225Ac-PSMA-617 (B),

• 2 mo after one additional consolidation therapy (C)

J Nucl Med. 2016; 57:1941-4.

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.

Kratochwil C,et al. J Nucl Med. 2017; 58:1624-1631.

Reasonable treatment corridor between :

• Insufficient treatment response (red: patient died before reevaluation; orange: PSA progression; green: imaging or PSA response) • Intolerable toxicity (red: xerophthalmia; orange: xerostomia G2; green: no or only G1 xerostomia).

• During repeated therapies, insufficient PSA response was observed at 4-mo interval.

Targeting CXCR4

The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is overexpressed in many solid and hematologic cancers.

• Radiolabeled ligand for imaging: 68Ga-Pentixafor

• For Therapy: 90YPentixather / 177Lu-Pentixather

[68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer--initial experience.

Lapa C. Oncotarget. 2016; 7:9288-95.

68Ga-Pentixafor PET (left) and FDG-PET (right) in a patient with recurrent smal cell lung cancer

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.

Herrmann K. J Nucl Med. 2016; 57:248-51.

Patient with advanced Multiple Myeloma with bone as well as extra-medullary lesions

• 68Ga-pentixafor PET and 18FDG PET: There is good expression of CXCR4 in all lesions in this patient

• FDG-PET 2 weeks after targeted therapy with 177Lu-pentixather

Patient with Multiple Myeloma177Lu Whole-body imaging at 24h and day 15 after administration of 15 GBq 177Lu-pentixather

177Lu-3BP-227 for neurotensin receptor 1-targeted therapy of metastatic pancreatic adenocarcinoma- first clinical results.

Baum RP, et al. J Nucl Med. 2017 Oct 12. [Epub ahead of print]

177Lu-3BP-227 scan of patient 1.

(A) Planar scintigraphy 24 h p.i.

(B) Upper panel: SPECT MIP 45 h p.i.

Lower panel: liver lesions and primary tumor, 45h p.i.

177Lu-3BP-227 scans of patient 2

(C) Planar scintigraphy 48 h p.i.

(D) Upper panel: SPECT MIP 44 h p.i.

Lower panel: Large spinal lesion 44 h p.i.

Targeting neurotensin Receptor-1 (NTR1)

Martins CD, Kramer-Marek G, Oyen WJG.Expert Opin Drug Deliv. 2017 Sep 12.

Radioimmunothérapie : plusieurs molécules en cours d’investigation

Moek KL.J Nucl Med. 2017; 58(Suppl 2):83S-90S.

89Zr-trastuzumab PET imaging in a patient with HER2–positive metastatic breast cancer imaged 4 d after injection.

Dosimétrie dans le champ de la théranostique

• Sûrement très utile mais beaucoup de challenges :

• Dosimétrie 177Lu post-traitement:– Pourrait permettre d’évaluer la dose aux organes cibles

(reins notamment) et de moduler ainsi le nombre de traitements administrés

• Dosimétrie prédictive avant traitement:– Quel radioélément ?

• 68Ga: information qualitative Ok ; mais demi-vie trop courte pour dosimétrie

• 111In SPECT peu pratique• 177Lu à faible activité peu pratique et risque de « stunning »• Isotopes TEP d’avenir (44Sc et 43Sc, 64Cu, 152Tb, 89Zr)

Dosimétrie en théranostique

• Beaucoup de travaux suggèrent une utilité de la dosimétrie 177Lu post-traitement pour prédiction de la réponse tumorale et/ou de la tolérance/toxicité (rénale) :

• Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

Ilan E, Sandström M, Wassberg C, Sundin A, Garske-Román U, Eriksson B, Granberg D, Lubberink M.J Nucl Med. 2015 Feb;56(2):177-82.

• Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.

Garske-Román U, Sandström M, Fröss Baron K, Lundin L, Hellman P, Welin S, Johansson S, Khan T, Lundqvist H, Eriksson B, Sundin A, Granberg D.Eur J Nucl Med Mol Imaging. 2018 Jun;45(6):970-988.

The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as

Exemplified by the Radionuclide Pair 86Y and 90Y.Rösch F, Herzog H, Qaim SM.

Pharmaceuticals (Basel). 2017; 10(2).

Uptake kinetics of a hypothetical radiotherapeutic compound labelled with, for example, 90Y, 177Lu or 225Ac, in the target tissue is given in grey. Note the logarithmic time scale.

• (A) Example of fast accumulation and fast clearance from the target tissue. • (B) Example of fast accumulation and slow release. • (C) Example of medium accumulation and medium release kinetics. • (D) Example of slow accumulation and slow release. The region of uptake kinetics, which can be covered by a 68Ga-labelled analogue, is given in orange.

Prediction of Normal Organ Absorbed Doses for 177Lu-PSMA-617 Using 44Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma.

Khawar A, et al. Clin Nucl Med. 2018 Jul;43:486-491.

44Sc, demi-vie: ~4h

68Ga-PSMA68Ga-RM268Ga-DOTATOC

Any natural or unnatural amino acid

Linker

Chelating agent

Radioactive metal

68Ga-JMV6658

Western Blot

Immunofluorescence

Immunohistochimie

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Neuropeptides

Recherche de récepteurs de neuropeptides

Développements pré-clinique de ligands

Recherche clinique

en imagerie TEP

Radiothérapieinterne

vectorisée

Sélection radioéléments innovants ; Ex: Terbium-161

Nouveaux radiopharmaceutiques

177Lu-PSMA

177Lu-RM2 à moyen terme

Few words on our Projects

Merci pour votre attention

Dose response of pancreatic neuroendocrine tumors treated with peptide receptorradionuclide therapy using 177Lu-DOTATATE.

Ilan E, et al.J Nucl Med. 2015; 56:177-82.

• Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeatedcycles of (177)Lu-DOTATATE at 8-wk intervals.

• The absorbed dose calculations (sphere model from OLINDA) relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE.

• Only tumors larger than 2.2 cm in diameter were included for analysis.

• Tumor-absorbed doses until best response ranged from 10 to 340 Gy. • A significant correlation between absorbed dose and tumor reduction was found

CONCLUSION: The results imply a significant correlation between absorbed dose and tumor reduction. However, further studies are necessary to address the large variations in response for similar absorbed doses.

Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients withadvanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a

dosimetry-guided study protocol on outcome and toxicity.Garske-Román U, et al.

Eur J Nucl Med Mol Imaging. 2018 Jun; 45:970-988.

• This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

• 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours.

• A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy,

• In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached.

• Median progression-free survival was 27 months in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not.

• Dosimetry-based therapy with 177Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Radiation Dosimetry for 177Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: Absorbed Dose in Normal Organs and Tumor Lesions.

Okamoto S, et al.J Nucl Med. 2017; 58:445-450.

• A total of 34 cycles in 18 patients were analyzed retrospectively. • Whole-body scintigraphy was performed at least between 30-120 min, 24 h,

and 6-8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn.

• The mean whole-body effective dose for all cycles was 0.06 ± 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 ± 0.21 Gy/GBq for the kidneys; 0.12 ±0.06 Gy/GBq for the liver; and 0.55 ± 0.14 Gy/GBq for the parotid, 0.64 ± 0.40 Gy/GBq for the submandibular, and 3.8 ± 1.4 Gy/GBq for the lacrimal glands.

• Doses to tumor lesions gradually decreased, with 3.5 ± 2.9 Gy/GBq for the first, 3.3 ± 2.5 Gy/GBq for the second, 2.7 ± 2.3 Gy/GBq for the third, and 2.4 ±2.2 Gy/GBq for the fourth cycle.

• SUVs of pretherapeutic PET moderately correlated with absorbed dose (r = 0.44, P < 0.001 for SUVmax; r = 0.43, P < 0.001 for SUVmean) and moderately correlated with the change of SUV (r = 0.478, P < 0.001 for SUVmax, and r = 0.50, P < 0.001 for SUVmean).

Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specificmembrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer.

Kabasakal L, et al.Eur J Nucl Med Mol Imaging. 2015; 42:1976-83.

• The study included seven patients with progressive prostate cancer. • The injected 177Lu-PSMA-617 activity ranged from 185 to 210 MBq• To evaluate bone marrow absorbed dose 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. • The geometric mean of anterior and posterior counts was determined

through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations.

RESULTS: • Calculated radiation-absorbed doses per megabecquerel were

1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. • The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq

Prediction of Normal Organ Absorbed Doses for 177Lu-PSMA-617 Using 44Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma.

Khawar A, et al.Clin Nucl Med. 2018 Jul;43:486-491.

• Pharmacokinetics of Sc-PSMA-617 was evaluated in 5 patients with metastatic castration-resistant prostate carcinoma using dynamic PET/CT, followed by 3 static PET/CT acquisitions and blood sample collection over 19.5 hours, as well as urine sample collection at 2 time points.

• The maximum permissible activity of Lu-PSMA-617 was calculated for each patient considering external beam radiotherapy toxicity limits for radiation absorbed doses to kidneys, bone marrow, salivary glands, and whole body.

• The predicted mean organ-absorbed doses were highest in the kidneys (0.44 mSv/MBq), followed by the salivary glands (0.23 mSv/MBq).

• The maximum permissible activity was highly variable among patients; limited by whole body-absorbed dose (1 patient), marrow-absorbed dose (1 patient), and kidney-absorbed dose (3 patients).