THE EXPERIENCE IN A SINGLE INSTITUTE OVER TWO

DECADES OF INDIVIDUALIZED RADIOPEPTIDE

THERAPY: FROM BENCH TO BEDSIDE

GS LIMOURIS, MD BSc PhD, PROF IN NUCLEAR MEDICINE,

NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS

Μ PAPHITI-DEMETRIADI, BSc MSc, RADIATION PHYSICIST,

NATIONAL HEALTH SYSTEM

DECLARATION

➢ By the present all mentioned authors declarethat their regular residence is in Europe themajority of them are member of the EANM andthe work has been done in Europe.

➢ The authors declare any conflict of interest withnthe present report, approved by the ClinicalEthics Committee of the ‘Aretaieion’ UniversityHospital. A written consent was obtained fromall participating patients.

Introduction:

In recent years, radio-molecular therapy(RMT) based on radionuclide-tagged peptidereceptors has firmly established its positionas first-line therapy for the management ofneuroendocrine tumors (Netter-1) **.

(**) NETTER-1: A III Phase Multi-Center Study

comparing the Progression Free Survival (PFS) after

treatment with 177Lu-DOTA0-Tyr3-Octreo-tate) plus

best supportive care (30 mg Octreotide LAR) to

treatment with High Dose (60 mg) Octreotide LAR

in Patients With inoperable, midgut carcinoid

tumors), as determined by Response Evaluation

Criteria in Solid Tumors [RECIST] Criteria.

Traditionally, radionuclide therapy admi-nistered systemically (i.e., either intra-arterially or intravenously) can delivertherapeutic doses to both primary tumorand their metastases as well.

Even more, individualized dose assessment

can further improve and document the

clinical outcome in terms of tumor control

with concomitant reduction of the radiation

damage in normal tissues, sparing critical

organs.

Subject and Methods:

Peptide Receptor Radionuclide Therapy(PRRT) in man is being performed routinely inour Institution with 111In-DTPA-Phe1 Octreo-tide, 90Y- DOTATOC, n. c. a. 177Lu- DOTATATEand n. c. a. 177Lu- DOTANOC in non-resectableliver metastasized neuro-endocrine tumors,positive for somatostatin sst2 receptors,almost exclusively after selective cathe-terization of the hepatic artery.

In the case of intra-arterial radiopharma-ceutical infusion, a high target-to-back-ground ratio was observed.

Additionally, the radiopharmaceutical accu-

mulation and retention in the tumor mass,

along with the rapid clearance from the

non-target structures plays a crucial role in

minimizing the radiation burden of the

critical organs.

Our initial experience [1997 to 2011, more than800 sessions] was based on the intra-arterialinfusion of [111In-DTPA-D-Phe-1]-octreotide, inhigh activity (5.4 ± 1.7 GBq) performed in 12consecutive therapeutic schemes in 68patients, with an 8-10 weeks’ time interval

between treatment cycles [1] *.

1997 to 2011:[111In-DTPA-D-Phe-1]-octreotide

Limouris et al: EJNMMI Vol. 35 Number 10, Oct 2008;Published Date:09/30/ 2008; DOI: 10.1007/s00259-008-0779-0

In – 111 physical characteristics

Emission type Energy (keV) Yield(%) Particle Range (μm)

Photon 171 90 -

Photon 245 94 -

Conversion e- 21.8 – 24.5 15.6 200 – 550

Auger e- 0.5 – 25 118 0.02 – 10

Tph ½ : 2.8 days

Interactions of ionizing radiations on the

scale of DNA. (Courtesy of Thomas

Tunningley, ANU)

For myeloprotection, 75 mg DTPA in 250 mlnormal saline solution was administered in triptrop intravenously, starting 30 minutes prior tothe initialization of the catheterization proce-

dure and lasting 4 hours thereafter*.

177Lu

cot r

eot

ide

B

l

o

o

d

P

o

o

l

DTPA infusion

urine excretion

D

T

P

A

177mLu+3

DT

P

A

111In+3

The biochemical response, during and after thetherapeutic intervention, was followed andassessed by serial Chromogranin A (CgA)measurements *.

Serum CgA vs sessions in In-111 therapy

0 5 10 150

200

400

600

800

1000PR

SD

PD

sessions

Cg

A (

ng

/ml)

Planar scintigraphic images were obtained at 30min, 24, 48 and 72h post-injection along with a24h blood and urine sampling to determine theamount of activity uptake in preselectedregions of interest in liver nodules and criticalorgans *.

The absorbed dose was calculated by theOLINDA/EXM code, assuming a sphere for tu-mor having 10 g mass density, and it was cor-related thereafter to the response asses-sment, according to the RECIST criteria(RECIST 1.1).

For the assessment of the radiomolecular

efficacy due to Auger and Internal

Conversion electron emission of In-111 as

well as for follow up reasons, CT/MRI/US

scans were performed before, during and

after treatment *.

US : liver tumor degeneration on the course of PRRT

A

Bii

A. Stage I (1st to 3rd session , absorbeddose (US: peripheral oedema)

B. Stage II (4th to 7th session , absorbeddose 16000 cGy (US: small multiplecavities Swiss-cheese type)

C. Stage III (more than 8 sessions)absorbed dose over 16000 cGy(US: marked cystic degeneration and relapse)

Bi

Often due to the consecutive catheterizations, thefemoral arteries get hardened; so the temporarysub-cutaneous implantation of a port system,ending at the common hepatic artery,

protects the patients from the discomfort of thecatheterization process as well as from the kidneyburden due to the administered contrast media.

This implantable port system allows normal every

day activity and a normal life style like that of

cardiac pace-maker patients, as well as partici-

pation in athletic activities, such as swimming.

The chamber septum of titan of the port-system

could be easily implanted subcutaneously by a

relatively simple surgical procedure, performed

under local anaesthesia. In our patients it was

implanted in the right iliac fossa **.

The distance: dorsal vein hand system - antecubital vein up to the liver tumor is more than 3-fold longer compared to the distance: femoral artery to hepatic artery

More than a decade later [2012-2016, 54 infu-sions], we started working with non- carrieradded (n.c.a.) 177Lu‐DOTATATE, administeredintra-arterially via the common hepatic artery. 9patients were treated with 6 cycles each (7.3±2.3GBq per cycle).

2012 to 2016:

(n.c.a.) 177Lu‐DOTATATE, 177Lu‐DOTATOC

For myelo-protection, 75 mg DTPA in 250 mlnormal saline to remove the tri-valent ioniccontaminants from blood pool to urine (The“Aretaieion Protocol”) and

For nephro-protection, 1000 ml amino acidinfusions [Aminosteril N-Hepa 8%( lysine andarginine) Fresenius Kabi, Germany] were in trip-trop concurrently administered, 30 min beforethe radiopeptide injection, lasting for theforthcoming 4 hrs.

The tandem i.v. co-infusion of 75mg of DTPA 30min before the commencement of the PRRTsession in trip-trop infusion continuing on thecourse of the procedure and lasting 4 hrs.thereafter in 250 ml normal saline competes withtransferrin and forms trivalent DTPA-contaminants complexes, rerouting the ionic(free) Indium, Yttrium and Lutetium fraction torenal clearance.

serial CgA measurements were assessedduring the treatment cycles.

Serum CgA vs sessions in Lu-177 therapy

0 2 4 6 80

200

400

600

800

1000PR

SD

PD

sessions

Cg

A (

ng

/ml)

Blood samples were collected at 30 min, 2h, 4h, 8hand 24 h post-infusion.

Α 24h urine sampling was collected, too.

Planar scintigrams were performed immediately,24, 48, 96 and 120 h post-infusion, and regions ofinterest (ROIs) were manually drawn on theanterior and posterior spot views for tumor, liver,spleen, and kidneys to determine their residencetime and uptake % .

Dosimetric calculations were performed using

the OLINDA/EXM (1.1) code, assuming a sphere

for tumor having 10 g mass density. Once more,

response was evaluated according to RECIST

criteria and dosimetry in relation to the

obtained Cg-A.

Results:

Regarding the organ average radiation

(absorbed dose in mGy /MBq) via the

implanted port system cases, compared to

those after simple arterial infusion (sai),

expressed as 111Insai /111Inport ratios were: (a)

liver tumor 11.2/15.4 mGy/MBq, (b) liver

0.14/0.18 mGy/ MBq, (c) kidneys 0.41/0.39 mGy

/MBq, (d) spleen 1.4/1.6 mGy/MBq and (f) bone

marrow 0.0035/0.0032mGy/MBq.

The organ average radiation dose(mGy/MBq) expressed as 111In /177Lu ratioswere: (a) liver tumor 11.2/35.0 mGy/MBq,(b) liver 0.14/0.03-0.1 mGy/ MBq, (c)kidneys 0.41/0.02-0.5 mGy/MBq, (d) spleen1.4/0.02-1.2 mGy/MBq and (f) bone marrow0.0035/0.008-0.04 mGy/MBq.

The [111In-DTPA-D-Phe-1]-octreotide treatedgroup exhibited a response starting at the8th session, whereas the 177Lu ‐ DOTATATEtreated group exhibited a response star-ting at the 3rd to 4th session.

The decline in CgA values was positivelycorrelated to the observed tumor shrinkage.

Conclusion:

Nowadays, in patients with unresectableliver primaries or liver metastatic neuro-endocrine tumors radio-molecular thera-py appears to be the therapeutic ma-nagement of choice and rightly recentlyconsidered as first-line therapy for theconfrontation of neuro-endocrine tu-mors with limited side-effects.

For this reason, accurate quantitativeimaging must be regarded as an essentialintegral part of the whole therapyprocedure and dosimetry is a “must”after each therapeutic scheme.

Regarding our PRRT experience withthe n.c.a. 177Lu‐DOTATATE, a 3-foldhigher absorbed dose to tumor tissuewas achieved compared to [111In-DTPA-D-Phe-1]-octreotide.

The drawback of 111In-[DTPA0] octreotide thera-py is that the number of administrations wouldneed to be almost doubled in order to achievean equal therapeutic outcome to 177Lu-[DOTA0,Tyr3]octreotate.

country population no soc Cent no priv Cent total

GREECE 10. 750. 000 28 119 147

CYPRUS 860. 000 1 4 5

Table 1. A WINDOW TO GREECE / CYPRUS REGARDING THE RADIOMOLECULAR THERAPIES

Only 33 / 147 Rad Nuc Cent in Greece while all 5 in Cyprus perform

radionuclide therapies. From the 33 centers in Greece, 12 are situated in

Athens, 6 in Saloniki-Macedonia, and the rest 19 located in Pireus, Herkleion-Crete, in Patras-Peloponess, Ioannina-Epirus and Alexandroupoli-Thrace.

No Rad /nucl Cent Diagn Therap 131 I Na PRRT SIRTBone Pain * Ra 223

147 (GR) 147 33 160 52 10 38 223

5 (CY) 5 5 41 --- --- --- ---

Table 2. A WINDOW TO GREECE / CYPRUS REGARDING THE RADIOMOLECULAR THERAPIES per yr

děkuji vám za pozornost!Ευχαριστώ για την προσοχή σας!

thank you very much for your attention!

Based on the manufacturer, the radiopharmaceuticals contain radio-contaminants consisting of trivalent free ions:

111In-therapy 177Lu-therapy 90Y-therapy

Free Ions 111In+3 / 114mIn+3 177 Lu+3 / 177m Lu+3 90Y+3

T1/2ph 2.83 d / 49.5 d 6.7d / 160.7 d 2.67 d

Percentage (%) 0.1 % ~ 0.05 % ~ 0.1%

Taken into account that a mean patient administration

activity per session using the aforementioned 3

radionuclides usually ranges from 4070 MBq to 7040

MBq the amount of these free Indium, Lutetium and

Yttrium ions is considerably increased 1 and according to

our data undesirable myelotoxicity (grade 2-3) might be

enhanced 2.

1Li WP, et al. Nucl Med Biol 2001; 28:145–154.

2 Limouris GS, et al (‘Aretaieion’ Protocol). Q J NMMI 2012; 56(6):551-58.

transferrin

liver bone

marrow

spleen

ferritinTra

ns-

ferrin

Tra

ns-

ferr

in

111In+3

114mIn+3

According to pharmaco-

kinetics, Indium, Yttrium

and Lutetium trivalent (+3)

ions accumulate in bone,

liver and spleen 1, bound to

transferrin, a 80 kDa iron

binding protein 2, inducing

unwanted irradiation in

bone marrow.

1 Jandl JH, et al. Journal of Clinical Investigation. 1963; 42(3):314.2 Chun-Ka Luk, et al. 1971; Bioch 10(15):2838-43.

The tandem i.v. co-infusion of 75mg of DTPA 30min before the commencement of the PRRTsession in trip-trop infusion continuing on thecourse of the procedure and lasting 4 hrs.thereafter in 250 ml normal saline competes withtransferrin and forms trivalent DTPA-conta-minants complexes, rerouting the ionic (free)Indium, Yttrium and Lutetium fraction to renalclearance 1 .

1 Breeman WA, et al.Nucl Med Biol. 2004;31(6):821-4

n.c.a. vs c.a. Lu-177

n.c.a. Lu-177

* higher specific activity* higher radionuclide purity(no 177m Lu contaminant)* every single atom is radioactive! [75% of thec.a. Lu-177 contains the non-radioactive Lu-175

and Lu176]

Carrier-free 177Lu-[DOTA0,Tyr3] octreotate blood and urinaryradioactivity, expressed as a percentage of the injected dose, wassignificantly lower compared as to carrier-added one (p <0.05);n.c.a. 177Lu-octreotate absorbed doses were (a) 8.6 fold higher forliver tumour [20 gr spherical mass], (b) 3.6 fold lower forkidneys and (c) 24.0 fold lower for bone marrow.