neuroendocrine tumors Daa filigoj, Petra Tome, Luka Jensterle 13. - - PowerPoint PPT Presentation

Targeted radionuclide therapy of neuroendocrine tumors

Daša Šfiligoj, Petra Tomše, Luka Jensterle

• 13. maj, 2015

Department of Nuclear Medicine University Medical Centre Ljubljana

NETs

 heterogeneous group of tumors that frequently express cell

membrane-specific peptide receptors, such as somatostatin receptors (SSTRs)

 NETs originate from the diffuse endocrine system. This

system includes endocrine glands, such as the pituitary, the parathyroids and the adrenal medulla, as well as endocrine islets within glandular tissue (thyroid or pancreatic) and cells disseminated between exocrine cells, such as endocrine cells of the digestive and respiratory tracts

NETs – sites of origin

Lung 27% Other 15% Pancreas 7% Rectum 17% Jejunum/Ileum 13% Stomach 6% Colon 4% Duodenum 4% Cecum 3% Appendix 3% Liver 1%

NETs

 Classification: different classification systems (ENET,

WHO, AJCC) according to different tumor characteristics

 Grade (inherent biological agressiveness): low-grade

malignant, intermediate-grade malignant, high-grade malignant

 Stage (extent of disease): organ confined, locally

invasive, metastatic

NETs

Traditional classification depending on site of origin (obsolete):

• foregut; thymus, esophagus, lung, stomach,

duodenum, pancreas

• midgut; appendix, small bowel, ascending colon
• hindgut; distal large bowel, rectum

Replaced by tumor-based classification by WHO

NETs – WHO classification

 WHO classification defines NETs according to tumor

differentiation, with specific clinicopathological features:

• biological behavior (malignancy)
• metastases
• Ki-67 index
• angioinvasion
• tumor size
• histological differentiation
• hormonal syndrome

NETs – prognostic factors

Well-differentiated neuroendocrine tumor Well-differentiated neuroendocrine carcinoma Poorly differentiated neuroendocrine carcinoma Biological behavior Benign or uncertain malignancy Low malignancy High malignancy Metastases

• +

+ Ki-67-index (%) <2 >2 >30 Infiltration, angioinvasion, necrosis

• +

+ Tumour size ≤2 >2 any size Prognosis good intermediate poor

NETs

 NETs occur either sporadically or as part of familial

syndromes

 the great majority are either benign or relatively slow

growing

 possession of specific receptors at the cell membrane,

such as somatostatin receptors (SSTRs) can be used for the identification, localization and therapy of NETs

 of the five major subtypes of SSTR, SSTR2 and SSTR5

are the ones most commonly expressed in NETs; however, there is considerable variation in SSTR subtype expression among the different tumor types and among tumors of the same type

NETs

 the excessive secretion of neuropeptides (serotonin,

kallikrein) may give rise to distinct clinical syndromes in approximately 5% of carcinoid tumors

NETs

 Diagnosis:

• increased urinary excretion of 5-hydroxyindoleacetic acid

(5-HIAA), a degradation product of serotonin

• chromogranin A
• imaging methods; morphological – US, CT scan, MRI

functional – SSTR scintigraphy hybrid – SPECT/CT, PET/CT

• biopsy/histology

NETs – morphological imaging

NETs – functional imaging

Radiolabelled (99m-Tc, 68-Ga) somatostatin analogue-derived peptides are radiopharmaceuticals that can be utilized for the identification and localization of NETs by their ability to bind to SSTRs. They form an imaging modality which is based on the physiological (the presence of functioning receptors) rather than the anatomical characteristics of the tumors. As the majority of NETs express SSTRs they form an ideal target for treatment with somatostatin analogue -derived radiolabelled (90-Y, 177-Lu) peptides.

Normal scintigraphic features include visualization of the thyroid, spleen, liver, pituitary, urinary bladder and

• ccasionally the bowel.

NETs – hybrid imaging SPECT/CT PET/CT

NETs - treatment

 Surgery – curative, paliative  Debulking – radiofrequency ablation, radio/chemo

embolization

 Medical therapy – chemotherapy

• biological targeted agent (SST

analogs)

• targeted molecular therapy (VEGF-R

inhibitors, mTOR inhibitors)

 Irradiation – external

• tumor-targeted radioactive therapy (PRRT)

PRRT – peptide receptor radionuclide therapy

 SST analogues are synthetic peptides that exert most of the

biological actions of the native peptide somatostatin, but have a longer half-life (2 min vs ~ 90 min), being resistant to plasma degradation

 the high affinity of these peptides for SSTRs (usually highest

affinity for SSTR2, moderately high for SSTR5 and intermediate for SSTR3) and the internalization of the receptor–peptide complex facilitate retention of the radiopeptide in receptor- expressing tumours, whereas their relatively small size facilitates rapid clearance from the blood

 specific binding to tumor cells can deliver an effective radiation

dose to the tumor without damaging healthy tissues, thus limiting adverse effects.

PRRT

* SST analogue * = 90-Y 177-Lu

S S T R

β−

PRRT

90-Y vs. 177-Lu?

90Y 177Lu

90-Y SST analogue 177-Lu SST analogue

90Y 177Lu

Kidneys and bone marrow are “critical

• rgans”

PRRT patient selection criteria

 Inoperable/metastatic NETs  Normal Hb ,WBC, PLT (Hb>10g/l, WBC>3.0 x 109/l,

PLT>100 x 109/l)

 Normal kidney function (urea<10 mmol/l, chreatinine<160

μmol/l, GFR>40 ml/min)

 Good performance status

PRRT patient selection criteria

 expression of SST

receptors 99mTc-EDDA/HYNIC- TOC scintigraphy is performed to confirm expression of SST receptors

PRRT contraindications

 Myelosuppresion, bone-marrow metastatic disease  Renal impairment  Poor performance status  Pregnancy/lactation  Exceeding a radiation dose limit (kidneys > 27 Gy) –

DOSIMETRY!

Zakaj individualna dozimetrija

 Uspeh terapije je odvisen od količine

radioaktivnosti in koliko časa ta ostane lokalizirana v tumorju. (Aktivnost in Efektivni razpolovni čas)

 Do nedavnega so pri terapijah aplicirali

standardne odmerke aktivnosti, včasih prilagojene na težo/površino pacienta, volumen ščitnice itd.

• > pri tem le redki prejmejo optimalno terapijo

Individualna dozimetrija

 Z modernimi slikovnimi tehnikami se pristop k načrtovanju

terapije individualizira

 Ko izmerimo privzem radioaktivnega izotopa, porazdelitev ter

zadrževanje v tumorjih in kritičnih organih, lahko izračunamo absorbirano dozo.

 Učinek na tkivo izražamo kot prejeto/načrtovano

absorbirano dozo v gray-jih (Gy)

 Za dozimetrijo uporabimo

• radioizotop, uporabljen za terapijo,

če ta seva -žarke (177Lu, 131I..)

• nadomestni izotop (111In, 86Y, 124I..)

 Skrbimo za varstvo pred sevanji

in optimiziramo načrtovano terapijo

EURATOM 97/43 directive “For all medical exposure of individuals for radiotherapeutic purposes, including nuclear medicine for therapeutic purposes, exposures of target volumes shall be individually planned; taking into account that doses of non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure.”

0,01 0,02 0,03 0,04 20 40 60 80 100 120 A/A0 t[h]

Primer: Individualna dozimetrija pri terapiji z Y90(In111)-DOTATOC (1)

3 1 i t i

i

e k A A

Geometrijsko povprečje; Označitev ROI na vsaki sliki Slikanje po aplikaciji diagnostičnega izotopa: 1h, 4h, 20h, 70h, 115h Določitev časovne odvisnosti aktivnosti v vsakem organu Biološki razpolovni čas je enak za diagnostični in terapevtski izotop; Fizikalni razpolovni čas pa ne.

• > Določimo št. radioaktivnih

razpadov za terapevtski izotop Izračun doze na posamezen

• rgan

• Iz podatkov za število radioaktivnih razpadov v posameznih organih

določimo prejeto/predvideno dozo apliciranega izotopa

• Ledvice so kritični organ pri terapiji z Y90-DOTATOC,

zato z omejevanjem doze na ledvice načrtujemo varno terapevtsko aktivnost Pogoj: Absorbirana doza na ledvice: < 23/27 Gy Terapija: A(90Y) ~ 6 GBq

Primer: Individualna dozimetrija pri terapiji z Y90(In111)-DOTATOC (2)

Omejitve klasične individualne dozimetrije

 Absorbirane doze navadno računamo po MIRD modelu, s

komercialnimi računalniškimi programi (OLINDA/EXM) Uporabljamo nekaj standardnih anatomij človeka

 Predpostavljamo homogeno porazdelitev radiofarmacevtika v

• rganu ali tumorju

~1990 ~2000.... 1975 ~1950

Primer izboljšane tehnike: Standardni in individualni volumen ledvic pri terapiji z 90Y-DOTATOC (Belgija, 2004)

 Po terapijah, kjer so predvideli podobne vrednosti absorbirane doze,

so našli zelo različne spremembe v funkciji ledvic.

 Kasnejša študija je pokazala, da je pomembno upoštevati

individualne volumne ledvic. Določijo jih navadno iz CTja -> CTVol

StdVol 288 mL 264 mL CTVol 373 ± 76 mL 317 ± 59 mL

Absorbirana doza na ledvice [Gy] D(StdVol) 25.6 - 38.6 D(CTVol) 19.4 - 39.6 BED 27.7 - 59.2

BED [biologicaly effective dose]: Upošteva absorbirano dozo in njeno učinkovitost – hitrost doze, deljeno terapijo,... Predlagana meja za povečano nevarnost poslabšanja ledvične funkcije BED>45 Gy

90-Y DOTATOC (~6600 MBq): prejete doze

• Op. najvišja “varna” doza za ledvice = 27 (23) Gy

Doza Celo telo (Sv) Kostni mozeg (Gy) Ledvice (Gy) Št. bolnika 1 0,62 0,25 10,7 2 2,7 0,5 16,7 3 3,0 0,6 24,8 4 1,1 0,2 11,1 5 0,59 0,2 9,9 x 1,6 0,35 14,6

Patient preparation

 99mTc-EDDA/HYNIC-TOC scintigraphy  Dosimetry with 111In-DOTATOC (185MBq)  Cold somatostatin therapy (SST analogs) is withheld

before the treatment

 Amino acid infusion at the time of treatment  Treatment with 90Y-DOTATOC (6000-6600MBq) or

177Lu-DOTATATE (~7000Mbq)

PRRT efficacy

 Because of high radiation exposure to normal tissues the

therapeutic dose is limited and usually not high enough to be curative

 Efficacy in literature (125 patients)*

CR : 2.4% PR : 25.6% MR : 19.2% SD : 35.2% PD : 17.6%

*Kwekkeboom et al. J Clin Oncol 2005;23: 2754 -62

before treatment 3 months after treatment=minor remission

before treatment 3 months after treatment=partial remission

Future prospects for PRRT of NETs

 new SST analogues with binding to different SST receptors

with better affinity

 targeting other receptors (glucagon-like peptide 1 (GLIP-1)

receptors, cholecystokinin receptors, bombesin or vasoactive intestinal peptide (VIP) receptors)

 Peptides labeled with α emitters

• energy: α (At- 211) : 5869 keV

β− (Lu-177): 497 keV

• reach in tissue: α = few micrones =less than cell 2r

β− = few milimeters =10-100 cell 2r