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

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 Well-differentiated Poorly neuroendocrine neuroendocrine differentiated tumor carcinoma neuroendocrine carcinoma Biological behavior Benign or uncertain Low malignancy High malignancy 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, SSTR 2 and SSTR 5 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 occasionally 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 SSTR 2 , moderately high for SSTR 5 and intermediate for SSTR 3 ) 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 S * SST analogue S T * = 90-Y R 177-Lu β −

PRRT 90-Y vs. 177-Lu? 90 Y 177 Lu

90-Y SST analogue 177-Lu SST analogue Kidneys and bone marrow are “critical 90 Y 177 Lu organs”

PRRT patient selection criteria  Inoperable/metastatic NETs  Normal Hb ,WBC, PLT (Hb>10g/l, WBC>3.0 x 10 9 /l, PLT>100 x 10 9 /l)  Normal kidney function (urea<10 mmol/l, chreatinine<160 μ mol/l, GFR>40 ml/min)  Good performance status

PRRT patient selection criteria  expression of SST receptors 99m Tc-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) EURATOM 97/43 directive  Za dozimetrijo uporabimo “ For all medical exposure of individuals for - radioizotop, uporabljen za terapijo, radiotherapeutic purposes, including nuclear medicine for therapeutic purposes, če ta seva - žarke (177Lu, 131I..) exposures of target volumes shall be - nadomestni izotop (111In, 86Y, 124I..) individually planned; taking into account that doses of non-target volumes and  Skrbimo za varstvo pred sevanji tissues shall be as low as reasonably achievable and consistent with the in optimiziramo načrtovano terapijo intended radiotherapeutic purpose of the exposure. ”

Geometrijsko povprečje; Označitev ROI na vsaki sliki Slikanje po aplikaciji Izračun doze na posamezen diagnostičnega izotopa: organ 1h, 4h, 20h, 70h, 115h Primer: Individualna dozimetrija pri terapiji z Y90(In111)-DOTATOC (1) 0,04 3 A A/A0 Biološki razpolovni čas je enak t k e i i A za diagnostični in terapevtski 0,03 i 1 0 izotop; 0,02 Fizikalni razpolovni čas pa ne. - > Določimo št. radioaktivnih 0,01 razpadov za terapevtski izotop t[h] 0 0 20 40 60 80 100 120 Določitev časovne odvisnosti aktivnosti v vsakem organu

Primer: Individualna dozimetrija pri terapiji z Y90(In111)-DOTATOC (2) Pogoj: Absorbirana doza na ledvice: < 23/27 Gy Terapija: A(90Y) ~ 6 GBq • 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

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