chianelli renal radiotoxicity firr12biotec.casaccia.enea.it/document-fold/workshop-14...j van der...
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Marco Chianelli, MD, PhD
Regina Apostolorum Hospital Rome, Italy
Radiotossicità renale nella terapia
rece8oriale radionuclidica
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somatosta9n
n 14 amino acids cyclic pep0de
n in 1975 n iden0fied and charachterised
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somatosta9n
n produc9on n in central and peripheral nervous systems n endocrine pancreas, gut n thyroid, the re0na, adrenals, submandibular n glands, kidneys, prostate and placenta
n func9ons n modulates neurotransmission n regulates the release of GH and thyrotropin (TSH) n has a regulatory role in the gastrointes0nal tract n plays a role in cell prolifera9on
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J van der Hoek et al Current Pharmaceutical Design, 2005, 11, 1573-1592
rece8ori per la somatosta9na nei tessu9 normali
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somatosta9n receptors
overexpression in several tumours radiolabelled somatosta9n
diagnosis and treatment of somatosta9n receptor posi9ve tumours
JC Reubi Endocrine Reviews 2003;24(4):389–427
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n very short half life n extremely sensi0ve to pep0dases
n cannot be used for imaging or therapy
na9ve somatosta9n
human somatostatin Octreotide (Sandostatin)
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DOTA-‐[Tyr3]-‐octreo9de (DOTA-‐TOC) n 111In-‐DOTA-‐[Tyr3]-‐octreo9de n 99mTc-‐HYNIC-‐[Tyr3]-‐octreo9de n 68Ga-‐DOTA-‐[Tyr3]-‐octreo9de n 90Y-‐DOTA-‐[Tyr3]-‐octreo9de
111In-Octreoscan 111In-DOTA-TOC
A Otte et Eur J Nucl Med (1997) 24:792-795
)
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DOTA-‐[Tyr3,Thr8]-‐octreo9de (DOTA-‐TATE)
n 111In-‐DOTA-‐ [Tyr3,Thr8]-‐octreo9de n 99mTc-‐HYNIC-‐[Tyr3,Thr8]-‐octreo9de n 68Ga-‐DOTA-‐ [Tyr3,Thr8]-‐octreo9de n 177Lu-‐DOTA-‐ [Tyr3,Thr8]-‐octreo9de
Forrer et al Eur J Nucl Med Mol Imaging (2004) 31:1257–1262
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68Ga-‐DOTANOC higher affinity and receptor specificity
Wild et al EJNM 2004
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sst2 in vitro in a carcinoid receptor expression
125I-SS autoradiography
mRNA sst2 in situ hybridization
JC Reubi Endocrine Reviews 24(4):389–427
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177Lu vs 90Y
90Y n emivita 64,8 h n decadimento
n beta puro n energia (max) 2,28 MeV
n penetrazione nei tessu0 (max) 1,1 cm
n di elezione nelle macrometastasi
177Lu n emivita 6,6 d n decadimento
n beta n energia 0,5 MeV
n gamma n energia (max) 110 KeV
n penetrazione nei tessu0 (max) 2 mm
n di elezione per le micrometastasi
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n 5 cicli di 177Lu-‐DOTA-‐TATE o 90Y-‐DOTA-‐TATE da 8 GBq n erogazione al tumore di circa 80 Gy
n organo cri9co n rene n limite di dose ai reni pari 26 Gy
n s0mato in base ai da0 della EBRT n effe8o determinis9co
n n
protocollo per pep9de receptor radionuclide therapy (PRRT)
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111In-‐octreoscan: biodistribuzione
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meccanismi di tossicità renale
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n personalizzato n calcolo individuale della dose assorbita n dose media: errore può superare il 40 %
n pianificazione del programma terapeu9co n maggiore efficacia
n aumento della a\vità somministrata n se il limite non è stato raggiunto
n minore tossicità n riduzione se è stato superato
calcolo della dose assorbita renale
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n il limite di dose calcolato per la EBRT
n non predice la probabilità di danno renale in PRRT
n perchè?
equivalenza tra EBRT e RNT
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n rateo di dose n EBRT high dose rate: 1-‐5 Gy/min n RNT very low dose rate: 2–8 Gy/day
n dose e rateo di dose n declinan9 nel tempo
n fa8ori di rischio clinici n 9po di radiazioni n energia n uniformità di dose
n distribuzione 9ssutale n distribuzione cellulare
fa8ori contribuen9 alla radiotossicità renale
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n increase in number of micronuclei
n treatment with 131I for thyroid diseases: n=32
n pa0ents treated with EBR for n cancer of the cervix the n=298 n Hodgkin’s disease n=640
"Es0ma0on of risk based on biological dosimetry for pa0ents treated with radioiodine" Monsieurs MA, Nucl Med Commun 1999, 20:911-‐917
experimental findings
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n riduzione della captazione renale n sviluppo di modelli radiobiologici adegua0
n dose e rateo di dose declinan0 nel tempo n non uniformità di irraggiamento
n frazionamento di dose n 90Y vs 177Lu n radioprote8ori
possibili strategie di riduzione del danno
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effect of dose rate
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effect of dose rate
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effect of dose rate
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effect of dose distribu9on
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effect of dose distribu9on
90Y 177Lu
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effect of radia9on energy
90Y 177Lu
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effe8o dei fa8ori di rischio
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effe8o dei fa8ori di rischio
Pazienti (n = 23) trattati con 90Y-DOTATOC
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effe8o dei fa8ori di rischio
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conclusioni
n Gli schemi di terapia più efficaci e con la maggiore tollerabilità sono n somministrare la massima aavità, frazionata
n compa0bile con la dose limite renale
n radiotossicità renale n faeori clinici predisponen0 quali diabete e ipertensione
n nel futuro l’organo cri9co n il midollo osseo