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INQUADRAMENTO DIAGNOSTICO E APPROCCIO TERAPEUTICO DEI TUMORI NEUROENDOCRINI Milano, 25 maggio 2007 La terapia radiore

Distribution of SST-Receptors in NETs in vitro studies. Gastrinoma, Glucagonoma100 %Insulinoma72

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INQUADRAMENTO DIAGNOSTICO E APPROCCIO TERAPEUTICO DEI TUMORI NEUROENDOCRINI Milano, 25 maggio 2007 La terapia radiore

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    1. INQUADRAMENTO DIAGNOSTICO E APPROCCIO TERAPEUTICO DEI TUMORI NEUROENDOCRINI Milano, 25 maggio 2007 La terapia radiorecettoriale: dalla diagnostica alla terapia molecolare Arturo Chiti Medicina Nucleare Istituto Clinico Humanitas, Rozzano - Milano arturo.chiti@humanitas.it

    2. Distribution of SST-Receptors in NETs in vitro studies Gastrinoma, Glucagonoma 100 % Insulinoma 72% Carcinoids 88% Paraganglioma 92 % Medullary Thyroid Carcinoma 38 % Small Cell Lung Cancer 57 % Pheochromocytoma 73 %

    3. SSTR Subtype expression in vitro Gastrinoma 64-100 86-100 0-50 22-86 86-100 Insulinoma 60-100 75-100 0-100 20-96 0-100 Carcinoid 44-83 67-100 0-53 33-83 44-100 Non functioning NETs 22-77 67-100 0-50 11-70 22-80

    4. Philosophy of Somatostatin Receptor Scintigraphy

    6. Clinical implications of immunohistochemical assessment of somatostatin receptors subtype 2 and 5 in the diagnostic and therapeutic management of gastro-entero-pancreatic neuroendocrine tumours Retrospective study on 26 patients SRS and immunohistochemistry (IHC) SSTR expression was detected in 17 patients (63%) by SRS and in 24 patients (89%) by IHC The expression of SSTR documented by scintigraphy was confirmed in all cases by IHC IHC revealed SSTR expression in 7 patients (26%) with a negative scintigraphy

    9. Why PRRT ? High tumour-background ratio can be achieved with radiolabelled somatostatin analogues Diagnostic scans with radiolabelled somatostatin can be used to identify suitable candidates for PRRT Radionuclides suited for therapy are available and can be linked to peptides

    11. high LET(-like) Auger electrons emitter, 111In: Emax 25 keV, very short path length (max. 10 µm). ? low LET ?-particles emitter, 90Y:Emax 2.3 MeV, path length max. 12 mm.

    13. Criteria for PRRT Non surgical, metastatic tumors No response to medical therapies (?) Receptor expression High affinity subtype High density Homogeneous distribution Radiosensitive tumors

    14. 111In-pentetreotide therapy Easily available Data on more than 100 patients 70% reported overall response Minor and biochemical response often reported PR are uncommon No significant toxicity Most common was bone marrow suppression Pre-treatment score

    16. [90Y-DOTA,Tyr3]octreotide CR and PR observed in 10-30% of patients Reversible grade 3 hematology toxicity with high doses Radiation dose to the kidney is the limiting factor Amino-acids and plasma expanders are effective in reducing kidney dose

    19. [177Lu-DOTA,Tyr3]octreotate Higher affinity for somatostatin receptors Gamma emission allow post-therapeutic biodistribution studies PR, MR and SD responses are reported in the majority of patients Tumor regression was correlate with a high uptake on Octreoscan imaging

    20. PRRT with 90Y-and 177Lu-labelled somatostatin analogues in patients with neuroendocrine tumours.

    21. Tumor type and tumor response

    22. Side effects and toxicity Haematological toxicity Dose to bone marrow due to circulating radioactivity Rare, mild and transient MDS reported in few cases Pre-treated patients Limited data on long term follow-up Renal toxicity Dose due to partial reabsorption of peptides in the tubular cells Physical characteristics of the radionuclide are important Administration of arginine and/or lysine reduce renal uptake Plasma expanders and amifostine are under evaluation

    23. Side effects and toxicity Gastrointestinal toxicity Acute nausea and vomiting in 30% of patients Liver toxicity Very rare, linked to liver metastases

    24. Side effects

    25. Which radiopharmaceutical?

    26. What are we doing 37 MBq/Kg up to 2600 MBq One cicle every 3 months Evaluation of toxicity and response Blood, kidney and liver function CT, Cga, other markers Stop for: Toxicity Progession of disease

    27. Patient’s selection Histological diagnosis of neuroendocrine tumor Non surgical, metastatic disease Measurable disease Imaging demonstration of SSTR At list one month since the last chemotherapy treatment Karnofsky = 70 Life expectancy = 6 months RBC = 3’500’000 Hb = 10 mg/dl WBC = 2500/dl PLT = 100’000/dl Creatinine = 1.5 mg/dl Bilirubine = 1.5 mg/dl Written informed consent

    28. Humanitas 1 year experience 19 patients 37 treatments 6 PD 10 SD 2 PR 1 under evaluation

    29. Open issues Availability of the technique Dosage Low dose hypersensitivity phenomenon Effectiveness Comparison to other approaches New radiopharmaceuticals New way of administration

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