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Arturo Chiti Medicina Nucleare Istituto Clinico Humanitas, Rozzano - Milano

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.

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Arturo Chiti Medicina Nucleare Istituto Clinico Humanitas, Rozzano - Milano

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  1. INQUADRAMENTO DIAGNOSTICO E APPROCCIO TERAPEUTICO DEI TUMORI NEUROENDOCRINIMilano, 25 maggio 2007La 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 NETsin vitro studies receptor status • Gastrinoma, Glucagonoma 100 % • Insulinoma 72% • Carcinoids 88% • Paraganglioma 92 % • Medullary Thyroid Carcinoma 38 % • Small Cell Lung Cancer 57 % • Pheochromocytoma 73 % Reubi et al. JNM 1999 adapted from Curr Med Chem 2000

  3. SSTR Subtype expression in vitro 1 2 3 4 5 • 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 Courtesy of R.P. Baum, adapted from EJNM 2001

  4. Philosophy of Somatostatin Receptor Scintigraphy Somatostatin-14 Octreotide Pentetreotide

  5. 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

  7. Affinity profiles (IC50, nM) for human sst1-sst5 Forrer et al. , Best Practice & Research Clinical Endocrinology & Metabolism, 2007

  8. Affinity profiles (IC50, nM) for human sst1-sst5 Reubi JC et al, Eur J Nucl Med 2000; 27:273

  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

  10. Radionuclides for Therapy max E(kev) max range half-life beta emitters 606 2270 1070 1710 135 497 2.4 mm 12.0 mm 4.3 mm 8.7 mm 0.8 mm 2.1 mm 8 d 2.7 d 3.8 d 14 d 6.9 d 6.7 d 131I 90Y 186Re 32P 161Tb 177Lu conversion- or Auger-electron emitters 110 m 2.1 m 20  m 15  m 550  m 10  m 93 (IC) 9.5 (Au) 35 (IC) 30 (Au) 245 (IC) 25 (Au) 3.2 d 60 d 2.8 d 67Ga 125I 111In alfaemitters

  11. Radionuclides 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. 90Y 111In Courtesy of Prof. Krenning

  12. Radiolabelled somatostatin analoguesfor sst2 receptor-mediated radiotherapy Tissue-Penetration (Maximal) • I [111In-DTPA,DPhe1]octreotide • II [90Y-DOTA,DPhe1,Tyr3]octreotide - III [177Lu-DOTA,DPhe1,Tyr3]octreotate 10 μm (+ γ) 12 mm 2 mm (+ γ)

  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

  15. 111In-pentetreotide therapy February 1999 April 1999 October 1999

  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

  17. [90Y-DOTA,DPhe1,Tyr3]octreotide therapy Tumor response assessed by SWOG criteria in Phase 1 Study “Stable” at baseline n=8 Planned dose given (mean 380 mCi) Progressive at baseline n=24 Planned dose given (mean 375 mCi) 13% 4% 25% 75% 37% partial response 46% minor response Median follow-up 29 Mo All alive Median follow-up 13 Mo 15/24 alive stable disease progressive Courtesy of Prof. Krenning

  18. [90Y-DOTA,DPhe1,Tyr3]octreotide therapy correlation between tumor dose and response UCLouvain in Brussels, 2000 Courtesy of Prof. Krenning

  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. Forrer et al. , Best Practice & Research Clinical Endocrinology & Metabolism, 2007

  21. Tumor type and tumor response Kwekkeboom et al., J Nucl Med 2005; 46:62S-66S

  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 Kwekkeboom et al., J Nucl Med 2005; 46:62S-66S

  25. Available Symptoms improve SD CR/PR Tox [111In-DTPA]-octreotide Easy Yes Yes ? No Low [90Y-DOTA,Tyr3]-octreotide Difficult Yes Yes Yes High ? [177Lu-DOTA,Tyr3]-octreotate More difficult Yes Yes Yes Moderate 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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