1. Biotherapy Interferon-  : IntronA 3–5 MUxIII–V/week PegInterferon alpha 50–100  gxI/week – – Adjust the dose according to tolerance and leukocyte count <3.0 Octreotide, Lanreotide: – – Sandostatin 100–500  gx2–3 – – Sandostatin LAR 20–30 mg/3–4 weeks i.m. – – Somatuline Autogel 90–120 mg/4 weeks s.c.

2. Biotherapy TreatmentObjective response Stable disease Biochemical/ symptomatic alpha-interferon10–15%40–60%≤50% octreotide/lanreotide<10%30–50%60–90% TreatmentObjective response Stable disease Biochemical/ symptomatic alpha-interferon10–20%33–100%≤50% octreotide/lanreotide<10%24–57%40–80% EPT Carcinoids

3. Treatment DiseaseObjective response alpha-interferonEPT, carcinoids12–15% octreotide/lanreotideEPT, carcinoids0–6% streptozocin + 5-FU/doxorubicinEPT6–69% cisplatin + etoposideEPT, foregut7–39% DTIC + 5-FU + epirubicinEPT27% PaclitaxelEPT, carcinoids4% DocetaxelCarcinoids0 TopotecanEPT, carcinoids0 GemcitabineEPT, carcinoids0 Granberg 2007

4. Treatment DiseaseObjective response TemozolomideEPT, carcinoids17% Temozolomide + capecitabineEPT59% Temozolomide + thalidomideEPT, carcinoids45%, 7% Temozolomide + bevacizumabEPT, carcinoids14% SunitinibEPT, carcinoids10% TemsirolimusEPT, carcinoids5% BortezomibEPT, carcinoids0 EndostatinEPT, carcinoids0 Granberg 2007

5. Temozolomide All patients (n=36) EPT (n=12) Bronchial carcinoids (n=13) Thymic carcinoids (n=7) Other (n=4) PR5 (14%)1 (8%)4 (31%)00 SD19 (53%)8 (67%)4 (31%)5 (71%)2 (50%) PD12 (33%)3 (25%)5 (38%)2 (29%)2 (50%) Ekeblad 2007

6. Temozolomide – before and after Decrease of the endocrine panceatic tumor

7. Temozolomide – before and after Decrease of the liver metastases

8. Temozolomide + capecitabine Isacoff 2006 Patients: 17 patients with advanced NET Treatment: Capecitabine 1000 mg b.i.d. day 1–14 Temozolomide 150–200 mg/m 2 day 10–14 Cycle length 28 days Results: CR 1/17 (6%) PR 9/17 (53%) – – Median response duration 9 months Biochemical response 6/7 (86%)

9. Temozolomide + bevacizumab Kulke 2006 Patients, n=29: EPT, n=17 Carcinoid, n=12 Treatment: Temozolomide 150 mg/m 2 p.o. for 7 days every other week Bevacizumab 5 mg/kg i.v. every other week Results : PRSDPD EPT, n=174 (24%)12 (70%)1 (6%) Carcinoid, n=12011 (92%)1 (8%) All, n=294 (14%)23 (79%)2 (7%)

10. Temozolomide + thalidomide Kulke 2006 Patients, n=28 (carcinoid, n=14 EPT, n=11, pheo, n=3) Treatment: Temozolomide 150 mg/m 2 for 7 days every 2 week Thalidomide 50–400 mg daily (median 100 mg) Results:CRPRCR+PRSDPD Carcinoid, n=1411 (14%) EPT, n=11145 (45%) All, n=287 (25%)19 (68%)2 (7%) Conclusions: Temozolomide + thalidomide is active in NETs Temozolomide + thalidomide seems more active in EPTs than in carcinoids

11. Sunitinib Kulke 2006 Patients: EPT, n=52 Carcinoid, n=41 Treatment: Sunitinib 50 mg/day for 4 weeks, followed by a 2 week break Results: PRSDPD EPT, n=527 (13.5%)40 (77%)3 (5.5%) Carcinoid, n=412 (5.1%)36 (92.3%)1 (2.6%)

12. Treatment Liver embolizationObjective response Carcinoids38–81% EPT25–60% All25–81% Chemo-embolization Carcinoids 7–44% EPT11–50% All7–50%

13. Treatment Liver embolizationObjective response % no Carcinoids81% 34/42 EPT25% 8/32 Chemo-embolizationObjective response % no Carcinoids44% 12/27 EPT50% 11/22 Gupta 2005

14. Targeted irradiation therapy 111 In-DTPA 0 -octreotide 90 Y-DOTA 0,Tyr 3 -octreotide 177 Lu-DOTA 0,Tyr 3 -octreotate 131 I-MIBG 90 Y-SIR-Spheres

15. Isotopes 111 Indium – –  -emitter – – T 1/2 2.83 days 90 Yttrium – –  - emitter – – T 1/2 2.67 days 177 Lutetium – –  - emitter(+ weak  - emitter) – – T 1/2 6.71 days 131 Iodine – –  - emitter +  - emitter – – T 1/2 8.02 days

16. Isotopes T 1/2 (days)Range in tissue AverageMax 111 In2.83 10  m 90 Y2.674 mm12 mm 177 Lu6.710.5 mm2 mm Breeman 2001

17. Grading of radionuclide uptake at somatostatin receptor scintigraphy Grade Appearance of somatostatin receptor scintigraphy 0 No radionuclide accumulation in known tumor lesions 1 Suspected but not certain uptake in known tumor lesions 2 Accumulation in known tumor lesions, intensity less or equal to normal liver uptake 3 Clear uptake in known tumor lesions, higher than liver uptake 4 Intense uptake in known metastases

18. 177 Lu-DOTA-octreotate therapy The Rotterdam experience Patients, n=131 – – 70 carcinoid (64 small bowel, 4 lung, 1 thymic, 1 gastric) – – 33 EPT non-functioning – – 8 gastrinoma – – 2 insulinoma – – 18 unknown Treatments: – – Dosage 100–200 mCi – – Cumulative dose 600–800 mCi (22.2 to 29.6 GBq) – – Interval 6–10 weeks Kwekkeboom 2005

19. 177 Lu-DOTA-octreotate therapy The Rotterdam experience CR3(2%) PR32(26%) MR24(19%) SD44(35%) PD22(18%) Higher remission rates: – higher uptake – limited no. of liver metastases – gastrinomas PD: low performance status extensive disease Median time to progression: 36 mo Serious adverse events: renal insufficiency (1 patient) liver failure (1 patient) Kwekkeboom et al, JCO, 2005 Results:

20. 177 Lu-DOTA-octreotate therapy The Uppsala experience 56 patients, (27 MGC, 11 EPT non-functioning, 5 gastrinoma) 152 treatments (1–6): Dose 200 mCi (7.4 GBq), interval 6–12 weeks Results, n=34, mean follow-up 7.6 months (2,8–22,6): – – 1 CR, 6 PR (21% CR+PR), 1 MR, 25 SD, 1 PD, 3 dead Toxicity: 26 hematological grade 3–4 (24 lymfopenia, 5 neutropenia, 3 leucopenia, 1 thrombopenia), 9 renal grade 1

22. Before After 15 months

23. Tumor responses in patients with GEP tumors, treated with different radiolabelled somatostatin analogs Tumor Response Center Ligand Pats. CR+PR SD PD Rotterdam ( 111 In-DTPA 0 )octr 26 0(0%) 16(62%) 10(38%) New Orleans ( 111 In-DTPA 0 )octr 26 2(8%) 21(81%) 3(12%) Milan ( 90 Y-DOTA 0,Tyr 3 )octr 21 6(29%) 11(52%) 4(19%) Basel ( 90 Y-DOTA 0,Tyr 3 )octr 74 18(24%) 48(65%) 8(11%) Basel ( 90 Y-DOTA 0,Tyr 3 )octr 33 11(33%) 19(57%) 3(9%) Rotterdam ( 90 Y-DOTA 0,Tyr 3 )octr 54 4(7%) 40(74%) 10(19%) Rotterdam ( 177 Lu-DOTA 0,Tyr 3 )octr 76 23(30%) 39(51%) 14(18%) Rotterdam ( 177 Lu-DOTA 0,Tyr 3 )octr 125 35(28%) 68(54%) 22(18%) Kwekkeboom 2005

24. Tumor responses according to tumor type in patients with GEP tumors, treated with different radiolabelled somatostatin analogs Tumor Response (CR + PR) EPT Carcinoid Unknown Center Ligand Funct Total G-I Bronch origin Total Basel ( 90 Y-DOTA 0,Tyr 3 )octr NA 37% 5% 20% 29% 24% Basel ( 90 Y-DOTA 0,Tyr 3 )octr NA 33% 25% 0% 36% 33% Milan ( 90 Y-DOTA 0,Tyr 3 )octr 63% 51% 35% 14% 21% 38% Rotterdam ( 177 Lu-DOTA 0,Tyr 3 )octr 71% 36% 20% 100% 42% 30% Kwekkeboom 2005

25. Side effects in patients with GEP tumors, treated with different radiolabelled somatostatin analogs Grade 3/4 hematologic Center Ligand Pats. Platelets Hb WBC Other Rotterdam ( 111 In-DTPA 0 )octr 50 10% 15% 2% 3 AML or MDS New Orleans ( 111 In-DTPA 0 )octr 27 7% 11% 7% 3 liver, 1 renal Milan ( 90 Y-DOTA 0,Tyr 3 )octr 40 7% 3% 7% Basel ( 90 Y-DOTA 0,Tyr 3 )octr 29 3% 7% 0% 4 renal Basel ( 90 Y-DOTA 0,Tyr 3 )octr 39 0% 3% 0% 1 renal Rotterdam ( 90 Y-DOTA 0,Tyr 3 )octr 60 12% 8% 13% 1 liver, 1 renal Rotterdam ( 177 Lu-DOTA 0,Tyr 3 )octr 200 3% 1% 2% 1 MDS, 1 renal Kwekkeboom 2005

26. Conclusion Somatostatin receptor mediated treatment provides a feasible, widely well tolerated therapeutic option for patients with neuroendocrine tumors beta emitters are promising Treatment with combination of 90 Y and 177 Lu seem to provide even better tumor control Best time for radioisotopes in the treatment of these patients is still to be established

27. 131 I-MIBG-treatment CarcinoidPheochromocytoma/ paraganglioma Response: No% % Radiologic10/7513 8/2138 Biochemical19/523712/2060 Symptomatic35/724919/2286 Toxicity: Hematologic13/9813 4/3312 Nausea/vomiting 4/98 4 2/33 6 Deaths 2/98 2 3/33 9 Safford 2003–2004 Results:

28. Treatment SIRT = Selective Internal Radiation Therapy Liver embolization with SIR-Spheres ® SIR-Spheres ® = 90 Yttrium-labelled resin microspheres Size ≈ 30–35  m

29. Selective Internal Radiation Therapy High dose of radioactivity delivered selectively to liver metastases Pre-treatment angiography to clarify the vascular anatomy Pre-treatment scintigraphy with 99 Tc macroalbumin to assess lung shunt (≤20%)

30. Diagnostic scan before SIRT

31. Selective Internal Radiation Therapy Patients, n=34: 15 carcinoids (10 small bowel, 2 cecum, 1 bonchial, 1 gastric, 1 rectum) 8 endocrine pancreatic tumor 2 medullary thyroid carcinoima 9 unknown Treatment: Single injection of SIR-Spheres ® in the hepatic artery Concomitant single 7 day systemic infusion of 5-FU 225 mg/m 2 Median follow-up 9.8 months King 2005

32. Selective Internal Radiation Therapy Results:PR SD No% % 1 month (n=34)824%2368% 3 months (n=29)621%1966% 12 months (n=10)220%660% 18 months (n=7)114%571% King 2005 4 patients died from progresssive disease Complications: 3 duodenal ulcers, 1 pancreatitis, 2 jaundice All patients experienced abdominal pain, nausea and lethargy

33. Selective Internal Radiation Therapy Conclusion: SIRT appears to have efficacy in treating unresectable neuroendocrine liver metastases King 2005

34. pre 6 month 9 month SIRT in NET – Pilot Study Patient 2:Morphological Response El-Sheik, Barcelona 2006

35. SIRT – before and after

36. Diagnosis of midgut carcinoids Biochemistry – Plasma chromogranin A – U-5’HIAA Radiology – CT – Ultrasonography + biopsy Octreoscan PET Echocardiography

37. Treatment of midgut carcinoids Cytoreductive procedures – Surgery: Primary tumour, lymph nodes, liver metastases – Radiofrequency ablation – Liver embolisation: Particles, SIRT Biotherapy: interferon- , somatostatin analogs Surgery of carcinoid heart disease Progression – Liver embolisation: Particles, SIRT – 177 Lu-octreotate, 90 Y-octreotide – Experimental: RAD001, antiangiogenesis

38. Diagnosis of lung carcinoids Biochemistry – Plasma chromogranin A Radiology – CT Octreoscan Bronchoscopy + biopsy (Ki67, CD44) PET

39. Treatment of lung carcinoids Radical surgery Primary tumour Lymph node metastases Frozen sections Long-term follow-up, at least 10 years

40. Treatment of lung carcinoids Low proliferative rate (Ki67<2–3%): Biotherapy –interferon- , somatostatin analogs Chemotherapy – temozolomide, STZ + 5-FU 177 Lu-octreotate, 90 Y-octreotide Intermediate proliferative rate (Ki67 5–10%): Chemotherapy – temozolomide, STZ + dox 177 Lu-octreotate, 90 Y-octreotide High proliferative rate (Ki67 >15–20%): cisplatin/carboplatin + etoposide temozolomide + capecitabine/bevacizumab taxanes + dox Experimental: RAD001, tyrosine kinase/angiogenesis inhibitors

41. Diagnosis of EPT Biochemistry – Chromogranin A – PP, glucagon, insulin, proinsulin, gastrin, calcitonin, VIP – Sectetin test – 72-hour gasting – Meal stimulation test Radiology – CT – Ultrasonography – Endoscopic ultrasonography Octreoscan PET

42. Treatment of EPT Low proliferative rate (Ki67<2–3%): Chemotherapy – STZ + 5-FU Biotherapy –interferon- , somatostatin analogs 177 Lu-octreotate, 90 Y-octreotide Intermediate proliferative rate (Ki67 5–10%): Chemotherapy –, STZ + 5-FU/dox, temozolomide 177 Lu-octreotate, 90 Y-octreotide High proliferative rate (Ki67 >15–20%): cisplatin/carboplatin + etoposide taxanes + dox temozolomide + capecitabine/bevacizumab Experimental: RAD001, tyrosine kinase/angiogenesis inhibitors

43. Treatment of EPT Cytoreductive procedures – Surgery: Primary tumour, lymph nodes, liver metastases – Radiofrequency ablation – Liver embolisation: Particles, chemoembolisation, SIRT Symptomatic – Proton pump inhibitors – Somatostatin analogs – Interferon-  – Ketoconazole – Metyrapone

44. Malignant neuroendocrine GEP-tumours Diagnosis Histopathology,tumour biology, localisation and staging Cytoreductive procedures Surgery, RF Low proliferating tumours (Ki-67 <3%) Biotherapy: SMS ± IFN STZ + 5 FU (EPT) Tumour targeted therapy: 90 Y, 177 Lu High proliferating tumours (Ki-67 5-10%) Cytotoxic therapy: STZ + 5 FU/doxorubicin, Temozolomide Tumour targeted therapy: 90 Y, 177 Lu Cisplatin + Etoposide (Ki-67 >20%) Progression Tumour targeted therapy: 90 Y-DOTA-Octreotide, 177 Lu-DOTA-Octreotate Embolisation, chemoembolisation, SIRT Experimental: RAD001, taxanes, tyrosine kinase/angiogenesis inhibitors

45. Acknowledgements Dept of Endocrine Oncology, Uppsala Barbro Eriksson Kjell Öberg Britt Skogseid Dept of Nuclear Medicine, Uppsala Ulrike Garske Lars-Göran Andersson Dept of Radiology, Uppsala Anders Sundin Rickard Nyman SIRTEX Medical, Bonn Ralph Peters