1. Diagnostic imaging with 111In-DTPA-octreotide: Clinical impact on the management of patients with neuroendocrine tumours Ulrike Garske MD Specialist in oncology, nuclear and internal medicine Kotka May 2010

2. Overview Neuroendocrine tumours: clinic and treatment Neuroendocrine tumours: clinic and treatment Indications for imaging Indications for imaging Somatostatin Somatostatin 111 In-DTPA-octreotide (OctreoScan®) 111 In-DTPA-octreotide (OctreoScan®) Imaging Imaging Normal Findings Normal Findings Uptake scale Uptake scale Typical and unusual findings Typical and unusual findings Some patients, that you have sent to us for treatment Some patients, that you have sent to us for treatment Thank you Thank you

3. Neuroendocrine tumours A small tumour group, with lots to learn from! A small tumour group, with lots to learn from! During the last decade, an evolving model for designing and studying tracers in nuclear imaging and therapy During the last decade, an evolving model for designing and studying tracers in nuclear imaging and therapy

4. Neuroendocrine tumours Gastro-entero-pancreaticoduodenal tumours (GEP-NETs) ”Carcinoids”: derived from embryonal foregut, midgut and hindgut ”Carcinoids”: derived from embryonal foregut, midgut and hindgut Foregut och midgut carcinoids: Production of 5-HIAA (classic carcinoid syndrom: flushing, palpitation, diarrhea) Foregut och midgut carcinoids: Production of 5-HIAA (classic carcinoid syndrom: flushing, palpitation, diarrhea) Endocrine pankreaticoduodenal tumours (EPTs): functioning or non-functioning Endocrine pankreaticoduodenal tumours (EPTs): functioning or non-functioning Different associated hormonal syndroms Different associated hormonal syndroms Gastrin, insulin, glucagon, VIP, somatostatin, ACTH…. Gastrin, insulin, glucagon, VIP, somatostatin, ACTH….

5. Neuroendocrine tumours Pheochromocytomas /paragangliomas Pheochromocytomas /paragangliomas Medullary thyroid carcinomas Medullary thyroid carcinomas Neuroendocrine cancers/ neuroendocrine tumours of unknown origin Neuroendocrine cancers/ neuroendocrine tumours of unknown origin …………..many rare entities …………..many rare entities

6. Treatment overview Surgery Surgery Local destruction of livermetastases Local destruction of livermetastases Leverembolisation Leverembolisation Radiofrequency ablation Radiofrequency ablation Biological treatment (alpha-Interferon, Somatostatinanalogs ) Biological treatment (alpha-Interferon, Somatostatinanalogs ) Chemotherapy Chemotherapy Radiation Radiation External Beam External Beam Brachytherapy of livermetastases (SIR-spheres®) Brachytherapy of livermetastases (SIR-spheres®) Peptide receptor radionuclide therapy (PRRT) Peptide receptor radionuclide therapy (PRRT)

7. Indications for diagnostic imaging Staging of recently diagnosed patients Staging of recently diagnosed patients Finding small tumours: important in case of significant hormone production (pancreas), or to rule out extrahepatic disease prior to livertransplantation Finding small tumours: important in case of significant hormone production (pancreas), or to rule out extrahepatic disease prior to livertransplantation Receptor status before chosing therapy Receptor status before chosing therapy Follow-up of therapy Follow-up of therapy

8. If finding small tumours is important….. …Maybe PET/CT is your choice …Maybe PET/CT is your choice

9. 11C-5-HTP (HTP)

10. 11 C

12. 11C-5-hydroxytryptophan

13. If the receptor status is important….. Imaging with somatostatin analogs! Imaging with somatostatin analogs!

14. Somatostatin

15. Somatostatin

16. Somatostatin Regulatory hormone, that Regulatory hormone, that Inhibits growth hormone Inhibits growth hormone Inhibits/suppresses release of a row of gastrointestinal hormones (VIP, glucagon, cholecystokinin, gastrin, motilin, secretin….) Inhibits/suppresses release of a row of gastrointestinal hormones (VIP, glucagon, cholecystokinin, gastrin, motilin, secretin….) Suppresses the exocrine function of the pancreas Suppresses the exocrine function of the pancreas Inhibits TSH Inhibits TSH

17. Octreotide (Sandostatin®)

18. Somatostatin receptors 5 subtypes (sstr1- sstr5) 5 subtypes (sstr1- sstr5) Sstr2 predominant in neuroendocrine tumours, followed by sst5 Sstr2 predominant in neuroendocrine tumours, followed by sst5 Octreotide somatostatin analog predominantly used in the clinic (Sandostatin®, Sandostatin LAR®), predominant affinity for sstr2 and 5 Octreotide somatostatin analog predominantly used in the clinic (Sandostatin®, Sandostatin LAR®), predominant affinity for sstr2 and 5 Golden standard för sstr- diagnostic in nuclear medicine: OctreoScan® ( 111 In-DTPA-octreotide) Golden standard för sstr- diagnostic in nuclear medicine: OctreoScan® ( 111 In-DTPA-octreotide)

19. Normal distribution Anterior Posterior Physiological uptake in: Pituitary Thyroid Liver Spleen Kidneys Adrenals Gut

20. OctreoScan® imaging Whole body scan: Scanning time (at least 30min) Whole body scan: Scanning time (at least 30min) SPECT/CT: so much better information SPECT/CT: so much better information Activity 200MBq for adults; one kit per patient Activity 200MBq for adults; one kit per patient Imaging after 24 hrs sufficient, SPECT/CT and patient preparation important Imaging after 24 hrs sufficient, SPECT/CT and patient preparation important Laxation: Toilax® (Bisacodyl) Laxation: Toilax® (Bisacodyl) 2 tabl. à 5mg noon and evening on day of injection 2 tabl. à 5mg noon and evening on day of injection klysma Toilax® morning of examination day klysma Toilax® morning of examination day Liquid food 12.00 noon inj. day until examination is finished Liquid food 12.00 noon inj. day until examination is finished

21. Intensity of uptake Arbitrary scale (according to Krenning): uptake in relation to liver uptake Arbitrary scale (according to Krenning): uptake in relation to liver uptake 0: no uptake 0: no uptake 1: weak uptake, less than liver 1: weak uptake, less than liver 2: moderate uptake equivalent to liver 2: moderate uptake equivalent to liver 3: intense uptake, higher than liver 3: intense uptake, higher than liver 4:very intense uptake, much higher than liver, more intense than spleen/kidneys 4:very intense uptake, much higher than liver, more intense than spleen/kidneys

22. OctreoScan® 1996: both diagnostics and therapy

23. Normal uptake

24.  Grade 1 Grade 3-4 Grade 3

25. Grade 4: Patient with hindgut carcinoid

26. Imaging: Midgut carcinoid ant post Static posterior Static anterior ?

27. Tornado sign

28. Massive mesenterial dissemination

29. ……and one thoracic lymph node

30. Midgut High proliferation Antpostant post

31. Cardiac metastases

32. Right liver lobe previously treated with embolization

33. Left liver lobe: untreated metastases

35. Imaging: Insulinoma Insulinomas: predominant pancreatic endocrine tumour group Insulinomas: predominant pancreatic endocrine tumour group Better prognosis than other GEP NETs Better prognosis than other GEP NETs Excellent surgical curation rate, if localized Excellent surgical curation rate, if localized express in only 50% sstr2 express in only 50% sstr2 Malignant insulinomas may have higher expression of sstr2 Malignant insulinomas may have higher expression of sstr2

36. 73yr-old lady with hypoglycemic fits

37. Isolated insulinoma in ectopic pancreatic tissue

38. Patient alive and well…….. Symptom free now 7 years after surgery Symptom free now 7 years after surgery Celebrating her 80th birthday this year Celebrating her 80th birthday this year

39. Malignant Insulinoma

42. Follow up of therapy Somatostatin receptor density Somatostatin receptor density may vary in different metastases in the same patient may vary in different metastases in the same patient May change over time May change over time Somatostatin receptor scintigraphy should only be interpreted together with radiological information Somatostatin receptor scintigraphy should only be interpreted together with radiological information

43. 56y-old lady, atypical bronchial carcinoid Previously pulmectomy Previously pulmectomy 3 years later pain in the back 3 years later pain in the back Treatment with temozolomide (Temodal®) Treatment with temozolomide (Temodal®)

44. Follow-up with OctreoScan®: not a given indication…. Baseline after 3 69 courses

45. …but it may help to interprete your CT-findings

46. Cave: Receptor up-regulation Treatment can change receptor expression Treatment can change receptor expression New uptake does not necessarily need to represent new lesions. New uptake does not necessarily need to represent new lesions. Example of a patient with malignant pheochromocytoma

47. OctreoScan®

48. OctreoScan® 123 I MIBG

49. Malignant Pheochromocytoma Diagnostic imaging Therapy 123I-MIBG 111In-Oscan131I-MIBG 177Lu-DOTA-tate October 08 October 08 April 09

50. Treatment

51. Treatment with radiolabelled somatostatin analogs A renaissance for imaging with 111 In-DTPA- octreotide?!! A renaissance for imaging with 111 In-DTPA- octreotide?!!

52. Octreotide

53. Lutetium

54. 177 Lu-DOTA-Tyr 3 -Octreotate

56. 111 In-DTPA-octreotide 177 Lu-DOTA-octreotate 24h ant post ant post

57. Diagnostic images and therapy control: tumour-to-background Oscan 24h Lu 0h24h96h168h

58. Treatments with 177Lu-DOTA-octreotate 2005 2006 2007 2008 2009

60. Hindgut carcinoid: therapy 1-4

61. Effect of therapy over time Feb 09April 09July 09Aug 09Jan 10

64. Ther 1Ther 6

65. Glomerular filtration rate before therapy Before ther1 ther2 ther3 ther4 ther5 ther6

66. Therapy effects 2: Patient with hindgut carcinoid ther 1 ther 2 ther 3ther 4 ther 5 ther 6 Anterior view, 177Lu-DOTA-octreotate 24 h pi

67. Therapy 1Therapy 3

68. CT-interpretation: take advantage of your scintigraphy! Therapy 1 Therapy 6

69. Therapy 1Therapy 6

70. 177 Lu-DOTA-octreotate therapy Results from Rotterdam Kwekkeboom et al, JCO, 2008 Result 3 months after completed therapy(n=310): CR5(2%) PR86(28%)46% MR51(16%) SD107(35%) PD61(20%) 4% with SD or MR improved further after 6 months 5% with SD or MR improved further after 12 months

71. Thank you to Mattias Sandström and collegue hospital physicists Mattias Sandström and collegue hospital physicists Prof emeritus Hans Lundqvist (Radiophysics) Prof emeritus Hans Lundqvist (Radiophysics) Prof Barbro Eriksson och Prof Kjell Öberg, endocrine oncology Prof Barbro Eriksson och Prof Kjell Öberg, endocrine oncology Doc Dan Granberg Doc Dan Granberg Prof Anders Sundin Prof Anders Sundin Collegues an staff at the department of nuclear medicine, Uppsala Academical Hospital Collegues an staff at the department of nuclear medicine, Uppsala Academical Hospital Research collegues and friends at Rudbecklaboratoriet Research collegues and friends at Rudbecklaboratoriet Med kand Daniel Lindholm Med kand Daniel Lindholm Our patients, and………. Our patients, and……….

72. … Thank You for inviting me to beautiful Finland !