1. MASOUD MOSLEHI
NUCLEAR PHYSICIAN

2. Nuclear Medicine in Neuroendocrine Tumors

3. Somatostatin Receptor Scintigraphy

4. Somatostatin receptors common sites
Nervous system
Endocrine glands
Immune system
GI tract

5. SSR: Normal sites Brain Kidney GI Pancreas PNS Vessels Thyroid Spleen
Immune system(activated lymphocytes and monocytes)

6. NETs with SSR
-Pituitary adenoma: GH or TSH producing, nonfunctioning, minority of prolactin producing
-VIP secreting tumors
-GIT and lung carcinoid
-Pheochromocytoma
-MTC
-Small cell lung cancer
-Gastrinoma
-Glucagonoma
-Insulinoma

7. Distribution of SST-Receptors in NETs in vitro studies
Gastrinoma, Glucagonoma %
Paraganglioma %
Carcinoids %
Pheochromocytoma %
Insulinoma %
Small Cell Lung Cancer %
Medullary Thyroid Carcinoma %
Reubi et al. JNM 1999 adapted from Curr Med Chem 2000

8. Ability to Detect Disease
Scintigraphy
In vitro
Medullary thyroid carcinoma
20/ %
10/ %
Pheochromocytoma
12/ %
38/ %
Carcinoid
69/ %
54/ %
Small cell lung cancer
34/ %
4/ %
Non-small cell lung cancer
36/ %
0/ %
Meningiomas
14/ %
54/ %
Breast cancer
37/ %
33/ %
Non-Hodgkin's Lymphoma
59/ %
Hodgkin's disease
23/ %
2/ %

9. SSR: other tumors -Breast cancer -Lymphoma -Renal cell ca. -Hepatoma
-Prostate cancer
-Gastric cancer
-Sarcoma
-Benign and malignant bone tumors
-Brain tumors (meningioma , neuroblastoma, medulloblastoma, astrocytoma)

10. SSR: Not specific for tumors
Granulation tissue (recent surgery)
Sarcoidosis
TB, Wegner
R.A.,SLE,
I.B.D. Celiac
Hashimoto th., Graves
Aspergillosis
Cavernous hemangioma
Pneumonitis( radiation, bacterial)

11. Imaging protocol
D/C octreotide 24 hours before, monitor patient for withdrawal
In suspected insulinoma, IV glucose should be available for potential risk of severe hypoglycemia
Well hydration before and after injection
Dose 111In: 222MBq or 6mCi and 5 Mbq/kg for children(enough for SPECT), not injected with IV line for TPN
Dose 99mTc : mCi

12. Imaging protocol Void before imaging
Planar and SPECT in 6-24h (decreased BKG)
Repeat scan after 24h if abdominal concentration (111-In)
Spot views with enough count instead of low count whole body scan
SPECT is necessary
Major clearance by kidneys (2%) by hepatobiliary system)
It is not known whether is removed by dialysis

13. Normal uptake Pituitary (faint) Thyroid (faint)
Salivary glands (faint)
Liver
Spleen
Bowel (heptobiliary excretion), necessitating laxatives
Kidneys (by receptors and re-absorption)
Bladder

14. Normal octreotide scan

15. Role of SRI in NET
Detect resectable tumors not recognized with conventional techniques
Prevention of surgery in widespread metastases
To select patients for radionuclide octreotide therapy

16. Role of SRI in NET (cont)
SRS will not detect the ~10% of tumors that fail to express somatostatin receptors
the detection limit is about 0.5 cm.
The advantage of SRS over CT and MRI: the ability to image all body regions , evaluation of tumors for potential octreotide palliation therapy .

17. Metastatic gastrinoma

18. Insulinoma

19. Insulinoma

20. gastrinoma

21. 73yr-old lady with hypoglycemic events

22. PET in Neuroendocrine Tumors

23. PET Scan >90% of NE tumors are visualized by PET Scan 1 8FDG
68Ga-DOTA
18F-Dopamin
11C-epinephrin (quantitative)

24. comparison of 111In-pentetreotide SSTR
scintigraphy (A) and 68Ga-DOTATATE (B) PET/CT in patient with metastaticlow-grade cecal NET evaluated before PRRT. In liver, retroperitonealand thoracic lymph nodes, and bones, PET/CT shows multiple metastases.

25. Small liver metastasis (A), not seen on contrast-enhanced (portal-venous phase) CT scan as well as small lymph node (B) and bone (C) metastases as detected by 68Ga-DOTA-NOC receptor PET/CT.

26. Treatment Of Neuroendocrine Tumor with Radionuclide

27. (Peptide Receptor Radionuclide Therapy)
PRRT
(Peptide Receptor Radionuclide Therapy)

28. Somatostatin receptor-based radionuclide Therapy
A new treatment modality for patients with inoperable or metastasized endocrine tumors.

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

30. PRRT
Diagnostic scans with radiolabelled somatostatin can be used to identify suitable candidates for PRRT.

31. PRRT: [111In-DTPA0] octreotide [90Y-DOTA0,Tyr3] octreotide
[177Lu-DOTA0,Tyr3] octreotate

32. [111In-DTPA0] octreotide:
Because at in the mid- to late 1990s no other chelated somatostatin analogs labeled with β-emitting radionuclides were available, early studies used [111In-DTPA0] octreotide for PRRT.
Initial studies with high dosages of [111In-DTPA0] octreotide in patients with metastasized neuroendocrine tumors were encouraging with regard to symptom relief, but partial remissions (PRs) were exceptional.

33. 111In-pentetreotide therapy
February 1999
April 1999
October 1999

34. [90Y-DOTA0,Tyr3] octreotide:
higher affinity for the somatostatin receptor subtype-2, and a different chelator, DOTA instead of DTPA, in order to ensure a more stable binding of the intended β-emitting radionuclide 90Yttrium (90Y).

35. [90Y-DOTA,Tyr3]octreotide
CR and PR observed in 10-30% of patients
Reversible 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

36. [177Lu-DOTA,Tyr3]octreotate
Higher affinity for somatostatin receptors
Gamma emission allow post-therapeutic biodistribution studies
PR, and SD responses are reported in more patients.
Tumor regression was correlate with a high uptake on Octreoscan imaging

37. 177Lu-DOTA-Tyr3-Octreotate

39. Side effects and toxicity
Haematological toxicity
Dose to bone marrow due to circulating radioactivity
Rare, mild and transient
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

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

41. 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
Markers
Stop for:
Toxicity
Progession of disease

42. Patient’s selection Histological diagnosis of neuroendocrine tumor
Non surgical, metastatic disease
Imaging demonstration of SSTR
At list one month since the last chemotherapy treatment
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

43. Future of Peptide Receptor Imaging
Radioligands
123I-VIP
99mTc-TP3654 (VIP analog)
111In-DTPA-D-Asp26- Nle29,31-CCK
111In-DTPA-Minigastrin
99mTc-RP527 (bombesin derivate)
99mTc-NT-XI (neurotensin analog)
111In-DTPA-Substance P
Receptor
VIPAC1-2 (sst3)
VIPAC1
CCK2
GRP
NTR1 NK
From Virgolini I et al. 2001, Reubi JC 2003
Future of Peptide Receptor Imaging

44. Treatment

45. MIBG Scintigraphy

46. MIBG Scintigraphy Meta iodo benzyl guanidine
First developed in 1979 by Wieland et al.
Analogue of neurepinephrine
123I-MIBG: superior sensitivity, better quality, preferred in children, SPECT (159kev, half life=13.2h)
131I-MIBG: most used (lower cost, availability), longer shelf life (2wks), possibility of delayed images

47. MIBG: Interfering drugs
Inhibition of uptake-1 mechanism : tricyclics, cocaine, opioids, labetolol, metoral, antipsychotics
Inhibition of granular uptake: reserpine, tetrabenazine
Competition of granular uptake: N.E., serotonin, guanethidine
Depletion from granules: Sympatomimetics, reserpine, guanethidine, labetolol
Increased uptake and retention: Ca channel blockers:

48. MIBG: Technique Lugol (1-2mg/kg/d KI) 2days before until 5-7days after
Dose injected over 1-2min (0.5-1mci for 131I and 3-10mci with 123I)
Voiding before imaging
Whole body scan (5cm/min) or planar scan
Time:
*24, 48 ,(72-120h?) for 131I-MIBG
*4h (seldom), 24h, 48h(?) for 123I-MIBG
*SPECT 24h

49. Normal MIBG Scan Heart Lung
Nasal mucosa, lacrimal glands and kidneys with 123I-MIBG
Bilateral upper thoracic symmetric activity in children (pleural or neck muscle?)
Uterus in menstrual cycle
No bone activity (even in child)
Lack of splenic activity in child is reported

52. DIAGNOSTIC APPLICATIONS
MIBG SCINTIGRAPHY
DIAGNOSTIC APPLICATIONS

53. Evaluating response to treatment Follow-up evaluation
MIBG SCINTIGRAPHY
Initial disease staging
Evaluating response to treatment
Follow-up evaluation

54. Catecholamine Producing Tumors
Pheochromocytoma
Paraganglioma.
Ganglioneuroma
Neuroblastoma

56. Pheochromocytoma

57. Pheochromocytoma Diagnosed on MIBG Scan

58. Pheochromocytoma (I-131 MIBG)

61. (131I-MIBG) therapy

62. Indications:
Tumours showing adequate uptake and retention of radiolabelled MIBG on the basis of a pretherapy tracer study.

63. Indications: 1. Inoperable phaeochromocytoma
2. Inoperable paraganglioma
3. Inoperable carcinoid tumour
4. Stage III or IV neuroblastoma
5. Metastatic or recurrent medullary thyroid cancer

64. Contra-indications:
The following are absolute contra-indications: 1.Pregnancy; breastfeeding. 2. Life expectancy less than 3 months, unless in case. of intractable bone pain. 3. Renal insufficiency, requiring dialysis on short term.

65. Relative contra-indications:
1. Unacceptable medical risk for isolation. 2. Unmanageable urinary incontinence 3. Rapidly deteriorating renal function-glomerular filtration rate less than 30 ml/min 4. Progressive haematological and/or renal toxicity because of prior treatment 5. Myelosuppression: – Total white cell count less than 3000/ml – Platelets less than 100,000/ml

66. Early side effects:
1. Nausea and vomiting (first 2 days). 2. Temporary myelosuppression ( after 4–6 weeks). Haematological effects are common in children with neuroblastoma after chemotherapy (60%) predominantly as an isolated thrombocytopenia, but are less frequent in adults.

67. Early side effects:
Bone marrow depression is likely in patients who have bone marrow involvement at the time of 131I-MIBG therapy and in patients with delayed renal 131I-MIBG clearance.

68. Early side effects:
3. Rarely, deterioration of renal function is observed in patients whose kidneys have been compromised by intensive pre-treatment with cisplatin and ifosfamide.

69. Possible long-term effects:
1. Hypothyroidism (after inadequate thyroid blockade). 2. Persistent haematological effects (thrombocytopaenia, myelosuppression) 3. There is sparse evidence for induction of leukaemia or secondary solid tumours, but this is a rare possibility, especially in conjunction with (longstanding) chemotherapy treatment.

70. Thanks For Attention