in Imaging and Therapy of NETs

Steven Burrell, MD

Division of Nuclear Medicine QEII Health Sciences Centre Halifax, Nova Scotia

23 May 2015 Outline: Nuclear Medicine in NETs

A. Imaging B. Therapy

1. Introduction to Nuclear Medicine in NETs

2. A Nuclear Medicine Tour of NETs Part 1:

Introduction to Nuclear Medicine in NETs Introduction to Nuclear Medicine

• injection of a tracer (“”) • tracer possesses 2 general properties:

1. a physiologic property – such as incorporation into certain cancer cells 2. a radioactive “tag” – emits energy, detected by a camera, depicting the distribution of the tracer throughout the body – including within tumors • Also known as “” • Complementary to anatomic imaging (CT, MRI) Nuclear Medicine Scanners

• 2 Flavours, depending on the type of radioactive decay:

SPECT PET (Single Photon Emission Computed ) (Positron Emission Tomography) • traditional type (and still most • newer common) • big impact in cancer ... but less so for NETs Nuclear Medicine Scanners

• Usually with a built-in low-dose CT scan • provides anatomic detail

PET CT Fused PET-CT

• What is most relevant however, is the radiopharmaceutical • specific process it assesses 3 Main Nuclear Medicine Tracers for Neuroendocrine Tumors

Octreotide Scan • most common scan for NETs

MIBG Scan • NETs derived from neural crest – pheochromocytoma, paraganglioma, neuroblastoma

PET Scan with FDG • niche role in NETs – eg some higher grade tumors Scan

Octreotide Scan ( 111Indium Pentetreotide, OctreoscanTM )

• Somatostatin: a regulatory peptide hormone • Neuroendocrine tissues often express somatostatin receptors • Tumors derived from these tissues (NETs) often overexpress somatostatin receptors

Octreotide Scan ( 111Indium Pentetreotide, OctreoscanTM )

• But half life of somatostatin is only 1-3 minutes • Octreotide: a somatostatin analog with half life of 90-120 minutes

• Bound to 111Indium (radioactive) Normal à Image somatostatin receptors à NETs Octreotide Scan

Technique: Octreotide Scan

Patient Preparation • well hydrated • withhold “cold” Octreotide: – 24 hours for short-acting Octreotide – 3-4 weeks for long-acting formulation

Imaging • 4 and 24 hours post injection • ~ 2 hours per session 2. MIBG Scan

MIBG Scan (123Iodine- or 131Iodine- Meta-Iodobenzyl Guanidine)

• a combination of the benzyl group of bretylium and the guanidine group of guanethidine • similar in structure and function to norepinephrine: – taken up in cells of neural crest origin

MIBG Uptake in Sympathetic Normal Nerve Terminal via Active MIBG Scan Uptake-1 Mechanism 123Iodine vs 131Iodine -MIBG

Anterior Posterior Anterior Posterior

123I-MIBG 131I-MIBG Technique: MIBG Scan

Patient Preparation • well hydrated • (if safe) withhold interfering medications: – long list!

Imaging • 4 and 24 hours post injection • (24 and 48 hours for 131I-MIBG) • ~ 2 hours per session 3. FDG Scan (PET Scan)

PET Scan ( 18F-FDG Positron Emission Tomography)

• uses the glucose analog (FDG) – there are other PET tracers: • some better in NETs • not widely / currently available

Normal FDG PET Scan Normal Cell Tumor Cell PET Scan ( 18F-FDG Positron Emission Tomography)

• PET has revolutionized imaging of many cancers – though less so with NETs: • generally low aggresivity/metabolism, so low FDG uptake • still, there are applications... Technique: FDG PET Scan

Patient Preparation • well hydrated • no food or drink (except water) x 6 hours

Imaging • 45 minutes post injection • ~ 30 minute scan Roles of Nuclear Medicine in NETs

Common • Localizing the primary lesion • Staging • Assessing response to therapy • Assessing for recurrence

Roles of Nuclear Medicine in NETs

Common • Localizing the primary lesion • Staging • Assessing response to therapy • Assessing for recurrence Less Common • Narrowing the differential of a pancreatic tumor • Establishing avidity for potential therapy • “cold” somatostatin analogs • high dose radioactive MIBG • Aiding intraoperative tumour localization using a gamma probe A Nuclear Medicine Physician’s Simplistic View of NETs Medullary Cancer Calcitonin

Pheochromocytoma, Paraganglioma, Neuroblastoma (children) Catecholamines (adrenaline, …)

Pancreatic NETs Gastrin, Insulin,Glucagon…

Gastrointestinal NETS (“”) Serotonin

Part 2:

A Nuclear Medicine Tour of NETs Part 1

Medullary Thyroid Cancer

Pheochromocytoma, Paraganglioma, Neuroblastoma (children)

Mainly Octreotide Scans Pancreatic NETs

Gastrointestinal NETS (“Carcinoid”) GI NET (Carcinoid)

111 Indium 123 Octreotide I-MIBG Another Carcinoid 111In Octreotide

Anterior Posterior Carcinoid Syndrome

• intestinal hypermotility (diarrhea, cramping, nausea and vomiting) • vasomotor instability (flushing, cyanosis, dermatitis) • bronchoconstriction (wheezing, dyspnea) • right heart problems Carcinoid Syndrome

• serotonin is metabolized in the liver and lungs into 5-HIAA which is excreted in the urine

• thus for a gastrointestinal carcinoid to produce the x carcinoid system, there must be liver metastases which produce serotonin and release it directly into the systemic circulation Carcinoid Heart

• Occurs in > 50% of carcinoid syndrome

• Predominantly right heart: – tricuspid regurgitation (virtually all) • valve thickened, retracted, fixed – pulmonic stenosis

– fibrosis of endocardium : Carcinoid Heart What About NETs of the Pancreas? Lewis et al. RadioGraphics 2010; 30:1445–1464 • Patient with diarrhea, stomach thickening, elevated gastrin levels… • No abnormality on conventional imaging: • where is the ?

• Patient with diarrhea, stomach thickening, elevated gastrin levels… • No abnormality on conventional imaging: • where is the gastrinoma?

• Octreotide Scan with SPECT-CT: • Patient with diarrhea, stomach thickening, elevated gastrin levels… • No abnormality on conventional imaging: • where is the gastrinoma?

• Octreotide Scan with SPECT-CT:

Anterior Posterior • Patient with diarrhea, stomach thickening, elevated gastrin levels… • No abnormality on conventional imaging: • where is the gastrinoma?

• Octreotide Scan with SPECT-CT:

Octreotide SPECT

CT

Anterior Posterior Fused SPECT-CT Another Gastrinoma Search Octreotide Scan Octreotide Scan Octreotide Scan FDG PET Scan PET

CT

PET-CT FDG PET Scan Zollinger Ellison Syndrome Gastrinoma PET

++ Gastrin

++ Gastric Acid

CT

++ Gastritis

PET-CT Patient with an Insulinoma Chronic hypoglycemia

Octreotide scan is negative: Sensitivity is lowest for insulinomas (~ 60%) Part 2

Medullary Thyroid Cancer

Pheochromocytoma, Paraganglioma, Neuroblastoma (children)

Mainly MIBG Scans Pancreatic NETs

Gastrointestinal NETS (“Carcinoid”) Patient with hypertension Patient with hypertension

Anterior Posterior 123I-MIBG Patient with hypertension

Axial slice (SPECT)

Anterior Posterior 123I-MIBG Patient with hypertension

Axial slice MRI (SPECT)

Anterior Posterior 123I-MIBG Another patient with hypertension Another patient with hypertension

123I-MIBG Another patient with hypertension

Axial Slice (SPECT)

123I-MIBG Another patient with hypertension

Axial Slice (SPECT)

123I-MIBG CT Same patient : elevated parathyroid hormone Same patient : elevated parathyroid hormone

99mTc-Sesta-MIBI Same patient : elevated parathyroid hormone

99mTc-Sesta-MIBI CT

à (Hyperfunctioning) parathyroid adenoma MEN Syndromes (Multiple Endocrine Neoplasias)

• Genetic disorders with a predisposition to tumour development within 2 or more components of the endocrine system

Scarsbrook et al. Radiographics, 2006;26:433-451 MEN Syndromes

MEN 1 1. Parathyroid Tumour (95%) 2. Pancreatic Islet Cell Tumor (40%) 3. Pituitary Tumour (30%)

MEN 2a 1. Medullary Thyroid Cancer (99%) 2. Pheochromocytoma (50%) 3. Parathyroid Tumour (20-30%)

MEN 2b 1. Medullary Thyroid Cancer (100%) 2. Pheochromocytoma (50%) 3. Associated Abnormalities (100%) – mucosal neuromas, marfanoid habitus, … Part 3

Medullary Thyroid Cancer Probably PET Scan Pheochromocytoma, Paraganglioma, Neuroblastoma (children)

Pancreatic NETs

Gastrointestinal NETS (“Carcinoid”) Prior MTC Rising calcitonin

18FDG PET What’s Coming: New Tracers for NET Imaging New Tracers for NETs

• new PET • targeted at NETs (like current Octreotide, MIBG) • but labeled with positron-emitters: – imaged in PET scanner: better images 18F-DOPA instead of MIBG

Pheochromocytoma FDOPA/MIBG

MIBG Scan 24 yr patient biochemistry positive 18F-DOPA PET 9 68Ga Labelled Somatostatin Analogs instead of current 111In-Octreotide

• 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE

Herrmann et al. J Nucl Med 2015; 56:70–75 68Ga Labelled Somatostatin Analogs instead of current 111In-Octreotide

• Better uptake, better quality images • Not yet in Canada – soon in Edmonton • CNETS is advocating for

Radioisotope Therapy of NETS

Radioisotope Therapy

• Consider: 1. Nuclear medicine radiopharmaceuticals target NETs 2. Some tumors are sensitive to radiation

• We can treat metastatic NETs with radiopharmaceuticals MIBG Therapy

• Currently 131I-MIBG for NETs that are MIBG-avid • 131Iodine emits 2 types of radiation: – Gamma photons: imaging – Beta particles: therapy • Overall, moderately successful – Slow tumor progression – Relieve symptoms • When no other therapy options • We do approx 2 per year at QEII – Cases reviewed by NET Tumor Board MIBG Therapy

• Admitted to hospital for 2-3 days • IV administration over ~ 1 hour • Immediate side effects rare in non-functioning NETs • Some marrow suppression, usually recovers • We have had good success in well-selected patients But many NETs are not MIBG-avid:

111In-Octreotide 123I-MIBG

Can Octreotide be labeled with a beta-emitter? 177Lu- DOTATATE

• Europe • Canada – Edmonton, London • Dr. Rayson and I visited Edmonton therapies – Not yet available in Atlantic Canada • CNETS is advocating for Conclusions Conclusions

• Tracer imaging with Nuclear Medicine plays a role at many stages of NETs • Assesses molecular processes – Complimentary to anatomic imaging • While there are nuances, generally: – Octreotide for most GI and Pancreatic NETs – MIBG for Pheochromocytoma, Paragangioma, Neuroblastoma – FDG PET in niche applications (MTC, high grade tumors) Conclusions

• High doses of radiopharmaceuticals can be administered for therapy

• Developing initiatives: – 68Ga-DOTA PET scans for NETs – 177Lu-DOTA therapies for NETs Questions ?

Back Up Slides Pheochromocytoma FDOPA/MIBG

24 yr patient biochemistry positive

Dr. PL Jager, MD,9 PhD University Medical Center Groningen, The Netherlands ParagangliomaParaganglioma FDOPA FDOPA

7 Dr. PL Jager, MD, PhD University7 Medical Center Groningen, The Netherlands Medullary Thyroid Cancer PET (Octreotide) Neuroblastoma MIBG (PET )

Pancreatic NETs Octreotide

GI NETS (“Carcinoid”) Octreotide (PET for high grade) Merkel Cell Tumour PET (Octreotide)