Neuroendocrine tumors: approaches to imaging

Transcription

1 Neuroendocrine tumors: approaches to imaging Thomas Hope, MD Assistant Professor of Radiology, UCSF Abdominal Imaging and Nuclear Medicine Chief of MRI, San Francisco VA Medical Center

2 Collaborators at UCSF Directors Sharmila Majumdar Dan Vigneron MRI side Jing Liu Peder Larson Anand Venkatachari PET side Youngho Seo Jaewon Yang Radiopharmaceutical Salma Jivan Jim Slater Henry VanBrocklin MD side Spencer Behr Thomas Hope Miguel Pampaloni Jane Wang Technologists and CRCs Rukayah Abdolcader Rosanna Horton Vahid Ravanfar Dora Tau Kenneth Gao

3 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

4 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

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6 CT (computed tomography) Measures density does so by measuring the number of x-rays (or photons) that make it through the body it is the attenuation that we are measuring

7 CT Typically study of choice freezes bowel motion Hyperenhancement is typical Often only see desmoplastic response in regional nodal metastasis nodal mets also commonly have coarse calcifications

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9 islet cell tumor Functioning NET of the pancreas Hyperenhance early DDx: hypervascular metastasis (RCC is most common) accessory spleen

10 CT: Contrast CT uses iodinated contrast agents Risks/side effects: Allergic reaction Extravasation Contrast induced nephropathy: usually 2-7 days after contrast administration most reported cases are arterial administration (cardiac cath)

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12 Role of MRI MRI is best for evaluation of liver metastasis HBP most sensitive pre T1 CT early arterial T2 late arterial hepatobiliary

13 Role of MRI - diffusion Diffusion has high sensitivity for hepatic metastasis Also helps differentiate regions of viability from necrosis using ADC maps B 20 hepatobiliary B 600 ADC

14 Nephrogenic systemic fibrosis: NSF 2004: found systemic manifestations and changed name 2006: associated with Gadolinium administration 2007: FDA black box warnings 2009: FDA adjusts black box warnings 1.!Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet Sep 16;356(9234): !Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. The American Journal of dermatopathology Oct 1;23(5):

15 Safety, what s the real question? 1.!Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast media reactions. American Journal of Roentgenology Feb;196(2):W

16 Gadolinium deposits in the body... Kanda 2014 demonstrated higher signal intensity in the dentate nucleus as people received more doses of gad Used Magnevist and Omniscan 19 patients with 6-12 injections of gad

17 FDA box warning July 27th: It is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects. To reduce the potential for gadolinium accumulation, health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary. Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols.

18 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

19 Somatostatin First discovered in 1972 Hormone made of 14 amino acids typically secreted from the hypothalamus Biologic half life of a few minutes Acts in the CNS and GI system in the GI tract it suppresses the release of hormones There are 5 subtypes of somatostatin receptors SSTR 2 is most commonly over-expressed on NETs subtypes not described till 1992! Somatostatin receptors are expressed on most NETs

20 Octreotide 8 amino-acid segment of somatostatin, which binds to the somatostatin receptors dramatically prolonged the half-life due to AA substitution 90% excreted by the kidneys at 24 hours Octreotide originally developed for symptom control in patients with functional tumors In-111 Pentreotide (Octreoscan, Covidian) First used in 1991, and became mainstay for evaluation of neuroendocrine tumors unknown primary, disease extent, treatment response

21 Octreotide protocol Typically hold sandostatin 3-7 days prior to imaging AP whole body AP SPECT/CT? AP SPECT/CT? inject 4 hrs 24 hrs 48 hrs may require laxatives to remove stool activity

22 Normal biodistribution Kidneys #1 Spleen > liver Biliary excretion (bowel etc) Urinary excretion (bladder) minimal thymus activity

23 Pancreatic neuroendocrine tumor

24 TI carcinoid Note that the tracer accumulated within the stool is as hot as the primary tumor SPECT would not help you: would require patient to return one day later to demonstrate that the stool moved and the tumor as static

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26 False positives? What s the differential? tumors: bronchial carcinoid small cell lung cancer inflammatory processes tuberculosis sarcoidosis other granulomatous processes

27 Issues with Octreotide 1. Labeled with indium gamma emitter (SPECT vs PET) long half life (67 hours or 2.8 days) 2. Biliary excretion often requires multiple delayed imaging 3. Low receptor affinity cannot image immediately (ie needs long half life agent) 4. SSTRs not expressed well on poorly differentiated tumors

28 PET/CT Radiolabeled compound typically 18F-FDG also Ga68, C kev Decays by releasing a positron positron range of F18 is roughly 2 mm Positron then travels a finite distance and decays into two photons FDG 511 kev

29 PET/CT: attenuation correction

30 PET/CT: various radioisotopes Isotope Emax Rmax Half-life Ga min O min N min C min F min

31 PET/CT: different radiotracers FDA approved: FDG: fluorodeoxyglucose, most common radiotracer NaF: calcium analog used for bone imaging Rubidium/Ammonia/Oxygen: cardiac perfusion tracers Amyvid: amyloid binder used for Alzheimer's Research compounds Ga-68 DOTA-TOC/TATE: somatostatin receptor analog used for neuroendocrine tumors Ga-68 HBED-CC PSMA C11/F18 choline

32 NaF FDG DOTA-TOC C11 choline

33 What s the role of FDG PET/CT? FDG is particularly useful in poorly differentiated NETs, which loose their SSR expression and become hypermetabolic Well differentiated tumors typically do not have good FDG uptake Increased FDG uptake is correlated with poor outcome

34 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

35 Gallium minute half-life Generator produced PET emitter (91%) 8 mm positron range Metal chemistry simple synthesis using modules Easily converted to therapy by replacing Ga-68 with Y-90 or Lu-177

36 Octreotide analogs DOTA somatostatin analog DOTA-TATE octreotide Antunes, EJNMMI 2007

37 Relative somatostatin receptor binding Table 1: Somatostatin receptor binding efficiency Compound SSR-1 SSR-2 SSR-3 SSR-4 SSR-5 DOTA-TATE > 10, > 1, DOTA-NOC > 10, DOTA-TOC > 10, > 1, Octreotide > 10, > 1, Antunes, EJNMMI 2007

38 Normal biodistribution Pituitary gland Adrenal glands Spleen > liver Kidneys and bladder Minimal uptake in the bowel, typically not focal

39 PET/CT: fusion with CT

40 Somakit (Ga-68 DOTA-TATE) status FDA is currently reviewing data from AAA Timeline is possible approval in the first half of next year Questions remain about distribution Do you need a gallium generator?

41 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

42 DOTA-TOC PET/MRI... perivertebral node internal mammary node perirectal node external iliac node

43 Hepatobiliary agents Eovist (Gadoxetate disodium) gadolinium based contrast agent with 50% biliary excretion (in addition to renal) Hepatobiliary phase delayed image (typically minutes after injection) when contrast is concentrated with in the bile ducts bile duct bile duct atocyte hepatocyte hepatocyte

44 Navigated HBP imaging Uses a diaphragm navigator Acquires location of diaphragm every ~200 ms Remember to use a high flip angle During the HBP, the liver is hyperintense and so the navigator is very robust Nagle SK, JMRI 2012

45 whole body acquisition (2:15) Hepatobiliary phase liver bed acquisition (15 min) Fused PET and HBP

46 PET/MRI: DOTA-TOC HBP fused PET B=50 B=600 T2 SSFSE

47 Pluses and Minuses of PET/MRI? Pluses: Improved hepatic imaging Decreased dose from removing CT component, but also possible to decrease radiotracer dose Minuses: Poor lung and small bowel imaging Longer time Loud noise, more claustrophobic

48 1. Cross sectional imaging 2. Octreotide 3. DOTA-TATE/TOC 4. PET/MRI 5. PRRT

49 Lutathera trial (Lu-177 DOTA-TATE) Has orphan drug status allows for longer exclusivity and no filing fees with the FDA Completed enrollment in February NETTER-1 first randomized trial to test efficacy or PRRT population: advanced mid-gut NETs control arm: double dose octreotide therapy arm: 4 doses of 200 mci Lu-177 DOTA-TATE (every 8 weeks) first look data shows impressive results for treatment response radiographic progression free survival and possibly overall survival