NUCLEAR MEDICINE: LOOKING AHEAD TO 2020

Eric M. Rohren, M.D. Ph.D. Professor and Chair, Department of Radiology Baylor College of Medicine Houston, Texas Objectives

. What is molecular imaging? . How do we think about molecular imaging? . What are the features of success? … and failure? Molecular Imaging Agents

2-[18F ]-2-Deoxy-D- • Analog of glucose • Uptake mirrors glucose utilization

HO O OH

HO OH 18F FDG-PET/CT: What are We Imaging Exactly?

. Imaging regional localization of FDG  FDG uptake and concentration at a cellular level  Glucose transporter receptor expression  Hexokinase expression  Low phosphatase activity  Cellular density

 Tracer delivery (perfusion/concentration) “METABOLISM”

 Scanner limitations (size, motion, etc.)

A Tale of Two … Gastric Cancers

. Patient 1  66 year old woman with upper abdominal pain and weight loss . Patient 2  58 year old man with weight loss and early satiety Patient 1 Patient 2 Molecular Imaging

Gene expression

Receptor Imaging Cellular Proliferation and Hypoxia

Protein and Membrane Catabolism

Glucose “Metabolism”

Instrumentation PET SPECT MR NIR/Optical U.S. Approved Clinical Use . 18F-FDG . 18F-fluoride . 82Rb-chloride . 13N-Ammonia U.S. Approved Radiopharmaceuticals Recent . 123I- . 99mTc-tilmanocept . 11C-choline . 18F-amyloid (, , flutametamol) 223 . RaCl2 U.S. Approved Radiopharmaceuticals In Development . 123I-ioflupane . 99mTc-tilmanocept . 11C-choline . 18F-amyloid (florbetapir, florbetaben, flutametamol) 223 . RaCl2 . 68Ga-DOTA-TOC/NOC/TATE . 177Lu-DOTATATE . 18F-PSMA . 18F-flurpiridaz . 131I-ultratrace (MIBG) Theranostic Approach

Cancer Cell for Therapy

Radionuclide Emission Energy (MeV) Range (mm) Half-Life

Indium-111 Auger / g 0.61 0.5 2.8 days Yttrium-90 Beta 2.27 11 2.7 days

Lutetium-177 B / g 0.49 2 6.7 days Bismuth-213 a 8.32 0.04 - 0.1 46 min Considerations . Performance . Time/Speed . dose . Availability/Access . Cost Case Studies Imaging Lymphoma 67Gallium Citrate

. Introduced to clinical practice 1969 . Physical characteristics  T½ 78 hours  Photopeaks 93 keV, 185 keV, 300 keV, 394 keV . Bound to transferrin and lactoferrin in plasma . Receptor-mediated uptake in tumor cells . Used for imaging a variety of malignancies 67Ga-SPECT and Lymphoma

. Uptake of gallium is dependent on tumor grade . Hodgkin lymphoma: 80-90% sensitivity . Non-Hodgkin lymphoma: 60-90% sensitivity

. Imaging Protocol  Injection of 370 MBq (10 mCi)  Planar imaging at 48 hrs, sometimes longer  SPECT 18F-

HO O OH

HO OH 18F . 2-deoxy-2-[18F]fluoro-D-glucose . Physical characteristics  T½ 110 minutes  Photopeak 511 keV . Cellular uptake via glucose receptors Retrospective Review: Duke Univsersity 1999

. 47 patients evaluated with both 67Ga-SPECT and FDG-PET . 7 day mean interval between studies (0-59d) . No interval treatment . Studies read with available clinical and radiological correlation Conclusions

. FDG-PET is more accurate than 67Ga- SPECT in staging patients with Hodgkin and Non-Hodgkin lymphoma  42 of 47 patients correctly staged by PET  34 of 47 patients correctly staged by gallium  8 of 10 discrepant cases resolved in favor of PET 67Ga (10 mci) 18F-FDG (20 mCi) Radiation dose ~25 mSv ~15 mSv Total Time 2-4 days 3 hours Scan Time 60-90 minutes 60-90 minutes Cost $$ $$$ Accuracy ++ ++++ Quantification No Yes Radiopharmaceuticals for Treatment of Bone Metastases – Radium-223

223 RaCl2 - Half life 11.43 days - Multistep decay  a (95%, 4 per decay event) - Low abundance b, g Decay Cascade of 223Ra

223Ra 11.4 d 211Po 0.5 s a 219Rn a 4.0 s b 207Pb stable a 211Bi 2.2 m 215Po b 1.8 ms b a 207Tl a 4.8 m 211  a-emitter (94% of emitted energy) Pb 36.1 m  Total Energy / decay: Approx. 28 MeV

(From Oyvind Bruland MD, PhD)

Bone Imaging 18F-Fluoride

18F 18F 18F 18F

18F

. Sodium [18F]fluoride . Physical characteristics  T½ 110 minutes  Photopeak 511 keV  18F- exchange for OH- in hydroxyapatite  18F- migration into crystalline matrix of bone  90% serum clearance at 1 hr

Imaging Comparison

. Study: 72 patients with advanced breast cancer at high risk for skeletal disease 99mTc SS NaF PET/CT Sensitivity 81% 100% Specificity 63% 75% PPV 81% 89% NPV 63% 100% Accuracy 75% 92%

. Change in patient management in 12 patients (17%) based on NaF-PET/CT

Damle N, et. al. 2007. J Nucl Med 48:142P. TFI10 VF10 TFI10 VF10 Baseline 2729 193 cc Baseline 5576 329 cc Post-Therapy 8389 522 cc Post-Therapy 898 76 cc % Change +207.4% +170.4% % Change -83.9% -76.9% J Nucl Med 2015; 56:1177-1184 99mTc-MDP 18F-FDG PET/CT (20 mci) (5 mCi) Radiation dose ~3-5 mSv ~20 mSv Total Time 3-4 hours 2 hours Scan Time 45 minutes 20 minutes Cost $ $$$ Accuracy ++ ++++ Quantification No Yes CMS Decision Memo

. Based on the result of data analysis . NOPR – Scanning under CED  2839 scans / 2217 patients  Change in management in 40.3% of patients

Concluded that NaF-PET/CT is NOT reasonable and necessary NO COVERAGE CMS Questions

. Does the addition of NaF-PET/CT imaging lead to:  A change in patient management to more appropriate palliative care; or  A change in patient management to more appropriate curative care; or  Improved quality of life; or  Improved survival? A Lingering issue: REIMBURSEMENT FLORBETAPIR PET SCAN FDA Decision

. Approved for clinical use 4/10/2012  Safe  Effective CMS Decision Memo

“… the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta (Aβ) imaging is reasonable and necessary for the diagnosis or treatment of [patients] … with or neurodegenerative disease, and thus PET Aβ imaging is not covered …” CMS Decision Memo

. Do the results of PET Aβ imaging lead to improved health outcomes?

Effective Treatment The Near Future

. Imaging with PET will replace some general applications NETTER-1 Trial