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(BQ) Part 1 book Principles and practice of PET and PET/CT presents the following contents: Production of radionuclides for PET, PET physics and PET instrumentation, radiotracer chemistry, data analysis and image processing, fundamentals of CT in PET/CT, standardized uptake values, image fusion, oncologic applications,...
LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page iii Aptara Inc PRINCIPLES AND PRACTICE OF PET AND PET/CT SECOND EDITION EDITOR RICHARD L WAHL, MD Professor of Radiology and Oncology, Henry N Wagner Jr Professor of Nuclear Medicine Director, Division of Nuclear Medicine and PET Vice Chairman for Technology and New Business Development The Russell H Morgan Department of Radiology and Radiological Sciences The Johns Hopkins University School of Medicine Baltimore, Maryland ASSOCIATE EDITOR: CARDIOVASCULAR PET SECTION ROBERT S.B BEANLANDS, MD, FRCPC, FACC Professor of Medicine (Cardiology)/Radiology Chief, Cardiac Imaging Director, National Cardiac PET Centre University of Ottawa Heart Institute Ottawa, Ontario LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page ii Aptara Inc LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page iv Aptara Inc Acquisitions Editor: Lisa McAllister Managing Editor: Kerry Barrett Project Manager: Rosanne Hallowell Manufacturing Manager: Benjamin Rivera Marketing Manager: Angela Panetta Art Director: Risa Clow Production Services: Aptara, Inc Second Edition © 2009 by Lippincott Williams & Wilkins, a Wolters Kluwer business 530 Walnut Street Philadelphia, PA 19106 LWW.com First Editon © 2002 by Lippincott Williams & Wilkins All rights reserved This book is protected by copyright No part of this book may be reproduced in any form or by any means, including photocopying, or utilizing by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Printed in China Library of Congress Cataloging-in-Publication Data Principles and practice of PET and PET/CT / editor, Richard L Wahl, Henry N Wagner Jr ; associated editor, cardiovascular PET section, Robert Beanlands — 2nd ed p ; cm Rev ed of: Principles and practice of positron emission tomography / editor, Richard L Wahl ; associate editor, Julia W Buchanan c2002 Includes bibliographical references and index ISBN 978-0-7817-7999-9 Tomography, Emission I Wahl, Richard L II Wagner, Henry N., 1927– III Principles and practice of positron emission tomography [DNLM: Positron-Emission Tomography—methods Tomography, X-Ray Computed— methods WN 206 P9568 2009] RC78.7.T62P75 2009 616.07’575—dc22 2008031561 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of this information in a particular situation remains the professional responsibility of the practitioner The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of health care providers to ascertain the FDA status of each drug or device planned for use in their clinical practice The publishers have made every effort to trace copyright holders for borrowed material If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity To purchase additional copies of this book, call our customer service department at (800) 6383030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 Visit Lippincott Williams & Wilkins on the Internet at LWW.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to pm, EST 10 LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page v Aptara Inc To my wife Sandy and my children, whose generous patience and support during my many hours of work on this book were essential to its genesis and completion The current state of PET/CT as a broadly applicable method, as reflected in this text, lies squarely on the shoulders of pioneers in nuclear medicine research, ambitious trainees, skilled technologists, and study participants LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page vi Aptara Inc LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page vii Aptara Inc CONTENTS Contributing Authors xi Preface xvii Preface to the First Edition xix Production of Radionuclides for PET Ronald D Finn and David J Schlyer Radiotracer Chemistry 16 Joanna S Fowler and Yu-Shin Ding PET Physics and PET Instrumentation 47 Timothy G Turkington Fundamentals of CT in PET/CT 58 Mahadevappa Mahesh Data Analysis and Image Processing 69 Robert Koeppe Standardized Uptake Values 106 Richard L Wahl Image Fusion 111 Charles A Meyer and Richard L Wahl Oncologic Applications 8.1 Principles of Cancer Imaging with 18-F-Fluorodeoxyglucose 117 Richard L Wahl 8.2 How to Optimize CT for PET/CT 131 Gerald Antoch and Andreas Bockisch 8.3 Artifacts and Normal Variants in PET 139 Paul Shreve 8.4 Monitoring Response to Treatment 169 Anthony F Shields 8.5 PET and PET/CT in Radiation Oncology 187 Michael P Mac Manus and Rodney J Hicks 8.6 Central Nervous System 198 Michael J Fulham and Armin Mohamed 8.7 Use of PET and PET/CT in the Evaluation of Patients with Head and Neck Cancer 221 Todd M Blodgett, Alexander Ryan, and Barton Branstetter IV vii LWBK053-3787G-FM-i-xxii.qxd viii 15/8/08 5:51 PM Page viii Aptara Inc Contents 8.8 Thyroid Cancer and Thyroid Imaging 240 Michele Brenner and Richard L Wahl 8.9 Lung Cancer 248 Patrick J Peller and Val J Lowe 8.10 Lymphoma and Myeloma 260 Sven N Reske 8.11 PET and PET/CT of Malignant Melanoma 275 Hans C Steinert 8.12 PET in Breast Cancers 287 Farrokh Dehdashti 8.13 Esophagus 310 Wolfgang A Weber and Richard L Wahl 8.14 Applications for Fluorodeoxyglucose PET and PET/CT in the Evaluation of Patients with Colorectal Carcinoma 320 Dominique Delbeke 8.15 Pancreatic and Hepatobiliary Cancers 331 Oleg Teytelboym, Dominique Delbeke, and Richard L Wahl 8.16 Cervical and Uterine Cancers 348 Perry W Grigsby 8.17 PET and PET/CT in Ovarian Cancer 355 Hedieh Eslamy, Robert Bristow, and Richard L Wahl 8.18 Genitourinary Malignancies 366 Heiko Schöder 8.19 Sarcomas 392 Janet Eary 8.20 Gastrointestinal Stromal Tumors 402 Annick D Vanden Abbeele, Sukru M Erturk, and Richard J Tetrault 8.21 PET and PET/CT Imaging of Neuroendocrine Tumors 411 Richard P Baum and Vikas Prasad 8.22 Carcinoma of Unknown Primary, Including Paraneoplastic Neurological Syndromes 438 Jennifer Rodriguez-Ferrer and Richard L Wahl 8.23 Pediatrics 443 Hossein Jadvar, Leonard P Connolly, Frederic H Fahey, and Barry L Shulkin 8.24 Hypoxia Imaging 464 Morand Piert 8.25 Newer Tracers for Cancer Imaging 472 Rodney J Hicks Neurologic Applications 9.1 Movement Disorders, Stroke, and Epilepsy 479 Nicolaas I Bohnen 9.2 Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 500 Satoshi Minoshima, Takahiro Sasaki, and Eric Petrie LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page ix Aptara Inc Contents 10 Psychiatric Disorders 516 Marc Laruelle and Anissa Abi-Dargham 11 Cardiac Applications 11.1 Evaluation of Myocardial Perfusion 541 Keiichiro Yoshinaga, Nagara Tamaki, Terrence D Ruddy, Rob deKemp, and Robert S.B Beanlands 11.2 Myocardial Viability 565 Robert S.B Beanlands, Stephanie Thorn, Jean DaSilva, Terrence D Ruddy, and Jamshid Maddahi 11.3 Oxidative Metabolism and Cardiac Efficiency 589 Heikki Ukkonen and Robert S.B Beanlands 11.4 Myocardial Neurotransmitter Imaging 607 Markus Schwaiger, Ichiro Matsunari, and Frank M Bengel 12 PET/CT Imaging of Infection and Inflammation 619 Ora Israel 13 PET and Drug Development 634 Jerry M Collins 14 Emerging Opportunities 14.1 Imaging Gene Expression 644 Uwe Haberkorn 14.2 The Kidneys 661 Zsolt Szabo, Jinsong Xia, and William B Mathews 14.3 Imaging the Neovasculature 676 Ambros J Beer, Hans-Jürgen Wester, and Markus Schwaiger 14.4 Progress in Amyloid Imaging: Five Years of Progress 690 Brian J Lopresti, William E Klunk, and Chester A Mathis 15 PET Imaging as a Biomarker 702 Wolfgang A Weber, Caroline C Sigman, and Gary J Kelloff Index 713 ix LWBK053-3787G-FM-i-xxii.qxd 15/8/08 5:51 PM Page x Aptara Inc LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 464 Aptara Inc CHAPTER 8.24 Hypoxia Imaging MORAND PIERT DEFINITION OF HYPOXIA CELLULAR REGULATION OF OXYGEN HOMEOSTASIS HYPOXIA IN CARDIOVASCULAR DISEASE HYPOXIA IN ONCOLOGY CHALLENGES OF HYPOXIA MEASUREMENTS DEFINITION OF HYPOXIA A continued source of molecular oxygen is essential for cellular respiration and energy supply Hypoxia is defined as a metabolic state in which the concentration of oxygen is below physiological levels (normoxia) but above the complete lack of oxygen (anoxia) Even under physiologic conditions, tissue oxygenation levels may vary considerably between different tissues and may display a marked heterogeneity even in tissues that are considered well perfused (1) Hypoxia should be differentiated from ischemia, the latter describing a lack of blood flow to a particular organ or tissue Although ischemia can be caused by prolonged severe tissue hypoxia and by anoxia, these terms are clearly not interchangeable CELLULAR REGULATION OF OXYGEN HOMEOSTASIS The transcription factor hypoxia-inducible factor (HIF-1) is a key regulator of hypoxia-induced gene expressions Since the discovery of the HIF-1 system by Semenza and Wang (2), HIF-1 has been of particular interest for cancer biologists HIF-1 is a heterodimeric protein that is composed of two polypeptides, the HIF-1a and HIF-1b subunits (3,4) With the completion of the human genome project, two additional HIF a members, the closely related HIF-2a (5,6) and more distantly related HIF-3a (7), were identified, although their function is less well defined The phosphatidylinositol 3-kinase (PI3K) and ERK mitogenactivated protein kinase (MAPK) pathways regulate the HIF-1a protein synthesis (8) HIF-1 activity is regulated at the posttranscriptional level by protein degradation of HIF a subunits (9) Under normoxic cellular conditions, HIF-1a is targeted by the oxygen-dependent prolyl hydroxylase to undergo ubiquitylation by E3 ubiquitin-protein ligases These ligases contain the von Hippel-Lindau (VHL) protein Ubiquitylated HIF-1a is rapidly degraded by the proteasome (8) By contrast, under hypoxic cellular conditions, the prolyl hydroxylation is inactive and the HIF a members are not complexed with VHL and remain available in the cell As a result, HIF-1b binds to the HIF-1a subunit, leading to the transcriptional activation of multiple genes responsible for cellular proliferation and cell survival, apoptosis, oxygen and nutrient delivery (angiogenesis), and anaerobic energy metabolism (glucose metabolism), all of which are 464 PET RADIOPHARMACEUTICALS FOR HYPOXIA IMAGING AND PRECLINICAL TESTING Nitroimidazole Compounds Copper Complexes APPLICATIONS OF HYPOXIA IMAGING IN ONCOLOGY involved in the basic biology of cancer (10,11) Chronic tumor cell hypoxia increases genomic instability and heterogeneity and selects for tumor cells that survive severe microenvironmental stresses (12) The regulation of HIF-1 signaling is a rather complex process Suppression of HIF-1a degradation has not only been observed as a result of intracellular oxygen depletion but also due to environmental stresses like extracellular acidosis (13) Most importantly, growth factors like insulin-like growth factor receptor, epidermal growth factor receptor, human epidermal growth factor receptor 2, and others can also stimulate HIF-1 signaling (14), indicating that the regulation of the HIF-1 oxygen sensing system is more complex than previously appreciated HYPOXIA IN CARDIOVASCULAR DISEASE The oxidative phosphorylation of adenosine diphosphate to adenosine triphosphate is the main source of energy needed to provide sustained contractility of the heart muscle Because of that, ischemic conditions (thus inadequate oxygen supply) are likely to cause hypoxia of variable degrees However, under certain pathophysiological conditions such as infections, hypoxia may occur in the heart muscle even if perfusion is well maintained One important consequence of coronary artery disease, left ventricular dysfunction, can result from acute myocardial ischemia or myocardial infarction In addition, transient postischemic “stunned” myocardium and chronic but potentially reversible ischemic “hibernating” myocardium are also associated with left ventricular dysfunctions It has been shown that hibernating myocardium is characterized by an upregulation of genes and corresponding proteins involved in antiapoptosis, cell growth, angiogenesis, and cytoprotection, including the activation of the HIF-1 cascade (15) Since hibernating myocardium can be significantly improved by successful revascularization, the identification of this condition is of great clinical importance Currently, accessible noninvasive imaging approaches for the detection of myocardial ischemia are based on the recognition of flow impairment or the identification of a mismatch between flow and regional myocardial metabolism All existing approaches are indirect methods assessing regional myocardial ischemia and are affected by sympathetic activation and substrate availability The direct visualization of myocardial tissue hypoxia has great potential It has been speculated that the assessment of tissue oxygenation LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 465 Aptara Inc Chapter 8.24 • Hypoxia Imaging using hypoxia tracers may potentially be the best indicator of the balance between blood flow and oxygen consumption (16) Consequently, hypoxia tracers have been suggested to identify dysfunctional chronically ischemic but viable hibernating myocardium HYPOXIA IN ONCOLOGY Tumor hypoxia is a common, if not characteristic, feature of malignant tumors It is related but not exclusively determined by a less ordered, often chaotic, and leaky vasculature The structure and function of the tumor microcirculation is often disturbed and results in a deterioration of the diffusion geometry Tumor-associated anemia further aggravates tumor tissue hypoxia The existence of tumor hypoxia had long been suspected by histological observation of necrosis and disordered vasculature and was confirmed in animals and humans by microelectrode and bioreductive drug measurements Tumor hypoxia has the well-known effect of decreasing the sensitivity of hypoxic cells to ionizing radiation It has also been identified as a major adverse prognostic factor for tumor progression and for resistance to anticancer treatment (17–19) Clinically relevant tumor tissue hypoxia is generally considered to be present at an oxygen partial pressure in tissue (tpO2) of less than to 10 mm Hg (12,20), while severely hypoxic tissue usually displays tpO2 values below to mm Hg Tumor tissue hypoxia plays an important role in radiation treatment because the extent of DNA damage following exposure to indirectly ionizing radiation is largely dependent on oxygen Severely hypoxic cells require two to three times higher radiation dose compared to well-oxygenated cells to produce an equivalent amount of cell kill following indirectly ionizing radiation or low linear energy transfer radiation (17) The difference in radiosensitivity between hypoxic and normoxic cells has been called oxygen enhancement ratio Oxygen is 465 believed to prolong the lifetime of the short-lived free radicals produced by the interaction of x-rays and cellular water In the absence of intracellular oxygen, free radicals formed by ionizing radiation are able to recombine without causing the expected cellular damage (21) Besides causing radioresistance, tumor hypoxia interferes with many chemotherapy regimes that require sufficient amounts of intracellular oxygen for the desired cytotoxic activities (22) The inefficient microvasculature of hypoxic tumors hampers sufficient drug delivery (17) Sustained hypoxia may also reduce tumor sensitivity by indirect mechanisms that include proteomic and genomic changes, the secretion of hypoxic stress proteins, and the loss of apoptotic potential (23–25) Fig 8.24.1 summarizes the current knowledge of mechanisms for hypoxia-related treatment resistance and their deleterious effects on tumor aggressiveness and metastatic potential CHALLENGES OF HYPOXIA MEASUREMENTS Many approaches to measure tissue hypoxia have been proposed Most of the clinical experience has been obtained with polarographic oxygen-electrode systems Although the measurements are quantitative, the results were generally reported as the fractional percentage of measurements below a certain cutoff tpO2 value Due to the heterogeneous distribution of tpO2 values, results were generally reported as the “hypoxic tumor fraction,” which was found to be a more robust parameter derived from such polarographic methods when compared to the average tpO2 in tissue In the past decade, a large body of evidence was derived from oxygen electrode measurements Studies have subsequently shown that pretreatment oxygenation can predict outcome of treatment in several solid tumors including head and neck cancer (26,27), lung FIGURE 8.24.1 Selected mechanisms for hypoxia-related treatment resistance LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 466 Aptara Inc 466 Principles and Practice of PET and PET/CT cancer, cervical cancer (18), and sarcomas (28) However, oxygen electrode measurements are rarely used routinely in human malignancies, mainly because they are invasive, limited to readily accessible tumor sites, and technically demanding (29) The exact localization of the probe’s tip within the tumor volume is difficult, and oxygen electrode systems are unable to determine the tumor’s oxygenation distribution on a truly regional basis, which is a necessary precondition for individually adapted therapeutic approaches A noninvasive identification and quantification of regional tumor tissue hypoxia is, therefore, nearly a necessity for effective treatment selection, individual treatment planning, and treatment monitoring in oncology PET RADIOPHARMACEUTICALS FOR HYPOXIA IMAGING AND PRECLINICAL TESTING Nitroimidazole Compounds The discovery of azomycin (2-nitroimidazole) (30) and its synthesis in 1965 (31) started decades of research in hypoxic cell radiosensitization and was the basis for the development of a whole group of nitroimidazole tracers for single-photon emission computed tomography and positron emission tomography (PET) imaging Chapman (32) suggested that nitroimidazoles should be useful for imaging of oxygen-deprived cells due to their radiosensitization capabilities and potential covalent binding to hypoxic cells Intracellular accumulation is related to radical formation following reduction by ubiquitous nitroreductases Under hypoxic conditions, reduction of these molecules involves a series of one electron steps (33) Products of this reduction are believed to covalently bind to intracellular macromolecules such as DNA, RNA, and proteins, which prevents back-diffusion across the cell membrane, causing the hypoxia-dependent accumulation of compound metabolites Conversely under well-oxygenated conditions, the nitro radical anion of these compounds are reoxidized, facilitating back-diffusion and contributing to clearance of radioactivity from tissue (34) However, even under hypoxic conditions, some diffusible compounds are formed indicating complex biokinetics Fluorine-18 labeled fluoromisonidazole (1-(2-nitroimidazolyl)2-hydroxy-3-fluoropropane) ([18F]-FMISO) was the first nitroimidazole PET tracer described and synthesized by Jerabek et al (35) and Grierson et al (36) The evaluation of this tracer was first performed using [3H]-FMISO, demonstrating that the FMISO uptake was dependent on the cellular oxygenation in rat myocytes (37) and tumor cell spheroids (38) Studies performed in several rodent tumor models using [3H]-FMISO revealed tumor-to-blood ratios suitable for in vivo imaging (39,40) The hypoxia-specific uptake mechanism of [18F]-FMISO was validated in an occlusion model and demonstrated tracer accumulation at radiobiologically relevant tpO2 levels (41,42) The radiopharmaceutical [18F]-FMISO is stable and robust and is currently the single most commonly used hypoxia PET tracer (43) However, its biokinetics suffer from relatively high lipophilicity (octanol/water partition coefficient of log P ϭ 2.6), which results in protracted in vivo accumulation in hypoxic tissues and slow plasma clearance, resulting in relatively low target-tobackground ratios Imaging with nitroimidazole compounds is, therefore, generally performed at later time points (2 to hours postinjection) when sufficient amounts of radioactivity have been cleared from plasma and normoxic tissues Several other nitroimidazole compounds have subsequently been labeled with positron emitters [18F]-fluoroetanidazole ([18F]-FETA) and [18F]-fluoroerythronitroimidazole ([18F]-FETNIM) were evaluated as hypoxia markers in animal models (44,45) and the latter also in humans (46,47) Tumor-to-background ratios did not indicate significant advantages over [18F]-FMISO for either tracer (45,48) Newer nitroimidazole tracers, 2-(2-nitroimidazol-1-yl)-N(3,3,3-[18F]-trifluoropropyl)acetamide ([18F]-EF3), and [18F]-EF5 ([18F]-2-(2-nitro-1[H]-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide) have undergone successful preclinical testing (49,50), but a direct comparison with [18F]-FMISO or human data are yet not available The iodine-124 labeled iodoazomycin galactoside ([124I]-IAZG) shows promise as a tumor hypoxia marker in preclinical testing (51) Because of its long physical half-life, the compound allows for imaging at very late time points (24 to 48 hours) In fact, tumor-to-background ratios were generally higher (factor 1.5 to 2) as compared to [18F]-FMISO at hours postinjection Very late time point imaging, however, may be compromised by deiodination as well as potential loss of initially bound radioactivity from hypoxic tissues Recently, [18F]-fluoro-azomycin arabinoside ([18F]-FAZA) had been evaluated in several rodent tumor models Like the iodinated parent compound,iodoazomycin arabinoside (IAZA) (52),it displayed rapid clearance from the blood and nontarget tissues, yielding more favorable tumor-to-background ratios hours postinjection as compared to [18F]-FMISO (factor 1.9 to 2.2) (53) [18F]-FAZA displays a lower octanol/water partition coefficient (log P ϭ 1.1), indicating the potential for both rapid diffusion through tissue and faster renal excretion (54) Moreover, the arabinosyl-N1-a-glycosidic bond displays enhanced in vivo stability against enzymatic cleavage The first clinical results in 11 head and neck cancer patients have been encouraging (55) Copper Complexes The development of newer radiopharmaceuticals involving copper isotopes has been pursued due to the relatively simple chemistry as well as an array of radiopharmaceuticals that are suitable for both imaging and radiotherapy of cancer Several copper isotopes ([60Cu], [61Cu], [62Cu], and [64Cu]) with different physical half-lives (between 0.4 and 12.7 hours) are positron emitters and are applicable for PET imaging Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a Cu-labeled dithiosemicarbazone that has been shown to be selectively retained in hypoxic tissues Cu-ATSM can be rapidly and quantitatively produced in high yields The uptake mechanism is less well understood than that of the nitroimidazoles Cu-ATSM retention is dependent on the inherent redox properties of the complex and uses reduction as the major trapping mechanism It was proposed that the selectivity of Cu-ATSM for hypoxic tissue is due in part to its redox potential of Ϫ293 mV, which enables more CuATSM to be reduced in hypoxic cells compared to normoxic cells (56) A similar compound Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) has been developed as a blood flow tracer for PET imaging in animals and humans (57) Cu-ATSM was shown to have an oxygenation-dependent retention mechanism in an isolated perfused rat heart model that varied the oxygen concentration in the perfusate (58) In subsequent experiments in canine models, the Cu-ATSM retention was found to be independent of blood flow, allowing the delineation of LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 467 Aptara Inc Chapter 8.24 • Hypoxia Imaging hypoxia in clinically relevant acute coronary syndromes and for demand-induced ischemia (59) In solid tumor models, the CuATSM uptake was found to correlate with the tpO2, which further strengthened the role of Cu-ATSM as an in vivo hypoxia marker (60) These studies involving oxygen electrode measurements, PET imaging, and autoradiography were the basis for subsequent testing of this compound in human cancers In comparison to [18F]-FMISO, Cu-ATSM exhibits higher uptake ratios between hypoxic and normoxic tissues (61) A particular advantage is the rapid kinetics of Cu-ATSM, which allows the identification of hypoxic tissue within 10 to 15 minutes postinjection using quantitative and semiquantitative approaches (62) This hypoxia marker is an attractive alternative to nitroimidazole-based compounds More recent studies of the Cu-ATSM kinetics in experimental tumors have uncovered more differentiated uptake kinetics O’Donoghue et al (63) investigated Cu-ATSM in comparison with [18F]-FMISO, using oxygen electrode measurements and immunofluorescence microscopy with pimonidazole The 24-hour postinjection Cu-ATSM uptake correlated well with the [18F]-FMISO uptake as assessed by autoradiography as well as with oxygen electrode measurements and pimonidazole stains However, early CuATSM imaging did not correlate with direct tissue assays nor with [18F]-FMISO imaging, indicating more complex kinetics than previously thought Yuan et al (64) found intertumoral differences in the hypoxia selectivity of Cu-ATSM that challenged the use of CuATSM as a universal PET hypoxia marker Newer semicarbazone complexes are currently being investigated McQuade et al (65) identified Cu-64-diacetyl.bis(N4ethylthiosemicarbazone) (Cu-ATSE) as being most promising with improved hypoxia selectivity and most suitable in vivo properties for hypoxia imaging compared to Cu-ATSM Cu-ATSM has also been used to study ischemic heart disease in experimental settings The principal advantage of hypoxia imaging in ischemic heart disease compared to the current approach of separate stress and rest imaging would be the potential necessity of only one imaging study Fujibayashi et al (58) used Cu-ATSM to visualize hypoxic rat heart tissue in a model of an acute occluded left anterior descending coronary artery Their results indicated that Cu-ATSM would be useful for the detection of hypoxia within minutes after tracer injection Using canine models of hypoxic myocardium, Lewis et al (59) reported on Cu-ATSM PET for the delineation of ischemic and hypoxic myocardium Using protocols of clinically relevant acute coronary syndromes and demand-induced ischemia, they demonstrated that Cu-ATSM was able to delineate hypoxic myocardium Although the direct visualization of hypoxic myocardium has great potential, it likely faces limitations in the clinical environment where the immediate availability of imaging is a requirement Several pathophysiological circumstances such as myocardial infarction, reperfusion following successful therapeutic intervention, hibernation, and stunning may complicate the interpretation of hypoxia imaging Further clinical studies are required to fully assess the potential of this promising imaging approach APPLICATIONS OF HYPOXIA IMAGING IN ONCOLOGY Since tumor tissue hypoxia is associated with poor response to treatment, the identification of tumor hypoxia holds great potential for a pretreatment prediction of the therapeutic outcome Recent studies have demonstrated this potential by identifying hypoxia as 467 an adverse prognostic factor for radiation treatment in several types of cancer Dehdashti et al (62) investigated a small group of patients with cervical cancers and found that the tumor uptake of Cu-ATSM was inversely related to progression-free survival and overall survival An arbitrarily selected tumor-to-muscle ratio discriminated tumors likely to develop recurrence In a second study involving 14 patients with non–small cell lung cancer, low pretreatment tumor uptake of Cu-ATSM was predictive for response to therapy, while FDG PET imaging results were not correlated with outcome measures (66) Rajendran et al (67) investigated the changes in [18F]-FMISO and fluorine-18-fluoro-2-deoxy-D-glucose ([18F]-FDG) uptake over the time course of neoadjuvant chemotherapy in a small group of patients with soft tissue sarcomas Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy However, there was a discrepancy between intratumoral [18F]-FDG and [18F]-FMISO uptake, indicating that regional hypoxia and glucose metabolism not necessarily correlate Similarly, they did not find any relationship between the hypoxic volume and vascular endothelial growth factor expression as an indicator for tumor angiogenesis In a study involving 40 patients with advanced head and neck (n ϭ 26) or non–small cell lung cancer (n ϭ 14), Eschmann et al (68) investigated the predictive value of [18F]-FMISO prior to radiotherapy with curative intent All patients with a FMISO tumorto-muscle ratio greater than 2.0 in non–small cell lung cancer and greater than 1.6 in head and neck cancer presented with tumor recurrence, further supporting the negative predictive value of significant hypoxia prior to radiation treatment Fig 8.24.2 shows the [18F]-FDG and [18F]-FMISO uptake of a large squamous cell cancer of the right lung and displays partial discordance between glucose consumption and tissue hypoxia Hypoxic but viable cells up-regulate glycolysis to maintain cellular energy production because adenosine triphosphate can be produced from glucose without requiring molecular oxygen In acute hypoxia, glycolysis can be increased as much as twofold, which was found to be associated with increased expression or modified forms of glucose transporters (GLUT1 and GLUT3) and increased levels and mitochondrial redistribution of hexokinase (69) Thus, hypoxia significantly contributes to the [18F]-FDG uptake, but [18F]-FDG is not generally considered a surrogate marker of tissue hypoxia as its uptake is dependent on a wide variety of factors One potential way to overcome resistance to radiation treatment would be to maximize the radiation dose to the hypoxic subfraction of malignancies Intensity-modulated radiation therapy (IMRT) allows selective targeting of tumor and improved sparing of normal surrounding tissues In a feasibility study, Chao et al (70) proposed hypoxia-guided IMRT using Cu-ATSM and investigated in a single case of head and neck cancer the ability to deliver a higher dose of radiation to the hypoxic tumor subvolume The plan delivered 80 Gy to the ATSM-avid tumor subvolume, while the remainder of the tumor received 70 Gy in 35 fractions without increasing the recommended doses to nearby critical organs (salivary glands) Fig 8.24.3 displays the simulation of hypoxia-directed IMRT using [18F]-FAZA in a patient with untreated floor of the mouth squamous cell cancer Tumor tissue hypoxia was arbitrarily defined as a tumor-to-muscle ratio of 1.5 or above Treatment simulation resulted in a moderate increase of the radiation dose to the “hypoxic” subvolume, while the remainder of the tumor volume received 95% of the typically prescribed dose As expected, hypoxia LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 468 Aptara Inc 468 Principles and Practice of PET and PET/CT FIGURE 8.24.2 Transaxial images of a primary squamous cell cancer of the right upper lobe of the lung A: 2-fluorine-18-fluoro-2-deoxy-D-glucose PET and (B) PET/CT fusion images obtained on a Siemens Biograph 16 (Malvern, Pennsylvania) high resolution scanner displaying a large tumor mass with central necrosis and inhomogeneous hypermetabolism in the periphery as well as two hypermetabolic mediastinal lymph node metastases (red arrows) C,D: Fluorine-18 labeled fluoromisonidazole (1-(2-nitroimidazolyl)-2-hydroxy3-fluoropropane) ([18F]-FMISO) PET images of the mass obtained from a GE Healthcare Advance (Uppsala, Sweden) PET scanner The maximum [18F]-FMISO uptake is at the lateral and anterior aspect of the tumor mass, while the remainder of the primary tumor, and especially the lymph node metastases, not show significant [18F]-FMISO uptake, indicating that glucose metabolism and hypoxia are not necessarily correlated (Courtesy of M Eschmann, PET Center Tuebingen, Germany.) A, B C, D tracers such as Cu-ATSM and [18F]-FAZA display heterogeneous uptake in tumor tissues This raises concerns regarding the stability of the hypoxic signal as it may change during the time course of radiation treatment If IMRT is used to enhance the radiation dose to the hypoxic subvolume, such behavior might necessitate in-treatment changes to the radiation plan Although the general concept of hypoxia-guided IMRT may be appealing, it remains to be established whether a moderate increase in the delivered radiation dose to the hypoxic tumor volume improves local control or overall outcome after radiation treatment Although tumor hypoxia is a negative prognostic factor, it also constitutes a major difference between tumor and normal tissues It, therefore, represents an opportunity for therapeutic exploitation Bioreductive drugs or hypoxia-selective cytotoxins such as tirapazamine (TPZ) are inactive prodrugs that are favorably activated by A, B reductive enzymes only in the hypoxic environment of tumors (71,72) Upon activation, they release toxic metabolites that can cause cell damage and death by various mechanisms Beck et al (73) investigated the effect of radiation, TPZ, and combined radiochemotherapy on murine breast cancers and compared the results with the pretreatment [18F]-FAZA uptake Radiochemotherapy involving TPZ displayed a synergistic effect in hypoxic, but not in well-oxygenated tumors Hicks at al (74) investigated the effect of radiochemotherapy with TPZ in a small group of patients with advanced head and neck cancers that had been found to be positive on [18F]-FMISO PET imaging These investigators have also compared the [18F]-FMISO and [18F]-FAZA uptake in a series of patients with head and neck cancer (personal communication) Fig 8.24.4 shows the superior tumor to background ratio that can be obtained with [18F]-FAZA C FIGURE 8.24.3 Transaxial realigned images of a left-sided floor of the mouth squamous cell cancer prior to primary radiochemotherapy A: PET image obtained hours after injection of 10.8 mCi of [18F]fluoro-azomycin arabinoside displaying inhomogeneous tracer distribution Individual regions of interest (ROI, orange lines) are defined in tumor areas exceeding an arbitrary threshold of 1.5 above muscle activity B: The radiation planning CT loaded into the planning software with ROIs defining the gross tumor volume (GTV, pink line) as well as the “hypoxic” subvolume (orange lines) of the primary tumor C: Treatment planning using IMRT (intensity-modulated radiation therapy) resulted in an increase of the radiation dose to the “hypoxic” subvolume to 113% of the typically prescribed single dose of Gy The remainder of the tumor volume received 95% of the prescribed dose, keeping the total radiation dose to the tumor tissue unchanged while reducing the radiation dose to the normal tissue (Courtesy of A L Grosu [radiation oncology] and M Souvatzoglou [nuclear medicine], Technical University of Munich, Germany.) LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 469 Aptara Inc Chapter 8.24 • Hypoxia Imaging [18F]FDG FIGURE 8.24.4 Transaxial (T), sagittal (S), and coronal (C) images of an oropharyngeal squamous cell cancer at primary diagnosis 2-fluorine-18-fluoro-2deoxy-D-glucose ([18F]-FDG) PET shows an extensive hypermetabolic mass in comparison with hypoxia imaging performed with [18F]-fluoro-azomycin arabinoside ([18F]-FAZA) and [18F]-fluoromisonidazole ([18F]-FMISO) [18F]-FAZA results in more favorable tumor-to-background image contrast compared to [18F]-FMISO [18F]-FDG and [18F]-FAZA PET imaging were performed within 24 hours, while the [18F]FMISO scan was performed days after the [18F]-FAZA scan Hypoxia scans were started hours postinjection of 5.8 mCi [18F]-FAZA and 6.6 mCi [18F]-FMISO using three-dimensional imaging This image indicates the two hypoxia agents are not equivalent to each other (Courtesy of R Hicks, Melbourne, Australia.) [18F]FAZA 469 [18F]FMISO T S C Evidence of the early resolution of [18F]-FMISO abnormalities during treatment, associated with excellent locoregional control in this patient cohort, supports further investigation of hypoxia-targeting agents in advanced head and neck cancer Based on these results, hypoxia imaging should be further investigated regarding the capability of guiding targeted chemotherapy using hypoxia-selective cytotoxins In summary, hypoxia imaging using PET can be recommended for further preclinical and clinical testing to identify tumor hypoxia in order to improve therapeutic strategies to either specifically target the hypoxic subvolume of tumors (via IMRT) or by taking advantage of the intratumoral lack of oxygen to apply hypoxiadirected chemotherapies The optimal agent for hypoxia imaging remains under study, but this area of research is one with great potential for altering patient therapies 10 11 12 13 14 REFERENCES Vanderkooi JM, Erecinska M, Silver IA Oxygen in mammalian tissue: methods of measurement and affinities of various reactions Am J Physiol 1991;260:C1131–1150 Semenza GL, Wang GL A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation Mol Cell Biol 1992; 12:5447–5454 Wang GL, Semenza GL Characterization of hypoxia-inducible factor and regulation of DNA binding activity by hypoxia J Biol Chem 1993; 268:21513–21518 Wang GL, Semenza GL Purification and characterization of hypoxiainducible factor J Biol Chem 1995;270:1230–1237 Tian H, McKnight SL, Russell DW Endothelial PAS domain protein (EPAS1), a transcription factor selectively expressed in endothelial cells Genes Dev 1997;11:72–82 Ema M, Taya S, Yokotani N, et al A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the 15 16 17 18 19 20 21 22 VEGF expression and is potentially involved in lung and vascular development Proc Natl Acad Sci U S A 1997;94:4273–4278 Makino Y, Cao R, Svensson K, et al Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression Nature 2001;414: 550–554 Semenza GL Targeting HIF-1 for cancer therapy Nat Rev Cancer 2003; 3:721–732 Kaelin WG Proline hydroxylation and gene expression Annu Rev Biochem 2005;74:115–128 Semenza GL Hypoxia-inducible factor and the molecular physiology of oxygen homeostasis J Lab Clin Med 1998;131:207–214 Carmeliet P, Jain RK Angiogenesis in cancer and other diseases Nature 2000;407:249–257 Hockel M, Vaupel P Biological consequences of tumor hypoxia Semin Oncol 2001;28:36–41 Mekhail K, Khacho M, Gunaratnam L, et al Oxygen sensing by Hϩ: implications for HIF and hypoxic cell memory Cell Cycle 2004;3: 1027–1029 Semenza GL HIF-1 and tumor progression: pathophysiology and therapeutics Trends Mol Med 2002;8:S62–S67 Depre C, Kim SJ, John AS, et al Program of cell survival underlying human and experimental hibernating myocardium Circ Res 2004;95: 433–440 Sinusas AJ The potential for myocardial imaging with hypoxia markers Semin Nucl Med 1999;29:330–338 Teicher BA Angiogenesis and cancer metastases: therapeutic approaches Crit Rev Oncol Hematol 1995;20:9–39 Hockel M, Schlenger K, Aral B, et al Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix Cancer Res 1996;56:4509–4515 Brizel DM, Dodge RK, Clough RW, et al Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome Radiother Oncol 1999;53:113–117 Vaupel P, Thews O, Hoeckel M Treatment resistance of solid tumors: role of hypoxia and anemia Med Oncol 2001;18:243–259 Holland, F Cancer Med 2003;6 http://www.ncbi.nlm.nih.gov/books/ bv.fcgi?rid=cmed6.chapter.9197 Harrison L, Blackwell K Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? 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radiotherapy response in head-and-neck cancer Int J Radiat Oncol Biol Phys 2004;59:971–982 48 Gronroos T, Bentzen L, Marjamaki P, et al Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma Eur J Nucl Med Mol Imaging 2004;31:513–520 49 Mahy P, De Bast M, Leveque PH, et al Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide [(18)F]EF3 Eur J Nucl Med Mol Imaging 2004;31: 1263–1272 50 Ziemer LS, Evans SM, Kachur AV, et al Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5 Eur J Nucl Med Mol Imaging 2003;30:259–266 51 Zanzonico P, O’Donoghue J, Chapman JD, et al Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning Eur J Nucl Med Mol Imaging 2004;31:117–128 52 Mannan RH, Somayaji VV, Lee J, et al Radioiodinated 1-(5-iodo-5deoxy-beta-D-arabinofuranosyl)-2-nitroimidazole (iodoazomycin arabinoside: IAZA): a novel marker of tissue hypoxia J Nucl Med 1991;32: 1764–1770 53 Piert M, Machulla H-J, Picchio M, et al Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside J Nucl Med 2005;46:106–113 54 Kumar P, Stypinski D, Xia H, et al Fluoroazomycin arabinoside (FAZA): synthesis, 2H and 3H-labelling and preliminary biological evaluation of a novel 2-nitroimidazole marker of tissue hypoxia J Label Comp Radiopharm 1999;42:3–16 55 Souvatzoglou M, Grosu A, Roeper B, et al Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study Eur J Nucl Med 2007;34:1566–1575 56 Dearling JL, Lewis JS, Mullen GE, et al Copper bis(thiosemicarbazone) complexes as hypoxia imaging agents: structure-activity relationships J Biol Inorg Chem 2002;7:249–259 57 Green MA, Mathias CJ, Welch MJ, et al Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II): synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion J Nucl Med 1990;31:1989–1996 58 Fujibayashi Y, Cutler CS, Anderson CJ, et al Comparative studies of Cu64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats Nucl Med Biol 1999;26:117–121 59 Lewis JS, Herrero P, Sharp TL, et al Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) J Nucl Med 2002;43:1557–1569 60 Lewis JS, Sharp TL, Laforest R, et al Tumor uptake of copper-diacetyl-bis (N4-methylthiosemicarbazone): effect of changes in tissue oxygenation J Nucl Med 2001;42:655–661 61 Lewis JS, McCarthy DW, McCarthy TJ, et al Evaluation of 64-Cu-ATSM in vitro and in vivo in a hypoxic tumor model J Nucl Med 1999;40: 177–183 62 Dehdashti F, Grigsby PW, Mintun MA, et al Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response—a preliminary report Int J Radiat Oncol Biol Phys 2003;55:1233–1238 63 O’Donoghue JA, Zanzonico P, Pugachev A, et al Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64-Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) positron emission tomography: comparative study featuring microPET imaging, pO2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models Int J Radiat Oncol Biol Phys 2005;61: 1493–1502 64 Yuan H, Schroeder T, Bowsher JE, et al Intertumoral differences in hypoxia selectivity of the PET imaging agent 64-Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) J Nucl Med 2006;47:989–998 65 McQuade P, Miao Y, Yoo J, et al Imaging of melanoma using 64-Cuand 86Y-DOTA-ReCCMSH(Arg11), a cyclized peptide analogue of alpha-MSH J Med Chem 2005;48:2985–2992 LWBK053-3787G-8.24[464-471].qxd 14-08-2008 05:08 PM Page 471 Aptara Inc Chapter 8.24 • Hypoxia Imaging 66 Dehdashti F, Mintun MA, Lewis JS, et al In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM Eur J Nucl Med Mol Imaging 2003;30:844–850 67 Rajendran JG, Wilson DC, Conrad EU, et al [(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression Eur J Nucl Med Mol Imaging 2003;30:695–704 68 Eschmann SM, Paulsen F, Reimold M, et al Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non–small cell lung cancer and head and neck cancer before radiotherapy J Nucl Med 2005; 46:253–260 69 Burgman P, Odonoghue JA, Humm JL, et al Hypoxia-induced increase in FDG uptake in MCF7 cells J Nucl Med 2001;42:170–175 471 70 Chao KS, Bosch WR, Mutic S, et al A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy Int J Radiat Oncol Biol Phys 2001;49:1171–1182 71 Stratford IJ, Workman P Bioreductive drugs into the next millennium Anticancer Drug Des 1998;13:519–528 72 Denny WA Prodrug strategies in cancer therapy Eur J Med Chem 2001; 36:577–595 73 Beck R, Röper B, Carlsen JM, et al Pretreatment [18F]FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine J Nucl Med 2007;48:973–9800 74 Hicks RJ, Rischin D, Fisher R, et al Utility of FMISO PET in advanced head and neck cancer treated with chemoradiation incorporating a hypoxia-targeting chemotherapy agent Eur J Nucl Med Mol Imaging 2005;32:1384–1391 LWBK053-3787G-8.25[472-478].qxd 14-08-2008 05:09 PM Page 472 Aptara Inc CHAPTER 8.25 Newer Tracers for Cancer Imaging RODNEY J HICKS MOST SUITABLE RADIONUCLIDE FOR NEW CANCER IMAGING TRACERS SUBSTRATE METABOLITES THAT ADDRESS RECOGNIZED LIMITATIONS OF FLUORODEOXYGLUCOSE EVALUATION OF BIOLOGICAL PROCESSES MORE SPECIFIC TO CANCER A lthough positron emission tomography (PET) has been recognized to have unique capabilities for the evaluation of neurological and cardiac diseases, the recent growth in clinical PET has been largely driven by its multiple roles in oncology This clinical growth has been based almost exclusively on a single tracer, fluorine-18-fluoro-2-deoxy-D-glucose (FDG) As detailed elsewhere in this book, FDG performs admirably in a wide range of malignancies However, despite its excellent diagnostic performance, it has recognized limitations Broadly, these relate to the nonspecificity of glucose metabolic changes for cancer, lack of contrast between physiological and pathological uptake, and low FDG avidity of some cancer types, which limit to varying extent the accuracy of FDG PET in some cancers Although pattern recognition, knowledge of typical locations and routes of spread of metastases, and clinical judgment based on all historical and clinical data play important roles in differentiating inflammatory from malignant processes (1), biopsy may be necessary to characterize FDG PET abnormalities definitively Even when cancer is known to be present, high uptake in adjacent tissues due to physiological processes can reduce lesion contrast and thereby impair the sensitivity of FDG PET for the detection of disease This is particularly evident in the brain where high glucose use by the normal cerebral cortex can mask the presence of brain tumors (2) Similarly, high background normal organ FDG accumulation can also adversely affect test performance in the liver, bowel, stomach, kidneys, genitourinary system, and in areas of brown fat distribution Low FDG avidity can also occur with certain tumors, including some adenocarcinomas of the lung, breast, and prostate, reducing contrast and thereby reducing sensitivity Despite these considerations, the diagnostic accuracy of FDG in cancer is so good in most clinical situations (3) that there is little incentive to develop new oncologic tracers These new tracers would first have to match FDG and then be demonstrated to improve on this already high sensitivity and specificity, particularly if proposed to be a replacement for FDG as the workhorse agent for cancer imaging However, the new tracers in development have the potential to combat the limitations of FDG and establish new applications for PET More probably, such agents will fill important gaps where FDG’s performance is substantially deficient 472 FUTURE DIRECTIONS IMPACT OF NEW PET TRACERS ON THE PRACTICE OF ONCOLOGICAL NUCLEAR MEDICINE CONCLUSION In an era when molecular profiling is identifying specific and mechanistically important genomic and proteomic alterations in diseased cells, a logical progression of PET tracer development is to go beyond the probing of basic substrate metabolism, which is simply an indicator of the extent of viable tumor cells The trend is toward evaluation of more specific features of cancer biology including proliferation and receptor expression (4) Many conventional nuclear medicine procedures are now performed in the oncology setting that could be replaced with PET tracers and provide superior spatial resolution and contrast, greater convenience, and lower radiation burden MOST SUITABLE RADIONUCLIDE FOR NEW CANCER IMAGING TRACERS One of the great theoretical strengths of PET is the availability of a wide range of cyclotron and generator produced radionuclides with varying physical and chemical characteristics (5) Of these, carbon11 ([11C]), has the greatest flexibility for labeling biological compounds, and it does not perturb the biological behavior of the chemical However, the short physical half-life of this radionuclide poses significant logistical problems in the clinical setting Carbon-11 requires rapid synthesis and quality assurance processes to allow administration of adequate quantities for human imaging It also significantly constrains the number of patients that can be imaged from each synthetic run, thereby increasing the cost per unit dose Also important is whether the short half-life of [11C] is best suited to the kinetics of the biological process that is to be addressed Slower biological processes may not be appropriate for [11C] imaging Fluorine-18 ([18F]), on the other hand, has an adequate half-life to allow both synthesis and distribution of PET radiotracers, even to sites remote from a cyclotron, but is also sufficiently short to allow relatively low radiation dosimetry The half-life of 109 minutes is well matched to many physiological processes Medical cyclotrons involved in the production of FDG routinely produce [18F]-fluoride, and increasing experience with fluorination chemistry enables an ever-wider range of PET tracers to be produced The low positron energy of [18F] provides high-quality images with modern LWBK053-3787G-8.25[472-478].qxd 14-08-2008 05:09 PM Page 473 Aptara Inc Chapter 8.25 • Newer Tracers for Cancer Imaging 473 PET scanners Based on these factors, the authors, and others, have focused on evaluating fluorinated PET tracers in oncology applications Generator-produced radionuclides such as gallium-68 may also have a role for facilities remote from a cyclotron (5), particularly for receptor imaging through chelation to peptides (6) Other longlived radionuclides may have particular advantages in tracing biological processes with slow kinetics An example of this is the use of iodine-124 to evaluate the localization of monoclonal antibodies in tumors (7) SUBSTRATE METABOLITES THAT ADDRESS RECOGNIZED LIMITATIONS OF FLUORODEOXYGLUCOSE PET metabolic imaging has traditionally focused on tracers of cellular substrate metabolism, especially FDG in oncology Extending this paradigm, multiple radiolabeled amino acids suitable for PET imaging have been developed (8) Up-regulation of amino acid transport and enhanced protein synthesis is a hallmark of cancer Amino acids are taken up much less avidly in inflammatory lesions, or by the brain, compared to FDG PET imaging of amino acid analogues has been seen as a means to address the limitations of FDG with respect to both specificity for cancer and for sensitivity of lesion detection in the brain where high background uptake can mask tumoral radiotracer accumulation Carbon-11-L-methionine has been shown to have a sensitivity similar to FDG for detection of various nonbrain cancers, including head and neck and lung cancers Its specificity is somewhat higher due to a reduced tendency to accumulate in inflammatory lesions Carbon-11-L-methionine is one of the few radiopharmaceuticals to compete favorably with FDG in terms of diagnostic accuracy in cancer (9) It is also significantly more sensitive than FDG PET for brain tumors including glioma (10) It is clearly superior to FDG when lesions have lower or similar uptake of FDG compared to normal brain (2) Unfortunately, as discussed above, the short physical half-life of [11C] makes this an impractical tracer for routine clinical applications Consequently, there has been a global effort to develop fluorinated amino acids for oncology imaging One of the most promising of these is [18F]-fluoroethyl-L-tyrosine (FET), which was developed as an alternative cancer-imaging agent (11) and was shown to have similar characteristics to [11C]-L-methionine in comparative studies (12) However, FET has the practical advantages of using [18F] as the imaging radionuclide Since this agent demonstrates very low uptake in the normal brain and relatively high uptake in brain tumors (12,13), it provides a more sensitive detection of disease and better characterization of the extent of tumor involvement than does FDG (Fig 8.25.1) Although the specificity of FET for ring-enhancing lesions of the brain is superior to that of FDG, it remains imperfect and necessitates biopsy of positive lesions (14) The experience with this agent suggests reasonable uptake in squamous cell carcinomas of the head and neck (15), but the sensitivity for other extra-cranial malignancies has been disappointing (16) (Fig 8.25.2) Other fluorinated amino acids are also currently in development (17–19) Unless the sensitivity of these tracers can be demonstrated to be comparable to FDG, the higher specificity may not be an advantage since it may falsely reassure clinicians that a negative FIGURE 8.25.1 A comparison of fluorodeoxyglucose (FDG) (upper row) and fluorine-18-fluoroethyl-L-tyrosine (FET) (lower row) uptake in a glioblastoma multiforme demonstrates much higher contrast between tumor and normal brain tissue with FET despite a lower measured standard uptake value This enables greater sensitivity for detection of tumor and particularly for defining the extent of tumor for surgical and radiotherapy planning result in patients with a positive FDG PET scan is indicative of inflammation rather than malignancy It may also be advantageous to have radiolabeled amino acids for patients who have poor glucose control and for low-grade brain tumors Thus, there may be a niche for such agents, even if they not generally replace FDG in FIGURE 8.25.2 A comparison of fused PET/CT images (upper row) of fluorodeoxyglucose (FDG) and fluorine-18-fluoroethyl-L-tyrosine (FET) uptake in a primary squamous cell carcinoma of the lung demonstrates substantially higher contrast with FDG and, therefore, despite theoretically higher specificity for malignancy, the lower sensitivity of FET decreases confidence in the veracity of a negative result Prominent FDG uptake at the site of recent laser surgery in the larynx (arrow) demonstrates no significant FET uptake (lower row), consistent with the lower uptake of FET than of FDG in regions of inflammation LWBK053-3787G-8.25[472-478].qxd 14-08-2008 05:09 PM Page 474 Aptara Inc 474 Principles and Practice of PET and PET/CT all applications Recently, nonmetabolizable amino acid tracers have been fluorinated and applied to human imaging, an area of considerable interest and promise Increased sterol synthesis is another potential cancer-imaging target based on substrate metabolism Tumor tissues have a requirement for increased synthesis of phosphatidylcholine, an important constituent of cell membranes Increased rates of transmembrane transport and subsequent phosphorylation of choline by the enzyme choline kinase in tumors have been demonstrated Carbon-11-choline (20) has been used to successfully image a variety of tumors, including prostate cancer, brain tumors, esophageal cancer, and lung cancer, but because of the short halflife of [11C] (20 minutes), fluorinated analogues are potentially more suitable for clinical studies Fluorine-18 fluoromethyldimethyl-2-hydroxyethyl-ammonium or fluorocholine (FCH) is one such tracer Preliminary studies suggested that FCH might be more sensitive than FDG for detection of nodal and bone metastases in prostate cancer (21) Subsequent studies in staging and restaging of patients with prostate cancer are continuing to define the potential clinical role of this tracer (22–27) The authors’ experience suggests that FCH is more sensitive than FDG PET for detecting sites of relapse in patients with rising prostate-specific antigen levels (Fig 8.25.3) High uptake in the liver and kidneys is a limitation of this tracer in detecting primary or secondary lesions in these organs This is not a major limitation for prostate cancer, which seldom spreads to these organs, but it is for breast cancer, which commonly does (Fig 8.25.4) A discussion of the use of [11C] and [18F]-choline analogues in genitourinary cancer imaging, especially prostate cancer, is present in Chapter 8.18 of this book Since FDG avidity of breast cancer is variable, FCH may have a role when there is a strong clinical suspicion of recurrence but a neg- FIGURE 8.25.3 Low fluorodeoxyglucose (FDG) avidity is a recognized feature of some adenocarcinomas, particularly prostate cancer In this patient with rising prostate-specific antigen levels, [18F]-fluorocholine (FCH) PET (top left) demonstrated extensive uptake in nonenlarged para-aortic and left supraclavicular lymph nodes (small arrows on maximum intensity projection [MIP] image) (top right) that were negative on FDG PET (bottom left) A positive right inguinal node on FDG PET (large arrow, bottom right) was negative on FCH PET, consistent with a reactive node FIGURE 8.25.4 Breast cancers can show variable fluorodeoxyglucose (FDG) avidity but are generally well visualized on FDG PET Physiological brown fat can be problematic for identifying axillary and supraclavicular nodal involvement In this patient, the lack of [18F]-fluorocholine (FCH) uptake in brown fat made identification of a left supraclavicular nodal metastasis much easier (top right) than on the corresponding FDG image (top left) However, high uptake of FCH in the liver decreased contrast and therefore detectability of a hepatic metastasis (bottom left) ative or equivocal FDG PET study Despite the high uptake of FCH in the liver, preliminary results suggest that FCH may also be a useful imaging agent for hepatocellular carcinoma (28), which has variable FDG avidity As with amino acid analogues, FCH is not taken up significantly in the normal brain, and preliminary studies suggest that this agent might also be useful for brain tumor imaging (29) [11C]-acetate is another substrate metabolite that has been used for cancer imaging (30–33), with potential application in urological malignancies A fluorinated analogue of this compound, [18F]-fluoroacetate has also been shown to have uptake in prostate cancer (34) These agents are also discussed in Chapter 8.18 as related to genitourinary cancer imaging Because most normal cells have some degree of versatility in their substrate metabolism, all the above tracers are, to some extent, nonspecific for cancer and measure processes that are well downstream from the key genetic mechanisms responsible for cancer An appropriate objective of PET tracer development has been to design and validate tracers that are more specific and enhance the rapidly advancing knowledge regarding the molecular biology of cancer cells EVALUATION OF BIOLOGICAL PROCESSES MORE SPECIFIC TO CANCER The discovery of oncogenes initially led to an overly simplistic view that cancer was caused by mutations in key individual genes It is now apparent that there are many genes that are involved in the LWBK053-3787G-8.25[472-478].qxd 14-08-2008 05:09 PM Page 475 Aptara Inc Chapter 8.25 • Newer Tracers for Cancer Imaging development, survival, progression, and metastases of cancer cells (35) This diversity of genomic abnormality and the interaction between tumor cells and host stromal cells accounts for the variability in the clinical behavior of cancers that by standard histopathological appearances may appear to be the same Increasingly, advances in molecular profiling are beginning to provide information regarding the natural history of cancers of any given histology For example, microarray analyses of breast cancer are providing prognostic insights and have the potential to suggest new treatment approaches (36) Although metastasis is clearly an adverse event in the natural history of any individual cancer, there are many patients with metastatic disease who may still be able to have a relatively long survival Other patients presenting with relatively small primaries and no evidence of metastatic disease may rapidly succumb to their diseases The prototypical examples of this are carcinoma of the breast and prostate For both malignancies, metastatic bone disease may be an indolent process that is well controlled by relatively innocuous therapies including hormone manipulation and bisphosphonates In other, generally younger, individuals, the progress from diagnosis of an apparently localized primary to death may be rapid and inexorable despite aggressive therapies including toxic chemotherapeutic combinations Although standard pathological parameters like mitotic rate, cellular differentiation, and hormone receptor expression provide useful prognostic information, it is likely in the future that molecular profiling techniques, such a gene microarrays and serum proteomics, will provide a much more robust prediction of the cancers that will be “bad players.” Inter- and intralesional heterogeneity related to genomic instability and microenvironmental factors will often limit the ability to extrapolate from a tiny pathological sample obtained at one point during the evolution of a cancer to a reliable prediction of its progress at later time points in individual patients The ability to assay presumptive biological targets in vivo and on a whole-body basis is likely to provide unique complementary information This is the intellectual rationale underpinning the current concept of molecular imaging and its application to molecular medicine Several of the key genes involved in cancer transformation lead to unrestrained proliferation This is one of the hallmarks of cancer and therefore is a target of several anticancer therapeutics The cellular uptake of thymidine provides evaluation of DNA synthesis, which is essential for up-regulated cellular proliferation DNA synthesis is regulated by thymidine kinase (TK-1) activity This enzyme increases more than tenfold during the DNA synthetic (S) phase of the cell cycle Radiolabeled thymidine analogues that are substrates for TK-1 show significant potential as PET imaging agents for this important process There has been a strong motivation to develop PET tracers of DNA synthesis Initial studies with [11C]-thymidine encouraged development of related fluorinated compounds, however, [11C] agents are quite limited by their half-lives to centers with or (near) cyclotrons Of these, the most promising currently is [18F]-fluorothymidine (FLT) Although this compound is not incorporated into DNA, a theoretical advantage in relation to potential mutagenic risk, it is a substrate for TK-1 that undergoes phosphorylation and is trapped in cells Its accumulation has been shown to closely correlate with tumor proliferation in a variety of situations (37–40) As with amino acid analogues, the lack of significant FLT uptake in the brain has encouraged evaluation of its role for brain tumor imaging, and the results have been encouraging (Fig 8.25.5), particularly with respect to grading of primary brain lesions (41) 475 FIGURE 8.25.5 [18F]-fluorothymidine (FLT) is a useful tracer of cellular proliferation There is normal visualization of proliferating hematopoietic marrow and of crypt cells in the small bowel Uptake in the liver in humans reflects the metabolism of this tracer Physiologic uptake in these sites can mask metastases (bottom right) However, the lack of uptake in the brain facilitates detection of brain metastases In this patient with non–small lung cancer treated with radiotherapy, FLT PET demonstrates reduced bone marrow activity in the sternum and thoracic spine, consistent with the prior radiation portal The persisting uptake in the primary tumor indicates recurrent local disease FLT PET also led to incidental detection of several previously unknown brain metastases, including a subcentimeter cerebellar metastasis (Corresponding CT, top left, PET, top right, and fused PET/CT, bottom left) A somewhat lower sensitivity in whole-body tumor imaging may limit the theoretical advantages of higher specificity (42), as does the relatively high uptake of FLT in bone, liver, and bone marrow, important sites of metastatic involvement It has been noted that active germinal centers in reactive lymph nodes draining areas of inflammation can be positive on FLT scanning, limiting the specificity of nodal uptake in cases of cancer that also have an associated infective or inflammatory process Nevertheless, the authors believe that this agent will have a major role in the assessment of therapeutic response, particularly for therapies that have a primarily tumoristatic rather than tumoricidal activity As tumors grow, they require formation of new blood vessels to maintain an adequate oxygen supply Generally, this requires LWBK053-3787G-8.25[472-478].qxd 14-08-2008 05:09 PM Page 476 Aptara Inc 476 Principles and Practice of PET and PET/CT formation of new vessels in a process known as neovascularization In many tumors this process is not adequate to provide the nutrient needs of the tumor cells, which leads to hypoxia and eventually to necrosis Hypoxia is also known to be associated with a proliferation block, limiting the ability of tracers such as FLT to identify these cancer cell populations Hypoxia within tumors is associated with a poor prognosis in a variety of cancer types and is a major factor implicated in resistance to radiation and cytotoxic drugs (43) A number of therapeutic strategies to target or exploit hypoxia have been developed and include the hypoxic cytotoxin tirapazamine (44), and radiation dose painting (45,46), resulting in a need to accurately identify hypoxia within tumors Extensive efforts have been made to develop PET tracers to enable the noninvasive imaging of hypoxia [18F]-fluoromisonidazole (FMISO) is the most extensively studied agent in human cancers (44,47–51) FMISO is, however, a relatively lipophilic compound and demonstrates relatively low uptake in hypoxic tissue relative to normal tissue This is due to its slow clearance from normal tissues This necessitates delayed scanning and the consequential reduction in statistical image quality or the administration of a high dose of radioactivity This has led to the development of other hypoxic probes that have more favorable imaging properties Fluorine-18-fluoro-azomycin arabinoside (FAZA) is one such agent (52,53) Preliminary results have been obtained at the authors’ institution with the use of FAZA to image hypoxia within head and neck squamous cell carcinomas (Fig 8.25.6) The authors have also used FAZA in lung cancer, cervical cancer, and sarcoma These early results suggest that FAZA is likely to be a superior agent, compared to FMISO, for imaging hypoxia due to more rapid clearance of background soft tissues but similar tumoral uptake and thus to higher tumor to background contrast This should provide more reproducible definition of hypoxic subvolumes and greater diagnostic confidence, but further studies to validate its ability to provide important prognostic stratification are required Other fluorinated hypoxia tracers have also been developed are being evaluated clinically (54–56), as well as copper- FIGURE 8.25.6 Noninvasive imaging of hypoxia may have both prognostic and therapeutic planning implications High contrast between normal tissues and tumor is an advantage in localizing sites of disease The new hypoxia agent fluorine-18-fluoro-azomycin arabinoside (FAZA) has more rapid soft tissue clearance than [18F]-fluoromisonidazole (FMISO), and this generally leads to a higher tumor to background contrast Comparison of fluorodeoxyglucose (FDG) PET (top row) and FAZA (bottom row) distributions can potentially identify hypoxic subvolumes for dose painting using highly conformal radiotherapy Unlike FMISO, FAZA is not appreciably concentrated in the brain labeled agents such as Cu-ATSM [Cu-diacetyl-bis(N4-methylthiosemicarbazone)] (see Chapter 8.16) FUTURE DIRECTIONS Proliferation and hypoxia are generic biological processes that are more common in cancer cell populations than in normal cells, but there are many other potential biological targets for cancer imaging The list of these is long and increasing and is beyond the scope of this discussion It is, however, likely that new targeted cancer therapeutics will become available and demonstrate the presence of a target expression in an individual lesion and its modulation by the targeting therapy This will provide an increasingly important role in proof-of-mechanism studies and possibly in personalized treatment selection and dosing (57) The favorable imaging characteristics and ready availability of [18F] make it likely that there will be an increasing focus on fluorinated tracers, but a wide range of both cyclotron and generatorproduced isotopes will also become relevant for cancer imaging These include yttrium-86, gallium-68, and iodine-124 These tracers lend themselves to form complexes with biological macromolecules, such as peptides (6) and antibodies The availability of long-lived positron emitting radionuclides offers opportunities for translational research in the labeling of larger molecular species, including monoclonal antibodies, which can have slow accumulation in tissues (7,58) IMPACT OF NEW PET TRACERS ON THE PRACTICE OF ONCOLOGICAL NUCLEAR MEDICINE FDG PET has already had a significant impact on the use of traditional oncological tracers such as gallium-67-citrate in lymphoma and melanoma, thallium-201 in sarcoma, and technetium-99m (99mTc)-sestamibi in breast cancer New tracers provide new applications for which no equivalent single-photon emission computed tomography tracer is available and will potentially also replace existing tracers One such example is the replacement of indium-111octreotide for the localization of neuroendocrine malignancy by gallium-68-DOTATOC ([DOTA0,Tyr3]octreotide) (6) and iodine-131 and iodine-123 for thyroid cancer staging by iodine-124 (59) In absolute terms, bone scanning remains one of the most commonly performed nuclear medicine tests for oncological staging A long experience with [18F]-fluoride as a bone tracer dates back to the time of rectilinear scanners This tracer fell out of favor, not because of its performance as a tracer of bone metabolism, but because of suboptimal imaging characteristics with the gamma camera and, perhaps more importantly, due to the availability of 99mTc-based radiotracers for bone metastases (60,61) Recent experience suggests that [18F]fluoride bone scanning with modern combined PET and computed tomography (CT) scanners will result in superior characterization of bone lesions with both higher sensitivity and specificity than conventional bone scanning (27) CONCLUSION The development of new PET tracers for oncology is littered with failures, in part because of the great success of the 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LWBK053-3787G-C 01[ 01- 15].qxd 08 /15 /2008 01: 48 Page Aptara Inc Principles and Practice of PET and PET/ CT a nuclear transformation, it usually has a great deal of excess energy imparted from the... 08 /15 /2008 01: 48 Page Aptara Inc Principles and Practice of PET and PET/ CT FIGURE 1. 1 Formation and disintegration of the compound nucleus energy of the incident particle in the compound nucleus