Pediatr Blood Cancer 2009;52:784–790 123 I-mIBG Scintigraphy in Patients With Known or Suspected Neuroblastoma: Results From a Prospective Multicenter Trial Terry A. Vik, MD, 1 Thomas Pfluger, MD, 2 Richard Kadota, MD, 3 Victoria Castel, MD, PhD, 4 Mark Tulchinsky, MD, 5 J.C. Alonso Farto, MD, PhD, 6 Sherif Heiba, MD, 7 Aldo Serafini, MD, 8 Sabah Tumeh, MD, 9 Natalie Khutoryansky, MA, 10 and Arnold F. Jacobson, MD, PhD 10 * INTRODUCTION Radiolabeled meta-iodobenzylguanidine (mIBG) or iobenguane was originally developed in the late 1970s as a norepinephrine (NE) analog for imaging of the adrenal medulla [1,2]. In the quantities administered for diagnostic imaging, uptake of mIBG is mediated primarily by the NE transporter (T) located on the surface of sympathetic neurons [3,4]. On the basis of this mechanism of uptake, mIBG has proven an effective agent for scintigraphic imaging of tumors which arise from the embryonologic precursors of the sympathetic nervous system, particularly the neural crest tumors neuroblastoma and pheochromocytoma [5,6]. During the past 25 years, both 123 I-mIBG and 131 I-mIBG have been extensively used in research and clinical imaging of neuro- blastoma [5 – 8]. Increased uptake of mIBG in tumor compared with surrounding normal or uninvolved tissue on scintigraphic imaging allows differentiation of tumor from non-neoplastic tissue at initial diagnosis, and later provides a means for evaluating for the presence of residual, occult, or recurrent disease. Although numerous publications have consistently documented sensitivity ranging from 80 to 100% for mIBG imaging of neuroblastoma [7–16], almost all these data were derived from single-center experiences with few defined controls to blind image reviewers to clinical data and clinicians to diagnostic imaging results. A small multicenter trial was performed in Japan prior to approval of the oncology indication for 123 I-mIBG in that country [17]. Although 123 I-mIBG was only recently approved by the Food and Drug Administration (FDA) for use as a diagnostic imaging agent, this agent had been available for clinical use for a number of years, both at sites with investigational new drug applications (INDs) and in locations where the product could be obtained from radiopharmacies that compounded and supplied it on a named patient basis. The objective of the present trial was to document the diagnostic performance of 123 I-mIBG scintigraphy for confirming or excluding the diagnosis of neuroblastoma in support of a regulatory submis- sion of a new drug application (NDA) to the FDA. METHODS Patient Selection This was an open-label, Phase 3 scintigraphy study designed to document that 123 I-mIBG was effective for imaging of subjects being evaluated for known or suspected neuroblastoma. Patients with a previous diagnosis of neuroblastoma or who were being evaluated for a new or suspected diagnosis were eligible to participate. Ten centers in the US and seven in Europe participated in the study. The protocol was approved by the ethical committees or institutional review boards at each participating institution. All patients (or parents/guardians as appropriate) provided written informed consent prior to performance of any study procedures. The primary inclusion criterion was a clinical indication for 123 I-mIBG imaging to evaluate for the presence, extent, or status of neuroblastoma. Primary exclusion criteria were history of renal insufficiency (serum creatinine >3.0 mg/dl [265 mmol/L]) and Background. A prospective trial was conducted to confirm the diagnostic performance of 123 I-mIBG scintigraphy in patients with known or suspected neuroblastoma. Procedure. One hundred patients (mean age 4.7 years) were enrolled, 86 with a previous diagnosis of neuroblastoma, 13 with suspected disease based upon symptoms, imaging findings, and elevated catecholamines, and one adult with an abdominal tumor thought to be of neuroendocrine origin. All patients underwent whole-body planar imaging 24 hr following IV administration of 1–10 mCi (37–370 MBq) 123 I-mIBG. SPECT imaging of the thorax/abdomen/pelvis was performed in 51 patients. Images were interpreted by three blinded readers, with consensus requiring agreement of at least two readers. Disease status was confirmed by histopathology, imaging results, catecholamine measurements, and follow-up. Results. Sixty-four patients had active disease, 30 were without disease, and 6 were judged indeterminate because of insufficient confirmatory data. 123 I-mIBG scintigraphy had a sensitivity of 88% (56/64) and specificity of 83% (25/30). Sensitivity was 91% (30/33) among the subset of subjects who had both planar and SPECT imaging. Among 53 patients with recent histopathology, sensitivity and specificity were 93% and 92%, respectively. Most false-negative interpretations were in patients with minimal residual disease (n ¼ 4), while false-positive interpre- tations generally involved atypical adrenal or other physiological uptake (n ¼ 4). Conclusions. This prospective multicenter trial of 123 I-mIBG scintigraphy documents high sensitivity and specificity of this imaging technique in patients with both newly diagnosed and previously treated neuroblastoma. Pediatr Blood Cancer 2009;52: 784–790. ß 2009 Wiley-Liss, Inc. Key words: iodine-123; mIBG; Neuroblastoma; scintigraphy ß 2009 Wiley-Liss, Inc. DOI 10.1002/pbc.21932 Published online 30 January 2009 in Wiley InterScience (www.interscience.wiley.com) —————— Additional Supporting Information may be found in the online version of this article. 1 Indiana University School of Medicine, Indianapolis, Indiana; 2 Department of Nuclear Medicine, University of Munich, Munich, Germany; 3 Rady Children’s Hospital, San Diego, California; 4 Hospital Universitario La Fe, Valencia, Spain; 5 Milton S. Hershey Medical Center, Hershey, Pennsylvania; 6 Hospital Universitario Gregorio Maranon, Madrid, Spain; 7 Mount Sinai School of Medicine, New York, New York; 8 University of Miami, Miami, Florida; 9 Piedmont Hospital, Atlanta, Georgia; 10 GE Healthcare, Princeton, New Jersey Natalie Khutoryansky and Arnold Jacobson are employed by GE Healthcare. None of the other authors report any relationships to disclose. Grant sponsor: GE Healthcare. *Correspondence to: Arnold F. Jacobson, GE Healthcare, Medical Diagnostics, 101 Carnegie Center, Princeton, NJ 08540. E-mail: arnold.jacobson@ge.com Received 19 September 2008; Accepted 11 December 2008