Journal of Nuclear Medicine, published on March 18, 2011 as doi:10.2967/jnumed.110.082784 CONTINUING EDUCATION Scintigraphic Techniques for Early Detection of Cancer Treatment–Induced Cardiotoxicity Lioe-Fee de Geus-Oei1, Annelies M.C. Mavinkurve-Groothuis2, Louise Bellersen3, Martin Gotthardt1, Wim J.G. Oyen1, Livia Kapusta4,5, and Hanneke W.M. van Laarhoven6 1Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2Department of Pediatric Hematology and Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3Department of Cardiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 4Children’s Heart Centre, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 5Heart Institute, Schneider Children’s Medical Center of Israel, Petach Tikvah, Israel; and 6Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the role of nuclear medicine imaging techniques in the assessment of cancer treatment–induced cardiotoxicity; (2) the mechanisms on which these scintigraphic techniques are based; and (3) the specific role the scintigraphic techniques could play in the future in the clinical work-up of patients at risk for cardiotoxicity. Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNM designates each JNM continuing education article for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, participants can access this activity through the SNM Web site (http://www.snm.org/ce_online) through April 2012. nal PET, with its wide range of tracers; 111In-antimyosin, which New antitumor agents have resulted in significant survival is a specific marker for myocardial cell injury and necrosis; 99m benefits for cancer patients. However, several agents may have Tc-annexin V scintigraphy, which visualizes apoptosis and serious cardiovascular side effects. Left ventricular ejection cell death; fatty-acid-use scintigraphy, which visualizes the fraction measurement by 99mTc multigated radionuclide angiog- storage of free fatty acids in the lipid pool of the cytosol (which 111 raphy is regarded as the gold standard to measure cardiotox- can be impaired by cardiotoxic agents); and In-trastuzumab icity in adult patients. It identifies left ventricular dysfunction imaging, to study trastuzumab targeting to the myocardium. To with high reproducibility and low interobserver variability. A define the prognostic importance and clinical value of each of decrease in left ventricular ejection fraction, however, is a rela- these functional imaging techniques, prospective clinical trials tively late manifestation of myocardial damage. Nuclear cardio- are warranted. logic techniques that visualize pathophysiologic processes at Key Words: cardiotoxicity; cancer treatment; early detection the tissue level could detect myocardial injury at an earlier J Nucl Med 2011; 52:560–571 stage. These techniques may give the opportunity for timely DOI: 10.2967/jnumed.110.082784 intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardio- toxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advan- he development of new antitumor agents, especially ces of scintigraphic techniques to measure cardiotoxicity. Both T first-order functional imaging techniques (visualizing mechani- molecular targeting agents, has significantly improved the cal [pump] function), such as 99mTc multigated radionuclide treatment options for cancer patients in the past decade. angiography and 99mTc gated blood-pool SPECT, and third- Although these advances have prolonged survival, several order functional imaging techniques (visualizing pathophysio- agents may have serious cardiovascular side effects. Tras- logic and neurophysiologic processes at the tissue level) are tuzumab (Herceptin; Genentech), a humanized monoclonal discussed. Third-order functional imaging techniques comprise antibody against human epidermal growth factor receptor 123 I-metaiodobenzylguanidine scintigraphy, which images the type 2 (HER2), is one such agent that is new and successful efferent sympathetic nervous innervations; sympathetic neuro- but has been associated with cardiac dysfunction (1). In a recent analysis of the incidence of cardiac adverse events in Received Aug. 29, 2010; revision accepted Dec. 8, 2010. patients with early breast cancer who were treated with For correspondence or reprints contact: Lioe-Fee de Geus-Oei, Department of Nuclear Medicine (internal postal code 444), Radboud trastuzumab in an adjuvant setting (Herceptin Adjuvant University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, Trial), trastuzumab was discontinued because of cardiac The Netherlands. E-mail: [email protected] disorders in approximately 5% of patients. At a median COPYRIGHT ª 2011 by the Society of Nuclear Medicine, Inc. follow-up of 3.6 y, the incidence of cardiac endpoints (se- 560 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 52 • No. 4 • April 2011 jnm082784-sn n 3/17/11 Copyright 2011 by Society of Nuclear Medicine. vere congestive heart failure, significant left ventricular of treatment and can be subacute or chronically progres- ejection fraction [LVEF] decrease) was higher in the tras- sive. Acute or subacute cardiotoxicity with anthracyclines tuzumab group than in the observation group (2). Prelimi- occurs during or immediately after infusion, is usually self- nary analysis from randomized controlled trials and case limiting, and resolves when therapy is discontinued. Late- control studies showed a pooled incidence of cardiotoxicity onset cardiotoxicity, however, occurs more frequently in of 10% in trastuzumab-containing arms, whereas the pooled children and can be noted more than 1 y after treatment incidence of cardiotoxicity in studies using a nontrastuzu- (10). Also, cardiac abnormalities may start early and can mab comparative arm was 2% (3). Therefore, close mon- progress over time to overt cardiomyopathy. Oeffinger et al. itoring of patients treated with trastuzumab is warranted. showed in a group of more than 10,000 survivors of child- Of the classic cytotoxic agents, anthracyclines are well hood cancer that the risk of dying from cardiac disease was known for their dose-dependent acute and chronic, irrever- 8 times higher than in the healthy population (11). In a sible and progressive cardiomyopathy. In trials of adjuvant recent study by van der Pal et al., 27% of adult childhood anthracycline-based treatment for breast cancer, a 5-y cancer survivors had an abnormal cardiac function (12). incidence of chronic heart failure of up to 3.2% has been The strongest predictors were anthracycline dose, cardiac reported, depending on the type of combination regimen irradiation, and younger age at diagnosis. At 6 y after and on the cumulative dose of anthracycline (4). It has been anthracycline therapy, subclinical heart failure occurs in suggested that the combination of anthracyclines and tax- up to 65% of childhood cancer survivors (13). Besides anes, which are currently the standard treatment for node- trastuzumab and anthracyclines, several other anticancer positive breast cancer, further increases cardiotoxicity (5,6). agents may have cardiotoxic effects (Table 1) (14). Patients ½Table 1 Furthermore, up to 0.5% of adults will be a survivor of who have been treated with both cardiotoxic chemotherapy some form of childhood cancer treated with anthracyclines and radiotherapy that included the heart in the irradiated (7). A large proportion of these survivors are at risk for volume are especially prone to cumulative negative cardio- developing cardiomyopathy, necessitating close follow-up vascular effects. evaluation and regular assessment. Furthermore, patients may be treated with both anthra- POTENTIAL MECHANISMS OF CARDIOTOXICITY cyclines and trastuzumab. It was recently demonstrated that Characterization of the mechanism of trastuzumab- and patients treated with anthracyclines and cyclophosphamide, anthracycline-induced cardiotoxicity may play an impor- followed by trastuzumab and paclitaxel, showed a 3-y tant role in developing strategies to prevent cardiac cumulative incidence of cardiac events, congestive heart dysfunction. However, a clear understanding of the patho- failure, and cardiac death of 4.1%, compared with 0.8% in physiology of cardiotoxicity is still lacking. This is patients treated with anthracyclines and cyclophosphamide particularly true for the pathophysiology of cardiac dys- alone (8). Also, a recent meta-analysis of the National Sur- function associated with trastuzumab. Trastuzumab trials gical Adjuvant Breast and Bowel Project B-31 and North report a high incidence of fall in ejection fraction (8,15,16). Central Cancer Treatment Group trials demonstrated that The end of trastuzumab and start of treatment for heart patients treated with trastuzumab in addition to sequential failure often results