Multiparametric Mapping for Assessment of Cancer Therapy Related Cardiotoxicity Cory V. Noel, M.D. Medical Director of CMR Pediatric Cardiology
Outline What is meant by the term cardiotoxicity? Scope of the issue of cardiotoxicity Current guidelines for cardiotoxicity detection Advantages of CMR in the identification of cardiotoxicity Integration of CMR into surveillance imaging Page 1 xxx00.#####.ppt 10/11/2017 8:58:56 AM
Cancer-Related Cardiotoxicity CV-related disease is leading cause of morbidity and mortality At 30 years of age, over 70% of survivors have chronic health condition Pediatric Cancer and Cardiotoxicity Establishment of a Cardio-Oncology Team 8 x more likely to die of heart disease 15 x more likely to develop HF Risk further increased when used with radiation therapy Oeffinger, et al., NEJM, 2006 Mertens, et al., J Clin Oncol, 2001 Landy, et al., Pediatr Cardiol, 2013d Page 2 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Cardiotoxicity Bloom MW, et al., Circulation: Heart Failure, 2016 Page 3 xxx00.#####.ppt 10/11/2017 8:58:57 AM
What is meant by Cardiotoxicity? No uniform definition Primarily concerns left ventricular systolic function Commonly used definition is > 5% drop in LVEF with HF symptoms or a > 10% asymptomatic drop to an LVEF below 55% Recent expert consensus for multimodality imaging recommends a decrease to 53% Cardiotoxicity versus Cancer Therapy-Related Cardiac Dysfunction (CTRCD) Seidman, et al., J Clin Oncol, 2002 Plana, et al., JASE, 2014 Page 4 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Defining the Issue Cardiotoxicity (NCI) Grade I: Asymptomatic biomarkers or abnormalities on imaging Grade II & III: Symptoms with mild to moderate exertion Grade IV: Severe, life threatening symptoms Grade V: Death Bloom MW, et al., Circulation: Heart Failure, 2016 CTRCD (ESC, ASE) Decrease in LVEF of > 10% to a value below 53%... Confirmed by repeat imaging Reversible if return to within 5% of baseline Partial if improved by 10%, but not within 5% of baseline Irreversible if improved <10%, and remains > 5% from baseline Page 5 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Scope of the Issue With variable definition, true prevalence is difficult to quantify Studies often do not account for baseline risks Bloom MW, et al., Circulation: Heart Failure, 2016 Page 6 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Timing of Cardiac Effect Acute toxicity (within 1 week) Uncommon (~1%), generally reversible Early-onset chronic form (within 1 year) Peak incidence in 3 months (1.6 2.1%) Typically irreversible Late-onset chronic form (after 1 year) 10 30 years (1.6 5%) Typically irreversible Bloom MW, et al., Circulation: Heart Failure, 2016 Wickramasinghe CD, et al., Future Oncology, 2016 Page 7 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Scope of the Issue Reasonable prevalence of early and late-onset chronic dysfunction Several risk factors playing a role Likely much higher prevalence of asymptomatic dysfunction that could be detected with improved surveillance Page 8 xxx00.#####.ppt 10/11/2017 8:58:57 AM
Importance of Early Detection St. Jude Lifetime Cohort 1853 adult survivors of childhood cancer Median age of 8 years at time of diagnosis Median age of 31 years at evaluation Mulrooney D, et al., Annals of Internal Medicine, 2016 Page 9 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Evaluation of LV Function Curigliano, et al., Annals of Oncol, 2012 Page 10 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Variability with Echo Assessment Plana, et al., JASE, 2014 Page 11 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Variability of Echo Assessment Commonly used definition of > 5% drop in LVEF with HF symptoms or a > 10% asymptomatic drop to an LVEF below 55% Longitudinal variability of 2D LVEF is about 10% Page 12 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Cardiac MRI versus Echo 114 adult survivors of childhood cancer 14% shown to have LVEF < 50% by CMR 2D echo overestimated the LVEF by 5% Armstrong, et al., J of Clin Oncol, 2012 Page 13 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Integration of Cardiac MRI Unable to obtain accurate baseline assessment Confirmation of significant LVEF drop or value below 55% When considering holding or stopping cancerrelated therapy When complete with cancer-related therapy Risk-based intervals in long-term surveillance Page 14 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Is There a Need for Earlier Detection? Is it possible to improve predictive analysis on which patients will develop heart failure and CTRCD? Page 15 xxx00.#####.ppt 10/11/2017 8:58:58 AM
Limitations of LVEF Relatively insensitive tool for detecting early damage Myocardial changes occur at doses below those typically associated with a drop in LVEF Morphological continuum of myocardial injury A drop in the LVEF appears to be a relatively late event in the cardiotoxicity cascade Ewer, et al., J of Clin Oncol, 1984 Cross, et al., Brit J of Pharm., 2015 Suter, et al., Euro Heart Journ., 2013 Page 16 xxx00.#####.ppt 10/11/2017 8:58:59 AM
Early Detection of Cardiac Dysfunction Allow for earlier identification of cardiac changes, particularly in cases of acute or early forms of cardiotoxicity Modify treatment regimen if needed Identify patients that may require more frequent surveillance imaging Goal to identify non-invasive imaging biomarkers to predict ventricular dysfunction Page 17 xxx00.#####.ppt 10/11/2017 8:58:59 AM
Importance of Early Detection Cardinale D, et al., JACC, 2010 Page 18 xxx00.#####.ppt 10/11/2017 8:58:59 AM
Utility of MRI in Early Detection Early anthracycline toxicity associated with inflammation, vacuolization and cardiomyocyte edema These changes occur before myocardial functional abnormalities Later stages of toxicity associated with fibrosis MRI offers the ability of myocardial characterization Regional wall deformation assessment Kajihara, et al., Pathol Res Pract, 1986 Friedman, et al., JAMA, 1978 Cottin, et al., Can J of Pharm, 1994 Page 19 xxx00.#####.ppt 10/11/2017 8:58:59 AM
Utility of MRI in Early Detection Cross, et al., Brit J of Pharm, 2015 Meyersohn N, et al., Curr Treat Options Cardio Med, 2015 Page 20 xxx00.#####.ppt 10/11/2017 8:58:59 AM
CMR Myocardial Characterization T2 T2 maps and weighted imaging is sensitive to both regional and global myocardial edema Myocardial edema occurs as a result of acute injury Edema occurs relatively early in the myocardial cascade prior to cardiomyocyte necrosis Mirakhur, et al., Euro J of Radiol, 2013 Francone, et al., Radiol Medicine, 2011 Page 21 xxx00.#####.ppt 10/11/2017 8:58:59 AM
CMR Myocardial Characterization T2 Mirakhur, et al., Euro J of Radiol, 2013 Thavendiranathan, et al., Circ Imaging, 2013 Page 22 xxx00.#####.ppt 10/11/2017 8:58:59 AM
CMR Myocardial Characterization T2 Smith et al have illustrated in 28 breast CA patients that increased SI on day 3 associated with drop in LVEF at 1 year Grover et al examined 46 breast CA patients 49% had abnormal T2 consistent with myocardial edema at 1 or 4 months after therapy commencement Thavendiranathan, et al., Circ Imaging, 2015 Grover, et al., Int J of Cardiol, 2013 Page 23 xxx00.#####.ppt 10/11/2017 8:59:00 AM
65 adult patients treated with anthracyclines CMR prior to and 3 months following chemo LVEF had a small but significant decline over the 3 month span (57±6% to 54±7%) T1-weighted imaging occurs diffusely and is associated with the drop in LVEF T2 imaging likely affected by timing of CMR Jordan, et al., Circ. Imaging, 2014 Page 24 xxx00.#####.ppt 10/11/2017 8:59:00 AM
Extracellular Volume Quantification Utilizes myocardial and blood T1 times, as well as hematocrit to calculate ECV fraction Highly accurate detection of diffuse myocardial fibrosis Moon JC, et al., JCMR, 2013 Ugander M, et al., Euro Heart J, 2012 Wong T, et al., Circulation, 2012 Page 25 xxx00.#####.ppt 10/11/2017 8:59:00 AM
CMR Myocardial Characterization T1 Schelbert E, et al., Radiology, 2016 Page 26 xxx00.#####.ppt 10/11/2017 8:59:01 AM
Extracellular Volume Quantification Shelbert E, et al., Journal of AHA, 2016 Kammerlander A, et al., JACC: Imaging, 2016 Page 27 xxx00.#####.ppt 10/11/2017 8:59:01 AM
CMR Myocardial Characterization T1 Jordan J, et al., Circulation: Imaging., 2016 Page 28 xxx00.#####.ppt 10/11/2017 8:59:01 AM
CMR Myocardial Characterization T1 Jordan J, et al., Circulation: Imaging., 2016 Page 29 xxx00.#####.ppt 10/11/2017 8:59:02 AM
CMR Regional Wall Motion Analysis Assessment of myocardial strain that may depict a decrease in myocardial function prior than EF Evaluation of 46 longterm childhood CA survivors Normal LVEF by echo Lower T1 values Toro-Salazar, et al., Circ Imaging, 2013 Page 30 xxx00.#####.ppt 10/11/2017 8:59:02 AM
Current Clinical Study 10 patients with diagnosis of solid bone tumor and expected anthracycline dose > 250 mg/m^2 CMR baseline prior to chemotherapy initiation 150-225 mg/m^2 12 months following final chemotherapy administration Exercise stress test with VO2 calculation at 12 months Page 31 xxx00.#####.ppt 10/11/2017 8:59:02 AM
Protocol Multiplanar Survey Cine Sequences btfe VLA, 4-Chamber, SAX Volumetric and Functional Quantification LV Mass T2 and Native T1 Mapping 45 minutes SPAMM and fsenc Myocardial Deformation Rest perfusion 1.5 Dose Gadobutrol Delayed Enhancement T1 Mapping and ECV Quantification Page 32 xxx00.#####.ppt 10/11/2017 8:59:02 AM
Patient Page 33 xxx00.#####.ppt 10/11/2017 8:59:02 AM
Myocardial Characterization by CMR Page 34 xxx00.#####.ppt 10/11/2017 8:59:03 AM
Myocardial Characterization by CMR Page 35 xxx00.#####.ppt 10/11/2017 8:59:03 AM
Myocardial Characterization by CMR Page 36 xxx00.#####.ppt 10/11/2017 8:59:03 AM
Potential Future Incorporation of CMR Utilization for early detection based upon myocardial characterization and myocardial strain Utilization in long-term survivors for prognosis with ECV and determining future surveillance Page 37 xxx00.#####.ppt 10/11/2017 8:59:03 AM
Thank you Page 38 xxx00.#####.ppt 10/11/2017 8:59:03 AM