1050 C ontinual advances in antineoplastic therapies have pro- duced better cancer outcomes with 13.7 million cancer survivors in the United States in 2013 1 . However, a significant number of survivors may develop cardiac disease as a result of cancer treatment, whether chemotherapy, radiation, or a combination of both. 2 Although radiation can cause significant heart disease 3 both alone and with chemotherapy, this review will only address cardiomyopathy induced by chemotherapy agents, especially anthracyclines, commonly used to treat pediatric and adult cancers. Whereas anthracyclines remain the most common cause of chemotherapy-induced cardiomy- opathy (CCMP), recently developed targeted therapies can also cause cardiac dysfunction. 4–6 Newer drugs that target survival pathways in cancer cells, such as the HER-2 (human epidermal growth factor 2) and vascular endothelial growth factor inhibi- tors, have been directly implicated in left ventricular (LV) sys- tolic dysfunction 7,8 through off-target effects. Because cancer and heart cells share many of the same survival pathways, it is likely that newer targeted therapies will continue to cause off- target impairment of cardiomyocyte survival and heart failure (HF). 9 However, whereas LV dysfunction associated with tar- geted therapies seems reversible, 10 anthracyclines remain the only agents that seem capable to cause end-stage HF. 11 In this review, we critically appraise the data available to support the use of advanced HF therapies in this patients with CCMP and end-stage HF. Specifically, we review treatments indicated for American College of Cardiology/American Heart Association stages C-D HF, including implantable car- diac defibrillators, cardiac resynchronization therapy (CRT), mechanical circulatory support devices, and orthotopic heart transplantation (OHT). Epidemiology Herein defined as cardiomyopathy caused by anthracy- cline damage with or without exposure to other cardiotoxic agents, 12 CCMP has been described in 1% to 5% of cancer survivors 13,14 and arguably portends the worst survival among cardiomyopathies. 15 Unlike any other cause of HF, CCMP is completely iatrogenic and predictably caused by escalating doses of anthracyclines. At cumulative doses of <400 mg/m 2 , the incidence of HF is 0.14% but increases to 5%, 26%, and 48% at 400, 550, and 700 mg/m 2 , respectively 16,17 . Factors that potentiate CCMP are age extremes (<4 years or >65 years), radiation, female sex, pre-existing cardiac diseases, hyperten- sion, liver disease, exposure to cyclophosphamide, and whole- body hyperthermia. 18,19 Consequently, the 2 groups of survivors most susceptible to CCMP are those with cancers commonly treated with anthracyclines: children and adults with hematologic malig- nancies and women with breast cancer. For example, among 607 children treated with doxorubicin, 2.8% to 5% devel- oped HF after 6 to 15 years, 20 and 3% of patients treated for Hodgkin lymphoma developed HF after 11 years of follow- up 21 . Furthermore, a sibling-controlled study from the child- hood cancer survivor registry showed that childhood survivors of hematologic malignancies were at 6× likelier to develop HF than their siblings and that the cumulative risk persisted >30 years after diagnosis. 12 Similarly, among 4000 women followed up >18 years after breast cancer treatment with che- motherapy and radiation, 382 (8.7%) developed HF 22 . Finally, in a retrospective analysis of the pivotal trastuzumab trials, HF developed in 40 (28%) of 143 patients who received combination chemotherapy (trastuzumab, anthracycline, and cyclophosphamide), 27 (67%) of whom had New York Heart Association (NYHA) class III or IV HF. 8,23 However, the exact contribution of CCMP to the estimated 150 000 to 250 000 patients with advanced HF in the United States in 2013 is not known. 24 Analyses of the largest registries of patients with advanced HF, the United Network of Organ Sharing, and the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS), found that patients with CCMP accounted for 0.8% to 2.5% of all OHT recipients 25,26 and 0.5% of those implanted with mechanical circulatory sup- port devices. 27 Therefore, extrapolating from large databases of highly selected patients, the prevalence of end-stage HF from CCMP is between 0.5% and 2.5%. These numbers likely repre- sent a gross underestimation because many patients with CCMP neither have access nor are eligible for advanced therapies. Demographics Large databases have unveiled unique characteristics of patients with CCMP treated with advanced therapies. They (Circ Heart Fail. 2014;7:1050-1058.) © 2014 American Heart Association, Inc. Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.114.001292 Received May 5, 2014; accepted July 7, 2014. From the Advanced Heart Failure and Transplantation Center and Onco-Cardiology Program, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH. Correspondence to Guilherme H. Oliveira, MD, University Hospitals Case Medical Center, 11100 Euclid Ave, Lakeside 3012, Cleveland, OH 44106. E-mail guilherme.oliveira@uhhospitals.org Advanced Heart Failure Therapies for Patients With Chemotherapy-Induced Cardiomyopathy Guilherme H. Oliveira, MD; Marwan Y. Qattan, MD; Sadeer Al-Kindi, MD; Soon J. Park, MD Advances in Heart Failure Downloaded from http://ahajournals.org by on June 12, 2020