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INTRODUCTION Cancer remains one of the leading ­ causes of morbidity and mortality worldwide. According to the World Health Organ­ ization, ­ there ­ were 14 million new diagnoses of cancer in 2012, and the incidence of new cancer cases is expected to increase by 70% over the next two de­ cades (1). The most common sites of cancer in men are lung, prostate, colorectal, stomach, and liver, whereas breast, colorectal, lung, cervix , and stomach are the most common sites in ­ women (1). Although ­ there has been a significant improvement in survival of most cancers over the past three de­ cades, one in ­ every four deaths in the United States is related to cancer (2). The improvement in survival is secondary to early diagnosis, improvement in treatment protocols, and new targeted therapies (2). For example, acute lymphocytic leukemia saw an increase in the five-­ year survival rate from 41% in 1970 to 70% in 2010 (2). In chronic myeloid leukemia, treatment with BCR-­ ABL tyrosine kinase inhibitors doubled the survival rate from 31% in 1990 to 60% in 2010 (2,3). As more patients survive cancer, ­ there is increased evidence of early and late consequences of chemotherapy. This chapter focuses on the cardiotoxicity of vari­ ous chemotherapy agents. Definition and Prevalence of Chemotherapy-­ Induced Cardiomyopathy Chemotherapy-­ induced cardiotoxicity is defined by the National Cancer Institute (NCI) as a toxicity of chemotherapy agents that affects the heart (4). As for other chemotherapy-­ related adverse events, NCI classifies cardiovascular (CV) adverse events into Grades 1 through 5: Grade 1 is for asymptomatic patients with evidence of cardiac abnormality on imaging or elevated cardiac biomarkers; Grade 2 indicates mild symptoms; Grade 3, moderate symptoms; Grade 4, severe life-­ threatening symptoms; and Grade 5, death (5). A commonly used clinical definition formulated by “the cardiac review and evaluation committee supervising trastuzumab clinical ­ trials” defines drug-­ associated cardiotoxicity as one or more of the following: (a) cardiomyopathy characterized by a decrease in cardiac left ventricular ejection fraction (LVEF); (b) symptoms of heart failure (HF); (c) associated signs of HF; or (d) a decline in LVEF of at least 5% to less than 55% with CHAPTER 8 Chemotherapy-­Induced Cardiomyopathy Edo Y. Birati and Mariell Jessup 78 / Chemotherapy-Induced Cardiomyopathy Myo­ car­ dial dysfunction can occur immediately ­ after exposure to chemotherapy, as usually occurs with anthracyclines. However, the change in myo­ car­ dial function may become apparent only years or even de­ cades ­ after therapy is given (7,12). ­ Table 8-1 summarizes the vari­ ous definitions. Classification of Cancer Therapeutics–­Related Cardiac Dysfunction CTRCD is classified according to the extent of injury and reversibility. Type I is dose related and irreversible. It is thought to be related to production of oxygen ­ free radicals, resulting in oxidative stress and subsequent influx of intracellular calcium ; the exact mechanism is not well understood . Anthracyclines as well as mitoxantrone may cause type I CTRCD (7,13,14). Type II is not related to cumulative dose and is thought to be reversible in 79% of patients ­ after discontinuation of therapy (2 to 4 months) (13,15). Trastuzumab is the common agent associated with type accompanying signs or symptoms of HF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms. The presence of any one of ­ these four criteria is sufficient to confirm a diagnosis (6). A joint committee of the American Society of Echocardiography (ASE) and the Eu­ ro­ pean Association of Cardiovascular Imaging (EACI) defined cancer therapeutics–­ related cardiac dysfunction (CTRCD) as a decrease in LVEF of more than 10%, to a value of less than 53%. This finding should be confirmed on repeat imaging done two to three weeks ­ after the initial study (7). Thus, the incidence of cardiotoxicity varies between studies and definition criteria, and depends on dif­ fer­ ent ­ factors including type of drug, cumulative dose, route of administration, combination with other cardiotoxic drugs, association with radiotherapy, patient’s age, and other CV risk ­ factors (8,9). For example, among patients treated with anthracyclines, 1% to 5% of the patients suffered from clinical HF and as many as 20% of the patients had an asymptomatic decrease in LVEF (10,11).­TABLE 8-1 ​ Definitions of chemotherapy-­ related cardiac dysfunction Authority Definitions Reference National Cancer Institute Toxicity of chemotherapy agents that affects the heart. 5 Grade 1 – Asymptomatic patients with evidence of cardiac abnormality on imaging or elevated cardiac biomarkers Grade 2 – Mild symptoms Grade 3 –­Moderate symptoms Grade 4 –­Severe life...


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