Cardiovascular Effects of Cancer Therapy

Cardiovascular Effects of Cancer Therapy

42 

Lori M. Minasian, Myrtle Davis, and Bonnie Ky

S UMMARY

OF

K EY

P OI NT S

• Cardiotoxicity in the context of anticancer therapy requires a deep appreciation for the differences and potential interactions between patient risk factors for cardiac disease and the cardiovascular risk profile for an anticancer drug. • Understanding the structural, functional, and physiologic changes in the cardiovascular system that occur over the lifetime of the patient with cancer is critical to cancer therapy delivery and long-term care. • There is a clear need for additional evidence-based guidelines tailored to cardio-oncology that are informed and in part derived from existing oncology and cardiology treatment guidelines. • Appropriate nonclinical strategies and models can enhance early capture of safety signals and assessment of human risk.

Cardiotoxic Effects of Anticancer Agents and Modalities

• Anthracycline cardiotoxicity can occur over a broad spectrum of time; recent data challenge the paradigm of irreversible and late toxicity. • ErbB2-targeted therapy, primarily trastuzumab, is associated with a clinically significant incidence of cardiac dysfunction and heart failure (HF). Cardiac dysfunction, as defined by declines in left ventricular ejection fraction (LVEF) is reversible in the majority of, but not in all, cases. • Vascular endothelial growth factor (VEGF)–targeted therapies are associated with several cardiovascular toxicities, including hypertension, left ventricular dysfunction, and HF. Of these, hypertension is the most prevalent adverse effect. • Proteasome inhibitor therapy, primarily carfilzomib, is associated

with a number of cardiotoxicities, including hypertension and HF. • Immune checkpoint inhibitors are associated with a low but clinically significant incidence of cardiomyopathy and HF, secondary to myocarditis. • Common types of radiation-induced cardiotoxicity include pericarditis, cardiomyopathy, coronary artery disease, and valvular disorders.

Detecting and Monitoring Cardiac Toxicity

• The Common Terminology Criteria for Adverse Events (CTCAE) grading criteria for cardiac adverse events do not necessarily correspond with specific prognostic stages for heart disease because an acute adverse event that occurs in the course of treatment may not follow the same trajectory as is typically seen with heart disease progression. • Acute and subacute cardiac events are captured during the course of treatment. • Late or delayed toxicities may not be identified during a trial, but years later through surveillance efforts. • Circulating biomarkers can be used to aid in the diagnosis of cardiac injury and dysfunction, have been studied as surrogate measures of toxicity, and also can be used as prognostic measures of clinical outcomes, particularly in HF. • Echocardiography remains the mainstay of routine cardiac structure and function assessment before, during, and after cancer therapy and is incorporated in many clinical algorithms. • Advantages of echocardiography include widespread availability and lack of ionizing radiation. • Disadvantages include greater variability in the estimation of key

parameters, in part related to limitations in image quality, particularly when acoustic windows are poor; and variability in interobserver and intraobserver interpretation.

Mitigation Strategies

• A number of epidemiologic studies and clinical trials have suggested that cardiovascular risk factors, such as hypertension, diabetes, obesity, hyperlipidemia, and a prior history of cardiovascular disease, play an important role in the development of cardiotoxicity, particularly as it pertains to the development of cardiomyopathy. • Mitigation of cardiotoxicity and the implementation of cardioprotective strategies can be considered before, during, or after therapy. • Strategies include altering dosage and administration of agents and delivering additional cardioprotective pharmacotherapies. • Multiple strategies are under investigation, including behavioral interventions. • The management of cardiomyopathy once it ensues largely follows conventional therapy for the management of HF and cardiomyopathy, including the use of β-blockers, renin-angiotensinaldosterone system antagonists, and diuretic therapy as indicated.

Cancer Survivors

• More than 15 million Americans with a history of cancer are alive. • Recent surveillance studies have demonstrated late cardiac effects of cancer treatment and the potential for competing health outcomes in cancer survivors. • There is a critical need to evaluate cardiovascular risk factors in patients Continued

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650 Part II: Problems Common to Cancer and Therapy

with cancer before they undergo cancer therapy to manage those complications during and after cancer treatment.

• A deeper scientific and molecular understanding of cancer treatment– induced cardiac toxicities will be the basis for predicting patient risk,

Systemic cancer treatment has evolved substantially over time. Although traditional cytotoxic chemotherapy is still widely in use, there have been significant increases in the development and use of molecular strategies that target signaling pathways involved in cancer growth.1 However, perturbation of these signaling pathways can result in offtarget adverse effects on the cardiovascular (CV) system, often referred to broadly as cardiotoxicity. Cardiotoxicity encompasses a number of potentially diverse CV adverse events, which may manifest as abnormalities in cardiac function (left ventricular ejection fraction [LVEF] declines, diastolic dysfunction, cardiomyopathy, and heart failure [HF]); valvular disease (stenosis, regurgitation); pericardial disease (pericarditis, pericardial effusion); arrhythmias (atrial arrhythmias, ventricular arrhythmias, prolonged Q-T intervals); abnormalities in cardiac structure (cardiomyocyte death, myocardial fibrosis, left ventricular [LV] cavity dilation); worsening pulmonary hypertension; and microvascular and macrovascular abnormalities (myocardial ischemia, endothelial dysfunction, accelerated atherosclerosis, coronary vasospasm, peripheral arterial disease). Moreover, cancer therapies can induce significant hypertension, dyslipidemia, and even metabolic syndrome, which are central risk factors for the development of cardiomyopathy and HF, coronary artery disease (CAD), and myocardial infarction. Any of these effects are superimposed on physiologic and structural changes that accompany aging. Finally, metastatic cancer itself can result in systemic biologic perturbations, including a prothrombotic state and increased inflammation, that can result in additional adverse CV effects. Understanding the structural, functional, and physiologic changes in the CV system that occur over the lifetime of the patient with cancer is critical to cancer therapy delivery and long-term care. Such an understanding forms a basis for determining the best strategies to mitigate CV toxicity and manage delivery of the most appropriate cancer treatment. This need has resulted in the burgeoning field of cardio-oncology, a growing collaboration between oncologists and cardiologists, and an increased attention to and awareness of the inherent and induced CV risk factors and disease in cancer patients and survivors.2 This chapter provides an overview of the basic mechanisms, epidemiology, and clinical manifestations of CV injury resulting from specific cancer therapies that are commonly used. Methods for monitoring and detection of cardiotoxicity and the use of cardioprotective strategies are also reviewed.

CARDIOTOXIC EFFECTS OF ANTICANCER AGENTS Classification of Cardiotoxicity Temporal Classification Cardiotoxicity can occur at any time during or after cancer therapy, depending on the pathophysiologic basis of the toxicity, inherent biologic variability, physiologic reserves of the patient, and secondary stressors. Acute cardiac injury occurs within hours to days of treatment and can manifest as acute LV systolic dysfunction—that is, a cardiomyopathy that may be asymptomatic or present as symptomatic HF with doxorubicin,3 arrhythmia with ibrutinib,4 coronary artery spasm with 5-fluorouracil (5-FU),5 hypertension with vascular endothelial growth factor (VEGF) inhibitors,5 or transient conduction abnormalities

developing effective management strategies, and ultimately designing drugs with improved cardiovascular safety profiles.

with paclitaxel. Early-onset cardiotoxicity occurs within 1 year after treatment. Patients may develop arrhythmia, left-ventricular dysfunction, and HF. Late-onset (or delayed) cardiotoxicity may become clinically evident years (possibly even 10 to 20 years) after the initial exposure and may represent a progression of injury that was not readily clinically evident, worsened by the cumulative effects of underlying patient CV risk factors. As an example, this is observed with the interaction of treatment factors such as anthracyclines and radiation, and CV risk factors such as hypertension, atherosclerosis, and obesity. The actual onset of clinical toxicity may be unclear given incomplete follow-up and the variable characterization of CV function in patients with cancer. Although some studies have estimated the incidence of late cardiac effects such as cardiomyopathy and HF to be about 1.6% to 5%, others have suggested an incidence of clinically overt HF of 7% to 15%.5 A true temporal classification of late-onset (or delayed) cardiotoxicity is dependent on evidence of a clear relationship between occult asymptomatic cardiotoxicity and the subsequent development of overt disease. For example, imaging and serologic biomarkers of subclinical myocardial damage may precede echocardiographic indices of systolic and diastolic dysfunction.

Reversibility Cardiac toxicity can be reversible or irreversible, with reversibility referring to recovery of cellular or organ function. Myocardial changes such as myocardial cell loss (by necrosis or apoptosis), myofibrillar loss, and mitochondrial degradation are generally considered irreversible in the context of cellular or tissue injury. For example, late anthracycline cardiotoxicity is often perceived to be “irreversible,” given evidence for cardiomyocyte death, and thus led to the classification of “Type 1” or irreversible cardiotoxicity (in contrast to “Type 2” cardiotoxicity with trastuzumab, viewed generally at least to some extent as reversible and occurring during therapy). The Type 1 and Type 2 classification has fallen out of favor, given a perceived oversimplification of the underlying pathophysiology and natural history of cardiotoxicity. Recent evidence suggests that cardiac function may recover and “reverse” in the setting of anthracycline cardiotoxicity. Moreover, trastuzumab cardiotoxicity is not always reversible. Finally, there may be common mechanisms to cardiotoxicity observed with both strategies. A functional definition of reversibility would mean the clinical signs and symptoms associated with cardiac dysfunction have resolved. For example, evidence for HF and profound myocardial dysfunction documented by radiography, echocardiography, and signs and symptoms of HF (e.g., lower extremity edema, jugular venous distention, pulmonary congestion, ascites, fatigue, dyspnea at rest or exertion, paroxysmal nocturnal dyspnea, orthopnea) that resolves after the discontinuation of treatment would be considered reversible. A number of compensatory mechanisms to maintain cardiac output and systemic vascular resistance can occur transiently and subsequently reverse LV dysfunction. However, over time and with additional exposure to the therapy or other insults, these compensatory mechanisms may be inadequate, and irreversible cardiomyopathy and worsening symptomatic HF may occur (Fig. 42.1).6,7 The epidemiology, basic mechanisms, clinical manifestations, and risk factors for cardiotoxicity for certain classes of agents are discussed in the following sections. Table 42.1 provides a broad overview of the CV effects reported with commonly used agents.

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 651 Hypertension and endothelial dysfunction (VEGF inhibitors; fluorouracil) Inhibition of cell survival pathways (e.g., ErbB2, proteosome) + Myocellular injury

LV remodeling

Apoptosis Necrosis

Hypertrophy Fibrosis Apoptosis

Direct injury to cardiac myocytes (e.g., anthracyclines, radiation, taxanes Myocardial ischemia

Timeline

+

Acute/Subacute Days-Months

Clinical/subclinical injury Symptomatic/asymptomatic LV systolic and diastolic dysfunction

Clinical heart failure

Chronic Months-Years

Figure 42.1  •  Pathophysiology of chemotherapy-induced cardiotoxicity. The specific mechanisms and clinical manifestations of cardiac injury may vary according to each chemotherapy class, but the final common pathway linking the initial injury to acute, subacute, and chronic manifestations are often overlapping. Acute and subacute injury is often asymptomatic and may or may not be associated with a measurable change in ejection fraction. Chronic cardiac injury is usually associated with left ventricular (LV) remodeling characterized by LV enlargement, reduced ejection fraction, and eventually symptomatic heart failure. Hypertension associated with inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway can exacerbate myocardial injury and cardiac disease progression in the acute, subacute, and chronic settings.

Anthracycline Toxicity Anthracyclines (doxorubicin, daunorubicin, epirubicin) and related molecules (mitoxantrone) have played an integral chemotherapeutic role in the successful treatment of breast cancer, leukemia, lymphoma, and sarcoma in pediatric patients, adolescents, and adults. Unfortunately, the oncologic successes of anthracycline chemotherapy have been accompanied by dose-dependent cardiotoxicity that has resulted in clinically important consequences. Despite a recognition of anthracycline cardiotoxicity since the 1970s, the molecular and cellular mechanisms involved in its pathogenesis are not completely understood. The generation of reactive oxygen species and increased oxidative stress is the most widely accepted mechanism of toxicity.8 Recent data have raised the intriguing hypothesis that this is dependent on topoisomerase IIβ,9 a target of anthracyclines that is expressed in adult mammalian cardiomyocytes. After doxorubicin exposure, cardiomyocytes from wild-type mice exhibit abnormalities in the p53 tumor suppressor gene, β-adrenergic signaling, and apoptotic pathways. In contrast, cardiomyocytes from a cardiomyocyte-specific Top2β knockout mouse (Top2βΔ/Δ) exhibited substantially fewer changes and preserved cardiac function.9,10 It is likely that anthracyclines engage multiple mechanisms of cardiotoxicity, with additional hypotheses including significant mitochondrial DNA (mtDNA) depletion and mtDNA rearrangements, increased calpain-dependent titin proteolysis, impaired calcium handling and contractility, depletion of cardiac progenitor cells, and impairment of prosurvival signaling pathways via inhibition of neuregulin and ErbB. On histopathology, anthracycline-associated abnormalities include mitochondrial and cytoplasmic vacuolization and myofibrillar and sarcomeric disarray. Biochemical evidence has also demonstrated elevations in circulating cardiac troponins with anthracycline exposure, indicative of cardiomyocyte injury and cell death.11–13 Clinically, acute anthracycline cardiotoxicity manifests as arrhythmias and transient changes in cardiac function. This occurs in less than 1% of patients.5 Subacute or early-onset chronic progressive

cardiotoxicity occurs in 1.6% to 8% of treated patients and typically within the first year. This manifests as declines in LVEF, cardiomyopathy, and HF. Late anthracycline cardiotoxicity is often perceived to be “irreversible,” but recent data challenge the notion of irreversible cardiotoxicity with anthracyclines. In one study of 201 patients with a reduced LVEF (≤45%) secondary to anthracyclines, 42% of the patients recovered their LVEF completely with institution of angiotensinconverting enzyme (ACE) inhibitors and/or β-blockers. Thirteen percent had partial recovery of their LVEF. The percentage of responders decreased as time to the initiation of cardiac medications increased. Every patient who experienced complete recovery had medications instituted within 6 months of recognition of cardiac dysfunction.14 Another study from the same group of investigators included 2625 patients treated with anthracycline therapy and further challenged the notion of “late” as well as irreversible cardiotoxicity. Patients were followed with serial echocardiograms every 6 months after the completion of chemotherapy for a median of 5.2 years. In this cohort, 98% of the cardiotoxic events occurred within the first year after chemotherapy completion. Cardiotoxicity rates were on the order of 9% and occurred at a median time of 3.5 months after the end of chemotherapy.15 Recovery of LVEF, either full or partial, was achievable in 11% and 71% of participants, respectively. Since the late 1970s, anthracycline cardiotoxicity has been noted to be dose dependent, resulting in specific guidelines to limit cumulative dosing.16 Although individual variation in tolerability exists, the risk for developing cardiomyopathy increases exponentially for cumulative doses greater than 400 mg/m2 with an average incidence of 5.1% at 400 mg/m2 that is estimated to be 15.7% at 500 mg/m2.17,18 Of note, recent data also suggest that genetic variants in single nucleotide polymorphisms (SNPs) may influence this risk.19 Additional risk factors include age at both ends of the spectrum, including children and adults older than 70 years; radiation to the chest wall; female sex; and preexisting CV disease or CV risk factors, such as hypertension, smoking, and diabetes mellitus.

652 Part II: Problems Common to Cancer and Therapy

Table 42.1  Classes of Anticancer Agents Associated With Cardiovascular (CV) Toxicities Categories of Drugs ANTHRACYCLINES

Cardiovascular Effects Reported

Target intercalation into DNA and disruption of topoisomerase II–mediated DNA repair; generation of free radicals and their damage to cellular membranes; DNA and proteins. Doxorubicin, epirubicin, idarubicin, daunorubicin

Reference Chlebowski, 1979154; Tjuljandin, 1990155; Anderlini, 1995156; Tong, 1980157

Acute cardiotoxicity (transient arrhythmias, especially sinus tachycardia with Q-T prolongation) reported; LVD manifesting as acute toxicity within 2 weeks of ending treatment; subchronic toxicity developing within 1 year of exposure; and late-onset toxicity manifesting many years after exposure

DNA CROSS-LINKERS AND FREE RADICAL–MEDIATED STRAND BREAKS Busulfan (bifunctional DNA alkylation)

Edema, tachycardia, hypertension (all grades), vasodilation, cardiac tamponade; left HF, complete atrioventricular (AV) block, endomyocardial fibrosis

ANTIMICROTUBULE AGENTS Exert their effect by binding to and subsequently polymerizing and stabilizing microtubules, thus preventing mitosis and resulting in apoptosis. Suppress both the growth and shortening phases of microtubule dynamic instability. Block cells in the G2/M phase of the cell cycle, and such cells are unable to form a normal mitotic apparatus. Docetaxel also decreases Bcl-2 and Bcl-xL gene expression. Paclitaxel, docetaxel (Taxotere) Eribulin Ixabepilone

Perez, 1998158; Kenmotsu, 2015159; Bollag, 1995160

LVD, cardiac ischemia; Q-Tc prolongation, edema, vasodilation, hypotension, HF (higher incidence with trastuzumab), bradycardia; syncope, phlebitis Q-T prolongation Adverse CV effects poorly specified in one study, where 7 of 48 patients were noted to have cardiac adverse effects, which were all grade 1 or 2

ANTIMETABOLITES Target DNA, incorporation of metabolites into DNA, the inhibition of DNA polymerase β, dihydrofolate reductase, thymidilate synthase, or ribonucleotide reductase. Fludarabine Capecitabine Cytarabine Pentostatin and cladribine Methotrexate

Senturk, 2009161; Schimmel, 2004162; Chanan-Khan163

Edema (mainly peripheral edema) Ischemia, vasospasm, pericarditis, HF, cardiogenic shock Pericarditis with effusion, rare incidence of vasculitis Angina pectoris, dysrhythmias, AV block, cardiac arrest, HF, hemorrhage, hypertension or hypotension, pericardial effusion, pulmonary embolus, sinus arrest Pericarditis, pericardial effusion, hypotension, thrombotic events, vasculitis

ALKYLATING AGENTS Target DNA, binding to DNA, producing a variety of interstrand or intrastrand cross-links called adducts, that alter DNA structure or function. A common site of alkylation is the N-7 position of guanine.

Cyclophosphamide Ifosfamide

Cisplatin Trabectedin Thalidomide

Gottdiener, 1981164; Goldberg, 1986165; Kandylis, 1989166; Tascilar, 2007167; Lebedinsky, 2011168; Bueren-Calabuig, 2011169; Feuerhahn, 2011170; Stephens, 2000171; Ito, 2010172; Zhu, 2011173; Hecht, 2000174

LVD at high dosages, HF within 3 weeks of administration, hemorrhagic myopericarditis that is rare Arrhythmias (including premature atrial contractions, premature ventricular contractions, supraventricular tachycardia, atrial fibrillation, atrial flutter), supraventricular tachyarrhythmia, HF (dose 10–18 g/m2) Thromboembolic disorders, HF, hypertension, orthostatic hypotension, myocardial ischemia or infarction, bradycardia Cardiac ischemia Thromboembolic events, hypotension, edema, bradycardia, orthostatic hypotension

ANTIBIOTICS Target DNA and RNA, formation of reactive intermediates resulting in selective degradation of DNA and oxidative degradation of all major classes of cellular RNAs. Mitomycin C HF, edema, thrombophlebitis Bleomycin Edema, Raynaud phenomenon, myocardial ischemia or infarction

HDAC INHIBITORS Target histone deacetylases (HDACs), leading to induction of gene expression or destabilization and degradation of growth factors.

Piekarz, 2009175; Atadja, 2009176; Richon, 2000177; Glaser, 2003178

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 653

Table 42.1  Classes of Anticancer Agents Associated With Cardiovascular (CV) Toxicities—cont’d Categories of Drugs

Cardiovascular Effects Reported

Romedepsin

Increased HR (average 11 beats/min) following infusion, ST segment flattening and depression, supraventricular arrhythmia, hypotension, edema, ventricular arrhythmia An early phase I study using an intensive intravenous panobinostat administration schedule led to initial safety concerns surrounding possible Q-Tc interval prolongation Analyses of electrocardiograms of patients with solid tumors and hematologic malignancies enrolled in subsequent phase I/II studies suggest that QT-cF prolongation is not an issue with intermittent weekly administration Isolated rare events of Q-Tc prolongation in previous vorinostat studies were observed Administration of a single supratherapeutic dose of the HDAC inhibitor vorinostat is not associated with prolongation of the Q-Tc interval

Panobinostat

Vorinostat (suberoylanilide hydroxamic acid [SAHA])

Reference

VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) INHIBITORS Target VEGFR1, VEGFR2, PDGFRα, and PDGFRβ, bFGF receptors, stem-cell factor (SCF) receptor (KIT), RET, TIE2, fetal liver tyrosine kinase receptor 3 (FLT3) compounds generally directed against the endothelium, inhibiting either endothelial growth factors or the receptors of such factors. They all have antiangiogenic effects. Bevacizumab Cabozantinib Regorafenib Axitinib Ponatinib (main target Bcr-Abl, Bcr-Abl T315I)

Heat failure, hypertension, ischemia Hypertension Hypertension, myocardial ischemia and infarction Hypertension HF, myocardial ischemia, peripheral ischemia (stroke, peripheral vascular disease)

Sunitinib

Hypertension is present in approximately 60% of patients; Q-T interval prolongation, decreased LVEF, LVD, HF, increased BP, HF linked to CV comorbidities, arterial thrombosis reported Q-T interval prolongation, sudden death (possibly ventricular repolarization related), ischemia, peripheral ischemia Q-T interval prolongation, sudden death (possibly ventricular repolarization related), HF (cardiomyopathy), ischemia, arterial thrombosis Cardiac dysfunction (HF and decreased LVEF), Q-T prolongation, cases of torsades de pointes, hypertension Q-T interval prolongation, torsades de pointes, acute cardiac failure, hypertension

Nilotinib (main target Bcr-Abl) Sorafenib Pazopanib Vandetanib

Awad, 2014179; Morabito, 2009180

MEMBRANE RECEPTORS OF TUMOR CELLS Target HER2 or EGFR. Trastuzumab, pertuzumab, lapatinib T-DM1 (HER2) T-DM1 (HER2)

Necitumumab (EGFR with gemcitabine or cisplatin)

Osimertinib (EGFR T790M mutation)

Awad, 2014179 Reduction in LVEF, cardiomyopathy, HF These effects are often reversed if the drug is withdrawn, but may also require HF treatment Anthracyclines exacerbate cardiotoxicity with trastuzumab In a phase II study, there was no symptomatic HF, but patients in each T-DM1 group showed reduction in LVEF One patient in the T-DM1 group had LVEF <40% In a phase III comparative study, only 1.7% of patients in the T-DM1 group experienced decreased LVEF at least 15% below the baseline value Grade III LVEF developed in only one patient (0.2%) Venous thromboembolic events (VTEs) and arterial thromboembolic events (ATEs), including fatal cases, were observed with necitumumab in combination with gemcitabine and cisplatin An increased frequency of cardiorespiratory arrest or sudden death was observed with necitumumab in combination with gemcitabine and cisplatin compared with patients treated with chemotherapy alone Cardiorespiratory arrest or sudden death Q-Tc interval prolongation, cardiomyopathy occurred in 1.4% and was fatal in 0.2% of 813 Tagrisso patients LVEF decline >10% and a drop to <50% occurred in 2.4% of (9/375) Tagrisso patients

INTRACELLULAR PATHWAYS OF TUMOR CELLS Target various kinases, mainly RAF/MER/ERK, anaplastic lymphoma kinase (ALK), BCR-ABL kinase. Symptomatic and asymptomatic decline in LVEF can occur Cobimetinib (BRAF Risk of cardiomyopathy is increased in patients receiving combination with vemurafenib V600E or V600K compared with vemurafenib as a single agent mutation)

Morabito, 2009180

Continued

654 Part II: Problems Common to Cancer and Therapy

Table 42.1  Classes of Anticancer Agents Associated With Cardiovascular (CV) Toxicities—cont’d Categories of Drugs

Cardiovascular Effects Reported

Trametinib

The early trials of trametinib reported that 8% of patients experienced LVEF dysfunction; however, few events were thought to be specifically related to trametinib and a recorded drop in LVEF was rarely symptomatic and was not associated with increased risk of Q-Tc prolongation as a single agent Q-T interval prolongation, cases of vemurafenib-induced pericarditis

Vemurafenib, dabrafenib Ibrutinib Imatinib, nilotinib, dasatinib, bosutinib

Atrial fibrillation, 10-fold increase in rate observed Peripheral arterial disease, metabolic syndrome, pulmonary hypertension, fluid retention

Crizotinib, ceritinib (ALK; other targets IGF-1R, INSR, STK22Dn, c-MET)

Q-T interval prolongation, bradycardia

Reference

IMMUNOMODULATORY AGENTS Antibodies directed against immune-related tumor or T-cell antigens. Rituximab (CD20) Cardiac arrhythmias, symptomatic polymorphic ventricular tachycardia Alemtuzumab (CD52) HF or arrhythmia that mostly improved after alemtuzumab discontinuation; patients with mycosis fungoides (MF) or Sezary syndrome may have a higher risk of cardiac complications Ipilimumab (CTLA4) Autoimmune myocarditis, cardiomyopathy, HF, cardiac fibrosis, and cardiac arrest Preexisting cardiac pathologic condition or peripheral arterial disease was present in some patients, but all patients were free of symptoms when starting therapy Nivolumab (PD-1) HF, cardiomyopathy, heart block, myocardial fibrosis, and myocarditis Pembrolizumab (PD-1) Rare occurrence of autoimmune myocarditis with severely impaired left ventricular function with dyssynchrony IL-2 Hypotension (capillary leak syndrome), 71% ventricular tachycardia, coronary artery thrombosis, myocarditis MAGE-A3a3a TCR cells Cardiac myonecrosis with an unusual lymphoid predominant infiltrate into the myocardium, a cross-reactive epitope derived from the human protein titin, presented in the context of HLA-A*01 Donor-derived Mainly sepsis-induced cardiomyopathy, tachycardia, and hypotension associated with anti-CD19 CAR T cells cytokine release syndrome Cumulative dose-related cardiotoxicity, primary cardiotoxicity via destruction of Mitoxantrone (broad myocytes range of actions and effects on many different types of immune cells)

Smith, 2003181

PROTEASOME INHIBITORS Targets 26S proteasome resulting in Bcl-2 phosphorylation associated with G2–M phase cell cycle arrest and the induction of apoptosis; may dysregulate intracellular calcium metabolism resulting in caspase activation. Carfilzomib (irreversible inhibitor) Bortezomib (reversible inhibitor)

Field-Smith, 2006182

Hypertension, HF, dyspnea, increases in pulmonary pressure; may be reversible when carfilzomib is discontinued Variable reports; systematic review and meta-analysis demonstrated that the use of bortezomib does not significantly increase the risk of all-grade and high-grade cardiotoxicity

OTHER CATEGORIES Pasquali, 2010183 All-trans retinoic acid (ATRA) Etoposide (topoisomerase inhibitor) Estramustine Arsenic trioxide Interferon-α

Tretinoin treatment has been associated with pleural or pericardial effusions, hypotension, and dysfunction in myocardial contractility Hypotension, HF, myocardial ischemia and infarction

Fluid retention, hypertension, electrocardiographic changes, myocardial infarction, and thromboembolic disease Ventricular premature contractions, Q-Tc prolongation, TdP, cardiac dysrhythmias, edema with pericardial effusion (during acute promyelocytic leukemia differentiation syndrome) Hypertension or hypotension, arrhythmias

bFGF, Fibroblast growth factor receptor; BP, blood pressure; CAR, chimeric antigen receptor; CTLA4, cytotoxic T-lymphocyte antigen 4; EGFR, epidermal growth factor receptor; FLT3, fetal liver tyrosine kinase receptor 3; HF, heart failure; IL, interleukin; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; PDGFR, platelet-derived growth factor receptor.

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 655

ErbB2 Antagonists Trastuzumab, pertuzumab, and lapatinib all target the tyrosine kinase receptor HER2/ErbB2, a receptor highly expressed in many breast cancer cells.20 In addition to the apparent role of HER2/ErbB2 in cancer cell survival, essential roles for this signaling pathway in the heart were revealed by cardiac-restricted knockout of HER2/ErbB2 in mice that developed a dilated cardiomyopathy and an impaired ability to respond to CV stress.21 Trastuzumab (Herceptin) is a humanized monoclonal antibody that targets the extracellular domain of the HER2/ErbB2 tyrosine kinase receptor. In the clinical setting, trastuzumab is widely used and has demonstrated remarkable efficacy in the treatment of HER2-positive breast cancer, but there is a clinically significant incidence of cardiac dysfunction (generally reversible) and HF. Based on the role of ErbB2 in providing a protective response to cardiac stress and the cardiac phenotype of ErbB2 conditional knockout mice, cardiotoxicity of trastuzumab is presumed to be secondary to ErbB2 inhibition. Additional preclinical data support this hypothesis. An antimouse ErbB2 has been shown to impair cardiac contractility and fibrosis in mice.22,23 In addition, trastuzumab treatment promotes oxidative stress and apoptosis in the myocardium of mice, and results in elevations in biomarkers of cardiac injury cardiac troponin I (TnI), and cardiac myosin light chain 1 (cMLC1).24 Recent data have also suggested that disruption of ErbB2 signaling also results in endothelial dysfunction and alterations in vascular function, which may contribute to cardiomyopathy development.25 The initial reports of trastuzumab-associated cardiac dysfunction were most frequently seen in patients with breast cancer with concurrent anthracycline chemotherapy. A change to sequential administration of anthracyclines followed by trastuzumab, as well as a decrease in the use of anthracyclines in patients with early-stage HER2-positive breast cancer, has resulted in a lower rate of cardiac dysfunction. Experience from large clinical trials, many of which have included combination therapy with anthracyclines and trastuzumab, demonstrates an approximate 9.8% incidence of LV dysfunction and a 2.7% incidence of severe, symptomatic HF.26,27 Retrospective analyses of registry data—for example, from the Cancer Research Network—suggest higher rates. In combination with anthracyclines, the 5-year cumulative incidence of HF or cardiomyopathy increases to 16% to 20%, with a sevenfold increased risk compared with patients not treated with chemotherapy. Retrospective analyses from the Ontario Cancer Registry, based on only HF International Statistical Classification of Diseases and Related Health Problems (ICD) codes, suggest a greater than fivefold increase in HF with adjuvant trastuzumab, although the majority of the events occurred within the first 1.5 years after chemotherapy initiation. In this study, the cumulative incidence at 5 years was 5.2%.28 Additional risk factors for trastuzumab-associated cardiotoxicity include older age, lower baseline LVEF, hypertension, obesity, renal dysfunction, diabetes, and arrhythmia.29–32 Although clinical experience suggests that recovery of LVEF occurs in the majority of patients within the first year after exposure, either with temporary cessation of trastuzumab or with standard HF therapy (Box 42.1), not all patients fully recover cardiac function, as defined by LVEF declines.26,27 The long-term effects of trastuzumab on cardiac function and HF remain to be determined, although clinical trial data suggest that most declines in LVEF occur during therapy. Newer HER2 antagonists include pertuzumab and trastuzumab emtansine (T-DM1). Pertuzumab is a recombinant humanized monoclonal antibody that targets an epitope of the extracellular domain II of ErbB2 and inhibits ErbB2 homodimerization and heterodimerization. The rates of cardiac dysfunction with pertuzumab remain to be further defined.33 One phase II study of pertuzumab found a low incidence of LVEF declines of 10% or more to less than 50% in 3 of 66 treated patients.39 The phase III CLEOPATRA study did not suggest an increased incidence of cardiotoxicity in patients receiving pertuzumab in combination with trastuzumab and docetaxel, compared with trastuzumab and docetaxel alone (6.6% versus 8.6% by Common

Box 42.1  CASE STUDY OF LEFT VENTRICULAR

EJECTION FRACTION MONITORING A 55-year-old woman with a history of HER2-positive breast cancer is undergoing therapy with doxorubicin, followed by trastuzumab. She has no cardiovascular (CV) risk factors except for obesity. At baseline, her left ventricular ejection fraction (LVEF) is estimated at 55% to 60%. After completion of 240 mg/m2 of doxorubicin, her LVEF is estimated at 55%, and subsequently declines to 40% after four cycles of trastuzumab. She denies any symptoms except for fatigue, and her physical examination does not reveal any findings of decompensated heart failure (HF). She is normotensive. What are potential management strategies? Declines in LVEF are observed with trastuzumab therapy and potentiated by anthracycline exposure. Risk factors also include older age, hypertension, and obesity. Guidelines from the American College of Cardiology and American Heart Association typically define exposure to any cardiotoxic therapy as stage A HF, and structural abnormalities including declines in LVEF as stage B HF.34 In the setting of stage B HF, β-blockers and/or angiotensin-converting enzyme (ACE) inhibitors are recommended in the American College of Cardiology and American Heart Association guidelines, although these guidelines are not specific to cancer patients. The European Society of Cardiology suggests that initiating one or more guideline-based HF therapies be considered, depending on the magnitude of decrease and LVEF value.35 Various working groups (e.g., National Cancer Research Institute36 and Canadian Trastuzumab Working Group37) have suggested management strategies based on practices adapted in clinical trials.38 It is unclear if these practices have been widely adapted, and the American Society of Clinical Oncology cardiac dysfunction guidelines emphasize that decisions regarding therapy need to be made on an individual basis. This patient would likely benefit from one or both of these HF therapies.

Terminology Criteria for Adverse Events [CTCAE], version 3, for LV dysfunction and HF).18 Trastuzumab emtansine (T-DM1), an antibodydrug conjugate that incorporates trastuzumab with the microtubule agent emtansine (DM1), is also in use for advanced HER2-positive breast cancer.40 Like pertuzumab, cardiotoxicity rates with T-DM1 also remain incompletely defined, although the phase III EMILIA study also did not suggest an increased risk of cardiotoxicity with this agent.40

Vascular Endothelial Growth Factor Signaling Pathway Inhibitors Cabozantinib, regorafenib, axitinib, sunitinib, sorafenib, vandetanib, and pazopanib are all VEGF tyrosine kinase inhibitors. Monoclonal antibodies such as bevacizumab also inhibit the VEGF signaling pathway, and additional multitargeted oral tyrosine kinase inhibitors such as ponatinib and nilotinib target BCR-ABL as well as VEGF receptors. VEGF-directed therapies have improved clinical outcomes for many solid tumors, including but not limited to metastatic renal cell cancer, pancreatic neuroendocrine tumors, thyroid cancers, gastrointestinal stromal tumors, and colorectal tumors. However, many of these agents have also been associated with several CV toxicities, including hypertension, LV dysfunction, and HF. Of these, hypertension is the most prevalent adverse effect for the multitargeted kinase inhibitors of the VEGF pathway. Nonclinical studies indicate that VEGF is expressed in virtually every tissue,41 with the highest density of VEGF-expressing cells being found in tissues with fenestrated vasculature such as in the kidney. Studies in animals support the notion that VEGF may have an

656 Part II: Problems Common to Cancer and Therapy

important effect on endothelial and vascular function and on blood pressure regulation in the adult animals, and alterations in nitric oxide (NO) have also been observed in some studies, but not all. Administration of a specific antibody against the major VEGF receptor, VEGFR2, to normal mice caused a rapid and sustained increase in BP of approximately 10 mm Hg, and significant reductions in the expression of endothelial and neuronal NO synthases in the kidney.42 In a swine model, sunitinib induced a compensatory increase in NO.43 In humans, VEGF inhibition with vandetanib was associated with decreased urinary nitrite/nitrate excretion and decreased serum levels of NO metabolites. However, no difference in flow-mediated dilation, a surrogate for NO bioavailability, was observed.44 The endothelium is a major target organ for the actions of VEGF; therefore it is reasonable to expect that the CV effects of these inhibitors may be related to VEGF-related compromises in normal vascular function, such as decreases in the production of endothelium-relaxing NO and prostaglandin, enhanced production of vasoconstrictive factors such as thromboxane and endothelin, alterations in neurohormones (such as vasopressin or norepinephrine), and marked downregulation of AMP-kinase (resulting in disruption of mitochondrial function). The complexity of the pathogenic mechanism is further confounded by the fact that VEGF tyrosine kinase inhibitors typically inhibit several pathways. For example, sunitinib blocks multiple pathways in addition to vascular endothelial growth factor receptors 1 to 3 (VEGFR1 to VEGFR3) that are fundamental to CV function, including the platelet-derived growth factor receptor α/β (PDGFRα/β), c-KIT, and Fms-like tyrosine kinase-3 (Flt-3). Inhibition of multiple kinase pathways and multiple VEGF family members may be essential to the adverse effect profile, and the development of effective means by which these events can be managed during treatment is critical. As an example, with sunitinib the overall incidence of hypertension in one meta-analysis was 21.6%, and it varied among tumor types (worse with renal cell cancer compared with other solid tumors) and sunitinib administration schedules (worse with continuous versus intermittent dosing). Clinical factors including preexisting hypertension, obesity, and older age are also associated with an increased risk of incident hypertension.45 Phase III trials and subsequent clinical experience have noted an incidence of hypertension ranging from 5% to 47%. In a phase III study comparing pazopanib with sunitinib, the rates of hypertension were 46% and 41%, respectively. Increases in blood pressure have been noted to occur early, within 24 hours of initiation of therapy (Box 42.2).46 The relationship between increases in blood pressure and the development of subsequent cardiomyopathy and HF remain unknown, although there is a long-standing recognition of the importance of afterload in the pathogenesis of LV dysfunction in HF. Retrospective analyses have suggested the overall incidence of HF in sunitinib-treated patients to be 4.1%, and the incidence of significant LV dysfunction was estimated to be on the order of 10% to 13%.48,49 One limitation of the comparison of findings across studies is the heterogeneity of definitions of LV dysfunction (e.g., symptoms of cardiac dysfunction; ≥15% absolute decline compared with baseline; or ≥10% decline in LVEF compared with baseline and below the lower limit of normal). Risk factors for LVEF declines include male sex and longer duration of therapy. Multiple prospective studies have suggested that with careful monitoring, these adverse CV effects are manageable.49 Many questions remain, such as the choice of antihypertensive agent in controlling antiangiogenic therapy–induced hypertension and whether better understanding of the mechanisms will provide clinically useful biomarkers.

Proteasome Inhibitors Proteasome inhibitors (PIs), such as carfilzomib and bortezomib, are frequently used in the management of multiple myeloma. The ubiquitin proteasome system (UPS) is a fundamental regulator of protein quality in all cells, including cardiomyocytes. The regulation of protein turnover

Box 42.2  CASE STUDY OF CLINICAL

MANAGEMENT CONSIDERATIONS FOR BLOOD PRESSURE MONITORING A 52-year-old man with metastatic renal cell cancer with no significant past medical history is newly initiating therapy with sunitinib. Before sunitinib therapy is started, he has been noted to be hypertensive with a blood pressure of 142/92 at multiple clinic visits. What are important strategies to mitigate his cardiotoxicity risk? This patient may experience further increases in his blood pressure once sunitinib is initiated. Guideline panel recommendations suggest that formal risk assessment for the risk factors for adverse consequences of high blood pressure be performed (e.g., evaluation of cardiovascular [CV] risk factors such as hypertension, older age, dyslipidemia, obesity, hyperlipidemia; established CV disease including myocardial infarction, ischemic stroke, peripheral arterial disease; renal disease), and that preexisting hypertension should be identified and managed before the initiation of sunitinib.47 Active monitoring of blood pressure, particularly in the first cycle, and institution of antihypertensive therapy in the setting of blood pressure elevations through treatment should also be performed. No recommendations currently exist regarding “optimal” pharmacologic strategies to treat hypertension, although β-blockers, angiotensin-converting enzyme (ACE) inhibitors, dihydropyridine calcium channel blockers, or diuretics may be used, depending on the individual patient. Comorbid conditions (e.g., renal insufficiency, history of nephrectomy, bradycardia) or drug interactions are part of the decision-making process. Thyroid function should also be carefully monitored during therapy, because sunitinib is associated with the development of hypothyroidism, which may also have CV consequences.

is critical to the cardiomyocytes because they have very limited regenerative capacity.50 Cardiomyocyte survival depends on the critical balance of protein synthesis and turnover regulated by UPS.51 Regulation of protein degradation also occurs during the process of cardiac hypertrophy and atrophy, as well as myocardial ischemia and infarction.52 With this in mind, it is not surprising that proteasome inhibition, although a successful means of treating multiple myeloma, can result in cardiac dysfunction.53 In nonclinical studies, increased heart weight, increases in TnI, cardiac myocyte degeneration, LV enlargement, and myocardial hypertrophy were observed in cynomolgus monkeys treated with high-dose carfilzomib, an irreversible PI.54 A pooled analysis of several clinical trials revealed that 22% of patients had any grade of any cardiac event, including 7% HF.55 Although cardiac disease in patients with multiple myeloma may be secondary to comorbidities such as chronic anemia and amyloidosis, there are still no guidelines addressing how patients’ cardiac status should be assessed before they receive potentially cardiotoxic myeloma therapy. Carfilzomib treatment is associated with a poorly characterized syndrome of dyspnea, increases in pulmonary pressures, hypertension, new and worsening HF, arrhythmia, cardiac arrest, myocardial infarction, and venous thrombosis.56 The risk for carfilzomib-associated cardiac events increases with age greater than 75 years.56 Of note, studies indicate that many adverse effects were largely reversible with prompt cessation of therapy and initiation of HF treatment. Unlike carfilzomib, bortezomib reversibly binds the proteasome. Several cases of patients demonstrating dyspnea as an initial presenting sign have been reported in the literature.57,58 However, reports of cardiotoxicity associated with bortezomib-based regimens have been variable, with incidences ranging from 0% to 17.9% in clinical trials; the incidence rates of all-grade and high-grade cardiotoxicity associated with bortezomib were 3.8% (95% confidence interval [CI], 2.6%–5.6%) and 2.3% (95% CI, 1.6%–3.5%), respectively, with a mortality of

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 657

3.0% (1.4%–6.5%). Awareness of the cardiotoxicity potential with PIs and subsequent close monitoring59 of patients receiving these agents is necessary to ensure that patients continue to gain the clinical benefit from them.

Immunomodulatory Therapy There are a growing number of cancer therapies focused on modulating the effects of the immune system. The immune system has been long-recognized as playing an important role in myocardial homeostasis in HF, with both beneficial and detrimental effects, influencing both myocyte growth and loss.60 Immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, have been successfully used in melanoma and lung cancer. These agents have been associated with a low but clinically significant incidence of cardiomyopathy and HF, secondary to myocarditis. Case reports of patients treated with anti-CTLA4 and anti-PD-1 monoclonal antibodies in combination have described case fatalities secondary to marked cardiac compromise, with autopsy revealing marked lymphocytic infiltration of the myocardium.61,62 Cardiotoxicity has also been described with cell-based therapies such as engineered anti-MAGE-A3 T lymphocytes, hypothesized to be secondary to cross-reactivity between T lymphocytes and the cardiac protein titin.63

RADIATION THERAPY Radiation injury to exposed CV tissue occurs in a dose-dependent manner.64 Radiation causes DNA damage resulting in an inflammatory cascade, and an increase in capillary wall permeability, with dilation of vessels leading to radiation erythema and cell death.65,66 Chronic inflammation leads to hypoxia and oxidative stress. The terminal differentiation of fibroblasts into myofibroblasts leads to greater collagen deposition, apoptosis rather than mitosis during wound healing, and ultimately scar formation.65,66 Fibrosis is the chief process through which chronic radiation damage occurs. Risk factors for radiation-induced cardiotoxicity include total dose (>30–35 Gy), higher dose and fraction (>2 Gy/day), size of the radiation field and volume of heart involved, technique of radiation delivery, and type of radiation, as well as younger age, time since radiation exposure, and receipt of cardiotoxic chemotherapy agents.67 In addition, the patient’s underlying risk factors for CV disease, including smoking, hypertension, hyperlipidemia, family history, and diabetes mellitus, increase the risk of development of radiation-induced cardiotoxicity.67 The common types of radiation-induced cardiotoxicity include pericarditis, cardiomyopathy, CAD, and valvular disorders.

Pericarditis Chronic pericarditis was a common cardiac complication seen with early mediastinal radiation regimens.68,69 The development of pericarditis is dose dependent; the condition is usually self-limiting but may predispose the patient to chronic pericarditis.70 Pericarditis may manifest with fever, pleuritic chest pain, and tachycardia, or with no symptoms. Associated pericardial effusions are characterized by fibrous adhesions, high-protein exudate, and elevated inflammatory markers.65 Chronic pericarditis can occur anywhere from 3 months to over a decade after exposure to radiation, with almost 20% of those patients developing a constrictive pericarditis.69 The reported incidence of pericarditis has declined as radiotherapy techniques have improved, probably because of reduced radiation exposure to the heart, but long-term follow-up is needed.

Cardiomyopathy Although the myocardium itself is relatively resistant to radiation because cardiomyocytes seldom undergo cell division, diffuse interstitial fibrosis can occur after relatively low doses of radiation through

microvascular ischemia and injury to capillary endothelial cells.70,71 The risk of cardiomyopathy from radiation increases after 5 years, but it may take decades to develop.71 Myocardial fibrosis is usually seen at radiation doses above 30 Gy with standard fractionation and is often asymptomatic. Restrictive cardiomyopathy is seen after highdose radiation exposure; dilated cardiomyopathy is seen after anthracycline exposure. Diastolic dysfunction is increased in patients treated with radiation therapy and can be detected in 5% to 9% of asymptomatic patients after mantle irradiation, increasing the risk of exercise-induced ischemia and CV events.72

Coronary Artery Disease Radiation-induced CAD differs from ordinary CAD in that the involved lesions tend to be longer, preferentially involve the ostium, and occur within the radiation field.73–75 The stenosis secondary to radiation may be due to intimal proliferation, and damage to the vascular intima or atherosclerotic lesions.74 The incidence of radiation-induced CAD is increased with the mean dose of radiation to the heart and chest wall and with the presence of standard CV risk factors, and continues to increase over time.67,76,77 The rates of coronary events increase with mean dose of radiation and length of time from treatment.76–80 Prospective careful characterization of cardiac function in asymptomatic breast cancer patients who have received radiation have shown functional abnormalities in arterial stiffness in the radiation portal.81 CAD has been demonstrated in patients with lymphoma within the first 5 years of treatment with radiation, and risk for CV events increases with time from treatment.79 These long-term follow-up studies for CV events, taken together with the smaller prospective phenotyping studies (careful CV characterization) of asymptomatic survivors, suggest that radiation causes asymptomatic injury to CV tissue that may manifest as late CV events, and that the risk for those events increases over time.

Valvular Abnormalities Valvular dysfunction has been reported in patients with Hodgkin lymphoma treated with mediastinal irradiation.82 Aortic and mitral valve regurgitation has been observed 10 years after initial treatment, with 30% of patients progressing to aortic stenosis over the next 12 years. The valves demonstrated thickening, calcification, and reduced leaflet motion on imaging.83,84 A study of 4122 survivors of childhood cancer diagnosed before 1985 demonstrated a linear relationship between dose of radiation to the heart (>5 Gy) and mortality from cardiac events.85 Modern radiation techniques, including image-guided treatment delivery, three-dimensional treatment planning, proton therapy, and intensitymodulated radiation therapy (IMRT), have been developed to focus radiation at the tumor and spare the surrounding normal tissue. Longterm follow-up studies of contemporary treatment cohorts are needed to confirm reduction in radiation morbidity associated with these newer techniques.

DETECTING AND MONITORING CARDIAC TOXICITY Understanding the mechanism of action of novel (or investigational) anticancer agents on the CV tissue may help to identify specific effects to evaluate in nonclinical studies. The CV effects seen in nonclinical studies of investigational agents can then help identify specific adverse events to monitor prospectively in clinical trials. Once the cardiac effects of agents and combinations of agents are known, patients receiving these agents can be prospectively monitored. Before starting these agents or combinations, patients should be assessed for their underlying CV risk with the goals of managing the CV risk, monitoring for early cardiac injury, and mitigating injury.

658 Part II: Problems Common to Cancer and Therapy

Nonclinical Safety Assessment Nonclinical safety assessment has a role in understanding mechanisms of toxicities, in order to inform clinical testing and treatment strategies to reduce CV risk. In general, nonclinical CV safety assessment includes a defined CV safety study performed before the onset of clinical testing or in tandem with clinical studies. These studies include measurement of cardiac biomarkers, evaluation of blood pressure, heart rate, and simple telemetry in nonrestrained animals receiving single doses of varying concentration of an experimental drug. In addition, a minimal electrocardiographic evaluation is often done in restrained nonrodent animals at the conclusion of dosing in repeat-dose studies.86,87 The sensitivity for telemetered models and cardiac troponins to detect acute drug-induced changes in cardiac function is considered robust and translatable to human patients. The most definitive means to collect hemodynamic data during animal studies involves surgical implantation of pressure transducers into a major artery, with data collection by means of a radio telemetry device implanted in the abdomen.88,89 Nonclinical evaluation can provide information on anatomic and histopathologic changes in nonclinical safety studies post mortem. For example, detection of cardiac hypertrophy in animal studies relies on heart weight measurement and routine heart histopathologic assessment, rather than imaging. The majority of detailed nonclinical evaluations seldom extend beyond 6 months. Thus toxicities that emerge with chronic exposure are challenging to identify in shorter-term nonclinical (or in vitro) models. A predictive biomarker of cardiac injury that is measurable and altered in advance of eventual adverse effects in both humans and animals would be ideal.

Adverse Event Reporting and Monitoring in Clinical Trials Clinical trials are designed to evaluate efficacy and toxicity (specifically, adverse events). The majority of cancer clinical trials use the CTCAE from the National Cancer Institute (NCI) to provide a standard and consistent approach to reporting of adverse events. The tool is a library of adverse event items with unique clinical descriptions for severity grading of each item.90 In version 4.0, there are 36 unique items for cardiac disorders and 17 unique items for vascular disorders. In addition to severity reporting, CTCAE grading is used for protocol-specific eligibility criteria, dose modifications, identification of maximumtolerated dose, and recommended phase II dosage. The grading criteria for cardiac adverse events do not necessarily correspond with specific prognostic stages for heart disease because an acute adverse event that occurs in the course of treatment may not follow the same trajectory as is typically seen with heart disease progression. Table 42.2 shows the differences between cardiac disease classification and CTCAE grading. The grading criteria for adverse events is designed to identify a level of severity that would necessitate interruption of therapy in order to reduce further harm. Whereas acute and subacute cardiac events are captured during the course of treatment, late or delayed toxicities are not often identified in the trial period, but years later through surveillance efforts. Typically, trials will exclude patients with preexisting CV disease or comorbidities, making it easier to attribute adverse events to the agents under study, but reducing the generalizability of the treatment regimen for patients with comorbidities or preexisting CV disease. To date, much of the understanding of cardiac late effects results from surveillance studies of survivors of pediatric cancers, Hodgkin lymphoma, and early-stage breast cancer. The treatment regimens used in these cancer patients from the 1960s through the 1990s included radiation therapy and anthracyclines. As new agents are successful in changing the expected trajectory for other malignancies, such as melanoma, renal cell carcinoma, and lung cancer, there is a need to understand CV risk, how best to monitor for CV events, and how to manage the CV issues through the cancer treatment regimens and beyond.

Prospective monitoring for events requires an understanding or expectation of the event such that the modality and frequency of monitoring can be appropriately established. Through monitoring, asymptomatic changes may be identified, although the clinical consequences are not fully understood. Data are emerging that asymptomatic declines in LVEF are associated with increased risk of progression to overt HF with longer patient survival.91,92 Late cardiac effects from cancer treatment may reduce overall survival for cancer patients. Identifying the best methods for monitoring cardiac effects during treatment is essential to avoid overtreatment and optimize cancer outcomes.

Biomarkers Circulating biomarkers can be used to aid in the diagnosis of cardiac injury and dysfunction, have been studied as surrogate measures of toxicity, and also can be used as prognostic measures of clinical outcomes, particularly in HF. The most widely studied cardiac biomarker in cardio-oncology is cardiac troponin.93 Troponins are derived from cardiac and skeletal muscle, and cardiac troponins are found in the contractile apparatus and released via proteolytic degradation.94 Release of cardiac troponins occurs with ischemic injury, as well as with apoptosis, with necrosis, with normal myocyte turnover, as part of a cellular release of proteolytic degradation product, and during states of increased cellular permeability. Troponins can be detected early after injury, with high precision and accuracy, facilitating their usefulness.

Troponin In a study of 204 patients receiving high-dose chemotherapy (regimens including combinations of epirubicin, cyclophosphamide, docetaxel, ifosfamide, carboplatin, etoposide, carmustine, melphalan, mitoxantrone, idarubicin, and methotrexate), TnI elevation was observed in 32% of patients and was predictive of subsequent LVEF decline (although not all were symptomatic).95 A follow-up study performed by the same group in 703 patients treated with high-dose chemotherapy used serial TnI monitoring at multiple time points in each treatment cycle (immediately after drug administration and 12, 24, 36, and 72 hours after each cycle) and 1 month after completion of therapy.96 Only the highest TnI levels were considered. The pattern of TnI elevation identified patients at various degrees of risk for adverse CV clinical events over a follow-up time of 20 plus or minus 13 months. Those patients with persistent elevations early and late after chemotherapy completion had the highest risk for subsequent events. The positive predictive value of TnI was 84%, and the negative predictive value was 99%. A similar study from these investigators performed in patients with breast cancer who were treated with trastuzumab demonstrated that an elevated TnI was associated with a risk of cardiac events and LVEF declines, and lack of LVEF recovery despite HF therapy,14 with a positive predictive value of 65% and negative predictive value of 100%. Whereas others have also determined significant associations between elevated troponin levels and risk of LVEF declines in the setting of anthracyclines and trastuzumab therapy, the prognostic ability of TnI has not been confirmed.97 In that study, the area under the curve (AUC) for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was only 0.56 and for Tn was 0.61 in terms of identifying patients with and without a significant LVEF drop. New high-sensitivity (hs) troponin assays are currently available that provide superior diagnostic accuracy for acute coronary syndromes, and have been under investigation for the early detection of cardiotoxicity in cardio-oncology. Some studies have suggested that changes in hsTnI immediately after anthracycline exposure are associated with risk of LV dysfunction in patients with HER2-positive breast cancer receiving anthracyclines and trastuzumab.98,99

Natriuretic Peptides Natriuretic peptides have been extensively studied for their diagnostic and prognostic role in HF. Brain-type natriuretic peptide (BNP) and

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 659

Table 42.2  Cardiac Disease Classification and Adverse Event Grading Criteria HEART DISEASE CLASSIFICATION American College of Cardiology /American Heart Association (ACC/ AHA) Heart Failure (HF) Stages American College of Cardiology /American Heart Association (ACC/ AHA) New York Heart Association Class

Stage A

Stage B

Stage C

Stage D

At high risk for HF but without structural heart disease

Structural heart disease but no symptoms of HF

Structural heart disease with prior or current symptoms of HF

Refractory HF requiring intervention

Class I

Class II

Class III

Class IV

No symptoms, no limitations of physical activity

Mild symptoms, limitations of physical activity with ordinary activity

Limitations of physical activity with less than ordinary activity

Symptoms at rest

CANCER ADVERSE EVENT REPORTING (CTCAE VERSION 4) HF

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Asymptomatic with laboratory or imaging abnormalities

Symptoms with mild to moderate activity or exertion

Severe with symptoms at rest or minimal activity or exertion; intervention indicated

Life-threatening consequences; intervention indicated (e.g., continuous intravenous therapy or mechanical support) Refractory or poorly controlled HF due to ejection fraction drop; indication for intervention Refractory heart failure or other poorly controlled cardiac symptoms

Death

Life-threatening consequences; intervention indicated (e.g., continuous intravenous therapy or mechanical support)

Death

Left ventricular dysfunction

Restrictive cardiomyopathy

Right ventricular dysfunction

Asymptomatic with laboratory or imaging abnormalities

Symptoms with mild to moderate activity or exertion

NT-proBNP are standard biomarkers used in clinical practice for the diagnosis and management of HF. However, studies of natriuretic peptides for the prediction and diagnosis of cardiotoxicity are inconsistent.

Newer Biomarkers Newer biomarkers that are diagnostic or predictive of cancer therapy cardiotoxicity, and the use of a multimarker strategy, are areas of active investigation. A number of biomarkers such as heart-type fatty acid binding protein, myeloperoxidase, placental growth factor, and growth differentiation factor 15 have been evaluated in small studies and have demonstrated some promise as diagnostic or prognostic markers. The combinations of multiple biomarkers, and an integrated strategy of biomarkers and imaging measures, are also areas of active investigation in cardio-oncology. One small study of patients with breast cancer receiving doxorubicin and trastuzumab suggested that the evaluation of changes in myeloperoxidase and hsTnI in combination provided increased usefulness in defining the risk of first cardiotoxic event. Changes in myeloperoxidase, placental growth factors, and growth differentiation factor 15 from baseline were independently associated with each cardiotoxic event over 15 months of follow-up.99,100

Unanswered Questions About Biomarkers In the diagnosis and prediction of CV events, questions remain regarding the “confounding” effects of cancer on CV biomarkers, potentially limiting the sensitivity and specificity of conventional CV biomarkers

Symptomatic due to drop in ejection fraction responsive to intervention Symptomatic heart failure or other cardiac symptoms, responsive to intervention Severe with symptoms at rest or minimal activity or exertion; intervention indicated

Death

for detecting cardiotoxicity. Particularly with advanced tumor stage, elevations in biomarkers that are potentially relevant to the cancer and CV systems may be observed. One study of a cohort of 555 patients with different cancer subtypes suggested that CV biomarkers are also associated with worse all-cause mortality. Markers such as NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were increased with higher tumor stage and were significantly associated with all-cause mortality.101 To date, consensus-based cardio-oncology guidelines (Table 42.3) have recommended that biomarkers may be used as a methodology to detect early cardiac injury and identify patients at high CV risk, but have also suggested that questions remain as to their application and true usefulness.35 Insufficient data exist to direct delivery of cancer treatment based on cardiac biomarkers because the precise timing and frequency of biomarker assessment, the appropriate cut points in cancer populations, and the optimal assay platforms have not been validated in the context of cancer pathophysiology and treatment. Clinical studies are needed to further define and validate.102

Imaging Strategies Echocardiography Echocardiography remains the mainstay of routine cardiac structure and function assessment before, during, and after cancer therapy and is incorporated in many clinical algorithms. Advantages of echocardiography include widespread availability and lack of ionizing radiation.

660 Part II: Problems Common to Cancer and Therapy

Table 42.3  Cardiology and Oncology Society Guidelines and Expert Consensus Statements Focus

Organization

Title

Link

Cardiovascular Imaging and Cardio-Oncology

American Society of Echocardiography and the European Association of Cardiovascular Imaging

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients During and After Cancer Therapy: A Report Expert Consensus for MultiModality Imaging Evaluation of Cardiovascular Complications of Radiotherapy in Adults: A Report ACCF/ACR/AHA/NASCI/SCMR 2010 Expert Consensus Document on Cardiovascular Magnetic Resonance: A Report 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults 2016 ESC Position Paper on Cancer Treatments and Cardiovascular Toxicity

Eur Heart J Cardiovasc Imaging. 2014;15(10):1063–1093 https://www.ncbi.nlm.nih.gov/ pubmed/?term=25239940 J Am Soc Echocardiogr. 2013;26(9):1013–1032 https://www.ncbi.nlm.nih.gov/ pubmed/?term=23998694 J Am Coll Cardiol. 2010; 55(23): 2614–62 https://www.ncbi.nlm.nih.gov/ pubmed/20513610 Circulation. 2013;128(16):e240–327 https://www.ncbi.nlm.nih.gov/ pubmed/?term=23741058 Circulation. 2014;129(25 Suppl 2):S1–45 https://www.ncbi.nlm.nih.gov/ pubmed/?term=24222016

European Association of Cardiovascular Imaging and the American Society of Echocardiography American College of Cardiology Foundation Task Force on Expert Consensus Documents Heart failure

Lipid management

Hypertension

American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines American College of Cardiology/ American Heart Association Task Force on Practice Guidelines

European Society of Hypertension/ European Society of Cardiology Panel Members Appointed to the Eighth Joint National Committee

Cardio-oncology

ESC Committee for Practice Guidelines: Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee European Society for Medical Oncology

Cancer survivorship

American Society of Clinical Oncology

Children’s Oncology Group

National Comprehensive Cancer Network

International Late Effects of Childhood Cancer Guideline Harmonization Group

Cardio-oncology research

National Cancer Institute/National Heart, Lung, and Blood Institute

Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors Cardiovascular Toxicity Induced by Chemotherapy, Targeted Agents and Radiotherapy: ESMO Clinical Practice Guidelines Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: Clinical Practice Guideline Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Version 4.0, 2013 Guideline Insights: Survivorship. Version 1.2016 Recommendations for Cardiomyopathy Surveillance for Survivors of Childhood Cancer: A Report Cancer Treatment–Related Cardiotoxicity: Current State of Knowledge and Future Research Priorities

Eur Heart J. 2013; 34: 2159–2219 https://www.ncbi.nlm.nih.gov/ pubmed/23771844 JAMA. 2014; 311(5):507–520 https:// www.ncbi.nlm.nih.gov/ pubmed/?term=24352797 Eur Heart J. 2016 https://www.ncbi. nlm.nih.gov/pubmed/27565769 J Natl Cancer Inst. 2010;102(9):596– 604 https://www.ncbi.nlm.nih.gov/ pubmed/?term=20351338 Ann Oncol. 2012;23(suppl 7): vii155–166 https://www.ncbi .nlm.nih.gov/pubmed/?term =22997448 J Clin Oncol. 2017;35(8):893-911 https://www.ncbi.nlm.nih.gov/ pubmed/27918725 http://www.survivorshipguidelines. org/pdf/LTFUGuidelines_40.pdf Access Date September 2016 J Natl Compr Canc Netw. 2016;14(6):715–724 https://www.ncbi.nlm.nih.gov/ pubmed/?term=27283164 Lancet Oncol. 2015;16(3):e123–e136. https://www.ncbi.nlm.nih.gov/ pubmed/?term=25752563 J Natl Cancer Inst 2014;106(9):10.1093/jnci/dju1232 2014 Sep. https://www.ncbi.nlm.nih.gov/ pubmed/?term=25210198

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 661

Disadvantages include greater variability in the estimation of key parameters, in part related to limitations in image quality, particularly when acoustic windows are poor; and there is variability in interobserver and intraobserver interpretation. To assess LV function, the most commonly used metric is LVEF.103 LVEF is defined as the stroke volume divided by the LV end-diastolic volume and can be estimated visually or by quantitative methods (e.g., single or biplane method of disks or by linear dimensions). A clinically significant decline in LVEF is a decrease by greater than 10 percentage points to below the institutional limit of normal. The most recent American Society of Echocardiography guidelines on cardiooncology define “cancer therapeutics related cardiac dysfunction” in this way, with a normal reference limit of 53%, as defined by a number of normal databases.103 From echocardiography, additional measures of cardiac structure and function are also easily derived. Measures of diastolic function, which provide insight into LV relaxation pattern, stiffness, preload, and volume status, can also be quantified. Moreover, degree of valvular disease, pericardial disease, wall motion abnormalities, and ventricular size and wall thickness and atrial size can also be assessed in great detail. Newer modalities, such as cardiac strain imaging derived from two-dimensional speckle tracking, and three-dimensionally derived measures of cardiac function, size, and mechanics are also under active investigation as diagnostic tools indicative of subclinical dysfunction and prognostic tools indicative of subsequent LVEF declines. A growing body of literature suggests that measures of longitudinal and circumferential strain are abnormal in cancer patients, including survivors, despite a normal LVEF, and may be useful in the identification of patients at risk for subsequent LVEF declines.98,104 Although there is a growing use of strain in the clinic, the additive value of this measure remains to be determined, and research defining the incremental usefulness of strain as a diagnostic or predictive measure is ongoing.

lack of geometric assumptions in determining LV volumes and LVEF. CMR also offers insight into tissue characterization. A number of recent studies have also elucidated abnormalities in tissue characteristics after exposure to cancer therapy, and myocardial tissue relaxation times (T1, T2 and T2 weighted) can be used to identify myocardial injury and fibrosis. T2-weighted images provide insight into changes in cellular water content that accumulates in the setting of myocellular or microvascular injury or inflammation. T1-weighted images provide insight into myocardial injury and fibrosis. Currently, the use of both T1- and T2-weighted images is still primarily limited to research clinical trials. Late gadolinium-enhanced MRI quantifies myocardial fibrosis. Small studies in cardio-oncology have suggested a potential role for each of these techniques in defining structural changes after anthracycline chemotherapy exposure. However, disadvantages of CMR include cost and lack of widespread availability. CMR is also contraindicated in patients with ferromagnetic devices, including metallic breast expanders.103,107

Exercise Testing

Exercise testing, and directly measured peak V̇ o2, is widely used in HF to objectively and quantitatively assess exercise tolerance and to understand the potential causes of impaired exercise tolerance.108,109 Peak V̇ o2 is the maximum oxygen consumption reached during exercise and is a function of hemodynamics, neurohormones, the peripheral skeletal muscle response, and pulmonary function. V̇ o2 is indicative of cardiopulmonary fitness and is associated with CV morbidity and all-cause mortality. A growing body of literature in cancer patients suggests that cancer therapy, including anthracyclines and radiation, may affect cardiopulmonary fitness. A number of studies have reported impaired V̇ o2 in patients with breast cancer after receiving adjuvant therapy as compared with healthy, sedentary women.109

Multigated Acquisition Scanning

Endomyocardial Biopsy

Additional imaging modalities for the assessment of LVEF certainly exist and are also used clinically.105 Expert consensus statements recommend that the same modality be used for serial monitoring of LVEF, given that the results obtained with different techniques may not be interchangeable.103 Multigated acquisition scanning (MUGA) was one of the first modalities used to measure LVEF and is still in use today. MUGA provides a highly reproducible assessment of LVEF, with low intraobserver and interobserver variability. However, use of MUGA involves ionizing radiation and provides limited information on other cardiac structures (e.g., valvular disease, wall thickness, pericardial disease) and diastolic function. Cardiac stress testing using either echocardiography or nuclear imaging techniques involving radioisotope tracers (e.g., technetium sestamibi or rubidium positron emission tomography–computed tomography [PET-CT]) are used when concerns of coronary disease exist.

Endomyocardial biopsy is not routinely performed in current clinical practice in the United States in the diagnosis or management of cancer therapy–induced cardiotoxicity. However, as per the American College of Cardiology and American Heart Association Heart Failure guidelines, endomyocardial biopsy is a Class IIa, Level of Evidence C recommendation (usefulness/efficacy less well established, made on diverging expert opinion, case studies, or standard of care).34 Its use is primarily as a strategy in the evaluation of patients with HF when a specific diagnosis is suspected that would influence therapy.

Cardiac Computed Tomography Assessment of CAD, as well as pericardial disease and cardiac masses, can also be obtained from CV computed tomography (CT).106 This scanning is not routinely used in the assessment of cancer patients before or during cancer therapy as part of any standard algorithm, unless a specific question of interest exists relevant to, for example, coronary artery calcification, pericardial disease, or cardiac masses, including intracardiac thrombus. The detection of subclinical abnormalities such as coronary artery calcification on routine imaging used for other purposes including cancer staging may result in additional diagnostic workup.

Cardiac Magnetic Resonance Imaging Cardiac magnetic resonance (CMR) imaging provides accurate and reproducible assessment of cardiac size, structure, and tissue characteristics.107 CMR is considered the reference standard in the assessment of LV volumes, secondary to discrimination of cardiac borders and

Genetics The role of genetics in cancer therapy cardiotoxicity has focused largely on the study of SNP variants in anthracycline-induced cardiotoxicity, derived from survivor studies in children and adults. Two retrospective reports from the Children’s Oncology Group have identified polymorphisms in carbonyl reductase (CBR) and hyaluronan synthase 3 (HAS3) to be independent modifiers of anthracycline-related cardiomyopathy risk.110,111 Additional studies in childhood cancer survivors have identified polymorphisms in genes that regulate intracellular transport (SLC28A3, SLC28A1) of anthracyclines as independent predictors of cardiomyopathy risk,112,113 and RARG, which has also been linked to Top2β expression, further providing a mechanistic link to anthracycline-associated cardiotoxicity.114 A study of adult hematopoietic cell transplantation patients treated with anthracyclines identified an association between a polymorphism in the doxorubicin efflux transporter (ABCC2) and cardiotoxicity, also suggesting an important role for alterations in anthracycline metabolism in the development of cardiotoxicity.115 This study also identified RAC2, involved in free radical generation, and HFE, a regulator of iron metabolism, as modifiers of risk. Another recent genome wide association study of childhood cancer survivors exposed to anthracyclines with and without cardiomyopathy identified SNP rs1786814 on the

662 Part II: Problems Common to Cancer and Therapy

CELF4 gene as a potential modifier of risk in patients exposed to more than 300 mg/m2 of anthracyclines.19 Clearly, there is a need for more extensive genetic studies. However, in order to advance our understanding of the genetic basis of cancer therapy–induced cardiomyopathy, larger cohorts with carefully annotated phenotypic exposures and outcomes and high-quality genetic data are needed. Moreover, recent data also suggest that human inducible pluripotent stem cells (IPSCs)–cardiomyocytes can recapitulate the patient predisposition to cardiotoxicity and be used to understand the genetic basis of this disease process.116

MITIGATION STRATEGIES A number of epidemiologic studies and clinical trials have suggested that CV risk factors, such as hypertension, diabetes, obesity, hyperlipidemia, and a prior history of CV disease, play an important role in the development of cardiotoxicity, particularly as it pertains to the development of cardiomyopathy. For example, hypertension is associated with a substantially increased risk of HF in survivors of childhood and adult cancers that is more than additive compared with the risk in noncancer controls. The burgeoning field of cardio-oncology has led to the increased recognition of the role of CV risk factors in the development of cardiotoxicity, acknowledgment of the critical need for careful monitoring and treatment of common CV risk factors, and the notion that CV toxicity is manageable through the close collaboration of cardiologists and oncologists.2 Continuing education programs from CV and oncology societies are being developed to help clinicians and patients understand the cardiotoxic effects of cancer therapies and existing management strategies. Mitigation of cardiotoxicity and the implementation of cardioprotective strategies can be considered before, during, or after therapy. Most cardioprotection clinical trials in cardio-oncology have focused on populations exposed to anthracyclines and/or trastuzumab, testing the effect of various strategies on surrogate measures of cardiac injury, remodeling, and function, with the overall goal of decreasing the risk of subsequent HF with reduced ejection fraction and cardiomyopathy development. Of note, the incidence of HF with preserved ejection fraction in the population of cancer patients treated with cardiotoxic cancer therapies remains unknown, as do effective therapies to decrease this risk. The role of strategies to decrease risk of other cardiotoxicities with other cancer therapies, such as hypertension with VEGF inhibitors, has not been tested, although expert consensus statements to guide management do exist.47

Administration of Cancer Therapy Some cardioprotective strategies have focused on altering dosage and administration of agents, particularly anthracyclines, in terms of formulation, infusion rate, or type of anthracycline.13 Continuous infusion over extended periods of time has been shown to reduce myocyte injury in mice but has not improved cardiac outcomes in childhood cancer survivors.117–119 Eleven randomized controlled trials with different anthracycline regimens have been completed and published (1980–2015), and no significant difference in clinical HF was seen.120 The sequential rather than simultaneous administration of anthracyclines and trastuzumab has resulted in a decrease in the incidence of cardiotoxicity.

Pharmacologic Strategies Pharmacologic strategies include dexrazoxane, a derivative of the iron chelating agent ethylenediaminetetraacetic acid (EDTA) that may help to prevent damage from reactive oxygen species. This agent is perhaps the most well studied in the pediatric population.121–123 A meta-analysis of 10 randomized controlled trials that evaluated dexrazoxane with different anthracycline-containing treatment regimens and enrolled a total of 1619 patients with different diseases demonstrated a clinically

important reduction in cardiotoxicity.120 Concerns over decreased oncologic efficacy and an increased risk of second malignancies, although quite controversial,124 have limited its use. Because of concerns that dexrazoxane could, in theory, decrease long-term survival in curable patients, it is approved currently for use only in metastatic breast cancer in patients who have received a cumulative dose of 300 mg/m2 and who will continue to receive doxorubicin.125 A number of additional pharmacotherapy strategies have been evaluated in phase I to II studies or retrospective analyses. Many of these agents are those that are typically used in the treatment of HF, and include β-blockers, renin-angiotensin-aldosterone inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists.10 Carvedilol and nebivolol have been shown to attenuate declines in LVEF that are observed with anthracyclines in small studies.126 A small study of patients with breast cancer receiving trastuzumab suggested that bisoprolol was able to attenuate declines in LVEF that were observed in the placebo group.127 Metoprolol alone has not been shown to have a beneficial effect on LVEF,128 although in conjunction with ACE inhibitors a modest attenuation in LVEF decline was observed.129 Studies with the ACE inhibitor enalapril alone have also demonstrated conflicting results. ACE inhibitors have been shown to decrease risk of cardiac events in patients with abnormal TnI.96 Studies with ARBs have also been conflicting; some have shown no effect,130 and others a very modest effect.131 Aldactone may have some promising effects on mitigating declines in LVEF or worsening in diastolic function measures,132 as may statin therapy.133 A number of additional studies are underway that may help to provide further insight into this question.134 Clinical trials designed to assess both cardiac and cancer outcomes are needed to evaluate mitigation strategies.

Nonpharmacologic Strategies The effects of nonpharmacologic therapy such as physical exercise and diet remain to be determined, although this is an area of active investigation. Promising studies in the field of HF suggest that aerobic exercise training improves cardiopulmonary fitness, exercise tolerance, and resistance to fatigue. Although there is basic evidence to suggest that aerobic exercise results in a decrease in oxidative stress, myofilament apoptosis, and improved ultrastructural changes and energy metabolism, this remains to be translated to humans.

Cardiomyopathy Management The management of cardiomyopathy once it ensues largely follows conventional therapy for the management of HF and cardiomyopathy, including the use of β-blockers, renin-angiotensin-aldosterone system antagonists, and diuretic therapy as indicated.34 Recent studies have suggested that with anthracyclines, declines tend to occur within the first year after chemotherapy completion,15 and the earlier initiation of treatment of LV dysfunction was associated with a greater likelihood of recovery of LVEF. In this study, as noted earlier, recovery of LVEF was observed in patients with initiation of cardiac medications within 6 months of identification of dysfunction.135

CANCER SURVIVORS More than 15 million Americans with a history of cancer are alive.136,137 More than half of the survivors (56%) were diagnosed with cancer within the past 10 years, and almost half of the total survivors (47%) were over the age of 70 at the time of diagnosis.136 Recent surveillance studies have demonstrated late cardiac effects of cancer treatment and the potential for competing health outcomes in cancer survivors. There is an increased incidence of common CV risk factors in survivors, and studies suggest that there may be a biologic interaction between CV risk factors and cancer in the development of subsequent CV disease. For instance, hypertension in cancer survivors is associated

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 663

Cardiovascular risk factors and disease

Cancer therapy past and present

CV OUTCOMES

Cardio-oncology

Cancer biology and disease

CANCER OUTCOMES

Figure 42.2  •  The cardio-oncology balancing act. CV, Cardiovascular. (Adapted from a figure provided courtesy of Michel Khouri [personal communication].)

with a greater risk of CV events than in noncancer patients.138,139 There is a need to understand the individual cancer patient’s risk of CV disease before the initiation of cancer therapy in order to manage both the cancer treatment and the CV complications that develop during treatment (Fig. 42.2). Increasingly, data demonstrate that CV disease competes with breast cancer as a cause of death in older women. In patients with breast cancer aged 66 or older (identified through the Surveillance, Epidemiology, and End Results [SEER] Program between 1992 and 2000) who lived 10 years, death from CV disease was more common than death from breast cancer.140 In women with preexisting CV disease at the time of cancer diagnosis, 41% were more likely to die of a cardiac event than from breast cancer recurrence. Of note, only 25% of those women who died of CV disease had preexisting CV disease risk factors at the time of cancer treatment.140 A separate study evaluated adjuvant breast irradiation and found that women older than 66 years with intermediate or high CV risk are at increased risk within the first 6 months after radiation therapy of hospitalization or death from a CV event.141 A separate evaluation confirmed that older women with preexisting CV disease have a higher risk of dying from CV disease than from breast cancer recurrence.142 In this analysis of the Ontario Cancer Registry, which included women from age 50, the younger women with no preexisting CV risk factors had a very low risk from dying from subsequent CV disease.

Long-term survivors of Hodgkin lymphoma are at risk for late CV disease, including CAD, valvular disease, conduction abnormalities, and HF.143 The combination of treatment with both radiation and anthracyclines likely exacerbates the risk. An analysis of the Teenage and Young Adult Cancer Survivor Study cohort in England and Wales also demonstrated that mortality from CV disease was greatest for individuals diagnosed between 15 and 19 years of age and that adult survivors of Hodgkin lymphoma who were older than 60 years had a substantial increase in death from heart disease.144 There are over 400,000 survivors of childhood cancer in the United States today.145 More than 80% of children diagnosed with a childhood cancer will survive at least 5 years.146 With the success of cancer treatment has also come the realization of important long-term morbidity and late complications.147–149 In particular, cardiac events are the third leading cause of early death in pediatric cancer survivors, with the increased risk of CV death persisting beyond 25 years after treatment.150 The CV complications are not limited to cardiomyopathy and HF. Radiation, in particular, increases the risk for CAD, valvular disorders, arrhythmias, and pericardial disease.151 Radiation is associated with increased atherosclerotic disease and risk for stroke.152 Many of these studies demonstrate a significant increase in the risk for developing cardiac disease in cancer survivors from their cancer treatment. Assessing a patient’s underlying CV risk factors and implementing standard CV interventions may reduce their risk of developing, or accelerating, cardiac adverse events as a result of cancer treatment. One encouraging finding is the recently updated evaluation of the Childhood Cancer Survivor Study, which demonstrated that lowering therapeutic exposure was associated with lower mortality from late effects.153 A comparison of 15-year mortality from pediatric cancer patients treated in the 1990s as compared with those treated in the 1970s showed a statistically significant decrease in death from cardiac and pulmonary causes. Improved successes of anticancer treatments have increased the numbers of cancer survivors. As survivors live longer, the CV complications of cancer treatment regimens have become more apparent. There is a critical need to evaluate CV risk factors in patients with cancer before they undergo cancer therapy to better understand the risk for CV complications and to manage those complications through cancer treatment.2 Studies that investigate mechanisms of toxicity and evaluate approaches to mitigating toxicity are needed so both oncologists and cardiologists understand how best to optimize the outcomes for patients with cancer.

ACKNOWLEDGMENT The authors would like to thank Gwen Moulton, Scientific Communications Editor at NCI, Division of Cancer Prevention, for her editing and collaboration skills. The complete reference list is available online at ExpertConsult.com.

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106. Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013; 26(9):1013–1032. 115. Armenian SH, Ding Y, Mills G, et al. Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br J Haematol. 2013;163(2):205–213. 120. van Dalen EC, van der Pal HJ, Kremer LC. Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy. Cochrane Database Syst Rev. 2016;(3):Cd005008. 123. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicintreated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351(2):145–153. 124. Chow EJ, Asselin BL, Schwartz CL, et al. Late mortality after dexrazoxane treatment: a report from the Children’s Oncology Group. J Clin Oncol. 2015;33(24):2639–2645. 128. Witteles RM, Bosch X. Myocardial protection during cardiotoxic chemotherapy. Circulation. 2015;132(19): 1835–1845. 138. Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. 2013;31(29):3673–3680. 145. Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14(1):61–70. 151. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606. 153. Armstrong GT, Chen Y, Yasui Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med. 2016;374(9):833–842.

Cardiovascular Effects of Cancer Therapy  •  CHAPTER 42 664.e1 664.e1

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