Chapter 54: Onco-Cardiology

Onco-cardiology is a fast-growing medical subspecialty focused on the management of heart diseases in patients with cancer. Although cancer remains a leading cause of morbidity and mortality worldwide, the survival rate of patients with cancer has increased in the last 25 years. In the United States, the 5-year relative survival rate of patients diagnosed with cancer between 1975 and 1977 was 50%; it increased to 68% between 1999 and 2005. The US National Cancer Institute estimates that at least 13.7 million cancer survivors were alive in the United States in 2012 (¹). With the survival improvement, the long-term adverse treatment effects have also become more apparent. A survey of 1,807 cancer survivors with a 7-year follow-up found that 33% died of heart diseases and 51% died of cancer (²). Historically, since the late 1970s, the interest in chemotherapy-induced cardiotoxicity was focused on cardiomyopathy related to few chemotherapeutic agents. As the field of cancer therapies has expanded, so has the finding of other cardiovascular side effects such as transient left ventricular dysfunction, hypertension (HTN), cardiac arrhythmias, pericardial effusions, and arterial ischemia. Patients with known or subclinical cardiac disease are more susceptible to the cardiotoxic side effects of cancer therapy, and those with known cardiac disease often need to alter their cardiac management to allow for the treatment of cancer. This can be associated with significant cardiovascular risks. Onco-cardiology has evolved to address the cardiovascular needs of patients whose optimal outcome mandates close and collaborative efforts between cardiologists and oncologists in a multidisciplinary approach. Involvement of cardiologists in cancer patients’ care has changed from focusing on management of the cardiovascular complications of therapy to an overall assistance in the care of these patients from the initial cancer diagnosis to survivorship as outlined in Fig. 54-1.

Clinical knowledge and basic science discoveries in onco-cardiology have grown over the last decade. There is better understanding of molecular mechanisms of cardiac toxicity of several cancer drugs. An example is the observation that the Bruton tyrosine kinase receptor is expressed in the atria of human heart tissue (³). This tyrosine kinase receptor is the target of a novel drug, ibrutinib, used in certain hematologic malignancies including chronic lymphocytic leukemia. Ibrutinib has been associated with a significant incidence of atrial arrhythmias, potentially mediated by its on-target effect and more specifically by inhibiting the PI3K-Akt signaling pathway (³). Similarly, trastuzumab targets ErbB2 in breast cancer cells and has been shown to improve outcome and prolong survival in HER2+/ErbB2 breast cancer. The same receptors within the cardiac myocyte are responsible for normal cell function and myocyte repair. When affected by ErbB2 inhibitors like trastuzumab, secondary mitochondrial dysfunction can be observed (⁴). Other mechanisms of toxicities have recently been reported with older conventional chemotherapeutic drugs like the anthracyclines; cardiovascular toxicity of this drug has been recently linked to inhibition of topoisomerase IIβ (⁵). This enzyme is responsible for normal myocyte function, and its inhibition partially explains the cardiovascular toxicity of doxorubicin. In addition to the benefit of improving strategies to prevent drug toxicities, a better understanding of these biologic pathways may also provide better understanding of certain heart diseases and their management. For example, the discovery of the key role of ErbB2 in normal cardiac function and its relation to trastuzumab toxicity was followed by the discovery of the benefit of an ErbB2 agonist called neuregulin-1 in the animal models of heart failure (⁶). Neuregulin-1 is currently being studied for the treatment of heart failure in humans.

Aside from the direct cardiac toxic effect of certain cancer drugs (Fig. 54-2), many aspects of the cardiovascular system can be affected by cancer or cancer therapy (Fig. 54-3), resulting in a variety of cardiovascular syndromes.

Myocardial Dysfunction

Onco-cardiologists are often asked to assess patients with cancer and clinical heart failure (HF) symptoms. Although the most feared etiology is the progressive, permanent, and irreversible myocardial damage related to anthracycline toxicity, this in fact constitutes only a small percentage of patients with clinical HF. The majority of patients with new-onset HF in the setting of cancer and cancer therapy have their symptoms triggered by mechanisms other than anthracycline toxicity. Despite some overlap, a clinically useful approach is to divide patients into two groups based on the initial clinical presentation (Table 54-1). The first group includes patients presenting with sudden and new-onset acute HF with associated systolic dysfunction. These patients include those with cardiomyopathy related to sepsis, stress cardiomyopathy, and myocarditis (toxic or infectious). The second group includes patients presenting with subacute or chronic HF symptoms and includes those with underlying structural heart disease, those with chemotherapy-induced cardiomyopathy, and those with infiltrative myocardial conditions related to their underlying malignancies or to cancer therapy (amyloidosis, iron overload). Evaluation of these patients typically includes obtaining a two-dimensional echocardiogram, brain natriuretic peptide, troponin, thyroid function tests, iron/ferritin level, ischemia assessment, and occasionally endomyocardial biopsy.

Acute Cardiomyopathy

Most of these cases are related to conditions referred to as reversible myocardial dysfunction or stress cardiomyopathy. This is a phenomenon typically triggered by sepsis, but also occurs in a wide range of acute illnesses (see Table 54-1). Myocardial dysfunction has been documented in up to 40% of patients with sepsis and is a major predictor of mortality in this population (^7,8). During the course of the malignancy management, patients are at risk of these acute illnesses, especially during chemotherapy with secondary neutropenic sepsis. Physiologically, both left and right ventricular systolic functions are diminished with variable degrees of myocardial depression. This is typically reversed within 7 to 10 days. The exact mechanism for myocardial dysfunction is not well defined, and multiple theories have been suggested including the possibility of altered microcirculatory flow, mitochondrial dysfunction, myofibrillary dysfunction, autonomic dysregulation, altered calcium cellular transportation, and others (^7,9) (Fig. 54-4). Clinically, patients with reversible myocardial dysfunction/stress cardiomyopathy are recognized when evidence of new-onset left ventricular (LV) dysfunction is documented in the appropriate clinical setting (see Table 54-1). It is frequently associated with repolarization abnormalities on electrocardiogram (ECG) and minimal rise in cardiac troponins. Echocardiographic findings of severe LV dysfunction are typically out of proportion to the ECG changes and the cardiac biomarkers rise. The severity of LV dysfunction, however, correlates well with the brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels (^7,9). The management is focused on stabilizing the patient’s blood pressure using vasopressors if shock is present and transitioning to cardioprotective drugs like angiotensin-converting enzyme (ACE) inhibitors and β-blockers after the patient is weaned off of pressure support and when blood pressure is stable for 24 to 48 hours. Improvement and recovery of myocardial dysfunction are typically observed within 7 to 10 days (⁷). Persistent LV dysfunction beyond 2 weeks should raise suspicion of possible underlying ischemic heart disease or viral myocarditis in these typically immunocompromised patients. These two conditions are associated with significant rise in cardiac biomarkers like troponin and creatine kinase (CK)-MB. Patients with suspected ischemic heart disease should undergo evaluation and management of coronary artery disease. The diagnosis of viral myocarditis is more challenging because viral cultures and antibody titers have limited diagnostic accuracy. Myocardial biopsy is the gold standard in the general population for diagnosis of viral myocarditis despite its limited diagnostic yield (60% and 80% sensitivity and specificity, respectively) (¹⁰). This can be more challenging and risky in patients with cancer because they often have coagulopathy with risk of procedure-related complications (bleeding, myocardial perforation). The use of empiric therapy with intravenous immunoglobulin for its antiviral and immunomodulatory effect in this setting is controversial, especially with the limited data to support the benefit of such intervention in the adult population (¹¹). It is also typically associated with high-volume fluid shift, which can exacerbate HF. Figure 54-5 summarizes a suggested algorithm for evaluation of new-onset cardiomyopathy and HF in patients with cancer.

Chemotherapy-Induced Cardiomyopathy

Definition

A large number of chemotherapeutic agents have been linked to cytotoxic myocardial injury. Table 54-2 lists several groups of chemotherapeutic agents known to be associated with LV systolic dysfunction or HF. The ones most commonly associated with cardiomyopathy include anthracyclines, alkylating agents, and tyrosine kinase inhibitors (TKIs). Cardiotoxicity in general is defined as a drop in LV ejection fraction (LVEF) by 5% or more, to less than 55% in the presence of HF symptoms, or an asymptomatic drop in LVEF by 10% or more to less than 55% (¹²). Myocardial toxicity is also classified into type I and type II based on the nature of myocyte injury.

Type I Myocardial Toxicity

Anthracyclines are the prototype of drugs causing type I, irreversible myocyte damage. Histologic findings include myofibrillar disarray, disruption of cellular organelles, myofibrillar loss, and myocyte death (¹³). Myocardial toxicity is dose dependent, with <5% chance of cardiomyopathy observed at a cumulative dose of <400 mg/m² in the case of doxorubicin (150 mg/m² for idarubicin and 900 mg/m² for epirubicin). This risk increases to 26% at a cumulative dose of 550 mg/m² (¹⁴). Anthracycline-related cardiotoxicity has also been classified as acute or chronic. The acute form manifests as nonspecific ECG changes, arrhythmia, myopericarditis, and transient LV dysfunction. The more feared chronic form is marked by LV systolic dysfunction occurring many months to years following exposure and manifests as progressive HF. It is not clear whether the acute form of anthracycline cardiotoxicity is the prodrome of the more delayed cardiomyopathy form, because it has been shown that myocyte dysfunction can be observed even after the first dose of the drug. It is plausible that myocardial reserve allows normal cardiac function despite initial injury and until a second insult leads to further myocardial cell loss and subsequent systolic dysfunction. The long-term prognosis of chemotherapy-induced cardiomyopathy is much worse compared to other etiologies (¹⁵). For years, the understood mechanism has been based on the free radical and iron hypothesis. The addition of an electron to the quinone moiety of anthracyclines within the cardiomyocytes leads to the generation of excess reactive oxygen species (ROS) and subsequent mitochondrial and intracellular protein damage. This toxicity is further increased when ROS interact with iron, generating a surge of oxidative stress (¹⁶). More recently, topoisomerase IIβ was found to be a key mediator of anthracycline-induced cardiomyocyte toxicity. Anthracycline-mediated inhibition of topoisomerase IIβ causes double-stranded DNA breaks, which can lead to cardiomyocyte death (⁵). The use of topoisomerase IIβ level in peripheral blood leukocytes has recently been reported to be of potential benefit for risk stratification and as a surrogate biomarker for individual susceptibility for anthracycline-induced cardiotoxicity (¹⁷). In a small study, the level of topoisomerase IIβ was significantly higher in the anthracycline-sensitive group. Close cardiac monitoring with early recognition and treatment of LV dysfunction using β-blockers and ACE inhibitors within the first 6 months of onset has been shown to be associated with stabilization and even recovery of cardiac function (¹⁸). These observations are the basis for the current recommendations of routine cardiac monitoring during anthracycline therapy. Different diagnostic tools have been useful in monitoring these patients including the use of cardiac biomarkers and/or cardiac imaging studies (¹⁹). There is no consensus regarding the best approach and optimal timing for testing. At the University of Texas MD Anderson Cancer Center (MDACC), we rely on serial imaging with two-/three-dimensional echocardiograms with myocardial strain to monitor these patients (Figs. 54-1 and 54-6).

Multiple primary preventive measures may be needed to lower the risks of anthracycline-induced cardiomyopathy. Continuous infusions instead of repetitive boluses are associated with a lower incidence of myocyte damage (²⁰). Drug peak plasma level correlates with the degree of myocyte toxicity, whereas the area under the curve determines antitumor efficacy. Modified preparations of anthracyclines such as liposomal doxorubicin are associated with lower risk. Dexrazoxane is thought to lower risk through iron chelation and interference with the topoisomerase IIβ complex by preventing it from binding to anthracyclines. Finally, the use of β-blockers and ACE inhibitors or angiotensin receptor blockers has been associated with mixed results in small prospective studies (^21,22). It is not clear if they exert a potential cell protection effect or if they only have a beneficial hemodynamic effect. Their role in primary prevention of chemotherapy-induced cardiotoxicity is uncertain.

Type II Myocardial Toxicity

This toxicity is associated with reversible disruption of myocyte contractile function. Trastuzumab is the prototype drug. Other targeted chemotherapy agents, including several small-molecule oral TKIs, are also suspected to exert type II cardiotoxicity. The mechanism involves disruption of signaling pathways responsible for tumor growth and also for cardiac cell repair (ErbB2 in the case of trastuzumab), resulting in myocyte dysfunction but not cell death (²³). Up to a third of patients treated with trastuzumab develop evidence of LV systolic dysfunction or HF symptoms that are often reversible upon discontinuation of this agent (²⁴). Re-initiation or continuation of trastuzumab after LV systolic function recovery is usually well tolerated. The US Food and Drug Administration (FDA) recommends monitoring LV function with imaging every 3 months during therapy. Not all patients are at the same risk, and several predisposing factors increase susceptibility for trastuzumab cardiotoxicity. These include concomitant use of anthracyclines, advanced age, and HTN or other underlying structural heart disease. There is an incremental increase in the incidence of LV systolic dysfunction or HF as the number of risk factors increases. For example, the risk of myocardial dysfunction increases from <1% in young women with no risk factors to 27% in elderly patients receiving concomitant anthracyclines (¹²). A clinical risk stratification model (National Surgical Adjuvant Breast and Bowel Project cardiac risk score) has been proposed to help risk stratify patients, but it needs to be validated (²⁵).

Tyrosine kinase inhibitor–related LV dysfunction has been reported since early phase I and II studies. The mechanisms of toxicity are not fully understood, and several theories have been proposed, including apoptotic versus nonapoptotic cell death, dysregulation of cellular energy hemostasis through inhibition of 5-AMPK (²⁶), mitochondrial toxicity, and HTN-mediated LV dysfunction (²⁷). The incidence of TKI-related cardiomyopathy and HF varies widely with different drugs (mostly reported with sunitinib, sorafenib, imatinib, nilotinib, and ponatinib) and differs between studies by almost 10-fold. This is partially related to the fact that cancer trials typically do not have cardiovascular events as outcomes, and this likely leads to an underestimation of the incidence of such events. Also, the usual clinical HF symptoms of fatigue, dyspnea, and leg edema are nonspecific in patients with cancer, leading to limitations in clinical diagnostic accuracy. The incidence of symptomatic HF necessitating medical therapy varies between 1.5% and 15%, and the rate of reported drop in LVEF is between 7% and 28% (^{27,28,29,30,31}). Time to onset of cardiomyopathy varies from a few weeks to several months after initiation of TKIs. Evidence of reversibility of significant LV dysfunction was seen in half of the patients after TKIs were discontinued.

Management

When clinical HF or LV systolic dysfunction is confirmed, patients typically are taken off of the TKI, and HF drugs are initiated (ACE inhibitors, β-blockers, and diuretics). Depending on the patient risk factors and clinical presentation, workup for other possible etiologies of cardiomyopathy should be performed when appropriate (ie, ischemic heart disease, HTN). In the absence of strong prospective data, there is not enough information to support the routine use of cardiac imaging to monitor asymptomatic patients. It is common practice to obtain a baseline two-dimensional echocardiogram study before initiating these drugs, with a low clinical threshold to obtain repeated echocardiographic studies if dyspnea or fluid retention symptoms develop on TKIs.

Preexisting Cardiac Dysfunction

This is usually observed in patients with underlying diastolic or systolic LV dysfunction including hypertensive heart disease, ischemic heart disease, or nonischemic cardiomyopathy. Decompensated HF symptoms are often triggered by large amounts of intravenous fluids given during certain chemotherapy infusions (eg, cisplatin). Patients typically respond well to withholding fluids and using diuretics. Standard HF therapy, including β-blockers and ACE inhibitors, is indicated if LV systolic dysfunction is present (³²).

Other Forms of Cardiomyopathies Observed in Cancer Patients

Infiltrative processes are another cause of cardiomyopathies commonly encountered. Examples include amyloidosis and secondary hemochromatosis. In patients with myelodysplastic syndrome, myocardial iron overload develops from frequent blood transfusions (ie, >100 units).

Ischemic Arterial Disease in Cancer

The association between malignancy and ischemic arterial diseases is well established. The clinical presentation and management of arterial ischemic events vary based on the arterial bed and the organ involved. The clinical spectrum includes stroke, myocardial infarction, and visceral and limb ischemia. In two large separate cohorts of patients with cancer, Khorana et al reported a 1.5% to 3.1% incidence of arterial ischemic events (^33,34). The most common events were cardiac, and less than 0.5% of events involved limb ischemia. The rate of arterial ischemic events is higher in specific cancer populations such as those with myeloproliferative disorders or hematologic malignancies with secondary amyloidosis. To assess the significance and outcome of these arterial events, Khorana et al prospectively followed 4,466 patients receiving active chemotherapy. Thromboembolism was a leading cause of death (9.2%) (³⁵), with a higher rate of death from arterial events compared to venous events.

Etiology and Mechanisms

In addition to the usual causes and the traditional risk factors typically associated with arterial ischemia in the general population, patients with underlying malignancy have added increased risks for arterial ischemic events related to the inherent thrombophilia associated with the cancer and its therapy (Table 54-3). From the clinical perspective, it is useful to divide these cancer-related etiologies into two broad categories; the first category includes mechanisms, and the second group includes cancer etiologies.

Specific Mechanisms of Arterial Ischemia

Hypercoagulability

Multifactorial mechanisms have been implicated in the pathogenesis of hypercoagulability and thrombosis. As shown in Fig. 54-7, circulating and in situ cancer cells can enhance activity of tissue factor and other cancer procoagulant factors and can activate platelets. These mediators can then trigger coagulation in previously damaged vessels like the coronary arteries or peripheral arteries or even in previously healthy vessels (³⁶). The end result is cancer-enhanced thrombosis, which manifests as (1) low-grade disseminated intravascular coagulation, (2) venous thrombophlebitis, (3) arterial thrombosis, (4) accelerated ischemic cardiac and peripheral vascular disease, and (5) nonbacterial thrombotic endocarditis. Another subgroup of patients with a hypercoagulable condition present with digital ischemia with no evidence of large-vessel involvement (Fig. 54-8). The mechanism is thought to be due to capillary deposition of antigen-mediated antibody complexes from tumor cells. This paraneoplastic syndrome is usually very difficult to treat; symptoms do not respond to usual vascular therapy until the cancer is fully controlled (³⁷).

Other Mechanisms

Other reported etiologies include radiation therapy, tumor embolization, arterial wall invasion by tumor, and paradoxical embolization. Often, a specific cause is never identified. In our cohort of 74 patients (³⁸) with acute arterial limb ischemia, 24 confirmed pathology samples were available. The majority of patients (67%) had thrombus, and 21% had associated underlying significant atherosclerotic disease. Tumor invasion of the artery was observed in two cases, and only one patient with leukemia had leukemic cell aggregates (Fig. 54-9).

Thrombotic Events Associated With Specific Malignancies and Cancer Therapy

Myeloproliferative Disorders

Myeloproliferative disorders, such as polycythemia vera and essential thrombocythemia, are associated with vascular events characterized by microcirculatory dysregulation and thrombosis in various central and peripheral terminal arterial beds leading to ischemic strokes and acute coronary syndrome (^39,40). The incidence of thrombosis at diagnosis of polycythemia vera and essential thrombocythemia is 9.7% and 38.6%, respectively, in various studies, with 64% to 96.7% of these being arterial events (⁴¹). Primary prevention of thrombosis in myeloproliferative disorder involves the use of aspirin (⁴²).

Acute Leukemia

Although hemorrhage is the typical complication in acute leukemia, arterial ischemic events due to thrombosis can occur. De Stefano et al reported a 1.4% incidence of thrombosis at presentation in acute lymphoblastic leukemia and a 9.6% incidence in acute promyelocytic leukemia (⁴³). Thromboembolism was reported as the presenting manifestation in more than half of the patients in this study, with 80% venous thromboembolisms and 20% arterial ischemic events. Options for management include leukapheresis, immediate chemotherapy, and sometimes revascularization of large-vessel occlusion.

Cardiac Amyloidosis

Primary amyloidosis, particularly AL type, has been associated with intracardiac thrombosis and thromboembolic events despite preserved LVEF and absence of cardiac arrhythmias, with an incidence ranging from 26% to 33% (^44,45) and arterial thromboembolism–related mortality of 26% in one study (⁴⁵). A variety of mechanisms have been proposed for this phenomenon including endothelial dysfunction, endomyocardial damage (⁴⁶), direct myocardial toxic effect (⁴⁷), and hypercoagulability (⁴⁸). In managing these patients, the benefit of prophylactic anticoagulation needs to be balanced against the risk of hemorrhage from fragile blood vessels with amyloid deposition (⁴⁹).

Arterial Ischemic Events Related to Cancer Management and Therapy

Certain chemotherapeutic agents are known to have a stronger association with arterial ischemic events due to specific pathophysiological mechanisms. These drugs can be divided into two categories (Table 54-4). The first category includes several standard chemotherapeutic agents like L-asparaginase, cisplatin, 5-fluorouracil, capecitabine, and gemcitabine. In a study by De Stefano et al, the incidence of thrombosis in a population with acute lymphoblastic leukemia was shown to increase from 1.4% to 10.6% with L-asparaginase treatment (⁴³). Cisplatin is known to induce thrombosis by causing endothelial damage (⁵⁰) and increasing monocyte tissue factor activity and platelet activation with a reported 12% to 17.6% (⁵¹) incidence of thrombosis, including strokes, recurrent peripheral arterial events, and aortic thrombosis (⁵²). 5-Fluorouracil leads to a decrease in protein C and endothelial independent vasoconstriction via protein kinase C (⁵³). Gemcitabine has been associated with vascular events including systemic capillary leaks, thrombotic microangiopathy with digital ischemia, and venous thromboembolism (⁵⁴).

The second category of cancer drugs associated with arterial ischemia includes the group of angiogenesis inhibitors like thalidomide and several targeted therapy drugs also known as the vascular signaling pathway inhibitors. These include bevacizumab and several TKIs like sunitinib, sorafenib, axitinib, pazopanib, and ponatinib. Thalidomide is associated with a risk of vascular thrombosis due to its anti-angiogenic effects and modulation of adhesion molecules (^55,56). In a prospective cohort of 195 patients with multiple myeloma, 11 patients developed an arterial ischemic event over a period of 522 patient-years (5.6%) (⁵⁷). Several of these patients developed arterial thrombosis while receiving anticoagulation therapy. Bevacizumab has been linked to serious arterial ischemic events (^58,59) through mechanisms such as endothelial damage and overexpression of proinflammatory genes (^60,61,62). In patients receiving concurrent bevacizumab and chemotherapy, Scappaticci et al reported the absolute rate of arterial events as 5.5 events per 100 person-years (⁶³). Pereg and Lishner reported the efficacy of low-dose aspirin in preventing cardiovascular complications in patients 65 years of age or older who had a prior history of thromboembolic events and were receiving bevacizumab (⁵⁸). The mechanism of vascular toxicities associated with TKIs is not well understood and is thought to be partially mediated by nitric oxide inhibition versus accelerated atherosclerosis and possible interference with platelet function. In a meta-analysis by Choueiri et al, the incidence of arterial ischemia was 4% with a three-fold increase in risk in patients treated with sunitinib or sorafenib (⁶⁴). Arterial ischemia with ponatinib has been reported to be greater than 20%, leading to the implementation of major restrictions on indications and monitoring by the FDA (⁶⁵).

Management

The management strategy should be tailored to the patient’s clinical condition and the cancer type. Primary preventive strategies include life-long antiplatelet therapy and statins for radiation-induced and known underlying atherosclerotic disease, aspirin and/or hydroxyurea for myeloproliferative disorders (⁶⁶), and aspirin for patients with a history of prior cardiovascular events or who are over age 65 and receiving bevacizumab (⁵⁸). Treatment of the acute event varies by type of organ involved (cardiac, central nervous system, limb, or bowel ischemia) and is aimed at reversing ischemia and minimizing organ damage, followed by long-term therapy and secondary prevention. The decision to use medical therapy versus a surgical or percutaneous approach for revascularization is determined by the general condition of the patient and availability of local expertise. Management of these patients is often a challenge because of the bleeding risks, especially in the setting of associated thrombocytopenia. Although acute coronary intervention has been shown to be reasonably safe in these patients (⁶⁷), there is a significant concern regarding the need for dual antiplatelet therapy for an extended period of time. Drug-eluting coronary stents pose a special problem in this setting and should be avoided. We typically recommend using bare metal stents because many patients end up receiving more chemotherapy and/or surgery for the management of cancer. The type of long-term anticoagulation recommended for secondary prevention depends on the underlying mechanism and etiology. Table 54-5 summarizes some of the therapeutic interventions for arterial ischemic events observed in the setting of malignancy or hematologic disorders.

Cardiac Arrhythmia

Introduction

Patients with cancer have complex comorbidities that predispose to certain arrhythmias and limit the therapeutic options when using antiarrhythmic drugs. Patients with underlying malignancy can develop cardiac arrhythmia as a consequence of the malignancy itself or its therapy (Fig. 54-10). When patients present with cardiac rhythm disturbances, they typically have associated complex comorbidities. The presence of a rapid heart rate or rhythm irregularity can be simply a sign of a more complicated and severe acute illness (eg, atrial tachycardia or fibrillation in the setting of acute pulmonary embolism, polymorphic ventricular tachycardia triggered by severe metabolic derangements and electrolyte imbalance while on a QT-prolonging agent). Adequate patient management necessitates accurate diagnosis and identification of the potential etiologies and mechanisms that triggered the arrhythmias.

Diagnosis and Management

The management of cardiac arrhythmia should follow the well-established standard-of-care guidelines (^68,69). Treatment can sometimes differ slightly from those without malignancy. The difference is mainly related to the choice of antiarrhythmic drugs and atrioventricular-blocking agents and the timing and safety of anticoagulation. The choice of these drugs should take into consideration the possibility of drug-drug interactions. Cardizem and verapamil are potent cytochrome P inhibitors that can alter the pharmacokinetics of many chemotherapeutic agents. Several classes of antiarrhythmic drugs can potentiate QT prolongation observed with many cancer-targeted therapies. The decision for short- and long-term anticoagulation for atrial fibrillation or flutter should be tailored carefully in each case, because many patients face higher risks of bleeding in the setting of thrombocytopenia secondary to the malignancy or its therapy.

Bradyarrhythmias

Bradyarrhythmias can generally be categorized as sick sinus syndrome or heart block. The most common presenting symptoms of bradyarrhythmias include fatigue, lightheadedness, dizziness, or syncope. Many different causes have been linked to bradyarrhythmias. These include myocardial infiltration, atrioventricular nodal blocking drugs such as antiemetics, and certain chemotherapies. like paclitaxel and thalidomide. Possible suggested mechanisms include direct effect on the Purkinje system and extracardiac autonomic controls. The incidence of bradycardia with paclitaxel is as high as 30%. A less common but equally important cause of bradycardia is baroreflex failure. This is typically characterized by volatility of heart rate and blood pressure, including profound and severe bradycardia necessitating the use of a permanent pacemaker. This is most often seen in patients who undergo extensive head and neck surgery or receive neck radiation therapy causing dysregulation of the autonomic system at the level of the vascular baroreceptors, the glossopharyngeal or vagal nerves, or the brainstem (⁷⁰).

Treatment

Treatment of bradyarrhythmias begins with identifying and removing any potentially offending agents that can exacerbate bradycardia. For severely symptomatic patients, urgent medical therapy with atropine or an intravenous inotrope, such as dopamine or epinephrine, may be used. In emergency situations, transcutaneous or transvenous pacemaker therapy may be required to maintain hemodynamic support. Long-term support with permanent pacing will depend on the severity of the symptoms related to the bradyarrhythmia and whether it is reversible.

Tachyarrhythmias

These are typically classified into four different categories:

1. Irregular tachycardia: atrial fibrillation, atrial flutter, multifocal atrial tachycardia

2. Regular narrow QRS complex tachycardia: sinus tachycardia, atrial tachycardia, supraventricular tachycardia

3. Wide QRS complex tachycardia: ventricular tachycardia, supraventricular tachycardia with aberrancy, preexcited tachycardia

4. Polymorphic ventricular tachycardia

Sinus tachycardia is by far the most common cause of rapid heart rate. It is usually secondary to other concomitant acute illnesses (eg, infection, pneumonia, pulmonary embolism, surgery). Evaluation and treatment of the primary etiology and the precipitating causes are effective.

Atrial fibrillation has been shown in several epidemiologic studies to be more prevalent in patients with cancer compared to the general population (⁷¹). Guzzetti et al reported a three-fold increase in the prevalence of atrial fibrillation in patients hospitalized with colon cancer compared to those admitted for nonneoplastic diseases (⁷²). The highest incidence of malignancy-related atrial fibrillation has been reported in patients undergoing thoracic (6%-32%) (⁷³) and esophageal (9.2%) (⁷⁴) cancer surgery. Postoperative atrial fibrillation appears to be associated with higher in-hospital length of stay, intensive care unit admissions, and more importantly, higher short- and long-term mortality (⁷²).

Acute management of atrial fibrillation follows the general recommendations of urgent cardioversion for the hemodynamically unstable patient and initial rate control for stable patients. Ventricular rate control can be achieved using atrioventricular-blocking agents like digoxin, β-blockers, or the nondihydropyridine calcium channel antagonists (diltiazem hydrochloride [Cardizem] or verapamil). Amiodarone can also be considered for rate control in patients with marginal blood pressure or LV dysfunction. For the subgroup of patients with previously known and documented permanent atrial fibrillation, controlling the heart rate and reversing the cause of acute decompensation should suffice.

The clinical decision for short- and long-term anticoagulation for atrial fibrillation is challenging and should be tailored individually because patients can be at high thromboembolic risk based on the standard risk scores used in cardiology and concomitantly at high risks of bleeding in the setting of thrombocytopenia secondary to the malignancy or its therapy. On the other hand, a patient with low thromboembolic risks based on these same scores can still be at high risk secondary to an acquired hypercoagulable state related to cancer or its therapy. Figure 54-11 shows a suggested algorithm to help risk stratify patients for anticoagulation in the setting of atrial fibrillation, based on their thromboembolic and bleeding risk scores. (This algorithm has not been validated.)

Patients with cancer require special consideration due to the risk of QT prolongation and torsades de pointes from both chemotherapeutic agents and adjunctive medications. QT intervals as measured by ECG reflect the total duration of the action potential at the cellular level. QT prolongation is associated with increased risk for polymorphic ventricular tachycardia, also known as torsades de pointes, and subsequent sudden cardiac death. The corrected QT interval is considered prolonged when it is greater than 480 milliseconds in women and 470 milliseconds in men. The QT interval varies with the cardiac rate and is typically reported as corrected QT interval (QTc) after correction for the patient heart rate. Current ECG technology and digital diagnostic algorithms can generate immediate measurement of the QTc interval. It is important to recognize that an accurate measurement and interpretation of QTc is essential to minimize the chances of inappropriate drug discontinuation or overestimation of the true incidence of QT prolongation with these drugs.

In the cancer population, there are several risk factors predisposing to QT prolongation and subsequent torsades de pointes. These include electrolyte imbalance (hypomagnesemia, hypokalemia, hypocalcemia), metabolic derangements (hypothyroidism), and certain cancer therapies including chemotherapeutic agents (Table 54-6). It is of clinical importance to correct any concomitant contributing factors that may predispose to or worsen QT interval prolongation. Cancer treatment interruption is typically advised when a QT interval is above 500 milliseconds, and permanent treatment discontinuation is recommended if QT prolongation recurs or is associated with ventricular tachycardia or syncope. Figure 54-12 shows a useful algorithm to screen and monitor patients being considered for therapy with agents associated with potential QT prolongation or torsades de pointes.

Among TKIs, a high incidence of QT prolongation has been reported with several of these drugs, leading to an FDA black box warning mandating close ECG monitoring and management recommendations (Table 54-7).

Pericardial Diseases

Pericardial diseases are common in patients with cancer and can manifest as acute pericarditis, pericardial effusion, cardiac tamponade, or constrictive pericarditis. Triggers of pericardial diseases include infections, tumor invasion of the pericardium, and cancer therapy, specifically chest radiation or chemotherapy (Table 54-8). The lack of randomized clinical trials makes the management of these syndromes mainly empirical, based on expert opinion and limited data extrapolated from the few trials in noncancer populations (^75,76).

Acute Pericarditis

The diagnosis of pericarditis is based on the findings of pleuritic chest pain, fever, and ST elevation detected by ECG. Patients are typically hospitalized after they present with acute pericarditis if they show evidence of high fever, suspected myopericarditis, and/or the presence of a large (>20 mm in diameter) pericardial effusion or have tamponade physiology detected by echocardiography. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are the mainstay of therapy for acute pericarditis. Intermediate to high doses of NSAIDs are typically used for 10 to 15 days followed by a slow taper over an additional 1 to 2 weeks. Colchicine is often added to the regimen at a dose of 0.6 mg daily for 3 months to help minimize recurrence (^77,78). It is a well-tolerated drug with few side effects. However, the few contraindications to the use of colchicine are common in patients with cancer, particularly in recent stem cell transplant recipients. Contraindications include significant interactions with several drugs, including antifungal agents, antibiotics, and immunosuppressants such as tacrolimus. These drugs can alter colchicine metabolism such that the level is significantly increased.

The use of corticosteroids is typically discouraged in noncancer patients because of significant side effects and the association with an increased incidence of recurrent pericarditis. The situation is reversed in patients with cancer due to the numerous contraindications to the use of aspirin and NSAIDs. Steroids are typically used in patients with low platelet counts or patients with blood dyscrasias when NSAIDs cannot be used. The evidence comparing the effectiveness of low-dose versus high-dose steroids is weak. High-dose prednisone of 1.0 to 1.5 mg/kg (or its equivalent) over many weeks with a slow taper is associated with the lowest rate of recurrence but with a high rate of steroid-related side effects. A lower dose of prednisone of 0.2 to 0.5 mg/kg is associated with fewer side effects but a higher relapse rate. Because there are no strong data to support one option over the other, we typically use the protocol summarized in Fig. 54-13.

Pericardial Effusion

Pericardial effusion is a common finding and has been reported in up to 34% of autopsies performed on patients with cancer. Its management is guided by three main factors: (1) clinical significance of the effusion (presence or absence of associated symptoms), (2) effusion size, and (3) etiology of the effusion

Etiology

Up to two-thirds of pericardial effusions are nonmalignant. The mechanism of effusion in this setting is likely related to loss of adequate lymphatic drainage of the pericardial sac secondary to lymphangitic spread of the malignancy or mediastinal irradiation. Other etiologies include infection, radiation, and certain drugs (see Table 54-8). Clarifying the specific etiology of an effusion not only helps to define the treatment modality, but also helps to determine prognosis because malignant effusions are associated with a dismal prognosis (1-year survival rate of 16% compared with 55% with nonmalignant effusions) (⁷⁹).

Diagnosis

Patients with a pericardial effusion may be asymptomatic but may also present with mild symptoms of chest pain, cough, and/or dyspnea. Extreme cases can present with frank tamponade and shock. Clinicians should be very careful when relying on vital signs to guide the management in patients with a pericardial effusion. Stroke volume and cardiac output drop at an early stage (as the effusion builds up). Blood pressure (BP), however, is maintained by a progressive increase in heart rate until it reaches a plateau, after which a threshold is reached and a severe drop in BP follows. Waiting for these clinical findings to manifest (ie, rapid heart rate and drop in BP) may cause treatment to occur too late, and the patient can rapidly progress to shock. Echocardiography is the main diagnostic tool to confirm the diagnosis of a pericardial effusion and detect tamponade physiology. Pericardial effusion size is classified as small, moderate, or large (large effusions are >2 cm in diameter). Helpful echocardiographic findings to detect early tamponade physiology include the presence of chamber collapse and/or of significant respiratory variation in the mitral or tricuspid valve inflow; these features manifest much earlier than BP drop and heart rate increase.

Management

There is no evidence that medical therapy plays any role in the management of an effusion, except in the case of concomitant inflammation (ie, pericarditis). At MDACC, the three main indications for pericardial fluid drainage are large effusion (>2 cm in diameter), diagnostic purposes, and the presence of clinical or echocardiographic evidence of tamponade physiology. As shown in Fig. 54-14, the first step following the detection of a moderate to large pericardial effusion is to assess for clinical or echocardiographic evidence of tamponade. If there is no sign of tamponade, the effusion size dictates the next step in management. Small to moderate effusions (<2 cm in diameter) are monitored clinically and with serial echocardiograms; larger effusions (>2 cm in diameter) require drainage because about one-third of patients progress to tamponade (⁸⁰).

Draining a pericardial effusion can be achieved percutaneously or surgically by creating a pericardial window and, in some centers, by thoracoscopy. Surgery is preferred in the setting of recurrent effusions, purulent effusions, or high-output drainage (>100 mL/d for 5-7 days following percutaneous pericardiocentesis). The percutaneous approach is preferred in the majority of cases at MDACC, especially if the patient has hypotension or a coagulopathy. Following pericardiocentesis, pericardial fluid is sent for analysis (chemistry, microbiology, cytology, flow cytometry, and sometimes to check for tumor markers) (⁸¹). A pericardial draining catheter is typically left in place for 5 days because this approach has shown to lower the effusion recurrence rate by two-thirds. Sometimes the catheter is removed early if drainage output is less than 25 mL over 24 hours and if there is no significant residual effusion on an echocardiogram. When performed by experienced teams, pericardiocentesis is safe with a low complication rate (<5%) and a high success rate (98%) (⁸²). Recently, we demonstrated the feasibility and safety of this approach in a cohort of patients with severe thrombocytopenia related to leukemia or chemotherapy (⁸³). Following initial pericardiocentesis, 25% of patients will develop recurrent effusions. Chemical pericardiodesis can be considered, but this approach can be complicated by severe pain, risk of infection, and long-term constrictive physiology, in addition to a 10% recurrence rate despite chemical pericardiodesis (⁷⁹).

Hypertension and Cancer Management

Hypertension is known to be the most commonly diagnosed comorbidity in patients with cancer (37%). Its prevalence prior to chemotherapy exposure is similar to that reported in the general population (29%). A higher rate has been reported in association with certain cancer therapies including alkylating agents, angiogenesis inhibitors, immunosuppressants, and hormones like steroids, erythropoietin, and some TKIs (eg, ponatinib) (Table 54-9) (^84,85,86).

Etiology and Pathophysiology

The most common chemotherapeutic agents known to cause HTN include several of the angiogenesis inhibitors, also referred to as vascular signaling pathway (VSP) inhibitors. These drugs include anti–vascular endothelial growth factor (VEGF) antibody (bevacizumab) and several TKIs (sunitinib, sorafenib, pazopanib, vandetanib, and ponatinib). Hypertension is one of the most common side effects of these drugs. Vascular endothelial growth factor normally plays an important role in maintaining a balanced vascular tone by regulating nitric oxide (NO) production in endothelial cells. Hypertension develops when NO bioavailability is reduced, leading to vasoconstriction, increased endothelin production, capillary rarefaction, and increased peripheral resistance (^86,87). New-onset or worsening HTN with these agents can develop very early (within 24 hours) after initiation but is typically observed within the first few weeks. Blood pressure usually returns to baseline shortly after therapy has been discontinued. Several previous limited observations raised the interesting concept of using HTN as a biomarker of cancer response to VSP inhibitors (⁸⁸). More data are needed to further clarify the clinical significance of such observation.

Other classes of chemotherapeutic agents are known to cause HTN. The incidence and time to hypertensive effect for the VSP inhibitors and other agents used in cancer therapy are provided in Table 54-9. Alkylating agents are commonly used in a large number of oncology protocols to treat various solid tumors and blood cancers. Hypertension is frequent with these agents and is commonly seen with cisplatin and busulfan and much less often with cyclophosphamide. Their effect has been observed both acutely as well as years after therapy has been discontinued. The mechanism is thought to be the result of endothelial dysfunction and arterial vasoconstriction (⁸⁴). Calcineurin inhibitors, used for the treatment of graft-versus-host disease, are also associated with a high incidence of HTN. Cyclosporine and tacrolimus are the major drugs in this class. Their effects are generally seen within the first 6 weeks of therapy and are thought to be the result of sympathetic system activation and an increase in endothelin-1 synthesis leading to vasoconstriction (⁸⁶). Following transplant, many patients receive immunosuppression with mycophenolate mofetil and the mammalian target of rapamycin inhibitor sirolimus. The mechanism by which these agents cause HTN is not well understood. Corticosteroids are frequently used and have been associated with variable rates of dose-dependent HTN. The mechanism by which they cause HTN is complex but likely involves increased production of angiotensinogen that induces salt and fluid retention, activation of the sympathetic nervous system, and an increase in patient sensitivity to vasoactive substances. Patients receiving erythropoietin for anemia are also at risk for experiencing severe HTN. The driving mechanism behind the HTN is complex and goes beyond just volume expansion. It is also the result of an activation of the renin-angiotensin system and an increase in endothelin-1 with a decrease in NO production due to changes in the erythropoietin receptor (⁸⁶).

Diagnosis and Management

Because HTN is a risk factor for chemotherapy-induced cardiotoxicity and poorly controlled HTN can lead to discontinuation of certain cancer therapies, a prompt and adequate intervention is essential to prevent potential irreversible damage. The Investigational Drug Steering Committee of the National Cancer Institute established a panel of experts to address the concern regarding VSP inhibitor–induced HTN. The recommendations published in 2010 focused on the evaluation, surveillance, and management of BP problems in patients receiving VSP inhibitors (⁸⁹). Treatment of HTN should begin at the time of diagnosis, without a concern of negatively impacting cancer treatment outcomes.

The choice of a pharmacologic regimen to manage HTN should take into consideration several factors. For example, the underlying pathophysiology leading to BP elevation in calcineurin-induced HTN is caused by excessive vasoconstriction that responds well to dihydropyridine calcium channel blockers. Diuretic agents can help relieve fluid retention associated with steroid-related HTN. Clonidine has been recommended for the management of severe BP swings in patients with baroreflex failure. Other important factors that need to be considered include the risk of drug-drug interactions. It is also important to consider agents that may have compelling indications in specific types of cancer. Several recent epidemiologic studies reported potential oncologic benefit of β-blockers in melanoma, breast, lung, and colon cancers with the mechanism suspected to be mediated by altering β-adrenergic signaling in cancer (⁹⁰). It is also important to consider the risks and benefits of medications that target NO or angiotensin II production when determining management strategies for patients on specific agents like the VSP inhibitors. Because these anticancer agents cause vasoconstriction in part through a decrease in NO production, medications such as nitrates, phosphodiesterase-5 inhibitors, and nebivolol, an NO-producing β-blocker, would in theory seem beneficial. However, there is a theoretical concern that by targeting this pathway these anti-HTN medications might compromise the efficacy of the antitumor therapy.

Radiation Therapy–Related Cardiovascular Toxicity

Radiation therapy to the mediastinum, left breast area, and neck region is a risk factor for premature coronary and carotid atherosclerotic disease (Fig. 54-15). The risk of arterial ischemic events depends on the radiation dose, technique, extent of vasculature exposed, and type of cancer (⁹¹). Radiation therapy can accelerate atherosclerosis by triggering oxidative stress leading to endothelial damage (⁹²). The acute injury during therapy is sustained for a long period of time via activation of nuclear factor-κB (⁹³). Symptoms typically manifest after a long latent period of 5 to 10 years following exposure. Mediastinal exposure is also responsible for a spectrum of cardiovascular syndromes including acute pericarditis, chronic constrictive pericardial disease, valvular heart disease, and myocardial dysfunction with restrictive cardiomyopathy. There is no defined threshold level below which radiation therapy is safe to the cardiovascular system. Modification of radiation protocols (including field planning and breath-holding techniques) is currently being done to reduce radiation dose to the cardiovascular system. The challenge in managing these patients is the long latency period between exposure and clinical manifestation, with many affected patients being no longer under the care of a treating oncologist. The 2013 expert consensus by the American Society of Echocardiography and the European Association of Cardiovascular Imaging recommends yearly clinical evaluation, with a history and physical exam, and echocardiogram studies in symptomatic patients. They also recommend a screening echocardiogram at 10 years after chest radiation and every 5 years thereafter. Primary prevention in patients with documented atherosclerosis following radiation therapy includes management of traditional atherosclerotic risk factors (⁴⁹). Lifelong antiplatelet therapy and statin therapy are recommended for their anti-inflammatory and antithrombotic effects on the irradiated endothelium (⁹⁴). Radiation-induced scarring makes surgical intervention difficult; hence percutaneous angioplasty with or without stenting is becoming the preferred revascularization method with encouraging results for radiation-induced renal, iliac, and femoral arterial disease (⁹⁵). Figure 54-16 shows our recommended algorithm for management and monitoring of these patients.