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These are outlined in Table 101–1, and a detailed discussion of heart failure, myocardial ischemia, changes in blood pressure, arrhythmias and QT prolongation, and thromboembolism follows below.
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Heart Failure and Left Ventricular Dysfunction
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Heart failure related to cancer therapy is currently defined by a decrease in cardiac function and categorized into irreversible injury (type I) or reversible dysfunction (type II). Apart from the pathophysiological definition of cardiotoxicty, there is no consensus definition of cardiotoxicity in terms of cutoff for LV ejection fraction (LVEF) at present.15,16 Trials studying cardiotoxicity in anthracylines and trastuzumab have long relied on the definition of cardiac dysfunction as a ≥ 5% decline in LVEF to result in an LVEF < 55% with symptoms of heart failure, or a ≥ 10% decline to result in an LVEF < 55% without symptoms of heart failure.5,7,11
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The CTCAE by the National Cancer Institute defines LV dysfunction as a reduction in LVEF > 5% to < 55% with symptoms of heart failure or an asymptomatic reduction in LVEF > 10% to < 55%.4 A most recent document released by the American Society of Echocardiography (ASE) defines chemotherapy-related cardiac dysfunction (CTRCD) as a decrease in the LVEF of greater than 10 percentage points, to a value < 53%, which is deemed the normal reference value for two-dimensional (2D) echocardiography as per this society.15 Centers such as MD Anderson and the European Society of Medical Oncolgy (ESMO)16 define CTRCD as a reduction in LVEF of 10% or more to < 50% with or without symptoms. As a consequence, at present, a consensus definition for cardiotoxicity is still lacking.
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The basic pathophysiology of heart failure is essentially the same in both cancer and noncancer patients. The neurohormonal hypothesis that forms the basis of the diagnosis of heart failure and shapes the strategies for effective treatment is applicable in both groups of patients. Heart failure and cancer progression also share pathophysiologic characteristics. It is imperative to understand the cause of heart failure in these patients, because this is one of the most important comorbidities that affects the lifespan of a cancer patient. Although the triggering event of the heart failure may be the chemotherapy, the contribution of preexisting and coexisting cardiovascular risk factors may be difficult to quantify separately.
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Strategies for Diagnosing Heart Failure and Left Ventricular Dysfunction
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The importance of the physical examination in confirming the presence of heart failure and LV systolic dysfunction in cancer patients cannot be overemphasized (see Chap. 69). Certain physical findings, such as a third heart sound or jugular venous distension, can be highly predictive of heart failure (see Chap. 11).
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Table 101–3 summarizes the typical causes of LV systolic dysfunction and heart failure in cancer patients. All of the major contributors to heart failure need to be investigated and treated appropriately to optimally affect the course of illness (see Chap. 70).
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Among basic laboratory studies, the electrocardiogram (ECG) does not discern heart failure or LV dysfunction, although it can confirm suspected abnormalities or indicate potential underlying cardiac disease, such as ischemia, conduction abnormalities or chamber enlargement. Additional laboratory testing should include lipid panel to indicate risk for vascular disease and blood glucose monitoring to screen for diabetes, both clinical predictors for heart failure. Anemia, especially common in cancer patients, has been directly correlated with outcomes in heart failure patients and should be part of a basic laboratory screen (see Chap. 70). Other specific biomarkers that are crucial in the evaluation of patients with suspected heart failure, especially those with cancer, include cardiac troponin I as well as B-type natriuretic peptide (BNP). Troponins may have value in screening for LV systolic dysfunction that develops during the course of chemotherapy.17 The role of BNP levels to detect early cardiotoxicity, LV dysfunction, or to detect volume overload has not been validated in this population. It may be falsely elevated without the presence of LV dysfunction or heart failure in cancer patients. A careful physical examination is still the most reliable means of characterizing volume status.
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LVEF, most commonly determined by echocardiography, is currently the mainstay of detecting heart failure or asymptomatic LV dysfunction during chemotherapy. Monitoring protocols for patients undergoing anthracycline-based chemotherapy in the 1970s and 1980s were developed and validated based on radionuclide multigated acquisition (MUGA) scans. These, though highly reproducible, have been largely replaced by echocardiography today and, as such, the algorithms validated for MUGA may be applied to echocardiography imaging. Widespread availability, feasibility, lack of radiation exposure, and acquisition of additional cardiac imaging information (valvular, pericardial, and hemodynamic data) make echocardiography an attractive option for serial imaging. Echocardiographic strain imaging has recently emerged as a promising method for detection of early cardiotoxicity prior to LV dysfunction. Three-dimensional echo imaging has shown promising results with least inter- and intraobserver variability and reproducibility, which could be comparable to MUGA. However, there are certain circumstances in which one technique is favored over the other. In pediatric patients, echocardiography is preferred because of the lack of ionizing radiation. In obese patients, however, adequate echocardiographic windows will be difficult to attain. Furthermore, the usefulness of echocardiography is limited in other variations of thoracic anatomy, such as emphysema, tight intercostal spaces, and heavily calcified ribs. Three-dimensional echocardiography is dependent on patient ability to hold the breath and requires a longer offline analysis. MUGA is less feasible in patients with arrhythmias as a result of poor electrocardiography-based triggering, which is more often seen in patients with heart failure. Regrettably, the choice of technique used is often not determined by the question of which method is more accurate or more suitable for the individual patient, but is rather governed by the availability of local resources and personal experience. Therefore, all the described noninvasive techniques should be used as complementary.
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Of particular interest in detecting early cardiotoxicity is the application of strain imaging, which is a measure of regional deformation of the myocardium. It is mainly obtained by angle-independent 2D speckle-tracking echocardiography, which can evaluate all three domains of myocardial mechanics (longitudinal, circumferential, and radial) and derive data for deformation and rate of deformation for each myocardial segment (Fig. 101–2). Two-dimensional speckle-tracking echocardiography has been used in multiple independent studies, reporting changes in cardiac (mechanical) function before a decrease in LVEF and even before changes in diastolic function after chemotherapy.15 Based on numerous studies of strain rate imaging during cancer chemotherapy, a greater than 10% change in global longitudinal strain (GLS) after completion of anthracycline-based chemotherapy relative to baseline is predictive of a future decrease in LVEF (Fig. 101–3). Conceivably, but subject to further studies, abnormal strain values before cancer therapy may signal higher baseline risk for chemotherapy-induced cardiotoxicity. Based on the above discussion, it seems appropriate to include strain imaging in monitoring algorithms for cardiotoxicity. Thereby, the ASE recommends strain rate imaging as an inherent part of a compreshensive echocardiogram for patients undergoing cancer chemotherapy. It also recommends three-dimensional (3D) echocardiography as the preferred technique for monitoring of LV function and detecting CTRCD in patients with cancer, as LVEF determination by 2D echocardiography, with or without contrast, has inherent inter- and intraobserver variability that may vary by up to 10% (Table 101–4).
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Other specific cardiac testing is frequently necessary to evaluate the extent of underlying heart disease that may be present in a patient with cancer. Exercise or pharmacologic stress testing can help investigate for CAD (see Chap. 13), and CAD angiographically the extent of coronary artery disease, LV systolic dysfunction, valvular abnormalities, and other hemodynamic disturbances. A myocardial biopsy may be appropriate when it is necessary to confirm a diagnosis of amyloidosis or myocarditis. Cardiac magnetic resonance imaging (MRI) may be extremely useful in the diagnosis of constrictive pericarditis, myopericarditis, or amyloidosis.
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The Principles of Therapy for Heart Failure
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The principles of therapy for heart failure and LV dysfunction in cancer patients are similar to those in patients without cancer. An often overlooked management component is the education of both the patient and family members regarding early recognition of the symptoms of fluid overload and decompensation. Management of patients who develop heart failure from cardiotoxicity during or after cancer therapy should be in keeping with the American Heart Association (AHA)/American College of Cardiology (ACC) heart failure guidelines (see Chap. 71). There is no reason to suspect that standard medical therapy would not be effective in most cancer patients as well.
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ACE inhibitors and β-adrenergic blocking agents remain the cornerstone of therapy and have specifically been studied in cancer patients.18,19,20 The timing from completion of anthracycline-based chemotherapy to initiation of heart failure therapy was identified as the crucial determinant of the response rate. Early initiation of these agents is key as the recovery of LV function is dependent on early intiation of heart failure treatment. The usefulness of ARBs, as alternatives to ACE inhibitors, for the treatment of heart failure can be extrapolated to the cancer population as well. The combination of nitrates and hydralazine is of special benefit in African American patients, as well as in patients with renal insufficiency not able to receive ACE inhibitors or ARBs. The precise role of aldosterone receptor antagonists (eg, spironolactone) in the treatment of chemotherapy-induced cardiomyopathy is currently unknown, but may be considered in those with New York Heart Association (NYHA) class > 1 symptoms and an LVEF of 35% or less.
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Hemodynamic device support may become necessary if medical therapy fails. Acute hemodynamic support can be temporarily lifesaving, as in those with acute myopericarditis owing to drugs such as cyclophosphamide. Alternatively, chronic LV assist device support may become a bridge to transplant or destination therapy in some resported cases as reported recently.21 The most severe forms of heart failure are usually observed in patients receiving both chemotherapy and radiation therapy because of the profound injury and in those of young age.3 Two key processes have been noted in children developing cardiotoxicity: reduction in contractility and/or increase in afterload. These have not been described in adults, but may be of significance for the choice of therapy. At present, it is unknown whether the medical therapies outlined above are necessary for agents that cause type 2 cardiotoxicity. Initial studies on trastuzumab-associated cardiomyopathy reported improved cardiac function after withholding therapy alone.10,22 This has remained the primary approach common to all published management algorithms for trastuzumab-associated cardiotoxicity. However, HER-2 inhibition is a vital element in the treatment of patients with breast cancer overexpressing this receptor, and thus “drug holiday” is of concern. It is currently undefined whether institution of cardioactive medication is necessary and would allow continuation of therapy without concerns for cardiac adverse effects. HER-2 upregulation, which is involved in trastuzumab-associated cardiotoxicity, merits investigation in targeted therapy of this pathway. Intriguingly, statins and nebivolol induce potent upregulation of this pathway. Whether such strategies would be counterproductive to the anticancer effects of therapy, however, remains an unanswered question.
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In addition, risk factors for heart failure should also be aggressively treated in cancer patients. Moreover, the higher incidence of drug–drug interactions in cancer patients undergoing chemotherapy and heart failure therapy should be recognized. It is imperative that unnecessary medications are avoided in these patients and that the addition of a potentially beneficial heart failure medication is carefully weighed against the risk of possible interactions with anticancer agents. Several alternative approaches are being developed that may be particularly appropriate for use in cancer patients with heart failure. Stem cell therapy for LV dysfunction, for instance, may become an important strategy in the future; methods of delivery and the enhancement of engraftment remain subject of intense investigation. There are a variety of other potentially useful agents for treating heart failure in cancer patients. IV immunoglobulin, which is used in patients who have immune deficiencies or even an excessive graft-versus-host response after bone marrow transplantation, may have important future implications. However, one randomized, controlled study did not show any clear benefit.23
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Cardiac devices are an integral part of modern heart failure management. Placement of an implantable cardioverter-defibrillator is reasonable in patients with LVEF of < 30% to 35% of any origin with NYHA functional class II or III symptoms who are taking chronic optimal medical therapy and who have reasonable expectation of survival with good functional status of more than 1 year, as per the ACC/AHA heart failure guidelines. Similar considerations pertain to biventricular pacemakers in appropriate cancer patients.
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Surgical therapy for heart failure has been intensely investigated, but as yet, there is no clearly established surgical technique for the management of heart failure (see Chap. 70). Coronary artery bypass grafting for the treatment of severe ischemic heart disease may be appropriate when dysfunctional, yet viable, myocardium can be revascularized, thereby restoring function. Other surgical techniques may be appropriate in selected situations resulting in heart failure, such as pericardial stripping for constrictive pericarditis or removal of intracardiac masses. Ethical concerns are also important when deciding on the appropriate therapy for a cancer patient with heart failure. One must consider to what extent the two entities interplay and to what extent they affect the patient’s overall prognosis. It is important to openly address end-of-life issues with patients so that the treatment approach incorporates the wishes of the patient as well as the reality of the clinical condition. The diagnosis of cancer should not imply that the patient’s heart failure cannot or should not be aggressively treated. Treatment decisions should be individualized.
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In addition to standard treatment of heart failure, key management of LV dysfunction resulting from cancer chemotherapy includes correction of risk factors, early detection, and regular surveillance. Tables 101–5 and 101–6, adapted from the ESMO guidelines,16 include key points for consideration while evaluating patients before and during administration of potentially cardiotoxic chemotherapy.
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The ability to detect a cardiotoxic insult continues to be a major challenge. Recent use of established biomarkers, such as cardiac troponin I and myeloperoxidase (MPO), in patients receiving chemotherapy has shown promise as an effective tool for identifying toxicity at its earliest stages.24 Use of global longitudinal strain imaging is emerging as a useful echocardiographic tool, but vendor-specific measurements and protocols need to be validated. Prevention of LV dysfunction from cardiotoxicity by use of of specific drugs such as candesartan (see “Prevention of Cardiotoxicity” later in the chapter) are emerging. Future research will include mapping genetic polymorphisms to identify cancer patients who are at increased risk for cardiomyopathy as a consequence of chemotherapy or to serve as a marker of an impaired ability to recover from a cardiotoxic insult.25 This may be especially important when considering antiangiogenic therapy, in which the main goal is to decrease microvascular blood flow to a tumor.
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Chest pain is a common symptom in cancer patients who are undergoing various forms of anticancer therapy. Chest pain often necessitates the interruption of chemotherapy, while serial cardiac enzyme assessments and ECGs are performed. If non–ST-segment elevation myocardial infarction (MI) or Q-wave MI is confirmed, patients should be managed according to the current ACC/AHA guidelines (see Chaps. 11, 39, and 41). However, thrombocytopenia and brain metastases pose a particular problem for cancer patients with an ACS because anticoagulant/antiplatelet therapies may be contraindicated under these circumstances. Similarly continuing dual antiplatelet therapy after percutanetous coronary intervention in cancer patients with impending cancer surgery, active bleeding, or thrombocytopenia, or in those undergoing bone marrow transplant, poses a clinical challenge where risks for coronary thromboses have to be balanced against those for bleeding.
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It is well established that radiation therapy to the mediastinum promotes an increased risk for infarction, and it appears more prevalent in patients with left-sided chest radiation. Additionally, several chemotherapy agents are known to precipitate or exacerbate an ischemic response. Cisplatin infusions can cause chest pain; palpitations; and, occasionally, elevated cardiac enzyme levels indicative of an MI. Cisplatin can also cause cardiovascular complications such as hypertension, LV hypertrophy, myocardial ischemia, and MI as long as 10 to 20 years after the remission of metastatic testicular cancer.6 5-Fluorouracil (5-FU) can also cause an ischemic syndrome that may range from subclinical ischemia to acute MI. Subsequent rechallenge with 5-FU frequently reproduces the initial ischemic event. Nevertheless, the ischemia is usually reversed when 5-FU treatment is stopped and anti-ischemic therapy implemented. In some patients, pretreatment with nitrates and calcium channel–blocking agents has allowed therapy deemed crucial to be continued. Capecitabine, which is currently used in the treatment of breast and gastrointestinal cancers, is believed to be less toxic than 5-FU, although its use has been associated with cardiotoxic effects including ischemic phenomena7 arrhythmias, ECG changes, and (rarely) cardiomyopathy. Vinca alkaloids, such as vinorelbine, also have been reported to cause angina associated with ECG changes and arrhythmias, as well as MI. Angina and MI are serious, but relatively rare, consequences of interferon-α therapy. Fatal MI and thrombosis have also been noted after the use of all-trans-retinoic acid (ATRA). Bevacizumab, a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the activity of human vascular endothelial growth factor (VEGF), was recently shown to be associated with an increased risk of angina and MI, in addition to serious arterial thromboembolic events, including cerebrovascular accident and transient ischemic attacks. It is used for the treatment of metastatic colon carcinoma and is generally used in combination with other agents. A new class of chemotherapy agents, termed vascular disrupting agents, is currently undergoing clinical evaluation. These agents have been noted to cause asymptomatic creatinine kinase-myocardial bound release and may be associated with ACS.
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Blood Pressure Fluctuations
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The classic malignancy causing hypertension, often paroxysmal or episodic in nature, is pheochromocytoma, a rare catecholamine-secreting tumor most commonly benign, although malignant in 10% of cases. Pheochromocytomas may be isolated tumors, but can also be associated with multiple endocrine neoplasia (MEN) syndromes of the type 2 variety, particularly the MEN 2A and MEN 2B syndromes. Bilateral pheochromocytomas are also associated with von Hippel-Lindau disease and neurofibromatosis. Benign pheochromocytomas usually can be resected surgically, but patients with such tumors require special anesthetic considerations, including pretreatment with phenoxybenzamine followed by the administration of a β-adrenergic blocking agent. Other tumors may also cause hypertension, including hyperthyroidism associated with thyroid tumors.
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Several cancer therapies may cause hypertension or hypotension (see Table 101–1). Newer targeted cancer therapies, which inhibit angiogenesis, frequently cause hypertension in cancer patients. Sorafenib is a potent inhibitor of the VEGFR-2, VEGFR-3, FLT-3, c-kit, and platelet-derived growth factor receptor in vitro and may affect the regulation of endothelial cell proliferation and survival. In clinical trials, sorafenib increases blood pressure in 17% to 43% of patients, whereas sunitinib is associated with slightly less hypertension, seen in 5% to 24% of patients. Similarly, hypertension has been observed in 4% to 35% of bevacizumab-treated patients. The mechanism by which these agents induce hypertension is not fully understood; however, it is thought to be related to VEGF inhibition, which decreases nitric oxide production in the wall of the arterioles and other resistance vessels. When treating hypertension in these patients, some antihypertensive agents may be preferred over others, because each agent affects angiogenesis in different ways. ACE inhibitors may be selected as first-line therapy, because of their ability to prevent proteinuria and plasminogen activator inhibitor-1 expression. In addition, in vivo, ACE inhibitors have demonstrated the potential to reduce microcirculatory changes, decrease the catabolism of bradykinin, and increase release of endothelial nitric oxide. Phosphodiesterase inhibitors and nitrates have also been suggested for the treatment of hypertension in these patients, because of their ability to increase nitric oxide levels. Lastly, the β-blocker, nebivolol, which has the unique mechanism of action of blocking β-adrenergic 1 receptors as well as causing vasodilation through the nitric oxide pathway, may also be beneficial in the treatment of hypertension caused by antiangiogenic cancer treatments.17 Antirejection regimen such as cyclosporine A, especially when used in conjunction with corticosteroids, are associated with hypertension; the incidence may be greater than 50%. The complex mechanism of cyclopsporin-induced hypertension includes alterations in vascular reactivity that cause widespread vasoconstriction, vascular effects in the kidney leading to reduced glomerular filtration and impaired sodium excretion, stimulation of endothelin, and suppression of vasodilating prostaglandins. Effective therapy includes use of vasodilating agents, often calcium channel blockers.
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Hypotension is the most common side effect of etoposide. The infusion of monoclonal antibodies commonly causes hypotension as a result of the massive release of cytokines (an acute transfusion reaction); these agents may also cause fever, dyspnea, hypoxia, and even death. Careful monitoring for hypotension is especially important for patients with preexisting cardiac disease. Cetuximab, a human/mouse chimeric monoclonal antibody that binds to the human epidermal growth factor receptor, may cause severe, potentially fatal infusion reactions characterized by hypotension, bronchospasm, and urticaria; this phenomenon occurs in approximately 3% of patients.26,27 Rituximab, a chimeric murine/human monoclonal antibody directed against the CD20 antigen, may cause infusion-related side effects that occur within the first few hours of the start of infusion. Supportive measures that are usually effective include IV fluids, vasopressors, bronchodilators, diphenhydramine, and acetaminophen. Interferon-α usually causes acute symptoms during the first 2 to 8 hours after treatment; these include flulike symptoms, hypotension, tachycardia, and nausea, and vomiting.28 The retinoic acid syndrome appears in approximately 26% of patients who receive ATRA, typically within the first 21 days of treatment. This syndrome includes fever, dyspnea, hypotension, and pericardial and pleural effusions.29 High-dose treatment with IL-2 may result in adverse cardiovascular and hemodynamic effects similar to those of septic shock28 and may lead to hypotension, vascular leak syndrome (hypotension, edema, hypoalbuminemia), and respiratory insufficiency requiring pressor agents and mechanical ventilation support.
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Blood pressure variations that are unrelated to chemotherapy are much more common in cancer patients; the combination of malnutrition and dehydration is one of the most common causes of hypotension. Other complications of malignancy, most notably sepsis, may be accompanied by profound and refractory hypotension.
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Arrhythmia in cancer patients may be a consequence of cardiotoxic anticancer therapies, a response to an altered environment wherein the chemical, metabolic, or mechanical abnormalities promote abnormal impulse formation or propagation, or a manifestation of tumor spread. Cancer patients often require strategies for managing their arrhythmias that take into account the underlying condition responsible for the arrhythmia. Additionally, cancer-related arrhythmias encompass the spectrum from trivial to life threatening.
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Supraventricular Arrhythmias
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Supraventricular arrhythmias are a common occurrence in cancer patients. Atrial premature complexes are a well-recognized manifestation of early anthracycline cardiotoxicity and may be a harbinger of the more serious late LV dysfunction. More sustained supraventricular arrhythmias are seen commonly in patients with a chest malignancy, especially lung cancer, which is often associated with increased pulmonary artery pressure. Pulmonary hypertension often precedes atrial flutter or fibrillation. Mechanical effects of an expanding tumor mass, as well as atelectasis or infection in areas distal to occluded bronchi, further increase right-sided pressures and cause arrhythmias. Hypoxia confounds the problem. Supraventricular arrhythmias are especially frequent early in the postoperative period after lung resection. Supraventricular arrhythmias also occur in association with high-dose chemotherapy and stem cell transplantation. Various specific chemotherapeutic agents also have been associated with atrial fibrillation and include 5-FU, gemcitabine, docetaxel, and alemtuzumab. Radiation to the heart has a well-known association with arrhythmia; however, radiation to sites distant from the heart also has been associated with supraventricular arrhythmia. Other forms of sustained supraventricular tachycardia, including reentrant supraventricular tachycardia and multifocal atrial tachycardia, are also seen commonly in the cancer patient.
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Intracardiac masses, including benign tumors and malignant processes such as primary cardiac lymphomas and cardiac metastases from lung, breast, or melanoma, often present with supraventricular arrhythmias. Atrial fibrillation is often associated with acute pulmonary embolism (PE) and pericarditis, conditions that may be encountered in cancer patients.
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An important risk factor for sustained supraventricular arrhythmias is intrinsic cardiac disease. In particular, conditions resulting in increased atrial size or that are associated with inflammation contribute to elevated atrial pressure and result in atrial rhythm disturbances. Age, hypertension, lung disease, thyrotoxicosis, surgery, and other states that trigger increased catecholamine levels may all also contribute to elevated atrial pressure.
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Ventricular Arrhythmias
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Cancer patients are more prone to ventricular arrhythmias than the noncancer population. These patients are exposed to stressful and potentially cardiotoxic anticancer treatments, the increased ingestion of multiple noncancer medicines that may be proarrhythmic, and coexisting hormonal and metabolic abnormalities. Hypokalemia, alkalotic states, hypomagnesemia, thyrotoxicosis, pheochromocytomas, and the release of mediators such as serotonin and kinins associated with the carcinoid syndrome are all associated with potentially life-threatening ventricular tachycardia.
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Prolonged QT Interval and Torsade de Pointes
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Torsade de pointes, a form of ventricular tachycardia associated with prolongation of the QT interval, is related to an increasing list of medications, many of which are used in the management of malignancy and in their supportive care. Prolongation of the QT interval may also occur in association with the supplements that cancer patients sometimes ingest, among them cesium chloride, which is commonly used as an alternative therapy for various types of malignancies. Several anticancer agents may also lead to QT prolongation. Arsenic trioxide is associated with QT prolongation in more than 50% of treated patients.30 Other cardiac side effects include sinus tachycardia, nonspecific ST-T changes, and torsade de pointes.30 In one study, the most common acute side effect was fluid retention with pleural and pericardial effusions. Complete heart block and sudden cardiac death31 have also been reported in patients receiving arsenic trioxide. Several newer cancer treatments such as dasatinib, lapatinib, nilotinib, and vorinostat have also been shown to prolong the QT interval. It is important to monitor the QT interval with serial ECGs, with particular attention to patients who are simultaneously receiving other drugs that have the potential to further prolong the QT interval.
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Bradyarrhythmias and Atrioventricular Heart Block
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Thalidomide may cause sinus bradycardia that may be mitigated by adjusting the dosage and is often asymptomatic, but occasionally permanent pacing may be required. Paclitaxel is used extensively in the treatment of many solid tumors and has been reported to cause sinus bradycardia, heart block, premature ventricular contractions, and ventricular tachycardia.
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The conduction system of the heart can be interrupted at all levels by primary and metastatic tumors or by infiltrative processes such as amyloidosis. Pheochromocytomas, thymomas, high-dose chemotherapy, and stem cell transplantation are all associated with block at the level of the atrioventricular (AV) node. Individual chemotherapy agents associated with transient AV block include paclitaxel and octreotide.
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Treatment of Arrhythmias
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In managing arrhythmias in cancer patients, one must first consider possible cancer-related causes for the rhythm disturbance. In many instances, correcting metabolic abnormalities or removing arrhythmogenic agents is the most successful approach. The arrhythmia may be sufficiently serious that the permanent elimination of the offending agent from the treatment regimen must be recommended. In some settings, the arrhythmia may be controlled by the use of standard medications or procedures, thereby permitting completion of highly effective anticancer treatment. The use of implantable devices should not be denied to appropriate patients who have malignancy and who have reasonable expectation of survival with good functional status of more than 1 year, as per the ACC/AHA heart failure guidelines.
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General Considerations
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The incidence of thrombosis is higher in patients with cancer than in the general population and portends a worse prognosis. The prevention, recognition, and treatment of thromboembolism are clinical challenges for physicians treating patients with cancer. Venous thromboembolism (VTE) occurs in 5% to 7% of patients with malignancy, an incidence that is much greater than that for the general population (approximately 0.1%). Patients with cancer constitute nearly 20% of all cases of thrombosis. Approximately 10% of all noncancer patients with VTE will be diagnosed with malignancy within 2 years.
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The incidence of arterial thromboembolism is less than that of VTE in cancer patients, but occurs at a much higher incidence than in the general population. The source of arterial thromboembolism is most likely atherosclerosis, but the general inflammatory condition observed in patients with cancer and treatment with the new antiangiogenic agents are also important determinants. With the more widespread use of such agents, the incidence of arterial thrombosis likely will increase. Thrombotic events, such as deep venous thrombosis (DVT), PE, and arterial thrombosis have also been observed in approximately 11% of patients treated with IL-2.32 The risk of death for cancer patients diagnosed with a DVT or PE is substantially higher than that in cancer patients without such an event. The same is true for arterial thrombi. The in-hospital mortality may approach 20% to 30%, especially in those with pulmonary emboli. Nonbacterial endocarditis (marantic endocarditis) and disseminated intravascular coagulation are additional examples of life-threatening thrombotic conditions associated with cancer.
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Another agent most recently linked to increased risk of life-threatening arterial thrombotic events is ponatinib, a third generation tyrosine-kinase inhibitor (TKI), which was developed for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Although ponatinib, similar to the other TKIs, acts as a platelet antagonist, paradoxically, in contrast to the bleeding side effects common to TKI chemotherapies, it can cause severe prothrombotic complications,33 which resulted in the temporary suspension of the drug by the FDA in late 2013. The pathogenic mechanisms underlying the cardiovascular events observed in patients taking ponatinib remain poorly understood, but can cause arterial thrombosis in up to 20% of patients. The FDA has since lifted the suspension of ponatinib after issuing a “black box warning” regarding the risks of arterial thrombosis to be weighed against the oncological benefits.
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Pathophysiology of Thrombosis
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The pathophysiology of thrombosis is discussed in Chaps. 32, 33, and 75, and varies somewhat depending on the underlying cause. This section focuses on venous and arterial thrombosis in the cancer patient. However, there is an incomplete understanding of the initial triggers for thrombosis, and no single explanation pertains to all conditions in which thrombosis occurs (Table 101–7).
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VTE in cancer patients occurs as a result of the classic triad of stasis, endothelial disruption, and hypercoagulability. In each situation, one component may predominate and, if identified, can be effectively treated. If, for example, a patient has an abdominal tumor that is compressing the inferior vena cava, causing stasis, and this tumor can be removed or reduced by chemotherapy or radiation, then the likelihood of VTE may be markedly reduced. Indwelling IV catheters may cause thrombus formation (Fig. 101–4). Removal of an indwelling central catheter is also likely to be effective in reducing the risk of subsequent recurrence or progression of a thrombus after the stimulus for hypercoagulability has been removed.
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Arterial thrombosis in cancer patients is most commonly associated with platelet activation either in the presence or absence of atherosclerosis. The malignancy itself can lead to platelet activation. The exact mechanism also may include microvessel constriction and platelet activation.
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Clinical Manifestations
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The location of a thrombosis is of paramount importance with regard to how the thrombus will manifest itself. The extent and position of collateral vessels is also crucial in determining how the thrombus will affect the patient. A DVT in a lower extremity, for example, is likely to cause pain, swelling, and erythema of that extremity. A DVT of an arm may be revealed by unilateral arm swelling that develops fairly suddenly or a bluish discoloration caused by poor venous return. Arterial thrombi usually result in pain, pallor, and pulselessness in an extremity. An arterial thrombosis of an internal organ may be manifested by an episode of unstable angina, an ACS, a cerebral vascular accident, or intestinal ischemia that may be difficult to detect.
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The most common presentation of VTE is unilateral leg edema. This can be associated with erythema, but typically it is difficult to discern VTE from cellulitis. Unilateral extremity swelling is, therefore, a hallmark of VTE. Bilateral lower extremity edema may be caused by a proximal venous thrombosis or even congestive heart failure, malnutrition, or other causes of edema. PEs are most commonly manifested by a sudden onset of shortness of breath, chest discomfort, and tachypnea. In addition, patients may report hemoptysis and tachycardia. Syncope, hypotension, and sudden cardiac death are manifestations of PEs emboli. Long-term effects of PEs and DVT include pulmonary hypertension and the postphlebitic syndrome (see Chaps. 74 and 75).
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The diagnostic approaches used to detect thrombosis, either venous or arterial, in cancer patients are similar to those used in patients without malignancy; these techniques are highlighted elsewhere. Computed tomographic (CT) angiography (see Chap. 17) is a reliable and sensitive tool for detecting PE, and peripheral extremity ultrasonography remains important in the evaluation of venous flow and thrombus (Fig. 101–5). The techniques used to detect arterial thrombus may vary and are determined mainly by the location of the arterial insufficiency. A combination of ultrasonography, sequential pressure measurements, angiography, CT, and MRI forms the basis of diagnostic testing for patients with suspected arterial insufficiency.
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Treatment of Thromboembolism
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The optimal treatment of VTE is a challenge in cancer patients. Typically, these patients are at increased risk for bleeding and because they are often concurrently anemic, the consequences of bleeding are increased and disproportionate. Additional aggravating factors may be thrombocytopenia, hepatic failure, renal dysfunction, or development of a thrombus in a location that may predispose to bleeding complications. Antithrombotic therapy may consist of medications to prevent or limit the propagation of a thrombus or occasionally thrombolytic agents to promote thrombus dissolution. Furthermore, the risks associated with thrombus extension, distal embolization, or recurrence must be weighed against the risks of hemorrhage as part of the decision-making process.
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Guidelines for antithrombotic therapy for VTE have been published by the Ninth American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy.34 Standard treatment for VTE traditionally consists of low-molecular-weight heparin (LMWH), IV unfractionated heparin (UFH), or adjusted-dose subcutaneous heparin followed by long-term therapy with an oral anticoagulant. UFH has been superseded by LMWH as the initial treatment in most cancer patients with VTE in both inpatients and outpatients. Long-term treatment with warfarin may be complicated by several problems, including drug–drug interactions, malnutrition, nausea or vomiting during chemotherapy, and thrombocytopenia. Additionally, hepatic dysfunction in cancer patients may lead to unpredictable levels of anticoagulation and result in increased bleeding complications. LMWH is more effective than oral anticoagulant therapy with warfarin for the prevention of recurrent VTE in patients with cancer who have had acute, symptomatic proximal DVT, PE, or both.35 Further advantages of LMWH are that the doses are more easily adjusted, the pharmacokinetic properties are more predictable, laboratory monitoring is minimized, and fewer drug interactions occur than is the case with oral anticoagulants. Also in favor of heparin therapy in cancer patients are reports that the heparins have antiproliferative, antiangiogenetic, and antimetastatic effects and that LMWH may increase the response to chemotherapy, thereby prolonging the survival of cancer patients.36 For these several reasons, secondary prophylaxis with LMWH may be more effective and feasible than oral anticoagulant therapy in cancer patients with VTE, although the risk of bleeding is the same for both treatment approaches. More recently, low-dose aspirin was safely used to prevent thrombotic complications in patients with polycythemia vera and has been advocated as an alternative option in patients with cancer presenting with paraneoplastic thrombocytosis.
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Newer oral antithrombotic agents or NOACs (novel oral anticoagulants) include thrombin inhibitors, such as dabigatran, and factor Xa inhibitors, such as rivaroxiban, edoxaban, and apixaban. These seem to be as effective and safe as conventional treatment of VTE in patients with cancer, as suggested in some small studies and meta-analyses.37 Further clinical trials are warranted to validate effectiveness and safety of NOACs in patients with cancer-associated VTE. Moreover, mechanical treatments, such as compression stockings used to prevent postthrombotic syndrome, have value in the treatment of cancer patients with thromboembolism, as do selected surgical techniques to treat venous ulceration. Venacaval filters may be used instead of anticoagulation in patients with recurrent PEs who also have a high risk of serious bleeding.
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Prevention of Thromboembolism
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Prompted by the high incidence of VTE in patients undergoing ambulatory chemotherapy, the 2013 American Society of Clinical Oncology (ASCO) guidelines recommend a scoring method (commonly called the Khorana score) as a risk calculator for chemotherapy-associated VTE in the ambulatory setting.38 They recommend that patients with cancer be assessed for VTE risk at the time of chemotherapy initiation and periodically thereafter. The prophylactic anticoagulation of high-risk patients is feasible, safe, and effective as suggested by several randomized clinical trials, including the Prophylaxis of Thromboembolism During Chemotherapy Trial (PROTECHT) and the SAVE-ONCO investigation, the largest thromboprophylaxis study ever conducted in cancer patients.