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Cardiotoxicity of nonanthracycline cancer chemotherapy agents
Authors:
Justin Floyd, DO
James P Morgan, MD, PhD
Section Editors:
Reed E Drews, MD
David G Poplack, MD
Deputy Editor:
Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Jun 01, 2017.

INTRODUCTION — Cancer patients receiving chemotherapy have an increased risk of developing cardiovascular complications, and the risk is even greater if there is a known history of heart disease.

Among the serious complications that have been reported are:

Arrhythmias

Myocardial necrosis causing a dilated cardiomyopathy

Vasospasm or vasoocclusion resulting in angina or myocardial infarction

Pericardial disease

A wide range of chemotherapy agents have been associated with cardiotoxicity, for which the anthracyclines and related compounds (which may have been administered in childhood) are the most frequently implicated agents [1,2]. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

The cardiotoxicity of chemotherapy agents other than fluoropyrimidines, anthracyclines, and trastuzumab will be reviewed here. Most of these data are derived from patients who received these agents as adults rather than children.

The cardiotoxicity of trastuzumab and fluoropyrimidines (fluorouracil, capecitabine) is discussed separately. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)

ANTIMETABOLITES

Fluorouracil — Fluorouracil (FU) is widely used in various chemotherapy regimens and may cause cardiotoxicity, which is discussed in detail elsewhere. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)

Capecitabine — Capecitabine is a fluoropyrimidine that is metabolized to FU, which is the active anticancer moiety. The cardiac toxicity of capecitabine is similar to that reported with infusional FU and is discussed in detail elsewhere. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)

Fludarabine — Fludarabine, a purine antagonist used in hematologic malignancies, has been reported to cause hypotension and chest pain [3]. In addition, the combination of fludarabine and melphalan has been associated with severe cardiac toxicity in at least seven cases when used as the conditioning agent for bone marrow transplantation [4]. The use of either agent alone in high doses has only rarely been associated with cardiac toxicity.

Pentostatin and cladribine — Pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are additional purine antagonists used in hematologic malignancies. Both have rarely been reported to cause ischemia and heart failure [5,6].

Methotrexate — Although no definite cardiac toxicity has been associated with methotrexate, there are rare reports of syncope, myocardial infarction, and supraventricular and ventricular arrhythmias associated with its use [7-9].

Cytarabine — Multiple cases of pericarditis have been attributed to cytarabine, and this can progress to pericardial effusion and cardiac tamponade [10-12]. Corticosteroid therapy may be beneficial in the treatment of this complication.

MICROTUBULE-TARGETING DRUGS

Vinca alkaloids — Hypertension, myocardial ischemia and infarction, and other vasoocclusive complications have been reported with the vinca alkaloids. These complications have been reported most commonly with vinblastine, but have also been described with vincristine and vinorelbine [13-20].

Taxanes

Paclitaxel — Bradycardia and heart block are the most frequently described cardiac effects of paclitaxel, although these usually are asymptomatic [21,22]. The overall incidence of cardiac events in the National Cancer Institute database was low, and routine cardiac monitoring is not required for patients without risk factors [21].

This was illustrated by a phase II series of 140 women with ovarian cancer, in whom transient asymptomatic bradycardia occurred in 29 percent. More serious cardiac toxicity (atrioventricular conduction block, ventricular tachycardia, cardiac ischemia) was seen in 5 percent [22].

Cardiomyopathy is reported when paclitaxel is combined with doxorubicin. Heart failure has developed in up to 20 percent of patients treated with paclitaxel plus doxorubicin [23,24], although an increased incidence of cardiotoxicity was not seen in all studies [25]. The development of heart failure may occur at cumulative doxorubicin doses that are much lower than would be expected with doxorubicin alone [26-28]. (See "Systemic treatment of metastatic breast cancer in women: Chemotherapy", section on 'Anthracycline-containing regimens'.)

Nanoparticle albumin-bound paclitaxel (nabpaclitaxel, Abraxane) has the same cardiac toxicity profile as the nonalbumin-bound formulation. Asymptomatic electrocardiographic (ECG) changes, including nonspecific changes, sinus bradycardia, and sinus tachycardia, are most common [29]. Rare cases of chest pain, supraventricular tachycardia, and cardiac arrest have been reported.

Docetaxel — Conduction abnormalities, cardiovascular collapse, and angina have been reported in patients treated with docetaxel [30-33], although there is no convincing evidence that causally links docetaxel to these complications.

Like paclitaxel, docetaxel appears to potentiate the cardiotoxicity of anthracyclines. This was illustrated by a trial in which 50 women with newly diagnosed stage III breast cancer were treated with docetaxel plus doxorubicin [34]. Heart failure developed in 8 percent, with a mean decrease in ejection fraction of 20 percent. The total doxorubicin dose was <400 mg/m2 in all of these patients.

Eribulin — Eribulin mesylate, a synthetic analogue of halichondrin B, a substance derived from a marine sponge, inhibits the polymerization of tubulin and microtubules. In an uncontrolled open-label ECG study in 26 patients, corrected QT (QTc) prolongation was observed on day 8 of treatment, with no QTc prolongation seen on day 1 [35]. The US Food and Drug Administration (FDA)-approved labeling recommends ECG monitoring in patients who have heart failure or bradyarrhythmias, and for those who are receiving other drugs known to prolong the QTc interval (table 1). The drug should be avoided in those with congenital long QT syndrome.

Ixabepilone — Ixabepilone is an epothilone, a class of nontaxane tubulin polymerizing agents. It is approved as monotherapy and in combination with capecitabine for treatment of metastatic breast cancer.

In a trial comparing capecitabine with or without ixabepilone, the frequency of adverse cardiac events (myocardial ischemia, ventricular dysfunction) was higher in the combined arm than with capecitabine alone (1.9 versus 0.3 percent), and supraventricular arrhythmias were seen with combined therapy (0.5 percent) but not with capecitabine alone [36]. Given that cardiotoxicity was not reported in a phase II trial of ixabepilone monotherapy conducted in 126 women with advanced breast cancer [37], it is possible that it is the combination of ixabepilone plus capecitabine that is cardiotoxic. However, the approved manufacturer’s labeling for ixabepilone suggests caution in patients with a history of cardiac disease and discontinuation of therapy in patients who develop cardiac ischemia or impaired cardiac function during therapy.

ALKYLATING AGENTS

Cyclophosphamide — Cyclophosphamide has been associated with an acute cardiomyopathy that is associated with high dose protocols; the cardiotoxicity is not related to cumulative dose [38-42]. This was illustrated by a series of 32 patients treated with a dose of 180 mg/kg given over four days [38]. Nine of these patients developed heart failure within three weeks of treatment, and six died.

The incidence of cardiotoxicity may be particularly high in patients receiving cyclophosphamide as part of a program of high-dose chemotherapy followed by autologous stem cell rescue. Adverse prognostic features for this group include [43,44]:

Patients with lymphoma, as opposed to breast cancer

Prior radiation to the mediastinum or left chest wall

Older age

Prior abnormal cardiac ejection fraction

Other reported complications include hemorrhagic myopericarditis resulting in pericardial effusions, tamponade, and death, typically within the first week after treatment [38,40]. Most pericardial effusions can be treated with glucocorticoids and analgesics without serious sequelae. These complications may be due to endothelial capillary damage.

Ifosfamide — Ifosfamide has been associated with arrhythmias, ST-T wave changes, and heart failure in a dose-related manner [45,46]. These cardiac complications, when symptomatic, are generally reversible with medical management. Controversy exists whether there is increased cardiotoxicity when ifosfamide is used in combination with anthracyclines [46-50].

Cisplatin — Cardiotoxicity due to cisplatin can be manifested by supraventricular tachycardia, bradycardia, ST-T wave changes, left bundle branch block, acute ischemic events, myocardial infarction, and ischemic cardiomyopathy [51,52]. This toxicity may be related to electrolyte abnormalities secondary to cisplatin-induced nephrotoxicity. (See "Cisplatin nephrotoxicity".)

Cisplatin has also been associated with vascular toxicities that include Raynaud's phenomenon, hypertension, and cerebral ischemic events. The increased risk of late cardiovascular toxicity in young men who have been cured of testicular germ cell tumors using cisplatin-based chemotherapy is of particular concern. The long-term consequences of treatment in this group are discussed elsewhere. (See "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Treatment-related complications' and "Treatment-related toxicity in men with testicular germ cell tumors".)

Busulfan — Busulfan is used at high doses as part of the preparative regimen for bone marrow transplantation. One case of endocardial fibrosis has been reported that was attributed to busulfan [53].

Nonclassical alkylating agents

Trabectedin — Trabectedin is an alkaloid that is approved for use in soft tissue sarcomas after progression on an anthracycline. It has been associated with a low rate of cardiac toxicities, including congestive heart failure and rarely, cardiac arrest [54,55]. The median time to development of grade 3 to 4 cardiotoxicity on trabectedin is 5.3 months [56]. A baseline assessment of ejection fraction should be performed using echocardiogram or multigated acquisition (MUGA) prior to initiation of trabectedin and at two- to three-month intervals while treatment is continued. Trabectedin should be held for a decrease in ejection fraction below the lower limit of normal and permanently discontinued for symptomatic cardiomyopathy or for persistent left ventricular dysfunction that does not recover to the lower limit of normal within three weeks.

ANTITUMOR ANTIBIOTICS

Mitomycin C — Mitomycin C causes DNA alkylation and cross-linking [57]. Heart failure has been observed in patients treated with mitomycin C, with the incidence increasing at cumulative doses >30 mg/m2 [58]. Cardiotoxicity may be additive when mitomycin C is given with anthracyclines [59-61]. Histologically, the damage resembles radiation-induced cardiac injury [62].

Bleomycin — Bleomycin has been associated with several different forms of cardiotoxicity:

Pericarditis is an uncommon but potentially serious complication associated with bleomycin. In a series of 88 patients with lymphoma receiving bleomycin, pericarditis was observed in two cases [63].

The acute onset of substernal chest pain has also been reported in less than 3 percent of patients treated with bleomycin [64]. There are no consistent signs or symptoms associated with these events, and long-term cardiac sequelae have not been observed. Treatment is supportive, and discontinuation of the drug is not needed, as further infusions do not usually cause recurrence of the symptoms.

Coronary artery disease, myocardial ischemia, and myocardial infarction have been observed in young patients during and after treatment with bleomycin-based chemotherapeutic regimens [65-67]. (See "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Treatment-related complications' and "Treatment-related toxicity in men with testicular germ cell tumors".)

MONOCLONAL ANTIBODIES

Trastuzumab — Trastuzumab is a monoclonal antibody that binds to a specific epitope of the human epidermal growth factor receptor-2 (HER2) protein and inhibits signal transduction induced by peptide growth factors interacting with their receptors. Trastuzumab has been associated with the development of a cardiomyopathy that is typically manifested by an asymptomatic decrease in the left ventricular ejection fraction (LVEF) and less commonly, by clinical heart failure. The cardiotoxicity of trastuzumab and related agents is discussed separately. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

Rituximab — Rituximab, a monoclonal antibody against the CD20 antigen on normal and malignant B lymphocytes, is used to treat a variety of malignant and benign hematologic conditions.

Arrhythmias and angina have been reported during less than 1 percent of infusions, and acute infusion-related deaths have been seen in less than 0.1 percent. These deaths appear to be related to an infusion-related complex of hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock [68-70]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Long-term cardiac toxicity has not been reported with rituximab administration.

Bevacizumab — Heart failure associated with bevacizumab has been sporadically reported in several trials of bevacizumab given in conjunction with anthracyclines or paclitaxel in women with metastatic breast cancer, an indication for which bevacizumab is no longer approved. It has not been reported in patients treated with bevacizumab for other advanced cancers.

In contrast with heart failure, ischemic cardiac events, other arterial thrombotic events (such as strokes), and hypertension are increased in patients treated with bevacizumab for all indications. Cardiovascular toxicity in patients treated with bevacizumab is addressed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Left ventricular dysfunction and myocardial ischemia' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial thromboembolic events'.)

Aflibercept — Aflibercept (Ziv-aflibercept) is a recombinant fusion protein containing vascular endothelial growth factor receptors (VEGFR) 1 and 2 fused to the Fc portion of human immunoglobulin G1 (IgG1). Like bevacizumab, it functions as a VEGF inhibitor and is approved for the treatment of metastatic colon cancer, but an increased incidence of heart failure and ischemic events have not been reported. An increased incidence of hypertension as well as arterial thrombotic events has been associated with this drug. There is no clinical trial experience regarding the safety of Ziv-aflibercept in patients with New York Heart Association (NYHA) class III or IV heart failure. The topic of cardiovascular toxicity in patients treated with Ziv-aflibercept is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial thromboembolic events'.)

Ramucirumab — Ramucirumab is a monoclonal antibody that inhibits the VEGFR type 2 (VEGFR2); it has been approved for the treatment of advanced gastric cancer. Ramucirumab is associated with an increased risk of hypertension and arterial (including cardiac) thrombotic events. This subject is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Ramucirumab'.)

Alemtuzumab — Alemtuzumab targets the CD52 antigen that is present on the cell membrane of most T and B lymphocytes. Alemtuzumab is used to treat fludarabine-resistant chronic lymphocytic leukemia and other lymphoproliferative disorders. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Alemtuzumab'.)

Alemtuzumab therapy of patients with T cell lymphomas (mycosis fungoides, Sézary syndrome) is associated with a significant risk of heart failure and/or arrhythmias. Among eight patients treated at MD Anderson Cancer Center, heart failure developed in three, atrial fibrillation in one, and ventricular tachycardia in one [71]. Two patients previously had been treated with doxorubicin, but no other causes of cardiac toxicity were identified. The mechanism of this toxicity is not known, and all patients had partial or total resolution of symptoms after discontinuing treatment.

Cetuximab — Cetuximab binds to the epidermal growth factor receptor (EGFR), blocking interaction with its ligand. It is used in combination with irinotecan to treat refractory metastatic colorectal cancer. In a nested case control study, cetuximab was associated with an increased risk of heart failure [72]. Patients treated with combinations containing fluorouracil (FU) and cetuximab have also experienced a range of cardiac events; it is not clear that all of these events can be attributed exclusively to the FU [73].

TOPOISOMERASE INHIBITORS

Etoposide — Etoposide has been linked to the development of myocardial infarction and vasospastic angina in several case reports [74-76]. Additionally, etoposide is often a part of cisplatin-based regimens that have been associated with acute and delayed cardiac toxicity. (See "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Treatment-related complications'.)

BIOLOGIC RESPONSE MODIFIERS — The toxicities of biologic response modifiers are generally not due to a direct cytotoxic effect of the drugs, but rather reflect alterations of cellular physiology.

Interferon-alfa — Interferon-alfa (IFNa) is used as an adjuvant in patients with melanoma and to treat advanced melanoma and renal cell carcinoma. The cardiovascular side effects of IFNa include:

Myocardial ischemia and infarction, which are generally related to a prior history of coronary artery disease. These may be due to increased fever or associated flu-like symptoms that increase myocardial oxygen requirements [77].

Atrial and ventricular arrhythmias have been reported in up to a 20 percent of cases [78-81], and two cases of sudden death have been reported [77]. It is unclear whether prior heart disease is linked to an increased risk of arrhythmias.

Prolonged administration of IFNa has been associated with cardiomyopathy, manifested by a depressed ejection fraction and heart failure. The cardiomyopathy was reversible upon cessation of IFNa infusion in some but not all cases [82-85]. The pathogenesis of IFNa-induced cardiomyopathy is unknown.

Interleukin-2 — Virtually all patients receiving high-dose interleukin-2 (IL-2) develop a capillary leak syndrome associated with increased vascular permeability and hypotension. This results in cardiovascular symptoms similar to those of septic shock, with an increased heart rate and cardiac output and a decrease in systemic peripheral resistance. These symptoms are partially responsive to fluid replacement therapy but patients often require vasopressors as well. These symptoms usually peak about four hours after each dose of IL-2 and worsen with further treatment. The decreased systemic vascular resistance may not return to normal for up to six days after IL-2 has been discontinued [86]. It is not known whether the decrease in peripheral vascular resistance is a direct or indirect effect of IL-2. (See "Immunotherapy of renal cell carcinoma", section on 'Toxicity'.)

IL-2 also is associated with direct myocardial toxicity although the mechanism of this is unclear. In patients with underlying coronary artery disease, ischemia, myocardial infarction, arrhythmias, and death have been reported [87]. Ventricular and supraventricular arrhythmias have been reported to occur in 6 to 21 percent of patients [86,88,89]. This is illustrated by a series of 199 patients in which 6 percent developed arrhythmias, including ventricular tachycardia, and 2.5 percent had elevated creatine kinase (CPK) isoenzyme MB levels [89]. Supraventricular tachycardias were usually responsive to treatment [86].

DIFFERENTIATION AGENTS

All-trans retinoic acid — All-trans retinoic acid (ATRA) is used to treat acute promyelocytic leukemia. Approximately 10 to 15 percent of patients develop the differentiation syndrome (previously called the “retinoic acid syndrome”), which can cause pericardial effusions (including the potential for cardiac tamponade) and myocardial ischemia/infarction. The differentiation syndrome is discussed elsewhere. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Administration and side effects'.)

Arsenic trioxide — Arsenic trioxide is used to treat acute promyelocytic leukemia. Serious adverse events attributed to treatment with arsenic trioxide include the “differentiation syndrome” similar to that seen with ATRA, and cardiac abnormalities. These complications are discussed elsewhere. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'ATO plus ATRA'.)

TYROSINE KINASE INHIBITORS

Axitinib — Axitinib is a tyrosine kinase inhibitor (TKI) used to treat advanced renal cell carcinoma; it is relatively specific for vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3). Nevertheless, like the other VEGF-targeted TKIs, axitinib has also been associated with an increased risk of hypertension, arterial thrombotic events, and left ventricular dysfunction. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Brigatinib — Brigatinib is a TKI used in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). It is associated with both hypertension and bradycardia. Blood pressure and heart rate should be monitored regularly during treatment. If patients are symptomatic or have severe hypertension, brigatinib should be withheld, then dose reduced or permanently discontinued.

In a phase II study, hypertension was reported in approximately 20 percent and bradycardia was noted in 7.6 percent of those receiving the recommended dose of brigatinib [90,91]. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Brigatinib'.)

Cobimetinib — Cobimetinib inhibits mitogen-activated protein kinase (MEK) and is administered with vemurafenib for the treatment of advanced metastatic or unresectable BRAF-mutated melanoma. Given an increased risk for cardiomyopathy in patients receiving dual therapy with cobimetinib and vemurafenib compared with vemurafenib alone, baseline left ventricular ejection fraction (LVEF) should be evaluated prior to initiation of this agent, after one month of treatment, and every three months thereafter (FDA label). (See 'Vemurafenib' below.)

Crizotinib and ceritinib — Crizotinib and ceritinib are orally active inhibitors of the anaplastic lymphoma kinase (ALK); they are both approved for treatment of advanced or metastatic non-small cell lung cancer (NSCLC) if the tumor contains a characteristic EML4-ALK fusion oncogene. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Crizotinib' and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib'.)

Sinus bradycardia is common in patients receiving these agents and can be profound, although it is generally asymptomatic and not associated with other events such as other arrhythmias:

In two trials evaluating the efficacy of crizotinib for advanced NSCLC, bradycardia was reported in only 12 of 240 patients who were assessable for treatment-related toxicity; all were mild (grade 1 or 2) in severity [92].

In another report of 42 patients receiving treatment with crizotinib for advanced NSCLC, there was an average decrease of 26 bpm among all patients; 69 percent had at least one episode of sinus bradycardia (heart rate <60 beats per minute [bpm]) [93]. Profound sinus bradycardia (heart rate <50 bpm) developed in 13 (31 percent). None of the patients who developed bradycardia during treatment were symptomatic or had electrocardiographic (ECG) changes such as corrected QT (QTc) interval prolongation.

Less information is available with regard to ceritinib. In one report of 255 patients receiving ceritinib, bradycardia (heart rate <50 bpm) was reported as a new finding in only 1 percent [94].

The US prescribing information for both crizotinib and ceritinib recommends avoiding use in patients who are using other agents known to cause bradycardia (eg, beta-blockers, clonidine, nondihydropyridine calcium channel blockers, digoxin), and that heart rate and blood pressure be monitored regularly during therapy. Dose adjustment guidelines in the setting of symptomatic bradycardia are also provided.

In addition to bradycardia, QTc interval prolongation has been observed with both drugs, although it is uncommon. Three percent of 255 patients treated with ceritinib experienced a QTc interval increase over baseline of 60 msec; in a larger population of 304 patients treated with the drug, only one (<1 percent) developed a QTc interval of >500 msec [94]. The US prescribing information for crizotinib and ceritinib recommends avoiding both drugs in patients with congenital long QT syndrome and that patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking other medications known to prolong the QTc interval (table 1) undergo periodic monitoring with electrocardiograms and assessment of serum electrolytes. Treatment interruption and dose reduction is advised if QTc interval exceeds >500 msec during treatment, with permanent discontinuation if it recurs or is accompanied by an arrhythmia, heart failure, hypotension, shock, syncope, or torsade de pointes.

Given that both drugs are CYP3A4 substrates, they should be used with caution in patients who are receiving other drugs that inhibit CYP3A4 (table 2).

Practice is variable regarding cardiac monitoring during therapy, however, some clinicians perform a baseline ECG for patients starting crizotinib or ceritinib only if they have known history of heart failure or cardiac arrhythmia issues, and check ECGs during therapy if bradycardia (symptomatic or not) develops or if the patient is started on another drug with known side effect of QTc prolongation. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Toxicity'.)

Imatinib — Imatinib, a small-molecule inhibitor of Bcr-Abl, KIT, the PDGFR, and the SRC family of tyrosine kinases, is used in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML), which is characterized by the presence of the fusion protein Bcr-Abl that functions as a tyrosine kinase, and gastrointestinal stromal tumors (GIST), which are characterized by mutations in KIT or PDGFR genes. In an early report of patients treated for Ph+CML, imatinib was associated with the development of severe heart failure [95], prompting the manufacturer to revise the drug labeling to include warnings about possible heart failure.

Laboratory studies indicate that adverse cardiac events in patients receiving imatinib are likely mediated by inhibition of c-Abl:

Mice with an imatinib-resistant mutant of c-Abl are largely protected from imatinib cardiotoxicity, suggesting that c-Abl has a previously unrecognized function in myocytes [95].

A structurally reengineered form of imatinib that inhibits KIT but not c-Abl retains antitumor activity in a murine GIST model, but has fewer adverse effects on the heart [96].

Despite the biologic rationale for potential cardiotoxicity in patients receiving imatinib, subsequent publications indicate a low incidence of clinically significant heart failure in CML clinical trial settings (no more than 1 to 2 percent [97]); an increased risk for heart failure or left ventricular dysfunction has not been observed in patients receiving imatinib for the treatment of GIST [98-100]. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Cardiovascular' and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Side effects and their management'.)

However, the cardiac consequences of long-term imatinib therapy remain unknown. Importantly, none of these reports were based on studies in which cardiac function was prospectively monitored. Assessment was based primarily on adverse event reports, which may not reflect the true incidence of cardiac disease. In the only study to prospectively assess left ventricular function in 59 patients with CML who were treated with imatinib, there was no evidence of deterioration over the initial 12 months [101]. In the lone prospective study in which patients receiving imatinib for GIST were monitored with serum levels of brain natriuretic peptide (BNP), 2 of 55 patients followed over a three-month period had substantial increases in BNP (4 percent), suggesting the possibility of subclinical heart failure [102].

Additional information from well-designed prospective studies with objective cardiac monitoring is needed to determine the incidence and clinical significance of heart failure attributable to imatinib, both in patients with CML and GIST. Until then, some have suggested that patients receiving imatinib for either CML or GIST be thought of as stage A heart failure patients (ie, at risk for heart failure), but without structural heart disease or symptoms [100,103].

The 2005 American Heart Association (AHA) heart failure guidelines (with 2009 focused update) include recommendations for stage A patients [104]. These guidelines recommend that patients receiving cardiotoxic agents undergo noninvasive assessment of left ventricular function. Other recommendations for stage A patients at high risk for heart failure include monitoring for symptoms and signs of heart failure and management of cardiovascular risk factors including control of blood pressure.

However, obtaining a baseline assessment of LVEF in all patients receiving imatinib (particularly for GIST where it is not even clear that there is a risk of cardiotoxicity) is not supported by compelling data. In our view, patients receiving imatinib should be monitored for signs and symptoms of heart failure, and clinicians should have a low threshold for formal assessment of left ventricular dysfunction.

Guidelines for management of imatinib toxicity from the National Comprehensive Cancer Network (NCCN) suggest only that patients with cardiac disease or risk factors for heart failure who are receiving imatinib be monitored carefully, and that any patient with signs or symptoms consistent with heart failure be evaluated and treated [105].

We agree with these guidelines, and do not obtain a baseline assessment of LVEF prior to starting imatinib.

Lapatinib — Lapatinib is an orally active TKI that affects both human epidermal growth factor receptor 2 (HER2)/neu (erbB-2) and the epidermal growth factor receptor (EGFR, also called erbB-1). Biomarker data suggest that inhibition of HER2 is more important than is blockade of EGFR in stopping tumor growth. This effect on the HER2/neu has raised particular concern because of the cardiotoxicity associated with trastuzumab. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Trastuzumab'.)

Emerging data from the lapatinib trials suggest that lapatinib may differ from trastuzumab not only in terms of antitumor efficacy but also in terms of its cardiac safety profile. However, the patients enrolled on these trials were highly selected, and longer follow-up will be needed to ascertain whether lapatinib has a more favorable cardiac side effect profile. Cardiotoxicity in patients treated with lapatinib and combinations of lapatinib with trastuzumab is discussed in detail elsewhere.

Necitumumab — Necitumumab is an EGFR inhibitor approved in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non-small cell lung cancer. Cardiac arrhythmias have been reported in patients using this drug combination [106]. Therefore, close monitoring of serum electrolytes is recommended for patients being treated with necitumumab (FDA label).

Nilotinib, dasatinib, and bosutinib — Nilotinib, dasatinib, and bosutinib are three second-generation multitargeted TKIs that are used for the treatment of Ph+CML; all target Bcr-Abl, while nilotinib also targets KIT and PDGFR; dasatinib targets KIT, PDGFR, and the SRC family of kinases; and bosutinib targets the SRC family of tyrosine kinases.

Cardiac effects have been described with each of these agents:

Both nilotinib and dasatinib have been associated with QT prolongation [107]. Abnormalities in potassium and magnesium levels must be corrected prior to drug initiation, other drugs that may affect the QTc interval should be avoided, caution should be used in patients at risk for QT interval prolongation, and serial electrocardiograms should be followed. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Cardiovascular' and "Acquired long QT syndrome: Definitions, causes, and pathophysiology".)

Although a definite causal relationship has not been established, dasatinib has also been associated with chest pain, pericardial effusion, ventricular dysfunction, and heart failure [108]. The US prescribing information states that 1.6 percent of 258 patients taking dasatinib developed cardiomyopathy, heart failure, diastolic dysfunction, fatal myocardial infarction, and/or left ventricular dysfunction [109].

Although clinical heart failure is not described, fluid retention occurs with bosutinib and may manifest as pericardial effusion or pulmonary edema [110]. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Lapatinib'.)

Osimertinib — Osimertinib is active in non-small cell lung cancers harboring the EGFR T790M mutation. Given a small risk of cardiomyopathy, LVEF should be assessed at baseline and every three months on treatment (FDA label). Additionally, patients with predisposition towards or history of QTc prolongation or those taking medications known to cause QTc prolongation should have monitoring of electrocardiogram and electrolytes while on osimertinib (FDA label).

Pazopanib and lenvatinib — Pazopanib is an orally active multi-targeted kinase inhibitor that targets several kinases including VEGFR; it is used for the treatment of advanced renal cell carcinoma as well as soft tissue sarcoma. A similar cardiovascular risk profile has also been observed as has been reported with sunitinib and sorafenib. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Lenvatinib is another multi-targeted TKI that targets VEGFR, KIT, RET, platelet-derived growth factor receptor alpha (PDGFRA), and fibroblast growth factor receptor; it is used for treatment of refractory differentiated thyroid cancer. As with other agents that target the VEGFR, hypertension is a frequent complication. Cardiac dysfunction (decreased ejection fraction, cardiac failure or pulmonary edema) is reported in approximately 7 percent, the majority of which are findings of decreased ejection fraction by echocardiography. Lenvatinib is also associated with arterial thrombotic events and prolongation of the QTc interval. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Ponatinib — Ponatinib is a multitargeted kinase inhibitor that targets VEGFR, PDGFR, fibroblast growth factor receptor (FGFR), the SRC family of kinases, KIT, RET, TIE2, and FLT3; it is approved exclusively for treatment of refractory CML. The US Food and Drug Administration (FDA) issued a Boxed Warning for ponatinib regarding reports of serious and life-threatening blood clots and severe narrowing of blood vessels (both arteries and veins) in at least 20 percent of patients taking ponatinib for CML. In addition, approximately 4 percent of patients treated with ponatinib have developed serious heart failure or left ventricular dysfunction, with some fatalities. In addition, approximately 1 percent of patients have developed symptomatic bradyarrhythmias, and 5 percent supraventricular tachyarrhythmias (predominantly atrial fibrillation). (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Left ventricular dysfunction and myocardial ischemia' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.)

Regorafenib — Regorafenib targets VEGFR1, 2, and 3 in addition to RET, KIT, platelet-derived growth factor receptor (PDGFR) alpha and beta, FGFR 1 and 2, and several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes. It has been approved in the United States for treatment of refractory metastatic colorectal cancer. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Regorafenib'.)

In placebo-controlled clinical trials, regorafenib has been associated with hypertension and an increased incidence of myocardial ischemia and infarction, but heart failure has not yet been reported. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Regorafenib'.)

Sorafenib and sunitinib — Sorafenib and sunitinib are orally active multi-targeted TKIs that are used for the treatment of metastatic renal cell carcinoma. In addition, sorafenib is used in the treatment of advanced hepatocellular cancer, and sunitinib is used for imatinib-refractory gastrointestinal stromal tumors (GIST) and for advanced pancreatic neuroendocrine tumors. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma" and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Sunitinib' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Sunitinib' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Sorafenib'.)

In clinical trials, both drugs have been associated with a small but definite risk of hypertension and cardiotoxicity.

However, a major problem with defining the precise rate of cardiotoxicity associated with both drugs (and its reversibility) is that phase III trials have not pursued cardiac endpoints, and the identification of cardiac side effects with both drugs has predominantly been based on the occurrence of clinical symptoms. Further detailed prospective study of cardiotoxicity of these agents is needed. This subject is addressed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Left ventricular dysfunction and myocardial ischemia'.)

In addition to declines in LVEF and clinical heart failure, reported ECG changes have included changes in rhythm, conduction disturbance, change in axis or QRS amplitude, ST or T wave changes, and QTc prolongation with sunitinib. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.)

Some have suggested that patients receiving these drugs be treated as “stage A” heart failure patients (ie, at risk for heart failure), but without structural heart disease or symptoms [103]. Year 2013 guidelines for management of stage A heart failure from the AHA suggest that it may be reasonable to evaluate those who are receiving potentially cardiotoxic agents for left ventricular dysfunction [111].

In our view and that of others, patients receiving these drugs should be monitored closely for signs and symptoms of heart failure, and clinicians should have a low threshold for evaluating for left ventricular dysfunction. However, obtaining a baseline assessment of LVEF in all patients receiving these drugs is not supported by compelling data. This subject is addressed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Sunitinib and sorafenib'.)

Trametinib — Trametinib is an orally active inhibitor of the mitogen-activated protein kinase enzymes MEK1 and MEK2; it is approved for treatment of metastatic melanoma with a specific BRAF mutation. (See "Molecularly targeted therapy for metastatic melanoma", section on 'Trametinib'.)

In clinical trials of trametinib in patients with metastatic melanoma, left ventricular dysfunction has been seen in up to 11 percent of treated patients:

In a phase II trial in which all 97 patients underwent assessment of LVEF at baseline, week 4, and every 12 weeks thereafter, three patients (3 percent) developed asymptomatic and reversible grade 3 LVEF reduction [112].

In a phase III trial comparing trametinib versus chemotherapy with dacarbazine plus paclitaxel, 14 of the 211 patients who received at least one dose of trametinib developed cardiac toxicity (7 percent), 11 developed decreased LVEF, and 3 had left ventricular dysfunction [113]. Cardiomyopathy resolved in 10 of the 14, but four patients had serious cardiac-related events that were considered to be drug related and led to permanent discontinuation of the study drug [114].

Across clinical trials of trametinib at the recommended dose, approximately 11 percent of patients have developed evidence of cardiomyopathy (decrease in LVEF below the institutional lower limits of normal with an absolute decrease in LVEF ≥10 percent below baseline), and 5 percent have developed decrease in LVEF below the institutional lower limits of normal with an absolute decrease in LVEF of ≥20 percent below baseline [114].

The US prescribing information recommends the following:

Assess LVEF before initiation of therapy, one month after treatment initiation, and then at two- to three-month intervals during treatment.

Withhold treatment if the absolute LVEF decreases by 10 percent from pretreatment values to less than the institutional lower limit of normal.

Permanently discontinue for symptomatic heart failure, any absolute decrease in LVEF of >20 percent from baseline that is below the lower institutional limit of normal, and persistent LVEF decrease of ≥10 percent from baseline that does not resolve within four weeks.

Vandetanib — Vandetanib is an orally active multi-targeted TKI that is used mainly for treatment of medullary thyroid cancer. In clinical trials, vandetanib has been associated with prolongation of the QTc interval, torsades de pointes, and sudden death. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Vandetanib'.)

Because of the risk of cardiotoxicity, the US prescribing information includes a black box warning to correct hypocalcemia, hypokalemia, and/or hypomagnesemia prior to drug administration. In addition, given the long half-life of the drug (19 days), ECGs are recommended to monitor the QT interval at baseline, at two to four weeks, 8 to 12 weeks after starting treatment, and every three months thereafter. Monitoring of serum potassium, calcium, and magnesium levels as well as thyroid stimulating hormone (TSH) is recommended on the same schedule. Concurrent administration of drugs known to prolong the QTc interval should be avoided (table 1). Largely because of the cardiovascular risk, vandetanib is only available through a restricted distribution program (the Vandetanib Risk Evaluation and Mitigation Strategy [REMS] Program). (See "Medullary thyroid cancer: Chemotherapy and immunotherapy", section on 'Vandetanib'.)

Vemurafenib — Vemurafenib, an orally available inhibitor of some mutated forms of BRAF, is approved for treatment of metastatic melanoma with a V600E BRAF mutation. (See "Molecularly targeted therapy for metastatic melanoma", section on 'Vemurafenib'.)

Vemurafenib has been associated with prolongation of the QTc interval. The US prescribing information recommends that the drug not be given to patients with congenital long QTc syndrome, or to those who are receiving other drugs that prolong the QT interval (table 1).

Furthermore, it is recommended that ECG and electrolytes be monitored before treatment and after dose modification. For patients starting therapy with vemurafenib, ECGs are recommended at day 15, monthly during the first three months of treatment, every three months thereafter, and more often as clinically indicated. If the QTc interval exceeds 500 msec, treatment should be temporarily interrupted and electrolyte abnormalities sought and corrected.

Given that vemurafenib is a CYP3A4 substrate, it should be used with caution in patients receiving other drugs that inhibit CYP3A4 (table 2).

Vemurafenib may be used in combination with cobimetinib in the treatment of BRAF-mutated melanoma. (See 'Cobimetinib' above.)

MISCELLANEOUS AGENTS

Diethylstilbestrol — Diethylstilbestrol (DES) is a synthetic estrogen that was used to treat advanced prostate cancer and breast cancer. Multiple studies demonstrated an increased risk of cardiovascular death in patients treated with DES. This agent is no longer commercially available in the United States. (See "Initial systemic therapy for castration-sensitive prostate cancer".)

LHRH agonist/antagonist — Increasingly more attention is being given to the potential cardiovascular toxicities associated with long-term androgen deprivation using luteinizing hormone releasing hormone (LHRH) agonists and antagonists and antiandrogen therapies. To date, conflicting data exist regarding cardiovascular toxicity of manipulation of the androgen axis. This subject is discussed elsewhere. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)

Estramustine — Estramustine is a conjugate of nitrogen mustard and estradiol that is used in the treatment of prostate cancer. A range of cardiovascular complications, including coronary ischemia, has been reported in as many as 10 percent of patients. (See "Chemotherapy in castration-resistant prostate cancer", section on 'Estramustine'.)

Serotonin antagonists — Although usually well tolerated, the serotonin receptor antagonists often used during chemotherapy as antiemetics have some potential for cardiac effects, notably corrected QT (QTc) prolongation [115]. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'ECG interval changes and cardiac arrhythmias'.)

Clinical trials in healthy subjects and patients undergoing chemotherapy have demonstrated transient asymptomatic electrocardiographic (ECG) changes (increases in PR interval, QRS complex duration, and QTc interval) following administration of ondansetron, granisetron, or dolasetron [116-121]; chest pain has been attributed to ondansetron [122]. Since almost all of these studies excluded patients with preexisting cardiac disease, the clinical significance of these events in such patients, particularly those receiving cardiac medications, is unknown.

Proteasome inhibitors — Bortezomib and carfilzomib are proteasome inhibitors that are used for the treatment of multiple myeloma.

In clinical trials of carfilzomib, a second-generation proteasome inhibitor, new onset or worsening of preexisting heart failure with decreased left ventricular function or myocardial ischemia has been reported in approximately 7 percent of patients, and deaths due to cardiac arrest have occurred within one day of drug administration [123]. In addition, pulmonary arterial hypertension has been reported in 2 percent of patients treated with carfilzomib.

In a phase II trial of 266 patients treated with carfilzomib monotherapy for relapsed myeloma, 10 experienced heart failure (3.8 percent), 4 had a cardiac arrest (1.5 percent), and 2 had a myocardial infarction during the study (0.8 percent) [124]. The risk did not appear to be cumulative, at least through 12 cycles of therapy. However, the magnitude of the attributable risk, risk factors, and natural history, including reversibility, of carfilzomib-related cardiac toxicity remain incompletely characterized. Recommended dose modification based upon cardiac toxicity is available in the US prescribing information.

Cardiotoxicity might represent a class effect, as heart failure events (acute pulmonary edema, cardiac failure, cardiogenic shock) have also been described in patients treated with bortezomib, a first-generation proteasome inhibitor. However, causality remains unclear. In a phase III trial comparing bortezomib versus dexamethasone for relapsed myeloma, the incidence of treatment-emergent cardiac disorders during treatment with bortezomib or dexamethasone was 15 and 13 percent, respectively; seven patients receiving bortezomib (2 percent) and eight patients receiving dexamethasone (2 percent) developed heart failure during the study [125]. There were eight deaths thought to be possibly related to study drug; four in the bortezomib group (including three from cardiac causes and one from respiratory failure), and four in the dexamethasone group (three from sepsis and one from sudden death of unknown cause). As with carfilzomib, cardiac dysfunction does not appear to be cumulative [126].

Abnormalities appear to be largely reversible with prompt cessation of therapy and initiation of traditional heart failure treatment [127].

Histone deacetylase inhibitors — The reversible acetylation of histones, a family of nuclear proteins that interact with DNA, is an important mechanism by which gene expression is regulated. Removal of acetyl groups by histone deacetylase (HDAC) stabilizes the interaction between DNA and histones, repressing transcription. Inhibitors of HDAC reacetylate histones, thereby reactivating transcription of dormant tumor-suppressor genes.

Two HDAC inhibitors (vorinostat [suberoylanilide hydroxamic acid, SAHA] and romidepsin [depsipeptide]) are approved in the United States for the treatment of cutaneous T-cell lymphoma. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Romidepsin'.)

Both drugs have been associated with transient ECG changes (including prolongation of the QTc interval (waveform 1) and ST segment and T wave changes) in some but not all studies [128-130]. Supraventricular and ventricular arrhythmias including nonsustained ventricular tachycardia are rare in patients receiving romidepsin, and evidence of acute or cumulative cardiac damage has not been seen [128].

Routine ECG monitoring is not recommended for either drug in the US prescribing information. However, both drugs should be used with caution in patients with significant heart disease, congenital long QT syndrome, and those who are receiving other drugs that prolong the QTc interval (table 1) or inhibit CYP3A4, which is the principal enzyme responsible for the metabolism of romidepsin and vorinostat (table 2) [131]. In addition, serum potassium and magnesium levels should be in the normal range before drug administration since hypokalemia and hypomagnesemia predispose to arrhythmias.

Another HDAC inhibitor, panobinostat, is approved for treatment of refractory multiple myeloma. This drug appears to have a greater potential for cardiotoxicity; the US Prescribing Information includes a Boxed Warning about the risk for severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes (ST segment depression, T wave abnormalities, prolongation of the QTc interval). The drug is contraindicated in patients with a history of recent myocardial infarction or unstable angina, and in those with a QTc interval >450 msec, or significant baseline STR-segment or T-wave abnormalities at baseline. ECGs and electrolytes should be monitored during treatment, and concomitant use of medications that prolong the QTc interval is not recommended. However, antiemetic drugs with known QT-prolonging risk can be used with frequent ECG monitoring. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'ECG interval changes and cardiac arrhythmias'.)

PREVENTION — Although the most information regarding the cardiovascular toxicity of cancer chemotherapy is available for anthracycline-like agents, which have been studied for over 40 years, all chemotherapeutic drugs have the potential to cause or exacerbate cardiac and/or vascular disease. (See "Prevention and management of anthracycline cardiotoxicity".)

An increased understanding of the molecular, cellular, and genetic mechanisms that distinguish malignant transformed cells from normal cells has facilitated the development of molecularly targeted approaches to therapy and helped to minimize treatment-related toxicity. However, unexpected toxicities, including cardiovascular toxicities, often occur with many of these agents despite efforts to limit their actions specifically to cancer cells that contain the molecular target of interest. In contrast to anthracycline and anthracycline-like agents, efforts at prevention with molecularly targeted agents are in their infancy. (See "Prevention and management of anthracycline cardiotoxicity".)

There are several reasons for this:

Molecularly targeted agents are generally newer drugs with less clinical experience with their toxicity or toxicity management than with anthracyclines. Furthermore, patients at the highest risk for developing such cardiac toxicity are often excluded from clinical trials evaluating efficacy and safety of mechanistically new anti-neoplastic agents. As a result, unexpected toxicities often become more evident in post-registry databases.

Despite the critical need to increase our mechanistic understanding of physiologic and pathophysiologic cellular mechanisms in order to design rational “targeted” anticancer therapy, the clinical correlates of basic science discoveries are in most cases too vague or unexplained to provide information about expected side effects and how to prevent them with rational drug design. In most cases, we simply don’t know if cardiovascular toxicity results from a direct effect of the drug on the intended molecular target, or if it represents an “off-target” effect [132].

To further complicate the development of generally applicable therapeutic approaches, evidence suggests that cardiovascular toxicity may not only occur during the course of treatment and worsen with higher cumulative doses, but it may resolve despite continued treatment, or may develop years after therapy is completed in some patients. We are also just beginning to understand how genetic predisposition may affect an individual’s risk and clinical pattern of cardiovascular toxicity. Additional fundamental, clinical, and epidemiologic research is required to resolve these questions around the use of each of the existing classes of anticancer drugs and those that will become available in the future.

Despite these limitations, some general principles apply for minimizing the development of cardiovascular toxicity across all classes of anticancer agents, including the molecularly targeted agents.

In general, the risk of cardiovascular toxicity and the need for treatment gradually increase if patients do not receive primary and secondary prevention measures (figure 1) [132].

Primary prevention to reduce cardiovascular risk may be achieved by measures “that rest on common sense” [94]. Management of pre-existing comorbidities (hypertension, systolic or diastolic cardiac dysfunction, arrhythmias, metabolic disorders) should reasonably be optimized and a healthy lifestyle encouraged (cessation of smoking, weight reduction towards ideal, increased exercise) both before and after cancer therapy is begun.

There is evidence that administration of certain cardiac agents (eg, beta-blockers and angiotensin converting enzyme [ACE] inhibitors) to patients without cardiac risk factors may be beneficial. As an example, ACE inhibitors have been shown to improve outcomes and slow disease progression in patients with left ventricular systolic dysfunction due to a variety of causes. However, the role of ACE inhibitors in the treatment of patients with chemotherapy-induced cardiotoxicity is less clear. (See "Prevention and management of anthracycline cardiotoxicity" and "Use of angiotensin converting enzyme inhibitors in heart failure with reduced ejection fraction".)

A separate question relates to the potential protective effect of ACE inhibitors for preventing the development of left ventricular dysfunction in response to chemotherapy in patients who are at risk. Patients with elevations in serum cardiac troponin levels in response to chemotherapy may be at an increased risk for developing impaired left ventricular dysfunction. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Troponins'.)

The potential protective effect of ACE inhibitors in patients with elevated serum cardiac troponin following chemotherapy was evaluated in a randomized trial; the high-dose chemotherapy regimen included a variety of anthracycline-containing and nonanthracycline-containing agents [133]. From a total population of 473 cancer patients, 114 with an elevated troponin T were randomly assigned to one year of treatment with the ACE inhibitor enalapril (2.5 mg daily, titrated to a maximum of 20 mg daily), or to no enalapril. After one year, patients assigned to no treatment had a significant reduction in left ventricular ejection fraction (LVEF), while those in the ACE inhibitor group did not (LVEF at 12 months 48 versus 62 percent). In addition, the primary endpoint, an absolute reduction in LVEF of 10 percent or more, was reached in 43 percent of the untreated patients, but in none of the patients treated with enalapril.

Secondary prevention measures such as these require that patients be monitored during and after cancer therapy and managed when toxicity signals appear. Potentially useful biomarkers for cardiotoxicity include elevation in cardiac markers (brain natriuretic peptide [BNP] or troponin) and the development of systolic or diastolic dysfunction on tests such as echocardiography. Unfortunately, there are no universally applicable imaging modalities or markers to reliably predict the risk of developing post-treatment cardiovascular toxicity, and routine serial testing with these modalities cannot be recommended for all patients in the absence of clinical indications. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Investigational tests'.)

In the absence of specific guidelines for cardiac monitoring for a potentially cardiotoxic agent, evaluation and monitoring of LVEF or other biomarkers should be considered on a case-by-case basis. The toxicity profile, patient, and disease characteristics should be considered when making this decision. When starting an agent that may cause or worsen hypertension, serial blood pressure monitoring should be performed and maintained while on the particular drug. Proposed guidelines regarding intervention for treatment-related hypertension are provided in the table (table 3).

Importantly, survivors of cancer tend to develop more comorbidities and reduce their overall levels of physical activity, which may cause subclinical cardiovascular toxicity to become manifest later in life (concept of “multiple hit hypothesis” for risk of cardiovascular disease) [134]). Hence, it is not surprising that outcomes may be improved when cancer survivors who have been treated with potentially cardiotoxic drugs are referred to centers with expertise in long-term surveillance and risk-based medical care [135]. (See "Cancer survivorship: Cardiovascular and respiratory issues" and "Alcohol and smoking cessation for cancer survivors".)

SUMMARY

Cancer patients receiving chemotherapy have an increased risk of developing cardiovascular complications, and the risk is even greater if there is a known history of heart disease.

Anthracycline and anthracycline-like agents, agents that target the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and fluoropyrimidines (eg, fluorouracil, capecitabine) are the most frequently known anticancer agents to be associated with cardiac toxicity. Cardiotoxicity associated with these agents is discussed separately. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)

A wide range of other chemotherapy agents has been associated with cardiotoxicity (see 'Introduction' above). Among the serious complications that have been reported are:

Arrhythmias (eg, histone deacetylase inhibitors, nilotinib, ponatinib, vandetanib, crizotinib, vemurafenib, taxanes)

Myocardial necrosis causing a dilated cardiomyopathy and clinical heart failure (eg, sunitinib and other multitargeted kinase inhibitors that target the vascular endothelial growth factor [VEGF], alemtuzumab, imatinib [in patients treated for chronic myelogenous leukemia], trametinib, taxanes [in combination with anthracyclines])

Vasospasm or vasoocclusion resulting in chest pain or myocardial infarction (eg, fluoropyrimidines). (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management", section on 'Clinical presentation'.)

Pericarditis (eg, cytarabine, bleomycin)

Pericardial effusions (all-trans retinoic acid)

Heart failure, myocardial ischemia, and cardiac arrest (proteasome inhibitors, antiangiogenic therapies, interferon, interleukin-2 [IL-2])

Fluid retention, which may be manifest as a pericardial or pleural effusion (bosutinib, IL-2)

For all patients receiving potentially cardiotoxic therapies, primary prevention to reduce cardiovascular risk may be achieved by measures “that rest on common sense” [94]. Management of preexisting comorbidities (hypertension, systolic or diastolic cardiac dysfunction, arrhythmias, metabolic disorders) should be optimized and a healthy lifestyle encouraged (cessation of smoking, weight reduction towards ideal, increased exercise) both before and after cancer therapy is begun.

In the absence of specific guidelines for cardiac monitoring for a potentially cardiotoxic agent, evaluation and monitoring of left ventricular ejection fraction (LVEF) or other biomarkers should be considered on a case-by-case basis. The toxicity profile, patient, and disease characteristics should be considered when making this decision. When starting an agent that may cause or worsen hypertension, serial blood pressure monitoring should be performed and maintained while on the particular drug. Proposed guidelines regarding intervention for treatment-related hypertension are provided in the table (table 3).

Outcomes may be improved when cancer survivors who have been treated with potentially cardiotoxic drugs are referred to centers with expertise in long-term surveillance and risk-based medical care (see 'Prevention' above). Secondary prevention of cardiac toxicity after treatment currently depends on clinical observation as research continues to identify reliable measures of subclinical disease.

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