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Abstract

Cardiovascular toxicity caused by cancer therapy is a challenging area which needs thorough evaluation and research. Numerous studies, meta-analyses and reviews have been published in the past discussing cardiotoxicity caused by chemotherapeutic agents. A brief review of the on-target and off-target cardiotoxicities caused by chemotherapeutic agents is presented here. Cardiotoxicities are broadly outlined in terms of left ventricular dysfunction, hypertension and thromboembolic events. The mechanisms leading to the cardiotoxicity profiles of various chemotherapeutic agents are discussed. The management of various cardiotoxicities of chemotherapeutic agents is also discussed.

Keywords

cardiotoxicity chemotherapy heart failure hypertension thromboembolism

Introduction

The targeted chemotherapeutic agents have changed the face of cancer therapy regimens, with good outcome benefits and low side-effect profiles. However, much of their toxicities have been underestimated because of a lack of evidence in terms of trials, meta-analyses or follow ups. No set exclusion criteria or classifications have been defined to label the baseline function or to gauge the worsening of physiological functions of chemotherapeutic agents. In particular, cardiovascular toxicity caused by cancer therapy is a challenging area which needs thorough evaluation and research. A review of the on-target and off-target cardiotoxicities caused by chemotherapeutic agents is presented here. These toxicities are broadly outlined in terms of left ventricular dysfunction, hypertension, thromboembolic events, electrocardiographic abnormalities and ischemic events.

Hypertension

A rise in blood pressure in patients with normotension or hypertension at baseline is a well-known side effect of the targeted agents. Increases in blood pressure have been noticed during the use of vascular endothelial growth factor (VEGF) inhibitor agents [Chen and Cleck, 2009]. Inhibition of VEGF leads to suppression of nitric oxide synthase, resulting in decreased nitric oxide production and reduced prostacyclin activity in the endothelium which leads to the elevation in blood pressure [Verheul and Pinedo, 2007]. The degree of blood pressure rise is determined by the baseline blood pressure of the patient, the type of agent chosen, the type of tumor being treated, the degree of angiogenesis inhibition that is being achieved and the setting (home/clinic/hospital) where blood pressure is being monitored.

Vascular rarefaction, functional (decreased perfusion) or structural (decreased capillary density) and endothelial dysfunction resulting in vascular stiffness are some of the other mechanisms proposed to explain the rise in blood pressure seen with use of chemotherapy [Veronese et al. 2006].

A meta-analysis of prospective randomized controlled trials comparing bevacizumab, a monoclonal antibody targeted against VEGF, and placebo reported that use of bevacizumab may lead to a rise in blood pressure and proteinuria, although this association was not statistically significant [Ranpura et al. 2010b; Zhu et al. 2007].

Patients with renal cell carcinoma and gastrointestinal stromal tumors on treatment with sunitinib, a multitargeted tyrosine kinase inhibitor, need close monitoring of blood pressure and cardiac function [Zhu et al. 2009]. Sunitinib use can lead to a reduction in left ventricular function by 10–15%, either due to direct cardiotoxicity or secondary to elevation of mean systolic and diastolic blood pressure. These adverse effects may worsen in the presence of underlying cardiac risk factors or coronary artery disease [Chu et al. 2007].

Sorafenib inhibits tumor angiogenesis by inhibiting raf kinase. In one study, a mean rise in blood pressure of 20 mmHg (p value = 0.0001) with a simultaneous increase in vascular stiffness was seen in patients on sorafenib [Veronese et al. 2006].

Side effects may be potentiated when complementary or combination regimens are used, as in some aggressive cancers. The current dose regimens are able to accomplish the antineoplastic effect in a heightened manner, but at the same time they cause worsening of the side-effect profile. The combination of sorafenib and bevacizumab has increased efficacy in ovarian cancer. However, dose profiles need to revised so that adverse effects are not increased and the therapeutic effect is maintained [Azad et al. 2008]. Bevacizumab and sunitinib, which target the VEGF pathway and have activity against advanced renal cell carcinoma, cause a high degree of hypertension and hematologic toxicities at current doses [Feldman et al. 2009].

Management of hypertension

Treating elevated blood pressure in patients with cancer on chemotherapy regimens, preventing any further rise in blood pressure after the start of chemotherapy and preventing adverse effects like hypertensive crisis, congestive heart failure or coronary artery disease from hypertension are some of the active issues that need to be addressed while a patient is on chemotherapy. Needless to say, all these issues require a multidisciplinary approach with a goal of continuing safe and uninterrupted administration of anticancer agents without dose modifications.

The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to review the aforementioned issues and made recommendations for safe and continuous administration of chemotherapy agents [Maitland et al. 2010]. The expert panel suggested having formal documentation of the cardiovascular risks and assessment of potential cardiovascular complications; identifying and addressing any pre-existing hypertension before the initiation of therapy; active monitoring of blood pressure throughout treatment with an intensive approach during the first cycle of chemotherapy; maintaining a set target blood pressure less than 140/90 mmHg in most patients, though the goal may vary depending on comorbidities; proper agent selection and dosing; and scheduling regular follow up which may help to achieve the neoplastic goals along with avoiding the complications of blood pressure elevation.

Henceforth, management includes defining a set target blood pressure based on the patient’s underlying characteristics and cardiovascular risk factors, frequent blood pressure measurements (most importantly in the first week), lifestyle modifications and careful titration of therapy. Appropriate drug selection should be made based on pharmacokinetics, cancer-related factors, a specific adverse reaction profile and patient comorbidities. Angiotensin-converting enzyme inhibitors and aldosterone receptor blockers are effective in reducing the blood pressure and proteinuria in the absence of any contraindications [Izzedine et al. 2010]. Calcium channel blockers have also been suggested. Increasing the concentration of nitric oxide with anti-VEGF agents, phosphodiesterase inhibitors or nitrates is another recommended approach to treat hypertension. This approach works especially well as an add-on therapy to other antihypertensive agents. Finally, a drug holiday may be considered in cases with refractory disease or hypertension crisis.

Thromboembolic complications

The thromboembolic phenomenon has been reported to be higher in malignancies, likely secondary to the hypercoagulable state. Several meta-analyses have been performed to study the effect of chemotherapeutic agents on the thromboembolic phenomenon and hemorrhagic toxicities. Arterial thromboembolism (ATE) is mostly related to cardiovascular or cerebrovascular events and could be life threatening, thereby raising serious concerns. ATE does not vary much with the kind of malignancy, dosage of the chemotherapeutic agent or in early versus advanced disease. However, some studies show that the risk of ATE increases with the high-grade disease process.

Angiogenesis inhibitors are notorious for causing venous and arterial thromboembolism along with hemorrhagic complications. These effects are more serious when angiogenesis inhibitors are used in combination with the standard chemotherapeutic agents. Many studies have been terminated during phase I because of the unacceptably high incidence of thromboembolic complications [Nalluri et al. 2008; Ranpura et al. 2010a; Scappaticci et al. 2007; Schutz et al. 2011]. The tyrosine kinase inhibitors have a better reputation with respect to thromboembolic complications, with a reported incidence of less than 10%. Mammalian target of rapamycin inhibitors were not found to be associated with significant thromboembolic risks [Choueiri et al. 2010].

Studies reviewing the complications of venous or arterial thromboembolic phenomenon for bevacizumab have yielded inconsistent results. Hurwitz and colleagues reported statistically insignificant results for the rise in venous thromboembolism after the addition of bevacizumab to the standard chemotherapeutic regimen. The authors also noted that most of the thromboembolic phenomenon was driven by the tumor or host risk factors [Hurwitz et al. 2011].

Management of thrombolic complications

The need for prevention, identification and treatment of thromboembolic complications related to chemotherapeutic agents is of utmost importance. Periods of immobility in the postsurgical period or due to deconditioning and morbidity put patients at additional risk for such events. Therefore, the need for thrombo prophylaxis has to be defined and followed up. Currently, there is not enough evidence to recommend the use of aspirin or any other form of anticoagulation against the risk of hemorrhagic complications [Zangari et al. 2009].

Heart failure

Due to high interobserver variation, diagnosing heart failure remains a challenge in the primary care setting, even more so in patients with cancer [Fonseca, 2006]. Fromme and colleagues compared patient reporting of eight symptoms using a validated instrument with physician reporting of the same symptoms and reported that physician reporting was neither sensitive nor specific for common chemotherapy symptoms [Fromme et al. 2004]. They recommended developing tools for collecting patient-reported adverse event data in chemotherapy trials. Various modalities are available for early detection of cardiotoxicity [Altena et al. 2009]. Ventriculography multiple-gated acquisition (MUGA) or echocardiography are frequently used to monitor cardiac function. But these methods can only detect cardiac damage after it has occurred. Intraobserver and interobserver variability are other drawbacks. Use of contrast has been shown to enhance accuracy, reduce interobserver variability and lead to better correlation with magnetic resonance imaging of ejection fraction [Hoffmann et al. 2005; Malm et al. 2004; Sugeng et al. 2006]. Three-dimensional echocardiography reduces the probability of chamber foreshortening and has been shown to be accurate in serial measurements. Walker and colleagues reported that, compared with MUGA scanning, real-time three-dimensional echocardiography is feasible, accurate and reproducible for serial ejection fraction monitoring in patients with breast cancer [Walker et al. 2010]. Two-dimensional echocardiography was found to be less accurate. New techniques are being applied in echocardiography to detect subclinical markers of cardiac dysfunction. Diastolic dysfunction markers like deformation and deformation rate are under investigation to detect early cardiac damage. The Tei index is also being studied as it provides a functional evaluation of the ventricles. Three-dimensional echocardiography has been reported to be feasible and as accurate as conventional methods for serial monitoring of left ventricular ejection fraction (LVEF) in patients with breast cancer [Walker et al. 2010].

Two molecular mechanisms have been proposed to explain chemotherapy-induced cardiotoxicity – on-target and off-target toxicities [Cheng and Force, 2010; Raschi and De Ponti, 2012]. On-target toxicity refers to the mechanism-based toxicity caused by a target which promotes both tumor growth and cardiac function. Off-target toxicity occurs when the drug inhibits a target which is not involved in tumor growth but only in cardiac function, the so-called bystander target. Chemotherapy-induced cardiotoxicity has been divided into type 1 and type 2. Type 1 cardiotoxicity refers to irreversible damage and is related to ultrastructural changes, while type 2 cardiotoxicity is at least partially reversible and without any structural changes on a biopsy.

Human epidermal growth factor receptor 2 agents

Preclinical studies have not reported any cardiac dysfunction with the use of trastuzumab (reference). In a randomized control trial comparing standard chemotherapy alone versus standard chemotherapy plus trastuzumab, Slamon and colleagues reported that the most important side effect was cardiac dysfunction of New York Heart Association class III or IV [Slamon et al. 2001]. Cardiac dysfunction occurred in 27% of the group given an anthracycline, cyclophosphamide and trastuzumab; 8% given an anthracycline and cyclophosphamide alone; 13% given paclitaxel and trastuzumab; and 1% given paclitaxel alone. The authors also noted that, although the cardiotoxicity was potentially severe, the symptoms generally improved with standard medical management. Nevertheless, combination therapy of an anthracycline and trastuzumab was subsequently abandoned in patients with metastatic breast cancer.

The exact impact of trastuzumab on cardiac function is difficult to assess also because of the concomitant administration of other cardiotoxic agents such as the taxanes and cyclophosphamide [Ewer and Ewer, 2008]. Presence of pre-existing cardiac disease further obscures this picture. As mentioned above, patients affected by trastuzumab-related cardiotoxicity do not exhibit the cellular death and the distinctive ultrastructural myocardial changes on electron microscopy. The cardiotoxicity of trastuzumab has also been reported to be at least partially reversible and unrelated to the cumulative dose [Ewer et al. 2005; Morris and Hudis, 2010; Suter et al. 2007]. The mechanism of toxicity is still unclear. Disruption of the epidermal growth factor signaling pathway in the heart, particularly ErbB2 and EbB4 which are expressed after birth, may be the underlying mechanism of injury [Ewer and Ewer, 2008]. Ligands like neuregulins bind to ErbB receptors and induce heterodimer formation and autophosphorylation. This causes activation of G proteins and mitogen-activated protein kinases. This pathway not only mediates the hypertrophic response of myocytes and sarcomeric organization, but also attenuates cardiac myocyte death [Clerk et al. 1998; Suter et al. 2004]. By disrupting this pathway, trastuzumab affects the ability to mount an intact stress response. The fact that ErbB2-deficient mice were also more sensitive to anthracycline-induced toxicity and that ErbB receptors were found to be upregulated in the heart within 3 weeks of anthracycline therapy further supports this hypothesis [Crone et al. 2002; de Korte et al. 2007]. This may explain the cardiotoxic synergism of trastuzumab with anthracyclines. It also appears that although trastuzumab may have a lower capacity to induce myocyte death, it has a high potential to augment anthracycline-induced cardiotoxicity [Ewer and Ewer, 2010].

Pertuzumab belongs to a new class of targeted anticancer agents known as human epidermal growth factor receptor 2 (HER2) dimerization inhibitors, which inhibit the ability of HER2 to pair with other HER family members which is essential for HER signaling and is required for cell growth and survival in many tumor types [Agus et al. 2002]. It is also capable of inducing antibody-dependent cell-mediated cytotoxicity [Scheuer et al. 2009]. It has been shown to be effective in combination with trastuzumab in patients with metastatic breast cancer [Baselga et al. 2007; Portera et al. 2008]. Pooled analysis of patients treated with pertuzumab found relatively low levels of asymptomatic left ventricular systolic dysfunction and asymptomatic heart failure [Lenihan et al. 2012]. More importantly, the analysis reported no increase in the cardiac side effects when pertuzumab was given in combination with other anticancer agents.

Lapatinib is an oral dual tyrosine kinase inhibitor of epidermal growth factor (ErbB1) and HER2 kinases. It has been approved by the US Food and Drug Administration (FDA) in combination with capecitabine in patients with advanced or metastatic breast cancer whose tumors overexpress the HER2 protein [Geyer et al. 2006]. In a review of 44 clinical studies, Perez and colleagues concluded that lapatinib had low levels of cardiotoxicity [Perez et al. 2008]. Cardiac events mostly occurred in the form of asymptomatic and reversible decreases in LVEF fraction. Notably, the rates of occurrence were similar in patients who had and had not been pretreated with anthracyclines or trastuzumab.

Vascular endothelial growth factor inhibitors

Bevacizumab (Avastin, Genentech, San Francisco, CA, USA) is an antiangiogenic monoclonal antibody against VEGF receptor. It was given accelerated approval in 2008 for patients with metastatic breast cancer after promising results from an Eastern Cooperative Oncology Group clinical trial. The trial showed an increase in the median progression-free survival of 5.5 months in patients receiving bevacizumab plus chemotherapy compared with those treated with chemotherapy alone [Miller et al. 2007]. In various meta-analyses, it was later reported that bevacizumab offered no benefit in overall survival and was associated with serious side effects like congestive heart failure and hypertension [An et al. 2010; Brufsky, et al. 2011; Choueiri et al. 2011; Valachis et al. 2010]. In November 2011, the FDA cancelled its approval for the treatment of metastatic breast carcinoma.

Recently, two studies have been published evaluating the efficacy and safety profile of bevacizumab added to neoadjuvant therapy: National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial [Bear et al. 2012; von Minckwitz et al. 2012]. They reported significant increases in pathological complete response with combination therapy compared with chemotherapy alone, though the rates of adverse effects like hypertension, heart failure, mucositis and hand–foot syndrome also increased. The use of bevacizumab will be justified only if progression-free survival and pathological complete response are shown to be predictive of survival benefits in early stage disease [Montero and Vogel, 2012]. Cost effectiveness will be one area that might predict the future of bevacizumab in treatment of metastatic breast cancer.

ABL-targeted agents

Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia and gastrointestinal stromal tumor by targeting bcr-abl and c-kit tyrosine kinases respectively [Baccarani et al. 2009]. In a study of 10 patients with normal left ventricular function, Kerkela and colleagues reported the development of congestive heart failure while on imatinib treatment as evidenced by both clinical signs and radionuclide imaging after a mean of 7.2 ± 5.4 months of therapy. They reported mitochondria as the main target of imatinib-induced cardiotoxicity, which was mediated by c-abl inhibition [Kerkela et al. 2006]. The authors reported that endoplasmic reticulum stress response, which is activated by imatinib, leads to a decline in adenosine triphosphate concentrations triggering cell death. Subsequent in vitro studies reported that imatinib-related cardiotoxicity is unlikely related to the drug’s inhibition of c-abl and also that imatinib is not cardiotoxic at clinically relevant concentrations [Wolf et al. 2010]. The endoplasmic reticulum stress response was only found at very high concentrations of imatinib.

Various retrospective studies and reviews have reported less than 1% incidence of heart failure in patients on imatinib therapy, which is usually manageable with standard medical therapy and does not require discontinuation of imatinib [Atallah et al. 2007; Breccia et al. 2008; Trent et al. 2010; Verweij et al. 2007]. A study of five patients reported no changes in brain natrituretic peptide (BNP) levels after 3 months of therapy with imatinib [Tiribelli et al. 2008]. Another study of 12 patients found no changes in BNP, electrocardiographic and echocardiographic measures after 12 months of therapy [Marcolino et al. 2011]. Estabragh and colleagues used the very sensitive MUGA scans to identify any change in cardiac function with imatinib therapy but found no significant changes after 1 year of therapy in 55 patients [Estabragh et al. 2011].

Dasatinib (BMS-354825, Bristol-Myers Squibb, New York, NY, USA) is an orally available ABL kinase inhibitor. It can bind to both the active and inactive conformations of the ABL kinase domain and hence can target many imatinib-resistant bcr-abl mutations [Lombardo et al. 2004; Shah et al. 2004; Talpaz et al. 2006]. Yeh and Bickford reported a 2–4% incidence of left ventricular dysfunction (about half were grade 3–4 heart failures) related to dasatinib therapy after reviewing phase III clinical data [Yeh and Bickford, 2009]. Asymptomatic QT prolongation and pericardial effusion have also been reported with the use of dasatinib [Johnson et al. 2010]. No cardiac events have been reported with nilotinib, except for QT prolongation on electrocardiogram [Wolf et al. 2011]. However, severe peripheral arterial disease has been reported for nilotinib and it is recommended that patients be screened for this complication before and during treatment [Aichberger et al. 2011].

Multikinase inhibitors

Sunitinib (Sutent, Pfizer, New York, NY, USA) is a multitargeted tyrosine kinase inhibitor which has been shown to prolong survival in patients with renal cell carcinoma and gastrointestinal stromal tumor [Demetri et al. 2006; Motzer et al. 2006, 2007]. It works by inhibiting VEGF receptors 1–3, platelet-derived growth factor (PDGF) receptors α and β, Flt-3, c-kit, colony-stimulating factor 1 receptor and the ret oncogene [Faivre et al. 2006; Mendel et al. 2003]. In a retrospective analysis of 75 patients, Chu and colleagues reported 11% of all patients had a cardiovascular event in the form of congestive heart failure or increase in blood pressure [Chu et al. 2007]. The authors noted that the left ventricular dysfunction responded to sunitinib being withheld and institution of medical management. In another retrospective analysis of 175 patients, Di Lorenzo and colleagues reported development of hypertension or heart failure in 19% of patients [Di Lorenzo et al. 2009]. It has been proposed that sunitinib-induced cardiotoxicity is likely the result of off-target inhibition of adenosine monophosphate activated protein kinase [Kerkela et al. 2009].

Sorafenib is another oral multitargeted tyrosine kinase inhibitor which is used in the treatment of metastatic renal cell carcinoma and advanced primary liver cancer. It inhibits many serine/threonine and tyrosine kinases, including VEGF receptors, PDGF receptors α and β, kit, flt-3, RAF1 and BRAF kinases [Chen et al. 2008; Strumberg et al. 2007; Wilhelm et al. 2004]. Sorafenib has been shown to be associated with cardiac ischemia or infarction (2.7% versus 1.3% for patients on placebo) and an increase in hypertension [Chen et al. 2008; Kane et al. 2009; Orphanos et al. 2009]. In an observational study of 86 patients, Schmidinger and colleagues reported an incidence of LVEF drop of 5% for sorafenib and 14% for sunitinib, although all patients recovered after cardiovascular management and were considered for continuation of therapy [Schmidinger et al. 2008].

Enhanced cardiotoxicity has been reported in sunitinib-pretreated patients subsequently treated with sorafenib when given within 2–3 weeks [Mego et al. 2007]. However, no such toxicity was observed if the interval between stopping sunitinib and starting sorafenib was increased to 7 months [Mego et al. 2007; Wong and Jarkowski, 2009].

Management of heart failure

The concept of therapeutic editing has been suggested, which is based on the premise that certain drugs can act as selective antagonists for chemotherapy at off-target sites but act synergistically at cancer sites. New protective strategies have also been natural compounds capable of improving antioxidant defenses against reactive oxygen species, such as N-acetyl cysteine, α tocopherol and vitamins [Ferrari et al. 2011]. Troponin I, BNP and amino terminal fragment of BNP have shown promising results in helping the physician to stratify the patient’s risk for cardiomyopathy and need for monitoring [Cardinale et al. 2000, 2010b]. β Blockers, angiotensin-converting enzyme inhibitors and diuretics may be used when pharmacological treatment is deemed necessary [Cardinale et al. 2010a].

Prevention of cardiotoxicity

Various therapies have been studied for prevention of chemotherapy-related cardiotoxicity. Reduction of the cumulative dose of anthracyclines should be aimed for whenever possible. Administration of anthracyclines as infusions rather than as bolus regimens has also been shown to be beneficial [Casper et al. 1991; Zalupski et al. 1991]. Other measures shown to be effective are structural modification of doxorubicin and the liposomal encapsulation of doxorubicin [Smith et al. 2010; Young et al. 2004]. Dexrazoxane has been reported to prevent doxorubicin- or epirubicin-associated cardiotoxicity, although it is used mainly in patients who receive a cumulative dose of doxorubicin of at least 300 mg/m² [Hensley et al. 2009; Smith et al. 2010]. Recently, selenium supplementation has been shown to prevent anthracycline-induced cardiac toxicity in children with cancer [Tacyildiz et al. 2012].

In a randomized study of 50 patients, carvedilol 12.5 mg once daily was shown to be associated with no change in the LVEF after 6 months, in contrast to the placebo group in which the LVEF significantly decreased by 17% [Kalay et al. 2006]. Enalapril has been shown to be associated with better cardiac outcomes in patients with higher troponin I value [Cardinale et al. 2006]. The incidence of decrease of LVEF by 10 percentage points was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; p < 0.001). Another randomized study of 125 patients with lymphoma examined the doxorubicin induced clinical or subclinical cardiotoxicity after concomitant prophylactic therapy with metoprolol or enalapril. The incidence of heart failure and subclinical cardiotoxicity was lower in the treatment groups (especially in the metoprolol group) than in the control group, although the results were not statistically significant [Georgakopoulos et al. 2010]. In a recent randomized study of 45 patients, nebivolol 5 g daily was found to be associated with higher ejection fraction and lower N-terminal pro-BNP levels [Kaya et al. 2012].

A randomized study of 40 patients with untreated non-Hodgkin’s lymphoma who were randomized to receive either valsartan 80 mg daily or placebo at the time of starting CHOP treatment demonstrated lower BNP levels, similar atrial natriuretic peptide levels and fewer changes in left ventricular end diastolic compared with the placebo group on day 3 [Nakamae et al. 2005]. The cardioprotective effect of telmisartan has been demonstrated in rats exposed to anthracyclines [Iqbal et al. 2008]. The effect was sustained through a decrease in oxidative stress, leading to reduced structural damage of cardiomyocytes. Telmisartan has also been reported to inhibit the proliferation of prostate cancer cells through activation of peroxisome proliferator-activated receptor γ [Funao et al. 2008]. Angiotensin receptor blockers were found to suppress the signal transduction mediated by growth factors, such as the epidermal growth factor by angiotensin 1 receptor antagonism [Ishiguro et al. 2007]. Cadeddu and colleagues reported that telmisartan reduced epirubicin-induced oxidative stress and chronic inflammation, and reversed early myocardial impairment [Cadeddu et al. 2010]. In a 12-month follow-up study, the same authors found that telmisartan reversed acute epirubicin-induced myocardial dysfunction and was associated with a normal systolic function [Dessi et al. 2011].

Conclusion

Different chemotherapeutic agents have significant cardiovascular effects, including hypertension, thromboembolism and heart failure. Recognition and management of chemotherapy-induced cardiotoxicity is challenging. Close monitoring of cardiac function during and after treatment is required.

Footnotes

Acknowledgements

All of the authors listed have contributed to this manuscript and are aware of its submission. All authors take full responsibility for the work submitted.

Funding

This manuscript was not funded by any outside sources.

Conflict of interest statement

The authors affirm that this manuscript is not simultaneously under review for submission in another publication. This manuscript is not a work for hire. None of the authors have any financial disclosures to make.

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Chemotherapy-related cardiotoxicity

Abstract

Keywords

Introduction

Hypertension

Management of hypertension

Thromboembolic complications

Management of thrombolic complications

Heart failure

Human epidermal growth factor receptor 2 agents

Vascular endothelial growth factor inhibitors

ABL-targeted agents

Multikinase inhibitors

Management of heart failure

Prevention of cardiotoxicity

Conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References