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State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: A literature review

Critical Reviews in Oncology/Hematology, 1, 88, pages 75 - 86

Abstract

Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival, regardless of the oncologic prognosis.

Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident months, and sometimes years, after completion of chemotherapy.

Cardiotoxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes.

The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent, that can serve as a tool in the clinical practice.

Keywords: Cardiotoxicity, Anticancer therapy, Cardiovascular toxicity, Targeted therapies, Chemotherapy.

1. Introduction

Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival.

Due to the increasing number of patients treated by chemotherapy and biological drugs (often in combination and at progressively higher cumulative doses), the incidence of cardiotoxicity is continuously growing [1] and [2].

1.1. Cardiotoxicity in the clinical practice

Predisposition to cardiotoxicity development is multifactorial and determined by the interaction between genetic and environmental factors [3] . Familial risk of coronary artery disease or congestive HF, age, sex, and other events related to personal history, including dyslipidemia, previous analysis of LV function or arrhythmias and medical therapies, have been associated with an additional risk of developing cardiotoxicity.

Premenopausal women have a lower risk than men of same age to develop atherosclerosis. However after menopause, the levels of protective hormones drop and therefore the rate of atherosclerosis in women rapidly increases [4] .

Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident a long period after completion of anticancer therapy. The actual magnitude of the problem is still unclear because only in few cases (i.e. trastuzumab and lapatinib) a prospective evaluation of cardiac function has been performed. Furthermore, the high incidence of cardiac dysfunction in patients undertaking combination regimens increase the complexity of the scenario [5] .

Chemotherapy and molecular targeted therapies can affect the cardiovascular system, both at a central level by deteriorating the heart function and in the periphery by enhancing hemodynamic flow alterations and thrombotic events.

Data regarding risk factors are contradictory and the relationship between abnormalities identified by non-invasive cardiac investigations and survival is not clear [6] . Furthermore, in many cases we still miss the rate of the cardiovascular adverse events and the reported rates were obtained from the literature; thus, they apply only to the available follow-up periods for each agent [7] .

Cardiotoxicity can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary LVEF decline, to life-threatening events such as congestive HF or acute coronary syndromes [8] . It can develop in a subacute, acute, or chronic manner. Acute or subacute cardiotoxicity is characterized by either the occurrence of abnormalities in ventricular repolarization and electrocardiographic QT-interval changes, by supraventricular and ventricular arrhythmias, or by acute coronary syndromes and pericarditis and/or myocarditis-like syndromes, observed any time up to 2 weeks after termination of therapy. Chronic cardiotoxicity may be differentiated in two subtypes based on the onset of clinical symptoms. The first subtype occurs early, within 1 year after completion of chemotherapy, and the second occurs more than 1 year after. The typical sign of chronic cardiotoxicity is asymptomatic systolic and/or diastolic left ventricular dysfunction (LVD) that leads to severe congestive cardiomiopathy and that may ultimately lead to death [6] and [9].

In general, cardiovascular side effects can be included into 5 categories:

  • 1. direct cytotoxic effects of chemotherapy and associated cardiac systolic dysfunction,
  • 2. cardiac ischemia,
  • 3. arrhythmias (especially torsade de pointes induced by QT prolonging drugs),
  • 4. pericarditis,
  • 5. chemotherapy-induced repolarisation abnormalities.

The agents that are most commonly associated with myocardial dysfunction, in particular with a LVD include: anthracyclines, monoclonal antibodies, tyrosine kinase inhibitors (TKIs), alkylating agents, and interferon-alpha [10] . Cardiac ischemia has been most commonly described in patients who received purine analogs, such as 5-fluorouracil (5-FU), topoisomerase inhibitors, and antitumor antibiotics [11], [12], [13], [14], [15], [16], and [17]. Cardiac arrhythmias have been related to the use of anthracyclines and other agents, due to cardiac ischemia or to metabolic changes. Pericarditis has been well described in patients receiving cyclophosphamide, cytarabine, and bleomycin [18] . Although neoplastic conditions might be associated with a hypercoagulable state, chemotherapeutic agents might result in vascular injury and a locally hypercoagulable state.

The antiangiogenic and multitarget TKIs sorafenib and sunitinib are associated with hypertension and cardiotoxicity [19] and [20]; the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is also associated with hypertension, thromboembolism, pulmonary hemorrhage, and pulmonary edema or gastrointestinal tract bleeding [20] . Thus, the antiangiogenesis class of drugs can also harbor cardiovascular toxicity, as indicated by a reduction of LVEF that over the long term may result in congestive HF [21] .

The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent that can serve as a tool in the clinical practice. We conducted a systematic literature search of reviews, articles, clinical trials and extracted data using the following keywords: cardiotoxicity; cardio-oncology; cardiovascular complications; cardiac side effects; chemotherapy agents and targeted therapies.

1.2. Mechanisms of therapy-induced damage to heart and blood vessel

The cardiovascular system has different targets that could be injured: cardiomyocytes, pericardium, coagulation system and vessel.

Traditional cytostatic, especially anthracyclines, cyclophosphamide, taxanes, fluorouracil, vinca alkaloids, busulphane, cisplatine and bleomycin have a cytostatic effect and the subsequent damage to the myocardium is usually irreversible since associated with myocite death (damage type I).

Arterial hypertension, arrhythmias, left ventricular dysfunction and heart failure are the most frequent cardiovascular adverse effects of the new anticancer drugs that specifically altered signaling pathways, but this cardiotoxicity seems to be reversible and more benign because associated with cell hibernation or myocardial stunning (damage type II) [22] and [23].

1.2.1. Direct effects on the heart

Anthracyclines cause an increase in myofibrillar disorder that is mediated by the signaling function of neuregulin1β. In addition, anthracyclines induce mitochondrial apoptosis pathways and free radical production [24] and [25].

There are several hypotheses on the mechanisms of anthracycline-induced cardiotoxicity, but free radical formation has been accepted as the main one. Free radicals cause direct damage to proteins, lipids and DNA and myocyte apoptosis seems to be related to increased oxidative stress caused by these processes [26] . Other mechanisms have also been postulated: apoptosis, transcriptional changes in intracellular adenosine triphosphate (ATP) production in cardiomyocytes, down-regulation of mRNA expression for sarcoplasmic reticulum calcium-ATPase, which decreases cardiac contractility, prolonged drug-related depression in cardiac glutathione peroxidase activity and respiratory deficiency associated with mitochondrial deoxyribonucleic acid damage [27] .

Recently it has been proposed that doxorubicin may cause cardiotoxicity through its interference with topoisomerase II-beta [28] .

The cardiotoxic potential of anthracycline is enhanced by the administration of trastuzumab. The trastuzumab target, ErbB2/HER2 (epidermal growth factor receptor, EGFR) is expressed on cardiomyocytes, where it exerts a protective effect on cardiac function [29] . Both HER receptors and their ligands are expressed in the heart and their activation creates a hypertrophic response [30] . Nevertheless, not all biological agents that target Erb proteins induce damage to the heart. In fact, lapatinib, an oral TKI targeting ErbB1 and ErbB2, was reported to show limited cardiotoxicity [31] .

The mechanisms by which several other chemotherapy drugs produce cardiac toxicities have also been investigated. 5-FU has direct toxic effects on vascular endothelium that involve endothelial nitric oxide (NO) synthase and lead to coronary spasms and endothelium-independent vasoconstriction via protein kinase C [32] . Several new generation TKIs (i.e. sorafenib and sunitinib), have been also been associated with direct cardiotoxicity [19] and [20].

1.2.2. Effects on the coagulation system

Cancer is known to produce a prothrombotic state and the risk of thrombosis appears to be highest in patients with metastatic disease and/or with established risk factors [33] . Moreover, chemotherapy can promote blood clotting, which is a precursor to thromboembolic events.

Life-threatening hemorrhage and arterial thromboembolism have been observed with agents that are broad-spectrum angiogenesis inhibitors, such as thalidomide and lenalidomide [34] . Angiogenesis inhibitors and vascular disrupting agents destroy the function or the integrity of the vascular endothelium [35] . Damage to the vessel can involve injury to the intimal layer or disruption of endothelial cell–cell communication. In either case, this activates the coagulation cascade. Venous thromboembolism has been associated with alkylating agents, angiogenesis inhibitors, histone deacetylase inhibitors, and TKIs. In particular, cisplatin can trigger platelet aggregation, enhance thromboxane formation by platelets, and activate arachidonic acid pathways in platelets [36] . The risk of hemorrhage and thromboembolisms increases with the use of drugs that modify the expression pattern of adhesion molecules on endothelial cells, such as integrins and cadherins, producing alterations on the cell–cell and cell–matrix connections and interruption of the endothelium integrity [37] .

1.2.3. Hypertension

In patients treated with antiangiogenic drugs hypertension is a common adverse event (i.e. bevacizumab, sorafenib, sunitinib) and it is not fully understood but seems to be related to VEGF inhibition, which leads to decreases in NO production in the walls of arterioles and other resistance vessels, through decreased NO-synthase activity [38] and [39].

NO is a natural vasodilator, thus, blocking NO production promotes vasoconstriction and increases peripheral vascular resistance and blood pressure [40] . Moreover, the decreased endothelial NO synthase activity may stimulate plasminogen activator inhibitor-1 expression, leading to an increased risk of hypertension [41] .

1.2.4. Atrial fibrillation (AF)

AF can be induced by various cytostatic agents, such as ifosfamide, gemcitabine, melphalan, cisplatin, docetaxel, 5-FU, or etoposide [42] and [43]. Inflammation plays an important role in carcinogenesis and could provide a possible explanation for a relationship between AF, inflammation, and cancer. Among the patients with history of cancer, 18.3% had AF compared with 5.6% of patients without [44] . A statistically significant elevation of serum levels of C-reactive protein were found in patients with AF and those with a history of cancer, implying systemic inflammation. However, cancer was not found to be an independent predictor of atrial arrhythmias.

2. Cardiotoxicity of conventional cancer therapy

Table 1 summarizes the incidence of cardiotoxicity due to chemotherapy.

Table 1 Incidence of cardiotoxicity due to chemotherapy [29] .

Chemotherapy agents Incidence (%)
  LV Dysfunction Ischemia Bradycardia
Anthracyclines
 Doxorubicin 3–26% _ _
 Epirubicin 0.9–3.3%    
Alkylating agents
 Cyclophosphamide 7–28% _ _
 Ifosfamide 17%    
Antimicrotubule agents
Docetaxel 2.3–8% 1.70%  
Paclitaxel   1–5% 0.1–31%
Antimetabolites
 Capecitabine _ 3–9% _
 Fluorouracil   1–68%  

2.1. Anthracyclines

Anthracycline cardiotoxicity is an irreversible non-ischemic toxic cardiomyopathy. In the most severe form, it may lead to severe left ventricular (LV) systolic dysfunction and HF, which may be progressive and can result in cardiac death [45] .

Anthracycline-induced cardiotoxicity has been categorized into acute, early-onset chronic progressive, and late-onset chronic progressive [46] and [47]. Acute cardiotoxicity occurs in <1% of patients immediately after infusion as an acute, transient decline in myocardial contractility, which is usually reversible. The early-onset chronic progressive form occurs in 1.6–2.1% of patients, during therapy or within the first year after treatment. Late-onset chronic progressive anthracycline-induced cardiotoxicity occurs at least 1 year after completion of therapy in 1.6–5% of patients [27] .

The risk of cardiotoxicity increases with a cumulative dose of anthracycline: the maximum lifetime cumulative dose for doxorubicin is 400–550 mg/m2 [27] , however, epirubicin or idarubicin appear to have less incidence of HF [26], [27], and [48].

It is noteworthy that diastolic dysfunction, although generally asymptomatic and subclinical, is considered to start even at cumulative doxorubicin doses of 200 mg/m2 [49] , and patients are more susceptible to the development of HF when sequential stresses are encountered [14] . Moreover, several risk factors that potentially increase cardiotoxicity have been identified, including age, prior chest irradiation, the concurrent use of other anticancer drugs such as cyclophosphamide, trastuzumab, and taxanes, female sex, pre-existing heart disease and hypertension [50] .

2.2. Taxanes

Taxanes exhibit their anticancer effects by promoting polymerization of tubulin, leading to the development of dysfunctional microtubules and disturbing cell division. Another possible mechanism is massive histamine release.

Although most cases of paclitaxel-induced cardiotoxicity are represented by subclinical sinus bradycardia (approximately 30%), paclitaxel may induce heart block with syncope, supraventricular or ventricular arrhythmias, and myocardial ischemia through unknown mechanisms [51] . Furthermore, taxanes potentiate anthracycline-induced cardiotoxicity by increasing the plasma levels of doxorubicin, and by promoting the formation of the toxic alcoholic metabolite doxorubicinol in cardiomyocytes [52] . Docetaxel causes less cardiac toxicity than paclitaxel.

2.3. Fluoropyrimidine

Although acute HF, arrhythmia, and ECG changes have been associated with 5-FU treatment, the most commonly described and severe cardiac side-effect is myocardial ischemia, which clinically varies from angina to acute myocardial infarction.

It has been shown that the frequency of cardiac events, including acute coronary syndromes is 7.6% and the mortality rate is 2.2% after continuous infusion of high doses of 5-FU. Patients with a history of coronary artery disease had a higher incidence of ischemic adverse events. Although the etiology is still unknown, cardiotoxicity seems to be related to endothelial dysfunction and vasospasm of coronary arteries [53] and [54]. Capecitabine may also elicit myocardial ischemia and ventricular arrhythmias, although it appears to have less toxicity than 5-FU [55] .

2.4. Cyclophosphamide

Cyclophosphamide generally does not cause relevant cardiotoxicity. However, high-dose rapid administration may induce lethal acute pericarditis and hemorrhagic myocarditis [56] . Although the etiology is not fully understood, direct oxidative cardiac injury has been implicated. Unlike the anthracyclines, the toxicity associated with cyclophosphamide appears to be related to a single dose and not cumulative doses. In addition, patients who previously received anthracyclines or underwent chest irradiation are more likely to suffer from cyclophosphamide-induced cardiotoxicity [57] and [58].

3. Cardiotoxicity of biological agents

Table 2 summarizes the incidence of cardiotoxicity due to targeted therapies.

Table 2 Incidence of cardiotoxicity due to targeted therapies [29] .

Targeted therapy Incidence (%)
  LV Dysfunction Ischemia Hypertension QT prolungation Arterial tromboembolism
Monoclonal antibody-based tyrosine kinase
 Bevacizumab 1.7–3.0% 0.6–1.5% 4.0–35.0% _ 3.80%
 Trastuzumab 2.0–28.0% _ _ _ _
Small molecule tyrosine kinase inhibitors
 Sorafenib _ 2.7–3.0% 17.0–43.0% _ _
 Sunitinib 2.7–11.0%   5.0–47.0% _ _
 Lapatinib 1.5–2.2%     16% _

3.1. Bevacizumab

Bevacizumab can be associated with HF or arterial thromboembolic events or venous thromboembolism, and it can induce severe hypertension.

The incidence of HF ranges from 1.7% to 3% and the mechanism may be related to uncontrolled hypertension and inhibition of VEGF/VEGFR signaling [59] .

Bevacizumab is also associated with hypertension and instances of thromboembolism, pulmonary hemorrhage, and pulmonary edema or gastrointestinal tract bleeding.

In clinical trials, grade 3–4 severe hypertension occurred in 9.2% of patients, with rare cases of hypertensive crisis, including encephalopathy or intracranial hemorrhage.

Hypertension developed at any time during therapy, and some data suggest there is a relationship with dose [60] and outcome [61] . Most patients were adequately treated with antihypertensive drugs and continued bevacizumab therapy.

In addition to the above cited mechanisms, it has also been hypothesized that VEGF may have effects on the renin-angiotensin system [62] . However, Veronese et al. [63] demonstrated that serum catecolamine, renin, and aldosterone levels did not change during anti-VEGF therapy, lessening the likelihood that the onset of hypertension has an adrenergic or a renovascular etiology.

Treating hypertension induced by antiangiogenic therapies, standard antihypertensive medications should be considered according to JNC guidelines [64] . Hypertension induced by bevacizumab will most likely require more than an antihypertensive medication and close blood pressure monitoring is recommended.

Thromboembolic events, such as myocardial infarction, ischemic cerebrovascular diseases, and pulmonary arterial embolism, are infrequent but life-threatening side-effects of bevacizumab that have been reported to occur in 3.8% of patients. Elderly patients (≥65 years) or those with prior arterial thromboembolic events (ATEs) may have a higher risk.

Bevacizumab-associated ATEs were reported to occur at any time during therapy and the median time to event was approximately 3 months. Events did not seem to be associated with dose or cumulative exposure [16] . Bevacizumab therapy should be discontinued in patients who develop severe ATEs during treatment.

The mechanism associated with bevacizumab induced arterial thrombosis is unclear.

The impact of antineoplastic therapies on the coagulation cascade can be basically ascribed to damage to the intima of the vessels and also to the interconnections of endothelial cells possibly with bleeding and hemorrhage. Again, hypertension, often seen with the antiangiogenic agents, has acute and long-term effects on cardiac hypertrophy and insufficiency. Finally, AF can be exacerbated by anticancer treatments.

Furthermore VEGF may be involved and anti-VEGF therapy may decrease the regenerative capability of endothelial cells in response to trauma, leading to endothelial cell dysfunction increasing the risk for thrombotic events to occur. In addition, inhibiting VEGF causes reduction in NO and prostacyclin, which may predispose patients to an increased risk of thromboembolic events [41] .

3.2. Trastuzumab

Up to a third of patients treated with trastuzumab might develop a drug-induced cardiomyopathy. Interestingly, trastuzumab induced cardiotoxicity does not appear to be dose dependent and is often reversible with discontinuation of this agent.

The incidence of cardiac dysfunction ranges from 2% to 7% when trastuzumab is used as monotherapy, 2% to 13% when trastuzumab is used in combination with paclitaxel, and up to 27% when trastuzumab is used with anthracyclines plus cyclophosphamide [65] and [66].

Potential risk factors include baseline LVEF, prior cardiac diseases, elderly age and previous chest irradiation. Patients predisposed to cardiovascular risk factors (e.g. smoking, hypertension, dyslipidemia, diabetes, and obesity) are more likely to experience cardiac damage after trastuzumab treatment [65] and [66]. Trastuzumab-induced cardiac dysfunction is often reversibile.

Serial assessment of LV function is suggested when treatment with anthracyclines, trastuzumab, TKIs, or antitumor antibiotics is being considered, although standards for surveillance screening intervals have not been established.

Cardiotoxicity caused by trastuzumab is most likely secondary to inhibition of cardiomyocyte human ErbB2 signaling, thereby interfering with normal growth, repair, and survival of cardiomyocytes [67] and [68].

By binding to ErbB2, it may regulate mitochondrial integrity through the BCL-X proteins, leading to ATP depletion and contractile dysfunction. Other mechanisms include drug– drug interactions and immune-mediated destruction of cardiomyocytes. There may also be a mechanism of cardiotoxicity independent of ErbB2 signaling, since both lapatinib and trastuzumab inhibit ErbB2, but with different incidences of HF [68] .

In addition, heregulin-HER signaling promotes cell survival and growth and protects against apoptosis. Heart is able to stand stress thank to a protein network leading to cell survival that is activated by HER ligands and involves the activator protein-1 and the nuclear factor-B. Activator protein-1 regulates the expression of a group of cardiac proteins that are important in the development of cardiac hypertrophy, and nuclear factor-B regulates the genes that are involved in the cellular response to stress and inflammation [30] and [68].

3.3. Lapatinib

Lapatinib is a TKI targeting HER2 and HER1/EGFR and it is effective against HER2p95 (truncated form of HER2)-positive cancer. Lapatinib seems to have a low incidence of HF or other adverse cardiac effects [69] .

The cardiac safety of lapatinib was recently evaluated in Phase I–III trials (3689 patients enrolled) that examined the cardiovascular safety of lapatinib: 1.6% of patients had a reduced LVEF by at least 20%, and 0.2% experienced symptomatic HF. Furthermore, the incidence of cardiac complications increased in patients who had previously received anthracyclines or trastuzumab [70] .

The QT prolongation potential of lapatinib was assessed in an uncontrolled, open-label dose escalation study in advanced cancer patients who may be particularly prone to QT prolongation because they have an high prevalence of comorbidies and they use concomitant medications prolonging the QT interval [30] .

Some of the most commonly cited risk factors include female gender, elderly age, myocardial ischemia/infarction, HF, electrolyte imbalances, bradycardia, and medications with QT-prolonging effects. A baseline and periodic ECG monitoring are recommended, as well as dosage adjustments or discontinuation of therapy that may be necessary in the face of QT prolongation.

3.4. Sorafenib

The incidence of sorafenib-associated cardiac dysfunction is lower than that of sunitinib and it appears to be reversible and responsive to general treatment.

Hypertension is a major adverse effect occurring in 17–43% of patients in clinical trials. Grade 3–4 hypertension occurred in 1.4–38% [16] .

Moreover sorafenib may induce acute coronary symptoms including myocardial infarction in 2.9% of patients. Temporary or permanent discontinuation of sorafenib should be considered in patients who develop cardiac ischemia.

The inhibition of RAF1 possibly explains the toxicity observed with sorafenib. RAF1 inhibits two proapoptotic kinases, ASK1 and MST2 which are important in oxidant stress-induced injury. Deletion of RAF1 gene in the heart led to a dilated, hypocontractile heart with increased cardiomyocyte apoptosis. The protection provided by RAF1 may be important only in the presence of stress.

The occurrence of hypertension can be attributed to the inhibition of VEGF receptors. It seems that reduction of capillary permeability causes increased pressure load, leading to hypertrophy of the heart and subsequently congestive HF [71] . Inhibition of PDGFRs may also increase its cardiac toxicity.

3.5. Sunitinib

Sunitinib addresses both tumor cell proliferation and tumor angiogenesis, taking advantage of the fact that cancer cell proliferation and neoangiogenesis are often driven by mutations of TK [72] .

A considerable proportion of patients treated with sunitinib develop hypertension, LVD and other cardiac events.

The cardiovascular safety of sunitinib was examined in phase I–II trials [73] : 11% of patients experienced cardiovascular events, including acute myocardial infarction and HF; 28% of patients showed an asymptomatic but significant reduction in LVEF of at least 10%. In addition, approximately half of the patients (47%) developed hypertension during sunitinib treatment.

In a large phase III trial comparing sunitinib to interferon in patients with previously untreated metastatic renal cell cancer [74] , 10% of patients in the sunitinib arm had a LVEF decline. However, this was not associated with clinical sequelae and it was reversible after a modification of the dose or discontinuation of treatment.

The mean time to development of HF ranges from 22 days to 27 weeks.

Sunitinib-induced HF appears to respond well to medical therapy, nevertheless patients who experience significantly reduced LVEF should be monitored after the completion of therapy [73] .

Patients with a history of coronary artery disease, HF, LVD or prior exposure to anthracyclines have been shown to be at increased risk for sunitinib-related cardiotoxicity, indicating that they should be carefully monitored.

About 8–15% of patients treated with sunitinib develop congestive HF and others develop asymptomatic LV systolic dysfunction.

However, the specific mechanisms regulating this injury are not known. Sunitinib inhibits a number of growth factor receptors including VEGFRs, PDGFRs, c-Kit, FLT3, CSF1R, and RET. PDGFRs are expressed in cardiomyocytes and over-expression of PDGF can signal cardiomyocyte survival. Inhibiting these receptors may promote apoptosis.

In clinical trials, sunitinib was associated with hypertension, with the incidence varying from 5% to 24% (grade 3 occurred in 2%–8%) [74] .

Several hypothesis have been formulated to clarify cardiotoxicity due to sunitinib.

For example, Khakoo et al. hypothesize that hypertension may also play an important role, since sunitinib may inhibit a TK receptor that helps to regulate the response of cardiomyocytes in the setting of hypertensive stress [75] .

Force et al. suggest that sunitinib may cause cardiotoxicity through inhibition of ribosomal S6 kinase, leading to the activation of the intrinsic apoptotic pathway and ATP depletion [76] .

Finally, Kerkela et al. suggest that AMPK inhibition is necessary for the full expression of the cardiomyocyte toxicity. It is possible that inhibition of AMPK in actively respiring cardiomyocytes may be sufficient to compromise energy status, while it is unclear whether inhibition of AMPK is the initiating step leading to toxicity [77] .

4. Diagnosis and monitoring

All patients being considered for chemotherapy should undergo a detailed cardiovascular evaluation. Nevertheless only a subgroup of patients will develop cardiovascular complications. Therefore early identification of high-risk patients should be a fundamental target for oncologists in the planning of a personalized antineoplastic therapeutic strategies.

4.1. Early detection

Patients considered for chemotherapy should undergo a baseline electrocardiogram and should be evaluated for conduction block or repolarization abnormalities.

Echocardiography measured LVEF is one of the most important predictors of prognosis even if there is no clear international opinion on the frequency and method of LVEF assessment. In fact both echocardiography and multiple gated acquisition scanning can be used to assess LVEF and both techniques have advantages and disadvantages to be evaluated [78] . However, echocardiographic LVEF assessment and angiography with radionuclides have shown low diagnostic sensitivity and low predictive power in detecting subclinical myocardial injury. A baseline Doppler echocardiogram with the evaluation of LVEF needs to be obtained particularly in the presence of cardiovascular risk factors, age >60 years, previous cardiovascular disease, prior mediastinal irradiation [79] . LV fractional shorthening and LVEF are the most common indexes for cardiac function assessment before starting anti-cancer therapy.

Further evaluations of LVEF are recommended after administration of half of the planned dose, or after administrating a cumulative dose of 300 mg/m2 for doxorubicin, of 450 mg/m2 for epirubicin, or after a cumulative dose of doxorubicin of 240 mg/m2 or epirubicin of 360 mg/m2 in patients aging >60 years; then after 3–6–12 months from the end of therapy [79] .

LVEF reduction of ≥20% from baseline despite normal function or LVEF decline <50% require reassessment or discontinuation of therapy and further clinical and echocardiographic checks.

The use of other indicators such as lipid profile and serum markers for monitoring cardiotoxicity is being investigated.

A predictive role for biomarkers is not defined enough to include them as routine screening measurements. It has been shown that the elevation of troponin I soon after chemotherapy predicts the future development of LVEF depression and it identifies patients at different risks of future cardiac events [80], [81], [82], and [83]. B-type natriuretic peptide (BNP) has also been shown to be positively correlated with cardiac events and subclinical cardiotoxicity and it seems to correlate more to diastolic as opposed to systolic dysfunction [84] and [85].

Biomarkers may provide important information regarding the pathogenesis of HF or may be useful in risk stratification, in the diagnosis of HF, or in monitoring therapy. Serum markers that detect damage of the myofibrils and of the cardiomyocytes, such as the different isoforms of troponin, are useful in detecting the acute cardiotoxicity that is mediated by therapeutic agents that induce cell death [86] .

Measurement of troponin I and BNP is a minimally invasive approach, less expensive than echocardiography and it can easily be repeated. Moreover, the interpretation of the results does not depend on the operator's expertise.

However, these markers do not appear to be valuable for detecting cardiotoxicity induced by non-classical therapeutic agents or for detecting cardiotoxicity at early stages.

Fig. 1 suggests an algorithm for monitoring cardiotoxicity.

gr1

Fig. 1 Alghoritm for monitoring cardiotoxicity.

4.2. Prevention

Patients undergoing anticancer therapy should be encouraged to follow standard guidelines for reducing CV risk, such as blood pressure control, lipid level reduction, smoking cessation and lifestyle modifications as suggested by ESMO guidelines [82] Furthermore, a medical treatment of patients, even asymptomatic, who show LVD at Doppler echocardiogram after anthracycline therapy is mandatory, especially if they could have a long-term survival. At present, the guidelines of the American College of Cardiology/American Heart Association and HF Society of America are available. All patients should receive a combination of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker and a beta-blocker unless contraindicated [87] .

5. Treatment and follow up

Patients with advanced HF usually require additional measures such as diuretics, digoxin, or aldosterone antagonists. Patients with end-stage HF with refractory symptoms at rest despite maximal medical therapy and without evidence of cancer recurrence could be considered for synchronized pacing, ventricular assist device, or cardiac transplantation [87] . Although anthracycline-induced LVD is frequently irreversible, a recent clinical study indicated that enalapril (ACE inhibitor) and carvedilol (beta-blocker; when possible) treatment resulted in a complete (42%) or partial (13%) recovery of LVEF, predominantly in patients in whom treatment was initiated at an early stage. Similarly, for trastuzumab-related cardiotoxicity, administering an ACE inhibitor is currently recommended when LVEF declines to less than 50% [82], [84], [85], [86], [87], [88], and [89].

To reduce the risk of anthracycline-induced cardiotoxicity, the cumulative dose should be limited. Other preventive measures include altering the anthracycline administration (i.e. continuous infusion vs. bolus administration), as the use of liposomal anthracyclines.

The addition of cardioprotectants as dexrazoxane is restricted only in adult patients with breast cancer who have received >300 mg/m2 doxorubicin or >540 mg/m2 epirubicin according to the Food and Drug Administration and the European Medicines Agency indications [86], [90], and [91].

Once cardiovascular side-effect occurs, the patients should be appropriately treated ( Table 3 ).

Table 3 Treatment of cardiotoxicity.

Cardiotoxicity Therapy Results
Heart failure ACE inhibitors; angiotensin II receptor blockers; β-blockers Reverse remodeling; recovery of cardiac function; improve survival [53] and [54]
Hypertension ACE inhibitors; angiotensin II receptor blockers Prevent proteinuria; restore adeguate blood pressure [29]
Cardiomyopathy ACE inhibitors Protect and slow the progression of chemotherapy-induced cardiomyopathy [94]
Ventricular dysfunction ACE inhibitors (enalapril); β-blocker (carvedilol) Preservation and complete or partial recovery of left ventricular systolic function [91]
Tromboembolism Anticoagulant therapy with warfarin or low-molecular-weight heparin Restore normal endothelial function [95]

A cardiovascular follow-up of the treated patients should be periodically scheduled (i.e. evaluations every 6–12 weeks during the anti-cancer therapy, and later during follow-up).

For other severe cardiovascular complications, including hypertension, arrhythmias, and thromboembolism, it is important, in addition to stopping cancer therapy, also considering intensive and appropriate treatments [92] .

Assessment of cardiac function should also recommended 4 and 10 years after anthracycline therapy in patients who were treated at age >15 years with a cumulative dose of doxorubicin of >240 mg/m2 or epirubicin >360 mg/m2 [82] .

The renin-angiotensin system (RAS) may play a key role in vasoconstriction and lead to hypertension. Therefore, inhibiting the RAS with an ACE inhibitor or ARB may be an optimal approach to manage bevacizumab and angiogenic inhibitor-induced hypertension [30], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], and [93].

Fig. 2 suggests an algorithm for the management of patients receiving molecular targeted therapies [92] .

gr2

Fig. 2 Algorithm for the management of patients receiving molecular targeted therapies [93] .

6. Conclusion

Cancer patients receiving chemotherapy or molecular targeted therapies which are at risk of developing cardiotoxicity require the same therapeutic approach to the cardiopatic patients. Therefore, a multidisciplinary treatment must become the standard approach to avoid a lack of or inadequate management of side effects and to improve clinical outcomes and quality of life. In addition, the multidisciplinary management of cardiotoxicity is a guarantee for an optimal continuation of specific cancer treatment.

Conflict of interest statement

All the authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. All authors declare that they have no competing interests. All authors contributed to the study, read and approved the final manuscript.

Reviewers

Pr Jeremy Whelan, MD, FRCP, MBBS, Harley Street at University College Hospital, Macmillan Cancer Centre, Huntley Street, London WC1E 6AG, United Kingdom.

Dr Giuseppe Curigliano, MD, PhD, Senior Deputy Director, Istituto Europeo di Oncologia, Department of Medicine, Division of Medical Oncology, Milan, Italy.

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Rossana Berardi, MD is a Consultant Medical Oncologist and Lecturer at University Hospital. She is also the Responsible of the Trial Unit at Dept of Oncology, Università Politecnica Marche, Italy. Dr Berardi usually deals with about 35 GCP trials/year with new drugs mainly in lung and GI cancer. Dr Berardi is Assistant Professor in Medical Oncology at Università Politecnica Marche, Ancona, Italy and at the Doctorate in Osteoncology, Università “Campus Bio-Medico”, Rome, Italy. She is Member and national representative of the Lecturer in Medical Oncology of the Academic Medical Oncology Committee, she is Member of the “Post-Lauream Education” Working Group of the Italian Association of Medical Oncology and she is Member of the “ESMO/ASCO Global Curriculum for Training in Medical Oncology Task Force” of the European Society for Medical Oncology. Dr Berardi has been awarded many grants and prizes (among the others, several ASCO and ESMO travel grants and merit awards). She has authored more than 100 manuscripts in peer-reviewed journals and she has been a speaker at national and international meetings. Dr Berardi has been selected as an expert evaluator in several boards of examiners (i.e. European Community, Italian University Ministry).

Footnotes

Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I – GM Lancisi – G Salesi, Ancona, Italy

lowast Corresponding author at: Medical Oncology Unit, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I – GM Lancisi – G Salesi di Ancona, Via Conca 71, 60126 Ancona, Italy. Tel.: +39 071 5965715; fax: +39 071 5965053.


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