Cardiovascular side effects of cancer treatments

Abstract
The cardiovascular side effects of cancer treatments remain a challenge in oncologic care. Patients with cancer and cancer survivors have an increased risk of adverse cardiovascular outcomes, including left ventricular (LV) dysfunction, heart failure (HF) and acute coronary events. The treatments most frequently associated with cardiovascular side effects include anthracyclines, monoclonal antibodies (mAbs) targeting the HER2 pathway, and small molecule tyrosine kinase inhibitors (TKIs), in particular vascular endothelial growth factor (VEGF)-signaling pathway (VSP) inhibitors. This review article focuses on the incidence and pathologic mechanisms of LV dysfunction observed with the most commonly implicated anticancer agents; summarises the existing clinical data on diagnosis, prevention and management of cardiac dysfunction related cancer therapeutics; and provides commentary on the cardiovascular risk associated with radiation, which may be used in conjunction with chemotherapy and biological therapies as part of multimodality cancer treatment.
Keywords: Anthracycline, cancer, cardio-oncology, cardiotoxicity, chemotherapy, doxorubicin, radiation, trastuzumab, tyrosine kinase inhibitor.
Original submitted: 23 May 2016; Revised submitted: 13 July 2016; Accepted for publication: 27 July 2016; Published online: 08 September 2016

Key points:

  • With advances in treatment and improved cancer survival rates cardiovascular safety of oncology therapeutics remains an important clinical challenge.
  • Novel targeted therapeutics are often combined with conventional chemotherapy and have the potential to increase cardiotoxic effects.
  • An increasing number of research studies is advancing prediction and treatment approaches to cardiotoxicity.

Introduction

The cardiovascular side effects of cancer treatments remain a challenge in oncologic care. Patients with cancer and cancer survivors have an increased risk of adverse cardiovascular outcomes, including left ventricular (LV) dysfunction, heart failure (HF) and acute coronary syndromes. These events are often a result of the cardiovascular toxicity of different cancer treatments and their synergism with cardiovascular risk factors and pre-existing cardiovascular disease.

LV dysfunction and HF have been linked to many cancer therapeutics and incidence reports vary widely depending on the agent, definition, diagnostic methods and population[1]
. The treatments most frequently associated with cardiovascular side effects include anthracyclines, monoclonal antibodies (mAbs) targeting the HER2 pathway and small molecule tyrosine kinase inhibitors (TKIs), in particular vascular endothelial growth factor (VEGF)-signaling pathway (VSP) inhibitors[2]
.

Anthracycline therapy and cancer treatment-related cardiac dysfunction

For decades, anthracyclines have been a core component of chemotherapy protocols for many malignancies. The UK Medicine and Healthcare products Regulatory Agency (MHRA), an executive agency of the Department of Health, the European Medicines Agency, a European Union agency for the evaluation of medicinal products, and the US Food and Drug Administration (FDA), the regulator for medicines in the United States, have similar labelling, which states that doxorubicin is indicated for several disseminated neoplastic conditions, including acute lymphoblastic leukaemia, breast carcinoma, ovarian carcinoma, sarcomas and malignant lymphoma[3]
,[4]
,[5]
. For more than 40 years it has been recognised that doxorubicin therapy causes dose-related cardiotoxicity, which commonly manifests as LV systolic dysfunction with or without clinical HF symptoms[6]
. Other anthracyclines also exhibit cumulative cardiotoxicity, consistent with a drug class effect. However, data supporting a specific relationship between dose and LV dysfunction are far less rigorous. Daunorubicin, epirubicin and idarubicin have been reported to be less cardiotoxic than doxorubicin but these studies remain limited and controversial[7]
,[8]
,[9]
. An additional challenge is that cardiotoxicity comparisons need to be made in oncologically equivalent dosages required to achieve similar myelosuppression levels (e.g. epirubicin has 0.67 relative myelosuppression potency compared with doxorubicin and its dose [mg/m2 per cycle] used in oncology protocols is usually about one third higher than the doxorubicin dose).

Historically, direct oxidative damage was given as the main explanation for the myocardial dysfunction observed after the use of anthracyclines[10]
; however, recently published data suggest that topoisomerase 2-beta-associated DNA damage[11]
and mitochondrial iron accumulation are key mechanisms leading to cellular injury and necrosis[12]
. This evidence highlights the relevance of multiple pathways, while simultaneously providing information on the protective mechanisms of agents such as dexrazoxane, as well as potential novel targets[13]
.

Genetic polymorphisms have also been studied, particularly in childhood cancer survivor cohorts, to understand the variability of doxorubicin-induced cardiotoxicity. Several gene variants involved in oxidative stress signalling and iron metabolism have been identified as potential markers of susceptibility[14]
,[15]
but prospective studies are awaited to lead implementation in clinical practice[16]
. These investigations continue to provide insights into new gene functions, such as the role of retinoic acid receptorγ (RARγ) gene; in a recent genome-wide association study, its nonsynonymous variant was found to be strongly associated with anthracycline-induced cardiotoxicity, which was explained by its actions on altering RARγ function and derepression of topoisomerase 2-beta[17]
.

The clinical paradigm of the history of doxorubicin cardiotoxicity has also been challenged. The established concept for many years was of discrete and unrelated presentations of early (during or within one year of completion of therapy) and late cardiotoxicity (occurring many years after the completion of treatment, without evident structural changes prior)[18]
. However, trials utilising early imaging demonstrated that the vast majority of incident anthracycline cardiotoxicity may be apparent within the first year of therapy with active echocardiography screening[19]
. Full understanding of the incidence and natural history of LV dysfunction and HF related to anthracyclines in survivors of adult cancers is limited by the lack of long-term cardiovascular data in these patients. Reports from adult survivor cohorts of paediatric malignancies indicate a high risk of long-term anthracycline-induced cardiotoxicity in children, and show that age at the time of cancer treatment, type of malignancy and dose of anthracycline play an important role[20]
. In contrast, acute clinical doxorubicin cardiotoxicity seems to be rare[21]
and recent reports implicate a pathologic mechanism, similar to stress-induced cardiomyopathy[22]
. A meta-analysis of 22,815 patients receiving anthracyclines with a median nine-year follow-up demonstrated that 6% of patients had cardiotoxicity with clinically apparent HF and 18% of patients had subclinical toxicity[23]
. In this meta-analysis, the greatest risk factor for cardiotoxicity was cumulative anthracycline dose, although chest radiotherapy, African-American ethnicity, very young or very old age, diabetes, hypertension, very high or very low body weight, and severe comorbidities were all additional independent risk factors on multivariate analysis. While left-sided HF symptoms and reduced LV systolic function remain the most common clinical presentations of anthracycline-induced cardiotoxicity, recent imaging studies reported impairment of right ventricular (RV) performance parameters after anthracycline treatment, suggesting global cardiotoxic effects on cardiac muscle[24]
,[25]
. However, the clinical relevance of these data needs to be determined in prospective studies with dedicated assessment of RV function and outcomes.

Defining anthracycline-induced cardiotoxicity

Earlier definitions for anthracycline-induced cardiotoxicity focused on the clinical signs and symptoms of HF. However, clinically asymptomatic decreases in LV ejection fraction (LVEF) have also been included in recent Common Terminology Criteria for Adverse Events (CTCAE) and clinical trials[26]
. At the same time, the pathogenesis of cardiomyopathy and the progression of HF is being increasingly investigated and the knowledge applied to the setting of cardiovascular toxicities of cancer therapies. The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) HF guidelines recognise anthracycline-associated injury as a risk for development of HF (stage A) that may progress to structural changes and decline in heart function (stage B), leading to the development of signs and symptoms of HF (stages C and D)[27]
.

Biomarkers

The concepts of early myocardial injury and cardiotoxicity as progressive disease have also advanced the science of injury biomarkers as tools for risk stratification and therapy considerations. Biomarkers, in particular cardiac troponins, have been investigated to aid the identification of patients at risk of cardiomyopathy, target cardioprotective therapies and optimise cardiac monitoring. In patients receiving anthracycline-based chemotherapy, Cardinale et al. demonstrated that both early (within three days of doxorubicin infusion) and late (four weeks later) troponin elevations identified a group of patients at highest risk of cardiac events and persistent reduction in LV ejection fraction (EF) at three years[28]
. Similarly, Ky et al. reported changes in high sensitivity troponin that predicted development of cardiotoxicity in patients with breast cancer after anthracycline-containing chemotherapy[29]
.

Natriuretic peptides, measured by both B-type (BNP) and N-terminal proBNP (NT-proBNP) assays, demonstrated associations with the development of LV dysfunction following doxorubicin therapy in some studies[30]
,[31]
, but not others[32]
.

Several biomarkers are under investigation as predictors of cardiotoxicity, including but not limited to C-reactive protein (CRP), myeloperoxidase (MPO), growth differentiation factor 15 (GDF-15), placental growth factor (PlGF) and cardiac specific fatty acids[33]
. However, at present, they remain only an important research tool to understand anthracycline-associated cardiovascular injury and myocardial processes that may contribute to the development and progression of cancer-treatment associated cardiomyopathy. In the future, biomarker assays should be standardised and require validation in large prospective, multicentre clinical trials before they can be applied and successfully used to direct clinical cardio-oncology practice.

Cardiac imaging

Various modalities of cardiac imaging are used to monitor the occurrence of potential cardiotoxic effects during chemotherapy administration. Transthoracic echocardiography is the most commonly used. The majority of early studies of anthracycline-associated cardiotoxicity used multigated acquisition scan (MUGA) assessment of LVEF because this older technique has the advantage of higher-reproducibility of 3D assessment of LV volumes compared with 2D echocardiograms[34]
. Although radionuclide imaging continues to be used, in particular with patients with poor echocardiographic windows, advances in echocardiographic imaging and its comprehensive assessment of cardiac structure and function, including pericardial, valvular and RV pathology, have made echocardiography the most common choice for initial assessment in patients undergoing cancer therapies[35]
. Cardiac magnetic resonance (CMR) imaging is another important technique, since it is considered the reference standard for evaluation of ventricular volumes and function and may represent a valuable resource in patients with suspected changes in LV function if echocardiographic data are equivocal. In addition to higher accuracy in the assessment of LV function, CMR offers the advantage of tissue characterisation that may provide an insight into the aetiology of a cardiomyopathy[36]
.

While LVEF continues to represent the key cardiac function parameter used to define cardiotoxicity and make clinical decisions, there has also been a focus on identifying novel cardiac imaging parameters that could overcome the inherent limitations of LVEF (i.e. primarily late occurrence of LVEF decline after the onset of myocardial injury, ventricular load dependence, and lack of ability to reflect regional changes in cardiac function)[37]
. Myocardial deformation, or myocardial strain, that can be measured from standard 2D echocardiographic images using a speckle tracking technique, has been investigated in patients undergoing serial imaging while receiving cancer treatment[38]
. In these patients, absolute decreases in global longitudinal strain (expressed as a percentage of myocardial shortening in longitudinal direction during systole) predicted later decreases in LVEF, indicating that change in myocardial strain may represent an early marker of myocardial injury during imaging [38]
,[39]
. Based on these studies, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) recommend utilising speckle-tracking echocardiography-derived strain imaging for the evaluation of subclinical LV systolic dysfunction in patients at risk of cancer-treatment related cardiomyopathy[40]
. The ASE/EACVI consensus document also emphasises the importance of comprehensive, standardised echocardiographic examination, including 3D measurements, with attention to test-retest variability in patients undergoing serial imaging and consideration of other techniques, such as CMR, when images are of limited quality.

Prevention and treatment

While monitoring for cardiotoxicity is essential for clinical care, preventing cardiotoxicity in the first place would be optimal. The mainstay of cardiotoxicity prevention has focused for many years on minimising the overall dose exposure to anthracyclines resulting in modifications of oncology regimens and alterations in dosing schedule[41]
. The US FDA drug labelling states that incident impaired myocardial function is dependent on total cumulative dose, with 1–2% at a dose of 300mg/m2, 3–5% at 400mg/m2, 5–8% at 450mg/m2, and 6–20% at 500mg/m2[3]
. While the European Medicines Agency does not report these data for epirubicin, which is more commonly used in European oncology clinical practices, its cardiotoxicity risk for oncologically equivalent dosages is considered to be similar to doxorubicin[7]
,[8]
,[9]
.

Slow infusion lasting longer than six hours (compared to bolus dosing)[42]
and liposomal preparation of doxorubicin have been shown to reduce the risk of developing heart failure[43]
and have been applied in the treatment of tumours often requiring larger cumulative doses, such as sarcomas. While bolus dosing of doxorubicin may lead to higher peak plasma levels and appears to increase the risk of cardiotoxicity in adults[7]
, there is no clear evidence for long-term cardioprotection with slower doxorubicin infusion in children[44]
. Liposomal doxorubicin has a much longer half-life than doxorubicin and a smaller volume of distribution, and therefore accumulates more selectively in abnormal, cancerous tissue[45]
,[46]
. Dexrazoxane is an intravenously-administered iron chelator that has been extensively studied for prevention of anthracycline-induced cardiotoxicity. A recent randomised, multi-year follow-up study of 537 paediatric and adolescent patients demonstrated a distinct difference in LV function and wall thickness in patients receiving dexrazoxane without compromising treatment efficacy[47]
. The Cochrane meta-analysis pooling of 1,619 patients enrolled in dexrazoxane-randomised trials demonstrated a decreased occurrence of HF in patients receiving dexrazoxane preparation prior to anthracycline treatment[48]
. The protective actions of dexrazoxane were attributed to its iron chelating effect and prevention of oxygen radical formation through reduction of doxorubicin-iron complex. However, novel mechanisms, in particular binding and inhibition of topoisomerase 2-beta, have been proposed to account for its cardioprotective effects[49]
,[50]
. Doxorubicin activity leads to increased levels of topoisomerase 2-beta-DNA covalent complexes and breakage of DNA strands[51]
. Variance in topoisomerase 2-beta levels and genetic polymorphisms, particularly in p53, Chk2 and Top2a, may predispose to sensitivity or resistance to doxorubicin therapy[52]
. Similarly, recent animal studies implicate dexrazoxane-induced depletion of topoisomerase 2-beta as a potential protective mechanism against anthracycline-induced cardiotoxicity[53]
.

Despite its apparent effectiveness, use of dexrazoxane has not been widely adopted in clinical practice because cost, need for intravenous administration, and questions of evidence of its benefit with specific lower anthracycline dose regimens represent barriers. It is worth noting that neither the 2008 American Society of Clinical Oncology (ASCO) nor the 2012 European Society of Medical Oncology (ESMO) guidelines recommend the routine use of dexrazoxane, while the 2013 ACC/AHA heart failure guidelines identify dexrazoxane as cardioprotective[27]
,[54]
,[55]
.

Another preventative approach for cancer treatment-related cardiomyopathy includes the use of cardiovascular agents approved to treat HF and coronary artery disease. Based on the concepts of early injury and progressive adverse LV remodelling, several studies have investigated the potential of neurohormonal blockade to prevent anthracycline-induced cardiomyopathy using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta blockers (BBs)[56]
. The results of small studies using ACE inhibitors have been mixed, with some[57]
but not all trials demonstrating benefit[58]
,[59]
. Recent primary prevention trials using ARBs[60]
, BBs[61]
,[62]
or combination ACE inhibitors/BBs,[63]
concomitant with anthracycline treatment have demonstrated benefit, mostly measured by preserved LVEF, compared with patients receiving placebo. Similarly, preclinical studies and a small, randomised trial of 40 patients reported favourable effects of statins in patients receiving anthracycline therapy[64]
. Oral administration, availability and good safety data (extrapolated from other populations) make these agents favourable candidates for cardioprevention. However, their validation in larger, prospective, multicentre trials with longer follow-up is required to allow translation into clinical practice[65]
. This approach is currently being applied in the example of statins with a multicentre, National Cancer Institute-supported trial testing the hypothesis that, in patients receiving anthracycline therapy for breast cancer and lymphoma, prophylactic administration of atorvastatin attenuates changes in LV remodelling and prevents decrease in LVEF (NCT01988571).

Treatment of anthracycline-induced cardiotoxicity

The traditional treatment of patients with symptomatic HF has focused on avoiding further chemotoxicity and initiating standard HF therapy, including ACE inhibitors and BBs. The US FDA drug label for doxorubicin recommends discontinuation in patients who develop HF[3]
. Similarly, the 2012 European Society of Cardiology (ESC) HF guidelines recommend that patients who develop systolic dysfunction do not receive further anthracycline-based treatment[66]
. Management of patients with asymptomatic reduction in LVEF is an area of active investigation and requires individualisation with the patient, oncologists and cardiologists[67]
. One trial implemented active screening in 2,625 patients receiving anthracyclines, followed by initiation of HF pharmacotherapy for an LVEF decrease of more than ten points or to less than 50%, and demonstrated full recovery of LV function in 11% of patients and partial recovery in 71% of patients[19]
. These data suggest a benefit of cardiac imaging for early detection of cardiotoxicity in patients receiving anthracycline treatment that has not been part of clinical practice in the United States or Europe, with the exception of patients receiving HER2-targeted therapies. Notably, there is little evidence for treatment of anthracycline-induced cardiotoxicity in survivors of childhood cancer[68]
, and treatment with ACE inhibitors and BBs is extrapolated to all patients with reduced systolic function, although efficacy data in these populations remain limited.

HER2-targeted therapies and LV dysfunction

Development of trastuzumab, a humanised mAb that targets the HER2 receptor, has revolutionised treatment of HER2-positive breast cancer and improved survival in patients with metastatic and adjuvant disease[69]
,[70]
. However, cardiac dysfunction is the main concern with trastuzumab use and ASCO clinical practice guidelines list decreased LVEF or clinical congestive HF as the single most important contraindication to trastuzumab therapy[71]
, while ESMO guidelines similarly state that patient selection should be founded on baseline cardiac function[72]
. In the seminal trial in patients with metastatic breast cancer, cardiac dysfunction developed in 27% of participants on trastuzumab and doxorubicin, 13% on trastuzumab and paclitaxel, and only 1% on paclitaxel monotherapy, an unexpected and alarming finding. Despite this, trastuzumab was associated with improved overall survival[69]
. Although not fully determined, the proposed mechanism for the cardiotoxicity of trastuzumab includes functional blockade of the ErbB2/HER2 pathway, which impairs normal cellular repair[73]
. In animal models, ErbB2 overexpression may protect against doxorubicin cardiotoxicity, which provides hypothetical support for increased cardiac risk with concurrent doxorubicin and trastuzumab[74]
. This led to important changes in the design of subsequent clinical trials that resulted in the approval of trastuzumab for adjuvant treatment of HER2 positive breast cancer[75]
. In these studies, drug administration was changed (with trastuzumab given only after, never concomitantly with, anthracyclines), and monitoring of LVEF was mandated prior to and during one year of trastuzumab treatment. Patients with a decrease in LVEF below specified cut-offs were not eligible to continue trastuzumab therapy. In this new design setting, the rate of symptomatic HF was much lower, ranging from 3% to 6%, and most of the events were asymptomatic LV dysfunction, reported in around 17% of patients[70],
[
76]
,[77]
. Seven-year follow-up of one of the largest trials demonstrated that the majority of affected patients had recovery of LV function after holding or discontinuation of trastuzumab[78]
. A meta-analysis of 12,000 patients with early breast cancer noted relative risks of 5.1 and 1.8 for the development of congestive HF and LV dysfunction respectively, but improved breast cancer free survival and overall survival with trastuzumab therapy[79]
. Two other currently approved HER2 targeted therapies, pertuzumab and ado-trastuzumab emtansine, have similar recommendations for cardiac function monitoring and therapy holding or discontinuation in patients with LVEF below normal values.

Detection of HER2 therapy-associated cardiotoxicity

Cardiac imaging is central to the detection of HER2 therapy-associated cardiotoxicity. Following the design of adjuvant trials, routine LVEF assessment has been recommended, including a transthoracic echocardiogram every three months during the first year of trastuzumab therapy[80]
. Other modalities, including MUGA and CMR, can also be used to monitor LVEF, particularly in patients who have difficult echocardiographic windows. Superior accuracy in the assessment of LV volumes, visualisation of all cardiac structures and lack of radiation favour CMR when available[40]
. Given the importance of LVEF decreases, which may lead to discontinuation of HER2 targeted therapy, several studies have tried to identify early markers of LV function using imaging and serum biomarkers in patients receiving trastuzumab. Global longitudinal strain assessment using speckle tracking echocardiography has evolved to be one of the most promising research tools, together with changes in biomarkers, for prediction of the risk of future LVEF decline, but their role in clinical practice has yet to be established[29]
,[40]
.

Novel preventive strategies to reduce HER2 therapy-related cardiotoxicity

Strict cardiac eligibility criteria and regulated withholding of trastuzumab treatment based on the changes in LVEF have reduced trastuzumab cardiotoxicity and raised questions about potential compromises in cancer outcomes to lower the risk of asymptomatic LV dysfunction[81]
. Several ongoing and two recent published trials have tried to overcome this challenge using a primary prevention approach with initiation of BB or ACE inhibitor/ARB therapy concomitantly with trastuzumab treatment. In the PRADA study, the early breast cancer patients undergoing adjuvant epirubicin-containing chemotherapy followed by trastuzumab who had been randomised to the candesartan arm had a small but statistically significant attenuation of LVEF decrease at the end of cancer treatment compared with placebo-treated patients[60]
. Metoprolol did not affect LVEF changes in this study, in contrast to the similarly designed MANTICORE trial, in which a different BB, bisoprolol, had a small advantage over perindopril in preventing decreases in LVEF at the end of trastuzumab treatment[82]
,[83]
. Of interest, both of these studies used CMR-measurements for the detection of changes in LV volumes and LVEF changes that constituted outcomes. There were no HF events and LVEF declines were small, many within normal LV function range or only mildly reduced LVEF, suggesting that higher risk patients have not been included in the studies. Despite their shortcomings, these investigations represent an important step forward in conducting interdisciplinary cardio-oncology research and managing cardiotoxicity. They also highlight gaps in our knowledge and the need for future studies to address questions about biological differences between BBs and angiotensin-pathway inhibitors on trastuzumab-induced cardiac toxicity, confounding effects of anthracycline therapy (used in all patients in the PRADA trial[60]
, but only in a portion of patients in MANTICORE[82]
,[83]
), and strategies for improved risk stratification to identify patients who may receive the highest benefit of primary prevention[84]
.

Treatment of trastuzumab-related cardiac toxicity

Holding or stopping therapy, as well as the initiation of standard HF regimens, are the main approaches in the treatment of trastuzumab-related cardiac toxicity, according to the extent of LV decline and symptoms[85]
. The majority of patients who experience reduced systolic function related to trastuzumab therapy have subsequent improvement in cardiac function[86]
,[87]
. This LVEF recovery has also been observed with prolonged therapy in a 200-patient case series from MD Anderson (Texas, United States), in which 28% of patients developed cardiac toxicity with a median of 21 months of trastuzumab therapy. Of note, 94% of these patients had improved LVEF or symptoms of HF with discontinuation of trastuzumab and appropriate medical therapy[88]
.

Synergism of trastuzumab and anthracycline cardiotoxicity

Given the beneficial efficacy of the combination therapy of anthracyclines and trastuzumab on oncologic outcomes, their potential synergism on cardiac toxicity is of particular concern. Concurrent therapy may increase the risk of cardiac toxicity more than either trastuzumab or anthracycline therapy alone[75]
. Trastuzumab interferes with innate cardiac myocyte survival mechanisms intended to counter cellular stressors, such as those induced by anthracyclines[89]
,[90]
. High incidence of HF in the initial trastuzumab trials in metastatic HER2-positive breast cancer (in which patients were given concomitant anthracyclines and trastuzumab) was in a large part attributed to this mechanism and has resulted in a change to drug administration in subsequent trials. Currently, standard anthracycline-containing regimens for HER2-positive breast cancer typically include initial treatment with doxorubicin or epirubicin-based standard chemotherapy followed by an assessment of LVEF prior to continuation of trastuzumab. Importantly, the concern for synergistic toxicity and decreases in LVEF after anthracyclines has focused interest on the use of non-anthracycline based treatment in patients with HER2-positive breast cancer: the recently presented ten-year follow-up of the landmark BCIRG-006 trial indicated comparable effects of doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) versus a non-anthracycline regimen of docetaxel plus carboplatin and trastuzumab (TCH) on disease-free and overall survival[91]
. At the same time, the TCH regimen was associated with a significant improvement in long-term cardiac safety leading to an updated ASCO guideline recommendation for its preferential use in patients who may be at higher risk of cardiotoxicity[92]
, while ESMO guidelines state that TCH is an alternative to anthracycline-based chemotherapy in patients at high risk of cardiac complications[72]
.

Novel targeted therapeutics and cardiovascular toxicity

Therapeutic targeting of kinases overexpressed in cancer cells using mAbs and small molecule kinase inhibitors has become an effective and standard treatment for many cancers, indicated by an increasing number of newly approved agents for clinical use[93]
. Cardiovascular effects of these targeted therapies initially came as a surprise, urgently prompting novel models and research investigating the role of different kinases on the heart and cardiovascular homeostasis[94]
,[95]
,[96]
. Both on-target (related to the intended target cancer kinase) and off-target (related to unintended kinase inhibition) actions may result in toxicities[97]
, which, coupled with the fact that a single small molecule inhibitor may target more than one kinase, has resulted in a wide spectrum of cardiovascular effects to be observed[98]
. At the same time, multitargeting characteristics have made these agents attractive therapeutic options for different cancers, often as part of distinct chemotherapeutic regimens, increasing the complexity of presentations, analysis and interpretation of cardiovascular phenomena. Categorisation based on the (main) cellular pathway inhibition offers one potential approach and inhibitors targeting the vascular endothelium signalling pathway (VSP) deserve a particular mention. Small molecule inhibitors in this category act by intercellular binding to, and blocking of, vascular endothelial growth receptors (VEGFRs) and include sunitinib, sorafenib, imatinib, nilotinib, axitinib, pazopanib, ponatinib, and lenvatinib, which are currently approved in the United States and Europe, vandetanib and cabozantinib, which are approved in the United States, and several other molecules being tested in clinical trials[97]
. Bevacizumab and ramucirumab are mAbs that target circulating VEGFA and extracellular VEGFR2, respectively. Cardiovascular toxicities, including LV dysfunction and HF, hypertension and arterial and venous thrombosis have all been associated with this class of agents. Similarly, nilotinib carries a black box warning for QT prolongation and sudden death[99]
. The exact mechanisms of these heterogeneous adverse effects remain the subject of active investigation but the interference with the numerous roles of VEGF signalling in cardiovascular homeostasis is likely to represent the critical component[94]
,[97]
.

VSP inhibitor-associated cardiomyopathy

Clinical trials using VSP inhibitors did not include routine screening for LV dysfunction or clinical HF and reports about cardiomyopathy and vascular toxicities are mostly based on retrospective studies. A meta-analysis of 6,935 patients treated with sunitinib for renal cell and non-renal cell carcinoma reported an overall incidence of 4.1% for symptomatic HF and 1.5% for high-grade HF[100]
. Single centre observational data that captured asymptomatic dysfunction found significantly higher incidence, with up to 28% of patients experiencing LVEF decline of at least 10%[101]
. The risk of cardiomyopathy appears to be increased with sorefenib[102]
and possibly imatinib[103]
, although industry data suggest that the incidence of imatinib induced cardiomyopathy is rare[104]
. Data regarding the cardiac dysfunction risk of other small molecule VSP pathway inhibitors remain scarce. In the absence of prospective cardiovascular follow-up with clearly defined baseline status and measured cardiac function parameters, presented numbers are likely to represent an underestimation of the true incidence of cardiomyopathy.

Despite shared propensity to block VSP signalling, different agents do not act the same, instead preferentially inhibiting multiple different kinases. In clinical practice this means that consideration of switching from one to another VSP inhibitor in case of cardiotoxicity may offer a viable option[105]
.

Vascular effects

The most commonly reported vascular effect of VSP inhibitors is systemic hypertension. Reported incidence of new or uncontrolled hypertension was 24% for bevacizumab, 36% for pazopanib, 22% for sunitinib and 23% for sorafenib[97]
. A subset of these patients, 7.0% of whom were treated with sunitinib and 5.7% with sorafenib, developed high-grade hypertension leading to drug dose reduction and/or discontinuation[106]
,[107]
. One of the proposed mechanisms of VSP inhibitor-induced hypertension includes functional (and/or structural) changes in the endothelium that result in decreased availability of nitric oxide as a consequence of VEGF inhibition[108]
. In this model, endothelial cardiovascular effects and hypertension develop as a result of an on-target effect of the cancer drug and may reflect the strength of VEGF inhibitory activity. It is of interest that development of hypertension has been associated with improved tumour response and outcomes, and has increasingly been recognised as a biomarker of sunitinib efficacy[109]
.

Detection, prevention and treatment of cardiovascular toxicities of novel targeted cancer therapies

In the

absence of prospective studies to elucidate the development of cardiomyopathy related to novel targeted therapies, early detection and prevention remain

challenging. While professional standards for treatment of these patients await development, it is reasonable to extrapolate from other populations at high risk of HF. In clinical practice a comprehensive cardiovascular exam prior to initiation of VSP inhibitors is recommended with consideration of a baseline echocardiogram, particularly in patients with cardiovascular risk factors[94]
. Patients with existing risk factors should be treated and followed closely and this is particularly true for patients with hypertension who may be at risk of worsening blood pressure control. New symptoms or signs of HF should prompt an evaluation and if HF is diagnosed, the VSP inhibitor should be stopped and HF treatment initiated. Successful re-challenges with a different VSP inhibitor have been reported[105]
but are still limited to individual cases and decisions should be made on an individual basis, in consultation with the oncologist and cardiologist, based on the potential of oncologic benefit and severity of cardiac prognosis.

In patients receiving VSP inhibitors, blood pressure should be monitored at least weekly during the first six weeks of therapy[110]
. Most patients with cancer treatment-induced hypertension respond appropriately to standard antihypertensive medications, including ACE inhibitors, ARBs, diuretics, dihydropyridine calcium-channel blockers and BBs, although discontinuation of cancer targeted therapy may be necessary until hypertension is properly controlled[111]
. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, interfere with the metabolism of certain TKIs via the CYP3A4 system and should be used cautiously[110]
. There are also limited case report level data that indicate refractory hypertension may respond well to treatment with nitric oxide donors, such as isosorbide dinitrate, presumably by targeting the underlying etiology of the hypertension[112]
.

Coronary artery disease

Incident or progressive coronary artery disease causing myocardial infarction is another feared adverse effect of some oncologic therapy. 5-fluorouracil (5-FU) cardiotoxicity, predominantly manifesting as coronary vasospasm, has been apparent for nearly three decades[113]
,[114]
. The mechanism of 5-FU cardiotoxicity remains unclear, but it is likely to be multifactorial and partially caused by endothelial injury and an increased risk of coronary vasospasm[115]
. Coronary vasospasm manifests as sudden onset chest pain with ST-elevation on electrocardiogram and can be effectively treated with vasodilators, such as calcium channel blockers, in addition to cessation of 5-FU therapy[116]
. Capecitabine, a prodrug of 5-FU, has also been associated with coronary vasospasm and more rarely coronary arterial thrombosis[117]
. Capecitabine-induced vasospasm, like 5-FU, responds to discontinuation and coronary vasodilator therapy. There is limited evidence for resumption of capecitabine therapy with concurrent secondary prophylaxis with diltiazem[118]
that continues to be used in clinical practice. A patient-tailored approach is important and there must be close collaboration between the oncologist and cardiologist to determine the benefit of continuation of 5-FU or capecitabine treatment (with attention to survival benefit) as well as risk of coronary ischaemia. It is important to exclude or, if found, treat coronary artery disease and aggressively control cardiovascular risk factors, such as hypercholesterolaemia, smoking and hypertension. Monitored 5-FU infusions can also be considered when oncological benefit and/or cardiac risks are high.

Radiation

Therapy using radiation represents a core component of multiple cancer treatment regimens, such as for Hodgkin’s lymphoma and early stage breast cancer, and its adverse cardiac effects have been known for decades[119]
. Radiation-induced heart disease can manifest as pericarditis, pericardial fibrosis, diffuse myocardial fibrosis, coronary artery disease and valvular disease[120]
. Unfortunately, even in an asymptomatic population, such radiation-induced heart disease is relatively common[121]
. The mechanism of radiation-induced cardiotoxicity is multifactorial and varies with the specific manifestation but inflammation and vascular lesions leading to cellular death have been proposed as the main mechanisms[122]
. Risk factors for radiation cardiotoxicity include earlier age of therapy and radiation dose[123]
.

The key to prevention has been modifications in radiation technique, including the deep inspiration breath-holding and intensity modulated radiation therapy that varies the radiation energy while treatment is delivered, in order to precisely contour the desired radiation distribution and avoid normal tissues[55]
. A recently published document by the European Association of Cardiovascular Imaging and the American Society of Echocardiography summarises recommendations for detection to include a yearly clinical history and physical exam[124]
. Targeted imaging and an echocardiogram should be considered five to ten years after radiation exposure with low threshold for stress test in high-risk patients[124]
. Additional echocardiography markers, strain rate imaging and diastolic dysfunction may detect subclinical cardiac dysfunction after radiation therapy and are recommended as part of a comprehensive exam[125]
,[126]
. Radiation-induced heart disease is associated with increased long-term mortality and extensive valvular and coronary calcifications, mediastinal fibrosis and radiation-related lung disease, which makes surgical management of these patient challenging[127]
,[128]
.

Conclusions

Cancer therapeutics can cause numerous cardiovascular toxicities, most notably LV dysfunction and HF, which can interfere with the efficacy of cancer treatment, decrease quality of life and adversely impact patient survival. With the advancement of the oncology and cardiology fields, opportunities to recognise and treat cardiovascular toxicities without compromising cancer or cardiovascular outcomes are increasing. Oncologists, cardiologists and other healthcare professionals, as well as patients, need to be aware of the potential effects of old and novel cancer therapeutics and formulate a plan for the baseline assessment and monitoring of symptoms. The rapid growth in novel cancer therapeutics and inherent complexity of balancing oncologic and cardiac care has created an important and frequently unmet clinical need[129]
. Professional societies are increasingly responding to this need; the American College of Cardiology, for example, recently pioneered a new Cardio-Oncology member section[129]
and the International Cardioncology Society and Canadian Cardiac Oncology Network published a call for multidisciplinary cardio-oncology training[130]
,[131]
. Hopefully, the increasing availability of cardio-oncology specialists will promote multidisciplinary care, from basic science to phase I trials of cardiovascular safety, through to large scale phase III clinical trials and most importantly to ongoing patient-focused clinical care.

Standard guideline-driven cardiovascular risk factor management and treatment for the identified cardiac pathology is an important start. However, at present, it is mostly based on extrapolation from non-cancer populations and validation studies are urgently needed. The implementation of comprehensive cardiovascular care along the continuum of cancer treatment from diagnosis to survivorship is critical to ultimately improve patient outcomes across a spectrum of cardio-oncology conditions (see Table 1). Specific cardiovascular monitoring with new targeted therapeutics and inclusion of cardiovascular phenotypes in oncology clinical trials and registries will be of paramount importance. Furthermore, individualisation and the identification of patients at high risk who may benefit from (primary) prevention strategies remains an important challenge that will be answered through further collaborative cardio-oncology trials.

Table 1: Approach to cardiovascular care across cancer treatment continuum*
Therapeutic agent/modality Pre-treatment During treatment Survivorship
AnthracyclineComprehensive cardivascular exam and LVEF assessment to assess for HF. Address other cardiac risk factors.No routine LVEF surveillance until more than 300mg/m2 of doxorubicin (or equivalent dose of epirubicin), then another assessment should be considered.Comprehensive cardiovascular exam and close attention to potential cardiovascular symptoms. Address other cardiac risk factors and consider an echocardiogram within one year if one or more cardiac risk factors are present[132]
.
TrastuzumabComprehensive cardiovascular exam and LVEF assessment to assess for HF. Address other cardiac risk factors.LVEF assessment while on treatment (current FDA recommendation is every three months while on therapy)[133]
.
Comprehensive cardiovascular exam and close attention to HF symptoms. Address other cardiac risk factors. LVEF assessment may be considered[133]
.
VEGF inhibitorScreening for hypertension.Monitoring and treatment of hypertension.Limited data.
Chest radiationComprehensive cardiovascular exam and LVEF assessment to assess for HF. Address other cardiac risk factors.Clinical monitoring for signs or symptoms of cardiovascular disease.Comprehensive cardiovascular exam and close attention to potential cardiovascular symptoms. Address other cardiac risk factors. Screening echocardiogram at five years for high-risk patients and ten years for others. Functional stress-test after five to ten years in high-risk patients[124]
.
*Reflects current clinical practice and recommendations of the authors. Cardiac risk factors: hypertension, dyslipidaemia, diabetes mellitus, family history of cardiomyopathy, age >65 years, history of other cardiovascular morbidities (i.e. atrial fibrillation or coronary artery disease). LVEF: Left ventricular ejection fraction, HF: Heart failure. 

Benjamin Kenigsberg is cardiology fellow, Umberto Campia is section director, vascular medicine and scientific lead in vascular research and Ana Barac is director, cardio-oncology programme at MedStar Heart and Vascular Institute, 110 Irving street, NW, Ste. 1F1218, Washington DC, United States. Correspondence to: 
ana.barac@medstar.net

Financial and conflicts of interests dislosure:

Ana Barac is a cardiology PI on an investigator-initiated study funded by Genentech Inc. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilised in the production of this manuscript.

  • This article was amended on 14 September 2016 to fix an error in the references

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Clinical Pharmacist, CP, September 2016, Vol 8, No 9;8(9):DOI:10.1211/PJ.2016.20201651