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FOCUS SEMINAR: CARDIO-ONCOLOGY

STATE-OF-THE-ART REVIEW

Cardiovascular Complications ofCancer TherapyBest Practices in Diagnosis, Prevention, and Management: Part 1

Hui-Ming Chang, MD, MPH,a Rohit Moudgil, MD, PHD,b Tiziano Scarabelli, MD, PHD,c Tochukwu M. Okwuosa, DO,d

Edward T.H. Yeh, MDa

ABSTRACT

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Modern cancer therapy has successfully cured many cancers and converted a terminal illness into a chronic disease.

Because cancer patients often have coexisting heart diseases, expert advice from cardiologists will improve clinical

outcome. In addition, cancer therapy can also cause myocardial damage, induce endothelial dysfunction, and alter

cardiac conduction. Thus, it is important for practicing cardiologists to be knowledgeable about the diagnosis, prevention,

and management of the cardiovascular complications of cancer therapy. In this first part of a 2-part review, we will

review cancer therapy–induced cardiomyopathy and ischemia. This review is based on a MEDLINE search of

published data, published clinical guidelines, and best practices in major cancer centers. With the number of cancer

survivors expanding quickly, the time has come for cardiologists to work closely with cancer specialists to

prevent and treat cancer therapy–induced cardiovascular complications. (J Am Coll Cardiol 2017;70:2536–51)

© 2017 by the American College of Cardiology Foundation.

H eart diseases and cancer are the top 2 lead-ing causes of death in the United States.Because these maladies share several

common risk factors, many of our patients, espe-cially the elderly, are afflicted by both cancer andheart diseases. Furthermore, cancer therapies, eitherradiation treatment or chemotherapy, can cause car-diovascular complications. Thus, it is important forpracticing cardiologists to be familiar with the pre-vention, diagnosis, and management of cardiovascu-lar complications of cancer therapy. This topic wasreviewed in the Journal in 2009 (1). The purpose ofthis new State-of-the-Art Review is to provide an up-date in this emerging discipline that abounds with

m the aCenter for Precision Medicine, Department of Medicine, Univers

rdiology, University of Texas, MD Anderson Cancer Center, Houston, Texa

iversity, Richmond, Virginia; and the dDivision of Cardiology, Rush Univ

eived support from the National Institutes of Health (HL126916); and is

ssouri, School of Medicine. All other authors have reported that they have n

disclose.

nuscript received July 3, 2017; revised manuscript received September 24

exciting new developments. Cardiovascular compli-cations covered in this 2-part review are heart failure(HF), myocardial ischemia, myocarditis, hyperten-sion (HTN), pulmonary HTN, pericardial diseases,thromboembolism, QT prolongation and arrhyth-mias, and radiation-induced cardiovascular diseases.A MEDLINE search for each of these complicationswas performed; clinically relevant complicationswere selected based on experiences at the MDAnderson Cancer Center and centers affiliated withauthors of this review. Diagnostic and treatmentrecommendations are based on the best practicesdeveloped at MD Anderson Cancer Center and recentguidelines (2–6).

ity of Missouri, Columbia, Missouri; bDepartment of

s; cDivision of Cardiology, Virginia Common Wealth

ersity Medical Center, Chicago, Illinois. Dr. Yeh has

the Frances T. McAndrew Chair in the University of

o relationships relevant to the contents of this paper

, 2017, accepted September 26, 2017.

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https://doi.org/10.1016/j.jacc.2017.09.1096

AB BR E V I A T I O N S

AND ACRONYM S

5-FU = 5-fluorouracil

ACS = acute coronary

syndrome(s)

ATE = arterial thrombotic

event

CAD = coronary artery disease

CIMP = chemotherapy-induced

cardiomyopathy

cTnI = cardiac troponin I

CVA = cerebral vascular

accident

ECG = electrocardiogram

EF = ejection fraction

FDA = U.S. Food and Drug

Administration

GLS = global longitudinal

strain

HF = heart failure

HTN = hypertension

MI = myocardial infarction

TDI = tissue Doppler imaging

VEGF = vascular endothelial

growth factor

VSP = vascular endothelial

growth factor signaling

pathway

J A C C V O L . 7 0 , N O . 2 0 , 2 0 1 7 Chang et al.N O V E M B E R 1 4 / 2 1 , 2 0 1 7 : 2 5 3 6 – 5 1 Best Practices in Cardio-Oncology: Part 1

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HEART FAILURE

HF due to chemotherapy has been long recognized as aserious side effect of daunorubicin, the first anthra-cycline used clinically (7). Although the anthracyclineclass of chemotherapy agents remains the major causeof chemotherapy-induced cardiomyopathy (CIMP),newer cancer therapy, such as trastuzumab or pro-teasome inhibitors, can also cause cardiomyopathy(Central Illustration, Table 1). It should also be recog-nized that patients can develop signs and symptoms ofclinical heart failure during chemotherapy; however,the cause of cardiac decompensation may be due tofluid overload, stress-induced cardiomyopathy, orprimary cancer, but not chemotherapy (2). CIMP hasbeen described in 1% to 5% of cancer survivors (8,9)and portends one of the worst survivals among car-diomyopathies (10). Early diagnosis and timely inter-vention has been shown to result in a superior clinicaloutcome in cancer patients treated with cardiotoxicchemotherapy (11).

DEFINITION. In the initial report by Von Hoff et al.(12), HF was defined as the presence of tachycardia,shortness of breath, neck vein distention, galloprhythms, ankle edema, hepatomegaly, cardiomegaly,and pleural effusion (12). With the advance of cardiacimaging, echocardiography or multigated acquisitionradionuclide ventriculography-based evaluation ofleft ventricular ejection fraction (EF) has recently beenincluded in the diagnostic criteria (4,13). In the tras-tuzumab clinical trials, drug-associated cardiotoxicityis defined as 1 or more of the following: 1) cardiomy-opathy characterized by a decrease in EF globally ordue to regional changes in interventricular septumcontraction; 2) symptoms associated with HF; 3) signsassociated with HF, such as S3 gallop, tachycardia, orboth; and 4) decline in initial EF of at least 5% to <55%with signs and symptoms of HF or asymptomaticdecrease in EF of at least 10% to <55% (14). This defi-nition does not include subclinical cardiovasculardamage, such as diastolic dysfunction and changesin LV strain, which may occur earlier in responseto some of the chemotherapeutic agents. CommonTerminology Criteria for Adverse Events has alsodefined cardiomyopathy and/or heart failure forthe purposes of uniform reporting. In CommonTerminology Criteria for Adverse Events 4.03,echocardiography and biomarkers were included toprovide a more precise definition of cardiotoxicity.

INCIDENCE AND PATHOGENESIS. Anthracyc l ines . In aretrospective review of 3 trials, the incidence ofdoxorubicin-related HF was found to be 5% at acumulative dose of 400 mg/m2, 16% at a dose of

500 mg/m2, and 26% at a dose of 550 mg/m2

(15). However, subclinical events occurred inabout 30% of the patients, even at thedoses of 180 to 240 mg/m2, about 13 yearsafter the treatments (16). Interestingly,histopathological changes, such asmyofibrillar loss and vacuolization, can beseen in endomyocardial biopsy specimensfrom patients who have received as little as240 mg/m2 of doxorubicin (17). Thesefindings suggest that there is no safedose of anthracycline. Even doses aslow as 100 mg/m2 have been associatedwith reduced cardiac function (16,18).Nonetheless, some patients had nosignificant cardiac complications despitereceiving doses as high as 1,000 mg/m2 (19).Individual susceptibility is most likely due togenetic variants in genes that regulateanthracycline cardiotoxicity (20). Other riskfactors for anthracycline toxicity includecumulative dose, intravenous bolusadministration, higher single doses, historyof prior irradiation, use of concomitantagents known to have cardiotoxicity, femalesex, underlying CV disease, age (young andelderly), delayed diagnosis, and increase incardiac biomarkers such as troponins during
and after administration (9,21–23).
Doxorubicin poisons topoisomerase 2 to causedeoxyribonucleic acid (DNA) double-strand breakand demise of cancer cells. In the cardiomyocytes,doxorubicin targets topoisomerase 2b to induceDNA double-strand breaks, and doxorubicin-boundtopoisomerase 2b binds promoters of antioxidativeand electron-transport genes to reduce their tran-scripts and protein expression (24,25) (Figure 1).Doxorubicin-treated cells have a marked increasein reactive oxygen species and are defective in mito-chondria biogenesis. Thus, topoisomerase 2b accountsfor the 3 hallmarks of anthracycline-induced car-diotoxicity: myocyte death, reactive oxygen speciesgeneration, and mitochondriopathy. Reduced topo-isomerase 2b expression has been linked to a codingvariant in the retinoic receptor g gene, which predictssusceptibility to anthracycline-induced cardiotoxicityin childhood cancer (26).Alky la t ing agents . Alkylating agents add an alkylgroup to the DNA of rapidly dividing cells and, in thecase of bifunctional alkylating agents, cross-link the2 DNA strands, thereby inhibiting DNA replication andcell proliferation (27). Symptoms may include ar-rhythmias, conduction disorders, and fulminant HF(28,29). Alkylating agents such as cyclophosphamide

CENTRAL ILLUSTRATION Management of Cancer Therapy–Induced Cardiovascular Complications

Cancer patients often have co-existing heart diseases;Cancer therapies can cause cardiovascular (CV) complications

Cardiologists and cancer specialists should work together to identify high-risk patients & modify CV risk factors

Strategies for reducing cardiotoxicity:Anthracycline: Dose reduction, continuous infusion, liposomal doxorubicin, dexrazoxaneTrastuzumab: Avoid concomitant anthracyclineVSP inhibitors: Treat hypertension

Consider cardio-protection (Beta Blocker/ACE Inhibitors), if:Ejection fraction (EF) <50% or EF drop>10% Global Longitudinal Strain >15% dropMyocardial damage (assessed via troponin)

Withhold certain cancer therapies as a last resort:Anthracycline (withhold if EF<45%)Trastuzumab (withhold if EF<40%)

Ischemia workup:Stress test, cardiac catheterization

Treatment:As per ACC/AHA guidelines

If platelet count lower than 100,000/microliter of blood:Aspirin if platelet >10K

Dual anti-platelet therapy with aspirin and clopidogrel for drug eluting stents if platelet >30K

Cardiac catheterizationvia radial approach

Cardiomyopathy Ischemia

Chang, H.-M. et al. J Am Coll Cardiol. 2017;70(20):2536–51.

Best practices in the management of cancer therapy–induced cardiomyopathy and ischemia. ACC ¼ American College of Cardiology; ACEI ¼ angiotensin-converting

enzyme inhibitor; AHA ¼ American Heart Association; CV ¼ cardiovascular; EF ¼ ejection fraction; VSP ¼ vascular endothelial growth factor signaling pathway.

Chang et al. J A C C V O L . 7 0 , N O . 2 0 , 2 0 1 7

Best Practices in Cardio-Oncology: Part 1 N O V E M B E R 1 4 / 2 1 , 2 0 1 7 : 2 5 3 6 – 5 1

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induce electrocardiogram (ECG) alterations in the formof low QRS voltage and nonspecific T-wave orST-segment abnormalities (28,30,31). Acute symptomsusually occur within 1 to 2 weeks, last for a few days,and in some patients, resolve without any lateconsequences (28,29,31). The incidence of high-dosecyclophosphamide-induced HF has been reportedto be as high as 28% (32). Autopsies of patientswith cyclophosphamide-induced cardiotoxicity showhemorrhagic myocardial necrosis with interstitialedema and fibrin deposition. The risk of complicationsis higher in elderly patients and in those exposed toanthracycline or mediastinal irradiation (1,29,31).

Ifosfamide is an alkylating nitrogen mustard usedfor the treatment of lymphomas; sarcomas; andtesticular, breast, and lung carcinoma (33). There is adose-dependent increase in HF associated withifosfamide administration (33,34). Autopsy studies

demonstrated increased heart weight, small pericar-dial effusions, subendocardial hemorrhage, andpetechial lesions in the epicardium (29).

TARGETED THERAPIES AGAINST HER-2 PATHWAY.

Trastuzumab is a monoclonal antibody against thehuman epidermal growth factor receptor tyrosinekinase (HER2 or ErbB2), which regulates cell growthand repair (35). Overexpression of HER2 occurs inapproximately 25% of breast cancers and confersincreased proliferative and metastatic potential.HER-2 is expressed in cardiomyocytes and is requiredfor survival of cardiomyocytes (36). Mice deficient inHER-2 develop dilated cardiomyopathy and are moresensitive to doxorubicin (36).

Trastuzumab administration in HER2-positivebreast cancers led to significant reductions in recur-rence rate and overall mortality. A pivotal study in

TABLE 1 Anticancer Agents Associated With HF/Left Ventricular Dysfunction

Chemotherapy AgentsFrequencyof Use

Incidence(%) Prevention/Treatment

Anthracyclines

Doxorubicin þþþþ 3–26 Monitor EF, GLS, troponindexrazoxane, continuous infusion,liposomal preparation, BB/ACEI

Epirubicin þ 0.9–3.3

Idarubicin þþ 5–18

Alkylating agents

Cyclophosphamide þþþþ 7–28

Ifosfamide þþþ 17

Antimetabolites

Decitabine þþ 5

Clofarabine þ 27

Antimicrotubule agents

Docetaxel þþ 2.3–8.0

Monoclonal antibody-basedtyrosine kinase inhibitors

Trastuzumab þþþ 2–28 Avoid concomitant use withanthracyclines

Bevacizumab þþ 1.0–10.9

Adotrastuzumab emtansine þ 1.8

Pertuzumab þ 0.9–16.0

Small molecule tyrosine kinaseinhibitors

Pazopanib þþþþ 0.6–11.0 Treat hypertension aggressively

Ponatinib þ 3–15 Ischemia workup and treatment

Sorafenib þþþþ 1.9–11.0

Dabrafenib þþþþ 8–9

Sunitinib þþþþ 1–27

Dasatinib þþþþ 8–9

Lapatinib þþþþ 0.9–4.9

Trametanib þþþþ 7–11

Proteasome inhibitor

Carfilzomib þþ 7

Bortezomib þþ 2–5

Miscellaneous

Tretinoin þþþþ 6

Frequency of use was determined using inpatient and outpatient doses dispensed at MD Anderson Cancer Centerduring the time period of January 1, 2014, through December 21, 2014. þ ¼ <1,000 dosesdispensed; þþ ¼ 1,000–5,000 doses dispensed; þþþ ¼ 5,000–10,000 doses dispensed;and þþþþ ¼ >10,000 doses dispensed (1,2,24,29).

ACEI ¼ angiotensin-converting enzyme inhibitor; BB ¼ beta-blocker; EF ¼ ejection fraction; GLS ¼ globallongitudinal strain; HF ¼ heart failure.


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the metastatic setting demonstrated a 33% reductionin mortality at 1 year and an increase in median sur-vival by 5 months (37). HF occurred in 8% of patientswho received an anthracycline with cyclophospha-mide; however, the incidence of HF increased to 27%with the addition of trastuzumab (37). Subsequently,several large trials confirmed efficacy of trastuzumabin increasing disease-free survival from cancer, butalso established trastuzumab’s association with HF(38,39). In these trials, 1.7% to 4.1% of trastuzumab-treated patients developed HF when anthracyclinewas not part of the therapeutic regimen (38,39).Trastuzumab-related cardiotoxicity includes variousdegrees of LV systolic dysfunction, occasionallyleading to HF (40). Symptoms are usually mild ormoderate and improve following medical manage-ment and termination of drug administration (41,42).Improvement is usually seen in about 4 to 6 weeksafter trastuzumab withdrawal (43). After symptom-atic improvement, reinstitution of trastuzumabtreatment is usually possible (41–43).

Other targeted therapies against HER-2 arerelatively less cardiotoxic (44–46). Perez et al. (46)reviewed cardiac safety data in 44 clinical trials thatused lapatinib. Of these study patients, only 1.6%experienced a cardiac event, and of those, only 0.2%was symptomatic. The rate of cardiac events in thelapatinib group was similar to those who did notreceive lapatinib (44,46). Similarly, there was nosignificant increase in left ventricular dysfunctionwith the addition of pertuzumab to trastuzumab inthe NeoSphere study (47,48). In the CLEOPATRA(Clinical Evaluation of Pertuzumab and TrastuzumabTrial in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer) trial, the incidenceof cardiac adverse events was 14.5% in the pertuzu-mab plus trastuzumab plus docetaxel arm comparedwith 16.4% in the control-placebo plus trastuzumabplus docetaxel arm (49,50). However, in a head-to-head comparison between lapatinib and trastuzu-mab, patients treated with lapatinib have shorterdisease-free survival but more noncardiac toxicity,such as rash and diarrhea (51). Thus, one mustconsider both efficacy and toxicity in choosing drugs.Vascular endothel ia l growth factor s igna l ingpathway inh ib i tors . Vascular endothelial growthfactor signaling pathway (VSP) inhibitors includeantibodies such as bevacizumab, which binds tovascular endothelial growth factor (VEGF), and smallmolecule tyrosine kinase inhibitors such as sunitiniband sorafenib, which inhibit the downstream kinaseinvolved in VEGF receptor signaling (52). Cardiovas-cular side effects of VSP inhibitors include HTN,cardiomyopathy, conduction abnormalities, acute

coronary syndromes (ACS), and arterial thromboses.Several VSP inhibitors also block receptors that areinvolved in the compensatory response to stress inthe cardiomyocytes. When the heart is unable tocompensate for HTN induced by VSP inhibitors, itcould lead to HF (53). Therefore, maintaining goodblood pressure control during VSP inhibitor therapycan prevent HF (54).

Bevacizumab is the first- or second-line chemo-therapy for advanced solid tumors (55–61). Its usehas been associated with HTN, thromboembolism,and cardiomyopathy (62). Approximately 2% to 4% of

FIGURE 1 Mechanism of Doxorubicin-Induced Cardiotoxicity

Doxorubicin inhibits topoisomerase 2b to induce DNA double-strand break, leading to p53 activation and death of cardiomyocytes.

Doxorubicin-bound topoisomerase 2b binds to promoters of antioxidative genes and PGC-1 that are required for expression of antioxidative

enzymes and electron transport chains. Thus, topoisomerase 2b is able to account for the 3 hallmarks of doxorubicin-induced cardiotoxicity:

cardiomyocyte death, generation of reactive oxygen species (ROS), and mitochondriopathy (24,25).



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patients treated with bevacizumab will develop HF(29). Predisposing factors include previous therapywith cardiotoxic chemotherapy drugs, such asanthracyclines (63) and capecitabine (64), as well asradiation to the mediastinum (29). In a meta-analysisof VSP inhibitors and their role in cardiovascularcomplications, the odds ratio for cardiac dysfunctioncaused by VSP inhibitors was 1.35 (65). More thanone-half of the clinical trials included in the analysis(40 of 77) utilized bevacizumab as the drug oftreatment (65). Another meta-analysis showed thatbevacizumab resulted in a significant decrease in EFwith a relative risk index of 3.4 (66).

In a large trial of sunitinib for the treatment ofmetastatic renal cell carcinoma, 13% of patientsdeveloped LV dysfunction and 3% had severe HF (67).Severe HF was more common in a single-centerstudy of 48 patients treated for metastatic renal cellcarcinoma or gastrointestinal stromal tumor (68). In ameta-analysis of 6,935 patients treated with suniti-nib, the incidence of HF was 4.1% with a relative riskof 1.81 compared with placebo (69). In a retrospectiveanalysis of a phase 1/2 trial of sunitinib for thetreatment of gastrointestinal stromal tumor, therewas a 2.5-fold increase in cardiotoxicity with higher

doses (70). Sorafenib has been associated with a 4%risk of mild LV dysfunction and a 1% risk of clinicalHF (71). HF due to VSP inhibitors is reversible withcessation of therapy (72).Proteasome inh ib i tors . Proteasome is a proteincomplex present in all cells that degrades otherproteins. Inhibition of proteasome blocks cellproliferation and induces apoptosis in tumor cells,especially in multiple myeloma. Bortezomib, areversible proteasome inhibitor, is not known to causeHF (73–75). However, 7% of patients treated withcarfilzomib developed new-onset or worsening ofpre-existing HF or myocardial ischemia (76). In aphase 2 trial of 266 patients treated with carfilzomibmonotherapy for relapsed myeloma, 10 experiencedHF (3.8%), 4 (1.5%) had a cardiac arrest, and 2 (0.8%)had a myocardial infarction (MI) during the study (77).The risk did not appear to be cumulative, at leastthrough 12 cycles of therapy. Cardiotoxicity appearsto be largely reversible with cessation of therapy andthe initiation of HF treatment (78).

SCREENING, RISK STRATIFICATION, AND EARLY

DETECTION STRATEGIES. Basel ine r i sk assessment .Patients undergoing chemotherapy should havecareful clinical evaluation and assessment of CV risk

TABLE 2 Best Practices for Prevention, Monitoring, and Treatment of CIMP

Oncologist Cardiologist

Identify high-risk patients (pre-existingheart disease, diabetes, hyperlipidemia,young or old, female, plan for high-doseanthracycline therapy)

Modify cardiovascular risk factors (optimizecardiac medications, glucose control,diet, weight, exercise)

Order pre-treatment imaging (If EF <50%or institution low normal, refer tocardiologist)

Repeat imaging studies (obtain high-quality EF,consider contrast, 3-dimensional, strain)

Order biomarkers (troponin and BNP)

Consider noncardiotoxic alternatives(consider noncardiotoxic alternatives inhigh-risk patients)

Advise on cardioprotection (interpret imagingand biomarker results and discusswith oncologist)

Adjust therapy protocols (for anthracycline:dose reduction, continuous infusion,liposomal doxorubicin, dexrazoxane; foranti-HER2: avoid concomitant treatmentwith anthracyclines; for VSP inhibitors,treat HTN aggressively)

Institute cardioprotective medications(start BB or ACEI if EF <50%, EF drop>10%, abnormal GLS [>15% drop],or abnormal troponin)

Monitor during therapy (monitor with echocardiography at 3-month interval or symptom-driven;if cardioprotective medications were given, monitor at 1-month interval)

Withhold cardiotoxic therapy only as the last resort (for anthracycline EF <45%; for anti-HER2therapy EF <40%)

Monitor after completion of therapy (obtain post-therapy EF; repeat echocardiography in6 months or 1 yr; if EF remains abnormal, follow ACC/AHA HF guidelines)

Data from Yeh (2), Plana et al. (3), Zamorano et al. (4), and Armenian et al. (5).

ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; BNP ¼ brain natriuretic peptide;CIMP ¼ chemotherapy-induced cardiomyopathy; HTN ¼ hypertension; VSP ¼ vascular endothelial growth factorsignaling pathway; other abbreviations as in Table 1.


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factors, such as coronary artery disease, diabetes, andhypertension (Table 2) (2–6). These risk factors shouldbe managed according to the American College ofCardiology (ACC)/American Heart Association (AHA)guidelines (79). This is especially important if cancertherapy is known to cause HF. Aggressive HTNmanagement is advised for patients treated with VSPinhibitors. Physical exercise has been shown toreduce cardiotoxicity in mouse models (80).

EF assessment is mandatory to establish baselinecardiac function before cardiotoxic cancer treatment(3). Echocardiography is the preferred modalityfor assessment of cardiac structure and function.A multigated acquisition radionuclide ventriculog-raphy scan has less interobserver variability; however,radiation exposure limits its utility as a cardiacmonitor. Cardiac magnetic resonance imaging can beused to obtain a precise EF; however, the use of car-diac magnetic resonance imaging is limited by its cost.Cardiac biomarkers, such as troponins and brainnatriuretic peptides (BNPs), can be used to monitor fordevelopment of cardiac dysfunction (3,5,6). However,it is not known whether routine monitoring of bio-markers is useful in changing clinical outcomes. Anumber of composite scores have been designed torisk-stratify cancer patients (81–83); however, theyhave not been validated in prospective studies.

Echocard iogram. The echocardiogram is the mostimportant tool for serial evaluation of the heartduring cancer therapy. EF should be determinedusing the biplane method of discs according to theAmerican Society of Echocardiography guideline (3).If the endocardial border is not distinct, ultrasoniccontrast should aid in endocardial border definitionand subsequent volume calculations. However,temporal EF variability may be up to 10%, with aconfidence interval of 95% in 2-dimensional EFreadings (84). Three-dimensional echocardiographyhas a temporal variability of 6% and is considered themost accurate EF measurement by echocardiography.Because CIMP is defined as a drop of EF of $10% or$5% or more in the presence of HF symptoms, anaccurate measurement of EF is paramount.

Myocard ia l s t ra in . Tissue Doppler imaging (TDI)and speckle-tracking strain imaging have emerged as2 quantitative techniques for estimating global andregional myocardial mechanical function and havethe potential to detect early signs of LV dysfunction(85,86). However, TDI is both user- and angle-dependent and is unable to differentiate trans-lational motion or tethering effects from myocardialcontractility. Speckle-tracking echocardiography isan angle-independent technique that uses an

image-processing algorithm for analyzing motion of‘‘speckles’’ or ‘‘fingerprints’’ within a 2-dimensionalechocardiography image, and it has replaced TDIstrain as the preferred method for quantitativeassessment of cardiac deformation (87,88).

Several studies have evaluated the utility of strainimaging for the detection of chemotherapy-associatedcardiotoxicity. Fallah-Rad et al. (89) evaluated 42patients with breast cancer overexpressing HER-2 whoreceived trastuzumab in the adjuvant setting afteranthracycline therapy. Within 3 months, peak globallongitudinal and radial strain detected preclinicalchanges in LV systolic function before a decrease inEF was observed several months later. A recentprospective multicenter study by Sawaya et al. (90)demonstrated that global longitudinal strain(GLS) <19% was predictive of subsequent cardiotox-icity and was present in all patients who laterdeveloped symptoms of HF. Negishi et al. (91) simi-larly showed that a$11% relative reduction in GLS waspredictive of subsequent trastuzumab-associatedcardiotoxicity.

Abnormalities in strain parameters can also beseen several years after a cardiotoxic exposure. In 75asymptomatic breast cancer survivors who receivedanthracycline with or without adjuvant trastuzumab,GLS was significantly decreased in the chemotherapygroup 6 years after therapy compared with controlsubjects (85,92). In another meta-analysis, GLSconsistently detected earlymyocardial changes during



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therapy (93). A 10% to 15% early reduction in GLSduring therapy appears to be the most useful param-eter for the prediction of cardiotoxicity. In late cancersurvivors, global radial and circumferential strain areconsistently abnormal, even with normal EF, but theirclinical value in predicting subsequent ventriculardysfunction or HF has not been explored (93).Biomarkers . The use of EF in the diagnosis of CIMPhas important limitations. First, the measurement ofEF is subject to technique-related variability, whichcan be higher than the thresholds used to definecardiotoxicity (14,84). Second, the reduction in EF isoften a late phenomenon (11,89,94,95). Hence, thereis a growing interest in identifying markers ofearly myocardial damage to predict the developmentof HF. Biomarkers are an economic and effectiveway of detecting myocardial dysfunction in appar-ently asymptomatic patients. The assessment oftroponin and BNP has shown incremental utility inidentifying patients at increased risk for adverseoutcomes (96–98).Troponins . Troponin is an important biomarker forACS and other myocardial damage (99–101). In anearly study, cardiac troponin I (cTnI) was elevatedin 32% of 204 patients receiving high-dose chemo-therapy, and an increase in cTnI occurred in morethan 50% of patients soon after drug administration(102). A follow-up study showed that patients withnegative cTnI (<0.08 ng/ml), immediately and1 month after chemotherapy, showed no EF reduc-tion and had low incidence of cardiac events (9). Incontrast, patients with positive cTnI had a higherincidence of adverse cardiac events, including HFand asymptomatic LV dysfunction (9).

Serial troponin measurements in patients withhematologic malignancies treated with anthracyclineshowed troponin elevation correlated with EFreduction (103). A persistent release of cTnI wasassociated with a probability of major cardiac eventswithin the first year of follow-up (9,22). In childrentreated with high-dose doxorubicin for acutelymphoblastic leukemia, cTnT increased in approxi-mately 30% of cases, and the amount of elevation waspredictive of cardiac dysfunction during follow-up(104,105). Thus, most studies showed a good corre-lation of elevated enzymes with LV dysfunction,especially in patients who were treated with high-dose anthracycline.

Dodos et al. (106) performed a series of cardiactroponin T (cTnT) measurements on the 3rd to 5th dayfollowing the first course of anthracycline and after thelast course. They did not observe troponin elevationfollowed by EF deterioration. In their study, cTnTlevels did not exceed the upper limit of the normal

range in all patients. Only 7% of patients had low-levelelevation of cTnT, and only 1 of these patients devel-oped a decrease in EF. McArthur et al. (107) studied agroup of patients treated with bevacizumab, doxoru-bicin, and cyclophosphamide followed by paclitaxel inearly-stage breast cancer. A total of 7 patients (9%)experienced either a symptomatic or asymptomaticEF decline. There was no association between EFchange and troponin elevation (107). These authorsspeculate that cTnI release could be missed becausesamples were drawn prior to chemotherapy (107).Thus, the utility of using troponins in predictingEF changes depends on the timing of blood drawnrelative to chemotherapeutic administration.

In patients with breast cancer who receiveanthracycline or trastuzumab, an elevation of high-sensitivity cTnI with a decrease in GLS of at least19% is highly specific in predicting CIMP (90). Basedon these data, an expert panel proposed thatcTnI should be measured at baseline and every3 weeks during trastuzumab therapy accompanied byechocardiography and GLS at baseline and every3 months (3). A small study concluded that anincrease in high-sensitivity troponins is a good pre-dictor of LV dysfunction (108). A high baseline levelof high-sensitivity troponins is also a predictor ofadverse outcomes (108).

BRAIN NATRIURETIC PEPTIDE. Natriuretic peptides areproduced by splitting a prohormone into the amino-terminal inactive form and the carboxy-terminalbiologically active hormone. The ventricle secretesbiologically active BNP and inactive amino-terminalpro-BNP in response to increased ventricular vol-ume and pressure (109). Clinical studies have utilizedBNP and amino-terminal pro-BNP as biomarkers ofCIMP, and although results are mixed, several studieshave indicated that these peptides could be goodearly indicators of cardiac damage (109–112).

In an early anthracycline study, an increase in BNPlevel correlated with E/A ratio increase, suggestingthat BNP level may be predictive of diastolicdysfunction. BNP increase during anthracyclinetreatment is usually transient and, in most cases, isnot predictive of clinical outcome. Only patients withpersistent elevation of BNP developed overt HF,which also suggests a potential use of BNP in long-term follow-up (113). Nousiainen et al. (114) foundno significant correlations between echocardiographyparameters and natriuretic peptides until the cumu-lative doxorubicin dose reached 500 mg/m2. Meinardiet al. (115) showed that during chemotherapy, con-centrations of BNP in plasma increase as EF decrease.Daugaard et al. (116) also found that neither baseline


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levels of N-terminal pro-atrial natriuretic peptide norBNP nor changes in these variables during therapywere predictive of a change in EF (116). However,persistent elevation of BNP may be an indicationof adverse cardiac outcomes (115,116). C-reactivepeptide (117–119), myeloperoxidase (117), galacetin-3(117,120,121), and ST-2 (121,122) have been investi-gated as potential biomarkers; however, they cannotbe recommended as routine tests at present.

PREVENTIVE STRATEGIES FOR ANTHRACYCLINE-

INDUCED CARDIOTOXICITY. Selecting a nonanthracyclineregimen. A randomized study of 3,222 women withHER-positive early breast cancer found that anonanthracycline-containing regimen has equalefficacy and less cardiotoxicity (123). With anonanthracycline regimen containing docetaxel,carboplatin, and trastuzumab (TCH), patients had a5-year disease-free survival rate of 81% comparedwith 84% in the anthracycline-containing regimen(ACT [doxorubicin, cyclophosphamide, docetaxel] orACT-H [doxorubicin, cyclophosphamide, docetaxel,trastuzumab]). Importantly, the TCH regimenhas much lower cardiotoxicity than ACT or ACT-H.Thus, TCH was proposed as an alternativenonanthracycline-containing regimen for HER-positive early breast cancers (Table 2).

Subst i tut ing doxorub ic in with less-card iotox icanthracyc l ines . Over the past 5 decades, morethan 2,000 modified anthracycline chemicals havebeen tested in an attempt to reduce cardiotoxicitywhile retaining tumoricidal efficacy. Although severalanthracycline derivatives have been evaluated inclinical trials, only epirubicin (124) and idarubicin(125) received approval for clinical use. However, acritical analysis by the Cochrane database identifiedno difference in cardiotoxicity between epirubicinand doxorubicin at equipotent doses (126).

Cont inuous infus ion . Replacing bolus administra-tion with slow infusions does not significantly affectanthracycline area under the curve, but it diminishesanthracycline Cmax and anthracycline accumulationin the heart (127). A Cochrane review (128) showed asignificantly lower rate of clinical HF with an infusionduration of 6 h or longer compared with a shorterinfusion duration in the adults. In the pediatricpopulations, the results of infusion of anthracyclinehave been disappointing. A randomized trial in chil-dren with high-risk acute lymphocytic leukemiafound that continuous infusion offered no additionalcardiac protection over bolus administration in amedian follow-up of 8 years post-diagnosis (129).A follow-up at 10 years also revealed no incrementaltherapeutic efficacy for infusion (130). Thus,

continuous infusion cannot be recommended in thepediatric population (131,132).PEGylated l iposomal doxorub ic in . PEGylatedliposomal doxorubicin comprises an aqueous coreof doxorubicin hydrochloride encapsulated in lipo-somes with a protective hydrophilic outer coating ofsurface-bound methoxypolyethylene glycol (133,134).Delivery of doxorubicin in a PEGylated liposomalform decreases the circulating concentrations offree doxorubicin and results in selective uptakeof the agent in tumor cells. In randomized trials,PEGylated liposomal doxorubicin was as effectiveas doxorubicin or other traditional combinationchemotherapies (135–140). Thus, PEGylated liposomaldoxorubicin is a useful option in the treatmentof various malignancies (141). However, the costassociated with administering this drug hasprevented its widespread adoption (142).Dexrazoxane. Dexrazoxane was originally devel-oped as an anticancer agent (143). Using fibroblastsfrom topoisomerase 2b knockout mice, Lyu et al. (144)showed that dexrazoxane is protective againstanthracycline-induced toxicity in a topoisomerase2b–dependent manner, linking dexrazoxane to thetopoisomerase 2b theory of anthracycline cardiotox-icity (25) (Figure 1).

The protective effect of dexrazoxane againstanthracycline-induced cardiotoxicity has beendemonstrated in numerous clinical trials in adultsand children (19,105,145–147). Dexrazoxane wasapproved in Europe and the United States forcardioprotection in patients treated with anthracy-clines (Cardioxane, Clinigen Group, Burton-on-Trent,United Kingdom; and Zinecard, Pfizer, New York,New York) with several generic preparations available(procard and cardynax). In addition, dexrazoxanehas been also approved for treatment of accidentalextravasation of anthracyclines (Savene, ClinigenGroup).

Unfortunately, 1 phase 3 trial suggested thatdexrazoxane may lower the efficacy of anthracyclinein treating breast cancer (19). In this trial, a significantdifference in objective response was reported(47% vs. 61%, respectively; p ¼ 0.019). Although ahigh response in the placebo group was quiteunusual, other endpoints (including survival or timeto progression) were not affected by dexrazoxane inthis study (19,148). A careful meta-analyses of allavailable randomized clinical trials found noevidence that dexrazoxane lowers doxorubicin’santicancer effect (149,150). However, the U.S. Foodand Drug Administration (FDA) has approved dexra-zoxane only in patients who have received more than300 mg/m2 of doxorubicin for metastatic breast

TABLE 3 Anticancer Agents Associated With Myocardial Infarction/Ischemia

Chemotherapy AgentsFrequencyof Use

Incidence(%)

Prevention/Treatment

Antimetabolites

Capecitabine þþþþ 3–9 Ischemia workupand treatment

Flourouracil þþþþ 1–68

Monoclonal antibody-basedtyrosine kinase inhibitors

Bevacizumab þþþ 0.6–8.5

Small molecule tyrosinekinase inhibitors

Nilotinib þþþþ 5.0–9.4

Ponatinib þ 12

Angiogenesis inhibitors

Lenalidomide þþþ 0–1.9

Antimicrotubule agents

Paclitaxel þþþþ <1.5

Frequency of use was determined using inpatient and outpatient doses dispensed at MD AndersonCancer Center during the time period of January 1, 2014, through December 21, 2014.þ¼<1,000doses dispensed; þþ ¼ 1,000–5,000 doses dispensed; þþþ ¼ 5,000–10,000 doses dispensed;and þþþþ ¼ >10,000 doses dispensed (1,2,24,29).



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cancer and who may benefit from continued doxo-rubicin treatment (151).

Another controversy about dexrazoxane pertainsto an increased risk of second malignancies in thepediatric cancer survivors. This was observed in sur-vivors of Hodgkin lymphoma who had receiveddexrazoxane in combination with doxorubicin andetoposide. It was postulated that combining thesedrugs could exceed a threshold above which topo-isomerase inhibitors caused genetic instability innormal tissues (152). This report led the EuropeanMedicine Agency to disapprove the use of dexrazox-ane in children. However, 2 studies of survivors ofchildhood acute lymphoblastic leukemia did notdetect an increased risk of second malignancies fromdexrazoxane (153,154). Thus, the risk/benefit analysissupports a wider clinical usage of dexrazoxane withthe possible exception of patients receiving etoposideor etoposide-anthracycline combinations.

PREVENTATIVE STRATEGIES AGAINST TRASTUZUMAB-

INDUCED CARDIOTOXICITY. The metastatic breastcancer trial showed that concurrent treatment oftrastuzumab and anthracycline had detrimentalcardiac outcomes (14,37). However, as anthracyclineand trastuzumab were not administered at the sametime, the incidence of HF drastically reduced. In theN9831 trial, the incidence of New York Heart Asso-ciation functional class III/IV HF or cardiac deathswas 0% in the control arm (anthracycline withouttrastuzumab) and 3.3% in the concurrent anthracy-cline/trastuzumab arm (155). In the B-31 study, thesetoxic effects occurred in 0.8% of the control group

(anthracycline without trastuzumab) and 4.1% ofthe anthracycline/trastuzumab arm. HF was notreported in the FinHer trial, in which trastuzumabwas omitted during the 3 cycles of epirubicin-containing regimen (156). These results were inmarked distinction to the 27% incidence of HF in theoriginal metastatic trials.

TREATMENT. Symptomatic and asymptomatic HFshould be treated according to the ACC/AHA guide-lines (Table 2) (157,158). We recommend HF treatmentwhen subclinical cardiotoxicity was detected by strainimaging and biomarkers (2,3). Many cancer patientswith overt or subclinical HF can be treated withangiotensin-converting enzyme inhibitors or beta-blockers to allow completion of the chemotherapy.Anthracycline-induced cardiotoxicity was consideredirreversible, whereas trastuzumab was reversible(43,159). Thus, a different EF cutoff threshold forwithholding therapy is recommended (Table 2) (2).It should be noted that cessation of cancer therapyshould be considered only as the last resort.Every effort should be made to manage HF to allowchemotherapy to continue. Patients with symptomaticand/or overt HF should be treated according to theACC/AHA HF guidelines (157,158).

ISCHEMIA

Cancer treatment, including radiation therapyand chemotherapy, is associated with accelerateddevelopment of coronary artery disease (CAD) and/orACS. Cancer itself can also create a pro-thromboticstate that promotes the development of ACS.Thus, chest pain in cancer patients needs to be inves-tigated promptly. Drugs that are commonly associatedwith ischemia in cancer patients were listed in Table 3.

INCIDENCE. Ant imetabol i tes . Chest pain is the mostcommon symptom associated with 5-fluorouracil(5-FU) administration. Less common side effectsinclude MI, arrhythmias, HF, cardiogenic shock,and sudden death (160,161). High doses of 5-FU(>800 mg/m2) and continuous 5-FU infusions arerecognized risk factors of cardiotoxicity (7.6%)compared with bolus injections (2%) (160,162,163).Other risks factors include pre-existingcardiovascular disease, prior mediastinal radiation,and concurrent use of other chemotherapeuticagents (161,162,164–170). Cardiac events are typicallyshort-lasting (up to 48 h) and tend to manifest within2 to 5 days after initiation of 5-FU (160). Ischemicalterations of the ECG have been reported in 68% ofpatients and are associated with biomarkerelevations in 43% of cases (163). The overallmortality ranges from 2.2% to 13% (162,166,171).


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Selective activation of capecitabine (oralprodrug of 5-FU), which occurs preferentially in can-cer cells, explains its lower cardiotoxicity comparedwith 5-FU. The incidence of capecitabine-inducedcardiotoxicity ranged between 3% and 9% (161,172–174). One prospective study that enrolled 644 pa-tients with no prior history of coronary artery diseasereported the occurrence of symptomatic ischemicchanges of the ECG in 5.2% of patients receivingcapecitabine (167). ECG changes, including ST-segment elevation, were seldom associated with anelevation of serum cardiac markers (163,165,175,176).Ant i -microtubule agents . Myocardial ischemiaand infarction have been reported in approximately3% of the patients receiving paclitaxel. In 198 patientstreated with paclitaxel for ovarian cancer, 0.5%experienced an MI (177). In the Cancer TherapyEvaluation Program’s Adverse Drug Reaction data-base, which followed more than 3,400 patients, theoverall incidence of grade 4 and 5 cardiac events wasonly 0.29% (177). These events occurred within2 weeks of paclitaxel administration (177) and wereobserved in patients with known cardiac risk factorsincluding HTN and CAD.

Cardiac ischemia has also been reported afteradministration of docetaxel. In a clinical trial withinoperable, locally advanced squamous cell carcinomaof the head and neck, 355 patients were randomized toreceive a standard regimen of cisplatin and 5-FU or thesame regimen plus docetaxel. Myocardial ischemiaoccurred in 1.7% of the docetaxel arm and in 0.6% ofthe control arm (178). Although not reported in theoriginal study, cardiac ischemia was listed as a sideeffect of docetaxel in the package insert (179).Ant ibody-based VEGF inh ib i tor . In a pooledanalysis of 1,745 cancer patients from 5 randomizedcontrolled trials, the overall incidence of arterialthrombotic events (ATEs) was significantly higher inthe bevacizumab group (3.8%) compared with thecontrol group (180). In the BRiTE (BevacizumabRegimens’ Investigation of Treatment Effects) study,1,953 patients receiving bevacizumab at 248 U.S. siteswere followed for over 20 months (181). The overallincidence of ATEs was 2%. Of these events, >57%were cerebrovascular cardiovascular accidents (CVAs)and transient ischemic attacks, whereas 30% were MI(50% lethal) (181). Independent risk factors for ATEsincluded age $75 years, poor performance status(Eastern Cooperative Oncology Group performancestatus score $1), pre-existing HTN, anticoagulationtherapy, and arterial disease (181).Smal l molecu lar tyros ine k inase inh ib i tors . In adouble-blind, international phase 3 trial that enrolled569 patients with unresectable, locally advanced, or

metastatic pancreatic cancer, CVAs and MI occurredin 4.6% of patients randomized to receive gemcita-bine plus erlotinib compared with 1.2% patientsassigned to gemcitabine plus placebo (182). Althoughthe incidence of CVA/MI was not published in theoriginal study by Moore et al. (182), it was reported bythe FDA in the erlotinib package insert (183).

Approximately 3% of patients in clinical trials haveexperienced myocardial ischemia with sorafenib.In an unpublished clinical trial, MI/ischemia occurredamong 2.7% of hepatocellular cancer patients treatedwith sorafenib compared with 1.3% of patients inthe placebo group (184). Similarly, sorafenib wasassociated with a higher incidence of MI/ischemiacompared with placebo in patients treated forrenal cell carcinoma (3% vs. <1%) (185). The incidenceof cardiac ischemia/MI in patients with differenttypes of cancer receiving sorafenib ranges from2% to 3% (184).

Proteasome inh ib i tors . The safety profile ofcarfilzomib was analyzed by Siegel et al. (186) in526 patients from 4 phase 2 clinical trials; based ontheir results, the use of carfilzomib was approvedby the FDA. In this analysis, the overall incidenceof myocardial ischemia was reported to be 3.4%.A significantly higher occurrence of ischemic eventswas reported in 2 subsequent phase 3, randomized,multicenter trials, the ASPIRE (Carfizomib, Lenalido-mide, and Dexamethasone vs Lenalidomide andDexamethasone in Subjects with Relapsed MultipleMyeloma) and ENDEAVOR (Carfilzomib and Dexa-methasone versus Bortezomib and Dexamethasonefor Relapsed Multiple Myeloma Patients) studies. Inthe ASPIRE study, the rate of ischemic heart diseasewas 5.9% versus 4.6% in the control group (187).Likewise, in the ENDEAVOR study, ischemic eventsoccurred at a rate of 3% compared with 2% in thecontrol group (188). Hence, high-risk patients shouldbe considered for an ischemic workup prior to startingcarfilzomib treatment (188).

PATHOPHYSIOLOGY. Persistent coronary spasmoccurring at the level of a pre-existing plaquewas observed during cardiac catheterization in apatient receiving continuous 5-FU infusion (189).Experimental work in rabbit aortic rings showed thatincremental doses of 5-FU–induced endothelium-independent vasoconstriction, secondary to proteinkinase C–mediated vasoconstriction of vascularsmooth muscle (190). An alternative mechanism ofcardiotoxicity postulates a direct toxic effect of5-FU on the coronary endothelium (191–193), withensuing endothelial injury leading to micro-thrombotic occlusions (191). Although undetectable



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by coronary angiography, endothelial injury andsmall vessel thrombosis could be key ultrastructuralfindings (192,193). 5-FU–induced endovascular injurycould be reduced by anticoagulants (194,195). Little isknown regarding the cardiotoxic effect of paclitaxel.Myocardial ischemia in association with paclitaxelis thought to be due to concurrent use of other drugsand pre-existing cardiac conditions (196). The poly-oxyethylated castor oil, known as Cremophor EL(BASF, Ludwigshafen, Germany), is used as a vehiclefor paclitaxel in the injectable formulation and maycontribute to the overall cardiotoxicity by inducinghistamine release (196).

VEGF stimulates endothelial cell proliferation tomaintain endothelial viability and vascular integrity(197). Consequently, bevacizumab administrationmay impair the regenerative potential of endothelialcells in response to stress. Exposed subendothelialcollagen can trigger tissue factor activation, resultingin thromboembolism (197,198). VEGF inhibition alsoimpairs the production of nitric oxide and prostacy-clin, as well as increases hematocrit and bloodviscosity via overproduction of erythropoietin, allof which heighten the thromboembolic risk (197).Carfilzomib was found to increase coronaryperfusion pressure and resting vasoconstriction tonein isolated rabbit heart and aorta (199). In addition,carfilzomib amplified the spasmogenic effectof noradrenaline and angiotensin II, curbed the anti-spasmogenic activity of nifedipine and nitroglycerin,and reduced the vasodilating effect of acetylcholine.

SCREENING, DIAGNOSIS, AND TREATMENT. Becausepre-existing CAD is a known risk factor for thedevelopment of chemotherapy-induced ACS, ischemicworkup should be initiated in all high-risk patientsbefore administration of drugs known to cause cardiacischemia (Table 3). Patients with suspected ACSshould be treated according to ACC/AHA guidelines(200,201). Besides statins and beta-blockers, the cor-nerstones of ACS treatment include percutaneouscoronary intervention as well as antiplatelet andanticoagulant therapy, all of which pose an incre-mental bleeding risk in cancer patients with throm-bocytopenia. Although prospective studies in thisspecific population are currently lacking, a retrospec-tive analysis carried out in cancer patients withthrombocytopenia and ACS showed that aspirinimproved the 7-day survival rate without increasingthe bleeding risk (202). Although case-specific con-siderations are warranted, life-saving interventionsshould not be denied to cancer patients withongoing ACS because of thrombocytopenia (203).The response to anticoagulants and antiplatelet

agents in patients with platelet counts >50,000/mlseems to be comparable to that observed in patientswith normal platelet counts (203). However, reducedheparin doses, ranging from 30 to 50 U/kg, maybe required for patients whose platelet countsare <50,000/ml (203). Dual antiplatelet therapy withaspirin and clopidogrel can be used for patients withplatelet counts >30,000/ml, whereas aspirin as a singleagent should be given to those with platelet counts>10,000/ml. With a platelet count below 10,000/ml,bleeding risk should be carefully evaluated against therisk of leaving the thrombotic event untreated (202).In cancer patients with ACS and thrombocytopenia,revascularization can still proceed with radial access,micropuncture kits, and closure devices for the arteryentry site. When the femoral access is chosen,prolonged groin pressure of at least 30 min should beinstituted to obtain hemostasis (204).

Patients treated with 5-FU or capecitabine shouldbe closely monitored for myocardial ischemia withserial ECGs. Preemptive use of coronary vasodilators,such as nitrates and calcium-channel blockers, shouldbe considered. In cancer patients who develop acutechest pain while receiving 5-FU or capecitabine, theoffending drugs should be withheld until diagnosticworkup is completed and anti-anginal therapy isinstituted. It is possible to re-challenge the patientswith close monitoring; however, an alternativeregimen that does not contain the offending drug is abetter option (160,164,166,173).

Temporary or permanent discontinuation of sor-afenib is also advised in the management of patientsdeveloping cardiac ischemia during or followingtreatment (184). There is a scarcity of data aboutre-challenge. Because patients who experienced astroke or MI within 12 months from enrollmenthave been excluded from the trials evaluating bev-acizumab, the safety of the drug in this high-riskpopulation is unknown (205). Treatment withbevacizumab should be promptly discontinued inpatients who develop severe ATEs during treatment.The safety of restarting bevacizumab after resolutionof an ATE has not been evaluated (205). As cardiaccomplications caused by carfilzomib are serious,high-risk patients, including those age $75 years,should undergo an ischemic workup prior to startingcarfilzomib treatment (202). Prompt discontinuationof carfilzomib is warranted when chest pain developsduring infusion.

ADDRESS FOR CORRESPONDENCE: Dr. Edward T.H.Yeh, Department of Medicine, University of Missouri,1 Hospital Drive, MA412, Columbia, Missouri 65212.E-mail: [email protected].

mailto:[email protected]


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KEY WORDS cancer therapy,cardiomyopathy, cardiovascularcomplication, ischemia














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