Author's Accepted Manuscript

Chemotherapy agents with known cardiovascular

side effects and their anesthetic implications
Adriana Dana Oprea MD, Raymond R Russell MD,
PhD, Kerry S Russell MD, Maysa Abu-Khalaf
MBBS, MD

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PII: S1053-0770(15)00570-4
DOI: http://dx.doi.org/10.1053/j.jvca.2015.06.020
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To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Cite this article as: Adriana Dana Oprea MD, Raymond R Russell MD, PhD, Kerry S
Russell MD, Maysa Abu-Khalaf MBBS, MD, Chemotherapy agents with known
cardiovascular side effects and their anesthetic implications, Journal of Cardiothoracic
and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2015.06.020

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Chemotherapy agents with known cardiovascular side effects and their anesthetic

implications

Adriana Dana Oprea, MD 1

2
Raymond R Russell, MD, PhD
3
Kerry S Russell, MD
4
Maysa Abu-Khalaf, MBBS, MD
1
Assistant Professor of Anesthesiology, Yale University School of Medicine, New Haven CT;
2
Associate Professor of Medicine (Cardiology) and Diagnostic Radiology, Yale University
School of Medicine, New Haven CT
3
Associate Professor of Medicine (Cardiology), Yale University School of Medicine, New Haven
CT
4
Associate Professor of Medicine (Medical Oncology) and of Obstetrics, Gynecology, and
Reproductive Sciences, Yale University School of Medicine, New Haven CT

Name of Department(s) and Institution(s)

From the Departments of Anesthesiology and Medicine, Yale University, New Haven, CT

Disclaimers

None

Corresponding author

Adriana Dana Oprea, MD

Department of Anesthesiology

Yale University

333 Cedar St, TMP 3

PO Box 208051

New Haven, CT 06520- 8051

Tel: 203 785 2802

Fax 203 785 6664

E-mail: adriana.oprea@yale.edu

Reprints

None applicable



Financial support

None

Conflicts of interest

None

Chemotherapy agents with known cardiovascular side effects and their anesthetic

implications

I. Introduction
II. Anticancer therapy related cardiac toxicity

A. Cardiomyopathy

1. Anthracyclines

Risk factors
Prevention
2. Trastuzumab
Risk factors
Prevention

3. Cyclophosphamide

4. Lapatinib

5. Bevacizumab

6. Imatinib



 7. Sunitinib

8. Dasatinib

9. Interferons

10. Other agents

Diagnosis of chemotherapy induced cardiomyopathy

Monitoring

B. Cardiac ischemia

C. Rhythm disturbances
D. Hypertension
E. Hypotension
F. Thromboembolic disease

 Pericardial effusion

Treatment of complications
A. Cardiomyopathy
B. Cardiac ischemia
C. Rhythm disturbances
D. Hypertension
E. Hypotension
F. Thromboembolic disease
III. Anesthetic considerations
IV. Conclusions



 I. Introduction

Many cancer patients undergo surgical resection of their primary cancers for curative intent or

may need surgery as part of palliative treatment of an advanced stage cancer. Chemotherapy is

often administered preoperatively (neoadjuvant chemotherapy) to facilitate adequate resection of

the primary tumor. Alternatively, cancer patients may require emergency procedures often due to

complications related to their progressing disease and ongoing pharmacotherapy or surgeries

1, 2
unrelated to their neoplasm. Therefore, the various side effects of the administered

chemotherapy regimens need to considered when such a patient receives general anesthesia,

especially those that may have serious implications during the anesthetic care.3 This is a review of

the anti cancer drugs with known cardiac side effects, the management of these cardiac effects

and their potential implications for the anesthesiologist caring for cancer patients in the

perioperative stages.

II. Anticancer therapy related cardiac toxicity

The development of anti-cancer agents is a rapidly evolving and growing field, comprising not

only the classical cytotoxic chemotherapy drugs but also, new molecular targeted agents. The

classes of chemotherapeutic drugs with cardiotoxic effects, their mechanism of action and uses

are summarized in the table 1. Table 2 comprises common combinations of chemotherapy agents

and their abreviations. Many of these agents, either used as monotherapy or in combination have

cardiovascular side effects, including heart failure, arrhythmias, hypo or hypertension, coronary

ischemia or pericardial disease. The risk of developing these side effects is higher in patients

with pre-existing morbidities, such as diabetes, hypertension, hyperlipidemia and coronary artery

disease.4 While for many chemotherapy drugs, a causal relationship between a certain cardiotoxic

event and the administration of an offending agent has been established, other drugs are thought

to be responsible for cardiotoxicity based on small case series.5-7 Table 3 sums up available data

regarding the cardiac side effects of different chemotherapy agents and their time course. In this



manuscript we detail the main cardiotoxic effects that have been reported with the use of anti

cancer therapies.

A. Cardiomyopathy

Several agents cause myocyte death, manifested either histopathologically (on endocardial

biopsy), through biochemical markers, imaging studies or clinically overt symptoms. (Table 4)

The Cardiac Review and Evaluation Committee supervising trastuzumab clinical trials defined

cardiomyopathy (CMP) as one or more of the following: 1) CMP with global (or more severe in

the septum) reduction in left ventricular ejection fraction (LVEF); 2) symptoms of heart failure

(HF); 3) clinical signs of HF, such as S3 gallop, tachycardia, or both; 4) a reduction from baseline

LVEF of > 5% to an LVEF < 55% in addition to signs or symptoms of HF, or a reduction in

LVEF > 10% to an LVEF < 55%, without signs or symptoms of HF.8

Anthracyclines and trastuzumab are the leading agents causing CMP in patients with breast
5
cancer, but other agents (cyclophosphamide) can also be responsible. The anthracyclines cause

irreversible cell damage and exhibit toxicity that is related to the cumulative dose. In contrast,

trastuzumab causes reversible changes that allow it to be administered for years without

permanent sequelae and to be reintroduced after recovery of cardiac function with acceptable

risk.9, 10

1. Anthracyclines

Anthracyclines are a class of agents widely used for treatment of lymphomas and solid tumors

(breast cancer). Their antitumor effects is thought to result from intercalation of the agent into

deoxyribonucleic acid (DNA) of actively cycling cells and inhibition of topoisomerase II. This

process leads to subsequent blockage of DNA synthesis and cell death. Anthracycline related

cardiotoxicity is a well-known side effect of this class of agents and was described in the 1970’s.

The mechanism appears to be different from their therapeutic mechanism, and has been attributed



to several processes, such as alterations in iron and calcium homeostasis in the mitochondria and

the sarcoplasmic reticulum, cellular apoptosis, and mitochondrial dysfunction. The mechanism

responsible for cardiotoxicity is thought to be free radical formation directly damaging the

myocardium through loss of myofibrils and vacuolization of myocytes but more recent data

implicates altered topoisomerase activity as key mediator of this process.11, 12

Anthracyclines can cause an early and reversible toxicity manifested as transient reduction in the

ejection fraction (EF). In addition to contractile dysfunction, patients can present with

arrhythmias (ventricular or supraventricular tachycardias, bradycardias), hypotension, ischemia,

myocarditis or pericarditis. 13 The incidence of the acute toxicity secondary to anthracyclines was

reported to be <1%.14 While the clinical picture of acute cardiotoxicity can be striking, patients

can present also a subclinical picture marked by increases in biochemical markers (brain

natriuretic peptide (BNP), troponin or EKG changes. The manifestations of acute cardiotoxicity

present within 4 weeks of therapy initiation and are usually reversible within a week of therapy

discontinuation. These patients do not appear to be at higher risk of cardiac dysfunction, should

anthracyclines be administered again.15

More commonly, there is a more severe, irreversible, chronic cardiotoxicity manifested as left

ventricular failure associated with a high one-year mortality (incidence varying between 7% when

anthracyclines are administered alone to 27% when in combination with other cardiotoxic

chemotherapy agents).16, 17 Chronic cardiotoxicity is currently classified as early onset (within the

first year of anthracycline therapy) or late onset (years after treatment was completed).18, 19 This

classification is based on early studies in patients who were diagnosed either after the heart

failure became symptomatic or incidentally during other investigations. Recent evidence from

patients closely monitored with echocardiographic studies every 3 months shows that

asymptomatic decrease in LV function occurs mainly (98%) in the first year after chemotherapy

(containing anthracycline) completion. The same study postulates that chronic cardiotoxicity is



one singular, continuous process; late cardiotoxicity may reflect a delay in diagnosis rather than

onset.20

Risk factors

The incidence of anthracycline related CMP has been reported to be in the range of 5-48%, the
21
number varying depending on the study population. Cardiotoxicity is more likely after a higher

single weekly bolus repeated for 3 weeks than with a schedule of administration of three times a
18
week repeated for 3 weeks, at the same cumulative dose. Although toxicity can occur at any
2
dose, it is more common at cumulative doses that exceed 550 mg/m in patients who receive

treatment during adulthood.21 In addition to the cumulative dose, CMP is more prevalent in

women and in patients older than 66-70 years of age. 11, 22-24

Adults who receive anthracyclines for childhood cancer treatment are also at increased risk of

developing CMP after age 30.25-27 In these patients, childhood cumulative doses of more than 300

mg/m2 may be responsible for the toxic effects.28, 29

Radiation therapy to the chest (previous or concomitant), preexisting coronary disease,

concomitant administration of other cardiotoxic agents (i.e. trastuzumab, paclitaxel,

cyclophosphamide), and liver dysfunction have additive cardiotoxic effects.11, 30-32 A lower EF at

the end of the chemotherapy treatment containing anthracyclines, as compared to the baseline is

also a risk factor.20 While hypertension has been a well described risk factor in many studies,

newer evidence does not confirm it.22

Prevention

Various cardioprotective strategies have been investigated and proven to decrease cardiac side

effects due to anthracycline therapy, including using different agents from the same class,

limiting the dose, avoiding boluses, using liposomal preparations and antioxidant or

cardiovascular drugs.33



 2
For doxorubicin, an empirical dose limit of 500 mg/m has been suggested and currently accepted

to minimize cardiotoxicity.11 Several studies confirmed that administering an anthracycline as an

34
infusion of at least 6 hours versus a bolus is associated with less cardiotoxicity.

The risk of clinical cardiotoxicity is also significantly lower with epirubicin or idarubicin as

compared with doxorubicin and with liposomal preparations versus non-liposomal doxorubicin.35-
38 39
Mitoxanrone use is also less cardiotoxic. The use of N-acetylcysteine (NAC),

phenethylamines, coenzyme Q10, L-carnitine and a combination of vitamins E and C may be

40-42
associated with less toxicity but the evidence is scarce.

While iloprost, sildenafil and amlodipine demonstrated in vitro protection, small in vivo studies

suggest protective effect of carvedilol, angiotensin converting enzyme (ACE) inhibitors and
41, 43-45
angiotensin receptor blockers (ARB).

Dexrazoxane is an iron chelator that interferes with the synthesis of oxygen-derived free radicals,

reducing myocyte apoptosis and damage.46-48 In combination with doxorubicin or epirubicin,

dexrazoxane leads to a significant decrease in cardiotoxicity, both clinical and subclinical.49, 50

Despite that, it may not alter outcomes, due to a potential reduction of the antitumor response rate

and increased myelosuppresion. Recently it was found to increase the incidence of

myelodysplastic syndromes and leukemias in children, limiting its usefulness to adult patients

with metastatic cancer who have received a high cumulative dose of anthracycline.51

2. Trastuzumab

Trastuzumab is a humanized monoclonal antibody targeting the human epidermal growth factor

receptor 2 (HER 2), currently approved for use in both early and advanced stages of breast

cancer. It has been shown to improve survival, especially when used in combination with other

chemotherapy agents. Approximately 25% of breast cancers express the HER2 receptor, making

trastuzumab one of the principal therapies for this patient population.52, 53

Trastuzumab-related cardiotoxicity has a different mechanism and clinical features compared to

anthracycline-induced CMP.

The mechanism of trastuzumab-induced cardiac toxicity is thought to involve two steps. The

stress of chemotherapy may increase the expression of HER2 and/or to activate HER2/HER4

signaling by neuregulin followed by blocking of the HER2 receptor by trastuzumab, process that

impairs the response to cardiac damage. Additional evidence supporting the different toxicity

mechanism as compared to anthracyclines refers to lack of vacuolization and loss of myofibrils

with trastuzumab, proven by endocardial biopsy. Despite that, trastuzumab seems to play a role in

sustaining the mitochondrial toxicity of anthracyclines.54, 55

Trastuzumab cardiotoxicity manifests mainly as a decrease in LVEF and is asymptomatic in most

cases. Unlike anthracyline-induced toxicity, it is not dose related and it is reversible in

approximately 50-80% of cases upon discontinuing the therapy. Many patients are successfully

reexposed to trastuzumab therapy.54, 56-58

In initial trials the incidence of cardiotoxicity appeared to vary- 7% with trastuzumab alone, 13%

when used in combination with paclitaxel and 27% when used in combination with

anthracyclines- but recent data suggests much lower numbers (4%).8, 54 59

Risk factors

The most important risk factor for the development of CMP is a poor baseline left ventricular

(systolic or diastolic) function.60-64 Data is inconclusive regarding age older than 70 years, the

presence of hypertension, diabetes or renal dysfunction as risk factors. Unlike anthracyclines,

radiation therapy is not a risk factor for the development of CMP.65, 66

Prevention

Avoiding anthracycline based regimens, limiting their dose or using liposomal preparations might

be effective strategies in minimizing the cardiac effects of trastuzumab, while optimizing the

antineoplastic action.67-70

 3. Cyclophosphamide

Cyclophosphamide is an alkylating agent widely used in the treatment of solid, hematologic

malignancies and in bone marrow transplant regimens. Cyclophosphamide metabolites form

cross-links with DNA resulting in inhibition of its synthesis and function. High dose

cyclophosphamide (> 150 mg/kg) regimens used for bone marrow transplantation have been

associated with significant cardiotoxicity, the incidence ranging from 7% to 28% after the first
4
dose. The clinical spectrum varies from decreases in LV function and decreases in QRS voltage

to a severe pericardiomyocarditis that can be lethal.71 Most patients present with features of

cardiotoxicity within 10 days of therapy initiation, however, patients surviving the episode do not

seem to be at increased future risk of death.

Pathologically, most patients who experience cardiotoxicity due to cyclophosphamide present

features of myocardial hemorrhage, necrosis and a serosanguinous pericarditial effusion.72 While

the mechanism of toxicity is not completely elucidated, cyclophosphamide causes extravasation

of toxic metabolites responsible for damage of cardiac myocytes and capillary endothelium.

Additionally, its cardiotoxicity may result from ischemic injury due to formation of intracapillary

microemboli in the setting of endothelial injury.

Cyclophosphamide induced CMP is dose related and more prevalent in the elderly even in the

absence of prior cardiac pathology, as described in patients with metastatic breast cancer.73 Unlike

anthracyclines, the toxicity is related to a high single dose versus the cumulative dose.74 In

addition, patients receiving radiation to the mediastinum and patients with prior low EF are at

increased risk.


 4. Lapatinib

Lapatinib is a dual inhibitor of the epidermal growth factor receptor (EGFR) and HER 2 receptor,

approved for the treatment of HER-2 overexpressing metastatic breast cancer. It is associated

with a lower risk of cardiac toxicity when compared to trastuzumab. The incidence ranges from
75, 76
0.2% to 7.7 %, with most patients sustaining EF recovery. The difference as compared to

trastuzumab could be explained by a protective effect of lapatinib on the myocytes, by activating

77
pathways protecting against cellular apoptosis or may represent only bias in patient selection.

5. Bevacizumab

Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor used for the treatment of

advanced lung and colorectal cancer and its use can result in HF in 1.6 % of cases. Patients on

bevacizumab are five times more likely to develop HF as compared to those not taking the drug.78,
79
Patients at older age, with prior thromboembolic events and who received anthracyclines

previously, are at increased risk.

6. Imatinib

Imatinib is a tyrosine kinase inhibitor (TKI) used in the treatment of Philadelphia

chromosome-positive chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors.

It has a low incidence of heart failure ranging from 0.5 to 2.3%, mostly in older patients with
80
preexisting heart disease.

7. Sunitinib

Sunitinib is a small molecule TKI used in the treatment of renal cell carcinoma and

gastrointestinal stromal tumors. It is a potent inhibitor of the platelet derived growth factor and

VEGF receptors. Sunitinib inhibits adenosine 5ƍ monophosphate activated protein kinase,


 81, 82
responsible for the systolic dysfunction and HF seen with this drug. The incidence of overall

LV dysfunction quite high (ranging from 8-28%), with overt HF in 3-15% of cases. In addition,

the EF drops 1-2% with each medication cycle. As with trastuzumab, there is no relationship with

the dose and the LV dysfunction is reversible at stopping the medication.74, 83, 84

8. Dasatinib

Dasatinib is an oral TKI approved for first line use in patients with chronic myelogenous

leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. The incidence of

74
HF in patients treated with dasatinib ranges from 2% to 4%.

9. Interferons

Interferons are cytokines able to "interfere" with viral replication within host cells.and are used in

the treatment of Kaposi’s sarcoma, hairy cell leukemia, renal cell carcinoma and multiple

myeloma. Patients with previous heart disease or older can develop HF, usually reversible, in

addition to arrhythmias and ischemic symptoms.85-87

10. Other agents

Reported series describe other agents including alemtuzumab, all trans retinoic acid (ATRA),

cisplatin, mitomycin C at cumulative drug doses (>30 mg/m2), 5-fluorouracil, cytarabine and

sorafenib (5%) as being responsible for impairment of contractile function.88 While it is unclear

that taxanes (paclitaxel and docetaxel) directly cause CMP, both potentiate anthracycline

toxicity, the latter occurring at much lower doses than in monotherapy. Proteasome inhibitors

such as bortezomib could also cause HF as a class side effect.89 (Table 4)

Diagnosis of chemotherapy induced cardiomyopathy

Assessment of the LVEF is a widely accepted method of detecting chemotherapy-induced

cardiotoxicity. This can be accomplished either with standard echocardiography or equilibrium


radionuclide angiography (ERNA). Both methods have advantages, the most important being the

ability to early detect subclinical CMP.90 Exercise or stress echocardiography may demonstrate

lower EF’s in patients with subclinical cardiomyopathy in whom resting echocardiogram shows a

normal LVEF. In addition to systolic dysfunction, diastolic parameters may be more sensitive in

detecting subtle cardiac dysfunction.

Echocardiography is generally preferred to ERNA due to low cost, wide availability, lack of

radiation exposure and the possibility of obtaining additional information about the cardiac

function (valvular and pericardial pathology). However, for echocardiographic assessment of

diastolic function, dobutamine stress echocardiography, tissue Doppler imaging and left

ventricular strain and strain rate assessment by speckle tracking have been studied and hold

important promise as methods of early detection of cardiotoxicity for both antracyclines and

trastuzumab.91-101

Although not widely used as a screening method, cardiac magnetic resonance imaging (MRI) has

several advantages. It can overcome technical difficulties in obtaining accurate LVEF information

in patients with morbid obesity and, given recent advances in tissue characterization by MRI, it

has the potential to become a method of early detection of cardiotoxicity.102, 103

Biochemical markers have been shown to be early predictors of myocardial injury in patients with

acute coronary syndromes and myocarditis, before the changes in LVEF are apparent. After high-

dose chemotherapy, troponin-I elevation has been shown to predict the future development of

LVEF reduction. More and more data are becoming available demonstrating that troponin-I

during potentially cardiotoxic therapy allows for identification of patients at risk for adverse

events and for persistent reduction in ventricular function despite therapy. Patients with persistent

troponin increases at one month have a higher incidence of future major adverse cardiac events,

including HF.104-106


Similarly, serum natriuretic peptides (atrial [ANP], brain [BNP], N-terminal pro atrial natriuretic

peptide [NT-proANP], N-terminal pro B-type natriuretic peptide [NT–proBNP]) are markers of

HF and have been recently evaluated in multiple studies as predictors of chemotherapy-induced

cardiotoxicity. Patients who developed an impairment of both systolic and diastolic function

demonstrate persistently increased serum NT-proBNP levels one year after chemotherapy but

data is insufficient to replace cardiac imaging at this time.107-109

Endomyocardial biopsy remains the gold standard for diagnosis because it is the most specific

method of diagnosing cardiotoxicity due to anthracyclines. However, it is an invasive and high-

risk procedure, requires considerable expertize for interpretation and may be nonsensitive, since

pathologic findings might not be uniformly present throughout the heart. 18, 110

Monitoring

There is no consensus as to whether all patients needing potentially cardiotoxic chemotherapy

require a baseline evaluation of their ventricular function. Most data is available for doxorubicin

and trastuzumab based regimens. Despite several studies showing that baseline LVEF assessment

prior to initiation of anthracycline based chemotherapy in younger females (less than 65 years)

without cardiac risk factors and not needing trastuzumab does not change management, many
111, 112
institutions still perform it. FDA labeling for doxorubicin recommends stopping therapy for

an EF less than 45% but no specific guidelines are available for the other anthracyclines.

When initiating trastuzumab, baseline function assessment is recommended. Following initial

assessment, the indication for trastuzumab (adjuvant or metastatic disease), dictates further

management. In both instances, the risk for trastuzumab-related cardiotoxicity should be carefully

acknowledged and weighed against the benefits of trastuzumab treatment. In the adjuvant setting,

trastuzumab therapy is likely to be held or discontinued for asymptomatic cardiac dysfunction,

and thus baseline and serial screening of LVEF is appropriate. The studies are repeated every 3


months during the first year of treatment and then as clinically necessary. In the metastatic

setting, the decision is more complex, given the clinical benefit provided by trastuzumab. 113, 114

For trastuzumab, in both the adjuvant and metastatic settings, clinical signs and symptoms,

including increased heart rate or weight gain (•22 kg in one week), edema, S3 gallop or new

dyspnea on exertion should prompt further evaluation and are in fact sufficient for a diagnosis of
113, 114
cardiotoxicity.

Several guidelines for monitoring and discontinuation of therapy have been proposed for both
115, 116
doxorubicin and trastuzumab based regimens. (Figures 1 and 2)

B. Cardiac ischemia

5-fluorouracil (5-FU) is a fluorine-substituted analogue of the pyrimidine uracil. Its primary

mechanism of action is inhibition of thymidylate synthetase, which reduces thymidine

monophosphate formation and thus blocks DNA synthesis. 5-FU is widely used in various

chemotherapy regimens and after anthracyclines, it is responsible for the second most common
117
cause of chemotherapy-related cardiotoxicity.

5-FU cardiotoxicity is rare as compared to anthracyclines with an incidence of 1.2 to 7.6%.118

Clinically it is manifested most commonly as ischemic symptoms ranging from angina, overt

myocardial infarction, to cardiac arrest and death with a mortality varying from 2.2 to 13.3%.119

Silent myocardial ischemia, diagnosed in the setting of EKG changes, seems to be more frequent

and is usually apparent within 72 h of therapy initiation. Several mechanisms have been proposed

for its toxicity: coronary vasospasm, thrombosis due to endothelial toxicity or a takotsubo (stress

induced) CMP.4,
120-122
Differentiation between coronary vasospasm and thrombosis may be

difficult without coronary angiography, although most patients with coronary spasm present with


transient ST elevations at rest, rapidly resolving after the angina episode subsides (unlike

coronary thrombosis when ST segment elevation persists).

Risk factors for 5-FU toxicity include the presence of coronary artery disease and the use of

concurrent radiation or anthracyclines. Additionally, the risk appears higher with infusion (both

long-term and short-term schedules) as opposed to bolus regimens. 123, 124

Cardiac symptoms usually resolve with termination of 5-FU treatment and antianginal treatment

(nitrates and calcium channel blockers). Due to the potential vasospastic component, literature

suggests avoiding   in this setting.118 Currently, re-exposing patients who have had 5-

FU related cardiac toxicity is not recommended due to increased mortality observed upon re-

exposure and lack of convincing data on efficacy of prophylactic coronary vasodilators.118, 119, 125

Given the increased risk of cardiotoxicity due to 5-FU in patients with preexisting coronary artery

disease, these patients may benefit from close monitoring, stress testing or coronary angiography

+/- revascularization, which may allow them to tolerate this therapy better.126

Capecitabine is an orally administered chemotherapeutic agent used for the treatment of

advanced breast and colorectal cancers. Capecitabine is a prodrug that is enzymatically converted

to 5-FU within the tumor, where it inhibits DNA synthesis and slows tumor growth. The

incidence of cardiac toxicity of capecitabine ranges from 3 to 9% and is similar to that reported

with 5-FU when administered as an infusion.127 Due to its metabolism, capecitabine is usually

avoided in patients experiencing cardiotoxicity to 5-FU. The most frequent clinical manifestation

is angina but arrhythmias, myocardial infarction and death have been reported but are much less

common. The mechanism is similar to that of 5-FU, with vasospasm being the most likely.

Similarly, re-exposure is not recommended and prophylactic vasodilators are not effective.128-130


All vinca alkaloids have been associated with myocardial ischemia and infarction, as the most

common manifestation of cardiotoxicity of this class of chemotherapy agents (incidence 10%).131-

133

Interferon use can result in myocardial ischemia in the setting of increased metabolic demand

due to flu-like symptoms superimposed on preexisting coronary artery disease. Myocardial

ischemia can manifest at any point during the therapy course and is usually reversible after drug

cessation.134

Etoposide is a topoisomerase inhibitor used for the treatment of small-cell lung cancer and

testicular cancer. Its toxicity can manifest as vasospastic angina as well as myocardial infarction.

While the incidence of cardiac ischemia due to etoposide is unknown, the mechanism seems to be

due to several phenomenons including direct myocardial toxicity, coronary vasospasm and an

autoimmune response. Myocardial ischemia occurs during or shortly after etoposide infusion and

recurs with reexposure.19

Cardiac ischemia has been also described with other anticancer agents such as bleomycin,

cisplatin, bevacizumab, paclitaxel, interleukin 2 and sorafenib.85 (Table 4)

C. Rhythm disturbances

Arrhythmias can be the result of direct toxicity to the cardiac tissue, due to myocardial ischemia

or related to electrolyte changes associated with the use of chemotherapy.

The taxanes including paclitaxel and docetaxel have been reported to cause arrhythmias. (Table

4) Paclitaxel is commonly associated with atrioventricular block, left bundle branch block and

bradycardia, but more serious complications including ventricular tachycardia can occur in up to

5% of the patients. These arrhythmias usually manifest within 24 hours to 14 days after

paclitaxel infusion and resolve within 24-72 hours.135, 136 Docetaxel has also been linked to


conduction abnormalities, angina and cardiovascular collapse but it is unclear whether these side

effects are the result of concurrent cardiotoxic chemotherapy.4

Platinum agents induce cellular apoptosis by covalently binding purine DNA bases and disrupting
137
its function. These agents are the current mainstays of therapy for lung cancer (small cell and

non small cell), aerodigestive malignancies, breast cancer, non–Hodgkin's lymphoma and

genitourinary malignancies.138 Cisplatin use is associated with nephrotoxicity in a third of cases.

Electrolyte abnormalities inherent to this complication (hypomagnesemia and hypokalemia) can

trigger supraventricular tachycardia, bradycardia and ST-T wave changes. Occasionally, late

effects (10-20 years after therapy) leading to LV hypertrophy manifested as left bundle branch

block, acute ischemic events, myocardial infarction and ischemic CMP have been described. The

pathophysiology of these late effects in unknown.4, 85

In addition to ischemia, interferon toxicity can manifest as ventricular tachycardia, ventricular

fibrillation, atrial flutter and fibrillation, atrioventricular block, and atrial and ventricular ectopy

in up to a 20% of cases, 2-8 hours after infusion.134, 139

Similarly, 5-FU use can lead to cardiac rhythm disturbances, such as atrial arrhythmias (including

atrial fibrillation) and ventricular ectopy (including ventricular tachycardia and ventricular

fibrillation), as well as ventricular dysfunction, which can persist for days to weeks after

discontinuation of 5-FU treatment. These arrhythmias have been reported in up to 23% of cases.4

Methotrexate, although not directly cardiotoxic, was described to rarely induce ventricular and

supraventricular arrhythmias. These occur mostly with high dose intravenous infusions, but also

after oral administration and resolve at discontinuation of the drug. It is prudent to monitor

patients with underlying heart disease undergoing methotrexate infusions with continuous ECG.
140-142


Interleukin 2 infusion is associated with ventricular and supraventricular arrhythmias (usually

resolving with treatment) that occur in 14% to 21% of patients, some patients also demonstrating

elevated levels of creatine phosphokinase MB.143, 144

Rituximab is a monoclonal antibody used for the treatment of lymphomas, leukemias and

autoimmune disorders. Arrhythmias have been reported during less than 1% of rituximab

infusions. Other potentially fatal side effects can occur including an adult respiratory distress

syndrome clinical picture, myocardial infarction, ventricular fibrillation and cardiogenic shock in

0.1% of cases.4

Half of the patients taking arsenic trioxide for treatment of promyelocytic leukemia may develop

significant QT prolongation and increased risk of ventricular arrhythmias, including torsades de

pointes in about one-third of the patients.4 Since arsenic inhibits cellular ion channel trafficking,

there is a lag between exposure to the agent and its electrocardiographic effects.

The histone deacetylase inhibitor vorinostat, used for the treatment of cutaneous T cell

lymphoma, has been reported to cause prolonged QTc interval and potentially serious

arrhythmias.

D. Hypertension

Blood pressure elevation is a class effect of vascular signaling pathway inhibitors, with

hypertension (HTN) reported in every trial of these drugs. The angiogenesis inhibitor,

bevacizumab and the TKI’s, sorafenib and sunitinib, have been reported to cause HTN. (Table

4) The mechanism of the increased vascular resistance is related to inhibition of endothelial cell

function. Endothelial nitric oxide (NO) synthase is up-regulated by VEGF and inhibition of

VEGF decreases NO production and prostacyclin activity by endothelial cell.145 Bevacizumab

related HTN may also be related to its nephrotoxicity. Recent literature reports the overall



incidence of HTN with angiogenesis inhibitors to be 19-47% for sunitinib and sorafenib and

23.6% for bevacizumab. The incidence also appears to be proportional to the degree of

angiogenesis inhibition: 67% with combined bevacizumab and sorafenib, 92% with combined

bevacizumab and sunitinib.146 As described above, HTN associated with the administration of

these agents can lead to more serious effects including ischemia and left ventricular dysfunction.

HTN has also been described with the use of alemtuzumab, a monoclonal antibody used for the

treatment of chronic lymphocytic leukemia, cutaneous T-cell lymphoma and T-cell lymphoma

(10% of cases). It has also been reported with the use of rituximab (5-6% of cases), cisplatin and

interferon.

E. Hypotension

Administration of most monoclonal antibodies (alemtuzumab, cetuximab and rituximab) may

trigger massive cytokine release during rapid infusion and consequentially an allergic response

manifested by hypotension, anaphylactic shock and even death in 3-9% of cases.147

High-dose interleukin-2 infusions (> 1 000 000 U/m2) can cause profound hypotension in

conjunction with vascular leak syndrome and respiratory insufficiency in 3% of cases.5

Etoposide can frequently cause hypotension as can paclitaxel and cetuximab.4 ATRA has also

been reported to cause hypotension.

F. Thromboembolic disease

Bevacizumab increases the risk of coronary or cerebral thromboembolic events, up to 5% of

patients developing thromboses. Risk factors placing patients in the high-risk group are age

greater than 65 years and previous arterial thromboembolic events.148 Coronary ischemia, venous

thrombosis, pulmonary emboli, and cerebrovascular ischemia have been reported in as many as


10% of patient receiving estramustine used to treat prostate cancer. The incidence of

thromboembolic events in patients with prostate cancer treated with estramustine was found to be

3 times higher than in the same patient population treated with zoledonic acic. Therefore it is
149
postulated that this difference is accounted for by the estrogenic effects of estramustine.

Thalidomide and lenalinomide, oral agents with antiangiogenic and immunomodulatory

properties and the antiestrogen agent tamoxifen are also reported to cause thromboembolic

complications.4 (Table 4)

G. Pericardial effusion

Pericardial effusions can form during treatment with ATRA or arsenic trioxide as part of the

‘‘retinoic acid syndrome’’, characterized by fever, dyspnea, infiltrates or pulmonary edema on

chest X ray, hypotension, coronary ischemia, pericardial effusion, acute renal failure and

peripheral edema. The symptoms usually appear within 2–3 weeks after the drug administration

and are present in 20-25% of patients.4

Other drugs such as busulfan, imatinib, bleomycin, cytarabine and cyclophosphamide are also

reported in the literature as being responsible for the development of pleural effusions or

pericarditis.85, 150, 151

Treatment of complications

A. Cardiomyopathy

There are few data available for treatment of left ventricular dysfunction due to chemotherapy

and currently, there are no HF guidelines developed specifically for these patients. The American

College of Cardiology/American Heart Association (ACC/AHA) and Heart Failure Society of

America consider all cancer patients receiving cardiotoxic chemotherapy to be at least stage A

HF (at high risk for HF but without structural heart disease or symptoms or HF).152, 153 In these


patients, management is focused of risk reduction strategies including blood pressure, diabetes,

and hyperlipidemia control, with the goal of preventing remodeling. For patients in stages B

through D HF, the goals of care aim to alleviate symptoms, slow disease progression and improve

survival. Unless contraindicated, these patients should receive a combination of ACE inhibitors or

ARB and a beta-blocker.20, 154

These medications improve survival by reversing ventricular

remodeling. In addition, prompt initiation of therapy leads to recovery (at least partial) of the
20
ventricular function. Patients in advanced stages of HF require additional medications such as

digoxin, diuretics and aldosterone antagonists. Patients with end-stage HF, refractory despite

maximal medical therapy could be considered for treatment with cardiac resynchronization

therapy, ventricular assist device or cardiac transplantation.155

A few studies support the use of ACE inhibitors in patients with anthracycline-induced CMP.20

(Figure 3 shows the impact of ACE inhibitor and -blocker therapy in a patient post-anthracycline

induced cardiotoxicity) Enalapril may prevent ventricular remodeling in a percentage of patients

and is efficacious when used within 6 months of chemotherapy initiation.156 The literature reports

the beneficial effects of enalapril might diminish after 6 to 10 years due to progressive left

ventricular wall thinning. Despite reduced wall stress, in pediatric cancer survivors, enalapril was

not associated with an improvement in exercise capacity or ejection fraction as compared to

placebo, but these results may be explained by late initiation of therapy after the onset of

ventricular dysfunction.43, 157, 158

In a small randomized trial, valsartan was efficacious in blocking acute anthracycline toxicity, but
44
it is unclear whether it decreases the risk of developing early or late cardiotoxicity.

Carvedilol administration was evaluated for the treatment of anthracycline-induced CMP in small

case series.159 Its antioxidant properties may offer therapeutic advantages as opposed to the other

-blockers in this patient population.160 Recent data support the use of prophylactic carvedilol for


protection of both systolic and diastolic function in patients treated with anthracycline

chemotherapy.41, 161, 162

116
Updated guidelines are available for addressing trastuzumab therapy. Despite that, these are

focused on the continuation/withdrawal/resuming of trastuzumab therapy rather than on the

treatment of induced HF. Generally, discontinuation of therapy is recommended when heart

failure occurs. Potential re-exposure can be considered with close monitoring in patients

demonstrating clinical benefit, who recover their LV function (usually within 1.5 months) and

who are started on cardioprotective medications. The potential efficacy of ACE inhibitors and 

 in improving LVEF in patients receiving trastuzumab remains uncertain. A second

episode of heart failure should prompt permanent discontinuation of trastuzumab.163

B. Cardiac ischemia

Chemotherapy related myocardial ischemia is usually managed using a combination of aspirin,

-blockers, calcium channel-blockers and with nitrates for symptom control. The combination of

aspirin and -blockers may also decrease the rate of ischemia episodes and increase the 7-day

survival in cancer patients presenting with acute coronary syndrome.164 Chemotherapy treatment

leading to vasospastic episodes may particularly benefit from calcium channel blockers while -

blockers may be detrimental. The underlying cancer (brain metastases) and potential hematologic

side effects of chemotherapy (thrombocytopenia) may pose significant problems when coronary

interventions requiring antiplatelet drugs are considered. Cardiac ischemia due to 5-FU and

capecitabine recurs at reintroduction of the drug and further treatment with these chemotherapy

agents is not recommended.4, 14, 85


 C. Rhythm disturbances

The most common arrhythmia encountered with the use of paclitaxel and thalidomide is sinus

bradycardia. Since it is mostly asymptomatic, no treatment is usually required, but

progressive/symptomatic heart rate decreases might require dose reduction, treatment

discontinuation or pacemaker placement.

Clinically significant QT prolongation (corrected QT (QTc) >500 ms or >60 ms over baseline)

is observed almost exclusively in patients treated with arsenic trioxide. Such patients require

serial electrolyte and EKG monitoring during the first post-infusion day. Ventricular arrhythmias

(torsade de pointes) caused by arsenic trioxide require intravenous magnesium and potassium

since they are often resistant to electrical and pharmacological cardioversion. Patients with

torsades precipitated by bradycardia may benefit from overdrive transvenous pacing with short-

term pacing rates of 90 to 110 beats/min. Isoproterenol titrated to a heart rate •90
90 beats/min can

be used temporarily.165 The use of other drugs causing QT prolongation should be avoided in

patients treated with arsenic trioxide.14

D. Hypertension

HTN is the most frequent comorbid condition reported in cancer patients and might impact the

overall prognosis. Since this complication is mostly associated with VEGF inhibitors, it is

prudent to carefully assess the patients considered for this therapy from the cardiovascular and

renal standpoint (screening for proteinuria). Patients with pretreatment HTN should have their

blood pressure optimized before starting treatment with VEGF inhibitors, with the goal of

uninterrupted and safe administration of these drugs without having to decrease the dose.166

The primary aim in the treatment of HTN is to lower morbidity, mortality and risk of associated

end organ damage (e.g., cardiovascular and cerebrovascular events, renal failure). In treating

HTN induced by VEGF-targeted therapies, standard antihypertensive medications should be


 167
initiated in concordance with Joint National Committee guidelines. All classes of

antihypertensives can be used to treat HTN in the cancer patients (diuretics, beta-blockers, ACE

inhibitors, ARBs and calcium channel blockers). Because endothelial NO is considered a

mediator in the pathogenesis of HTN in this population, agents acting by increasing NO such as

nitrates have been proposed as additional treatment in case of uncontrolled blood pressure.

After chemotherapy initiation, the patients’ blood pressure should be closely monitored (weekly

in the beginning, then every 2-3 weeks) and pharmacological intervention should be tailored

accordingly, to allow the maximal benefit of antineoplastic therapy. In cases of systolic blood

pressure >200 mmHg or diastolic >100 mmHg discontinuation or, where appropriate, dose

reduction, must be considered.146, 166, 168, 169

E. Hypotension

Hypotension is most frequently encountered as part of a hypersensitivity reaction (usually

associated with administration of taxanes, monoclonal antibodies or interleukin 2) and can lead to

undesirable consequences in patients with underlying cardiac pathology. Most of the time,

hypotensive episodes can be prevented by slowing the drug infusion and use of appropriate

premedication (i.e. steroids, diphenhydramine).

F. Thromboembolic disease

Thromboembolic events are frequently due to the cancer induced hypercoagulable state and

additionally, to specific antineoplastic therapy (thalidomide or lenalidomide). In patients with

cancer, guidelines have been proposed to prevent thromboembolism based on other patient

related risk factors (age, obesity, previous venous thromboembolism (VTE), central venous

catheter, immobility, comorbidities, concomitant medications, surgery, inherited thrombophilia)

or therapy-related risk factors (concomitant steroids, doxorubicin).170 Aspirin (81 to 325 mg) may


be beneficial in patients with less than one risk factor for VTE with low-molecular-weight

heparin (LMWH) equivalent to 40 mg enoxaparin or full-dose warfarin recommended for those

with 2 risk factors or those receiving concomitant high-dose dexamethasone or doxorubicin.

In general, for patients with VTE and cancer, the American College of Chest Physicians

guidelines recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy,

followed by anticoagulant therapy with warfarin or LMWH indefinitely or until the cancer is

resolved.171

As mentioned above LMWH (enoxaparin or dalteparin) should be used as the anticoagulant of

choice in patients with cancer, initially.172 Subsequently patients can be transitioned to warfarin

therapy targeting an international normalized ratio of 2 to 3, until they are cancer free. The

optimal duration of therapy remains controversial; however, extended therapy is recommended

due to the high risk of recurrence (>10%) in the year after discontinuation of anticoagulant

therapy in cancer patients who have had a VTE. Since thalidomide or lenalidomide are strongly

associated with thromboembolic events, they may be temporarily discontinued and resumed once

full anticoagulation has been established.14, 171

III. Anesthetic considerations

The preanesthetic evaluation for the oncology patients taking potentially cardiotoxic

chemotherapy implies a thorough knowledge of the chemotherapy potential side effects.1, 2, 173As

with non-oncology patients, the preoperative evaluation requires a comprehensive history and

physical examination in addition to reviewing medications, their potential implications for

anesthetic management and pertinent studies (laboratory values, EKG). While for emergent

procedures little can be done as far as optimization of patient’s status, this should always be the

goal for oncological patients scheduled for elective procedures.


There are no specific guidelines for the preoperative cardiac evaluation of the cancer patient,

therefore many practitioners rely on the latest guidelines from the ACC/AHA for perioperative
174, 175
evaluation and management for noncardiac surgery. Functional status, current and past

cardiac issues, and the proposed procedure need to be taken into account when assessing the

cardiac perioperative risk.176 The caveat is that a patient presenting with a declining functional

status may be sent for unnecessary testing, when this may related to the ongoing cancer

treatment rather that representing an ongoing cardiotoxicity or an underlying heart disorder.

From this respect, it is important to clarify the timing of symptom onset in relationship to cancer

treatment administration, and to review the potential side effects of the cancer treatment

regimens. Cardiac evaluation such as stress testing and angiography should be considered in

specific conditions, but any decision to delay surgery in high-risk patients should be made in

consultation with the patient's treating oncologist and a cardiologist, as preoperative

angiography and coronary artery stent placement can lead to significant surgical delay, which

may render a previously curable tumor unresectable.177 In this respect, as stated in the 2014

ACC/AHA Guideline for Perioperative Evaluation and Management of Patients Undergoing

Noncardiac Surgery, cancer surgery is considered a “time sensitive” procedure and can be

delayed up to 6 weeks to allow optimization of comorbidities preoperatively, without negatively

impacting the outcome.175

Patients on potentially cardiotoxic chemotherapy should undergo testing and potential treatment

of their cardiac complications, as described above. Patients who potentially may benefit from 

 (patients with cardiomyopathy or ischemia) merit special considerations. Starting these

agents immediately preoperatively may not be wise given the risks of intraoperative

bradycardia, hypotension or stroke.178 Should the timing/urgency of surgery allow,  

may be titrated slowly in the weeks preceeding the operation. Additionally, anesthesia may pose

specific problems in these patients, and latent or subclinical abnormalities in the patient’s


 2, 3, 179
cardiac reserve may become apparent during exercise or surgery.

In general, clinical data on interactions between anesthestetics and anthracyclines are scarce and

there are no available data on other cardiotoxic drugs (i.e. trastuzumab, TKI).180 Huettemann and

colleagues showed that, in the pediatric population, previous treatment with anthracycline may

enhance the myocardial depressant effects of anesthetics even in patients with normal cardiac

function at rest (assessed by echocardiography).181 Anesthesia-induced changes in cardiac

function differ in pediatric patients who received anthracycline therapy previously as compared to

those who did not receive anthracyclines, as demonstrated on patients who underwent removal of

a Hickman catheter under general anesthesia. In this pediatric population, anesthesia included

pretreatment with midazolam (0.5 mg/kg) orally then induction with thiopental, fentanyl,

rocuronium and maintenance with isoflurane. The study reported a significant reduction in the

shortening fraction and stroke volume index at 5 minutes and 20 minutes after intubation, the

difference being much greater in the anthracycline group than in controls. In this investigation

almost no correlation was found between the cumulative dose of anthracycline and abnormalities

of cardiac function during anesthesia. The investigators concluded that previous treatment with

anthracylines could enhance the myocardial depressive effect of anesthetic drugs, even in

children and adolescents with a healthy cardiac function at rest.181

Another study looked at the potentiating effect between previous treatment of anthracyclines and

isoflurane, investigating the effect of isoflurane anesthesia on the QT interval.182 This study

included 40 women undergoing breast surgery and QT and QTc intervals were measured before

anesthesia, after induction and tracheal intubation and after 1, 5, 15, 30, 60, and 90 minutes of

anesthesia. A tendency to QTc prolongation was recorded in both groups, but significant

differences between values at baseline and those during isoflurane-maintenance anesthesia were

recorded only in the group with previous anthracycline treatment. The researchers concluded that

in female patients pretreated with anthracyclines for breast cancer, the tendency to QTc


prolongation during isoflurane-containing general anesthesia was more strongly expressed than in

patients without previous chemotherapy.182

Cancer patients treated with anthracycline derivatives are also thought to be at risk of

perioperative cardiovascular decompensation. Thorne and colleagues studied hemodynamic

indices before, during, and after laparotomy in 14 anthracycline-treated patients with ovarian
183
carcinoma. General anesthesia was maintained with 70% nitrous oxide in oxygen and patients

were randomly assigned to receive supplementation with either isoflurane or fentanyl. The degree

of hemodynamic stability relative to the baseline was assessed. The researchers recorded a clear

tendency for nitrous oxide supplemented with isoflurane to result in an improved hemodynamic

stability during and immediately after surgery. These patients had significantly reduced

alterations in systemic vascular resistance and cardiac index. This study concluded that

anthracycline-treated patients with no overt evidence of CMP can be safely given either

anesthetic technique, but that during surgery and in the early postoperative period, use of a

combined isoflurane and nitrous oxide technique seems to offer enhanced hemodynamic

stability.183

In a study analyzing 111 anesthetic records of 68 patients with an age between 0.5 and 22 years,

seven (6.3%) cardiovascular complications during anesthesia (hypotension, defined as >25%

reduction of blood pressure as compared to preoperative values), were identified.184 Myocardial

dysfunction was diagnosed in two patients by increases in pulmonary arterial occlusion pressure

with unchanged right-heart filling pressures. In this study, induction techniques consisted of

inhalation of halothane and intravenous application of thiopentone, diazepam, and ketamine, and

maintenance technique was achieved with halothane, enflurane, and nitrous oxide.184

While there is very little literature addressing anesthetic management specifically for patients on

cardiotoxic chemotherapy, all the above considerations need to be taken into account. In addition

to thoroughly assessing and treating the patient’s preoperative comorbid conditions, patients with



myocardial dysfunction may need additional invasive intraoperative monitoring (arterial catheter,

central venous pressure or pulmonary artery catheter insertion) in addition to transesophageal

echocardiography depending on the severity of the preexisting left ventricular dysfunction and on

the planned procedure. Moreover, as detailed above, the anesthesiologist needs to be aware of

other cardiovascular complications (ischemia, QTc prolongation, arrhythmias, pericardial

disease) related to chemotherapy and ready to manage them, should they occur in the

perioperative period.173 Potential interactions with adjunct medications used in the perioperative

period (i.e. ondansetron in patients on chemotherapy agents known to prolong the QTc interval)

can lead to undesired consequences, therefore a thorough understanding of these side effects is

necessary.

IV. Conclusions

Cardiotoxic chemotherapy provides a considerable challenge to the physicians. Congestive heart

failure, myocardial ischemia, arrhythmias, and pericardial disease can be caused by various

chemotherapy agents. The anesthesiologist should be aware of these potential serious side effects

since they may be worsened or become apparent during anesthetic care.

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Figure legends


Figure 1.

Algorithm for the management of cardiotoxicity in patients receiving anthracyclines. (Adapted

with permission from Curgliano G et al. Ann Oncol. 2012 Oct;23 Suppl 7:vii155-66)

CTh, chemotherapy; LVD, left ventricular dysfunction; ECHO, echocardiogram; TnI, troponin I;

ACE, angiotensinogen converting enzyme inhibitor; BB, -blocker

Figure 2.

Algorithm for continuation and discontinuation of trastuzumab based on LVEF assessments.

(Adapted with permission from Curgliano G et al. Ann Oncol. 2012 Oct;23 Suppl 7:vii155-66)

LVEF, left ventricular ejection fraction

Figure 3.

2-Dimensional quantitative echocardiography of apical 4-chamber views in a female patient who

received high dose anthracycline chemotherapy.

Pre-chemotherapy ejection fraction (EF) was measured by Simpson’s 2-D assessment as 70%

(panels A&B, normal). Less than 1 year later, the patient presented with new symptoms of

congestive heart failure and EF was assessed as 33% (panels C&D, significantly decreased, lower

limit of normal is 55% by this method). After several months of optimal heart failure therapy,

including angiotensin converting enzyme inhibitors and beta blockade, patient recovered much,

but not all, cardiac function and was asymptomatic (EF 52%, panels E&F).



Table 1

Table 1. Chemotherapy drugs with known cardiotoxicity, their mechanism of action and therapeutic use (DNA, deoxyribonucleic acid; RNA, ribonucleic acid)

Class Subclass Mechanism of action Agents Therapeutic use

Alkylating agents Alkyl sulfonates The agent and nucleophilic cellular Busulfan Bone marrow transplantation, especially in chronic myelogenous
components, including DNA, form (Myleran, Busulfex) leukemia
covalent linkages, by alkylation, Cyclophosphamide Lymphomas
leading to cytotoxicity (Cytoxan, Endoxan) Leukemias
Solid tumors

Ifosfamide Testicular cancer

(Ifex) Ovarian cancer
Breast cancer
Cervical cancer
Lymphoma
Platinum agents Induce cellular apoptosis by Cisplatin Ovarian cancer
covalently binding purine DNA (Platinol, Testicular cancer
bases and disrupting DNA function Platinol AQ) Lung cancer (small and nonsmall cell)
Aerodigestive cancers

Antimetabolites Antifolates Inhibit dihydrofolate reductase, Methotrexate Breast cancer

leading to decreased levels of (Rasuvo, Osteogenic sarcoma
tetrahydrofolate necessary for Otrexup, Gestational trophoblastic cancer
purine and aminoacid formation Trexall, Non-Hodgkin's lymphoma
Rheumatrex) Primary central nervous system lymphoma
Acute lymphoblastic leukemia
Bladder cancer

Pyrimidine analogues Interfere with DNA/ RNA 5 Fluorouracil Breast cancer

synthesis and inhibit thymidylate (Adrucil) Colorectal cancer
syntherase Anal cancer
Gastroesophageal cancer
Hepatocellular cancer
Pancreatic cancer
Head and neck cancer
Cytarabine Hodgkin's lymphoma
(Cytosar- U) Non-Hodgkin's lymphoma
Acute myelogenous leukemia
Acute lymphoblastic leukemia
 Capecitabine Breast cancer
(Xeloda) Colorectal cancer
Gastroesophageal cancer
Hepatocellular cancer
Pancreatic cancer
Topoisomerase Anthracyclines Bind topoisomerase II, leading to Doxorubicin Leukemias
inhibitors inability to repair the DNA and (Adriamycin) Lymphomas
ultimately cell death Kaposi's sarcoma
Mycosis fungoides
Solid tumors
Multiple myeloma
Daunorubicin Acute leukemias
(Cerubidine)
Epirubicin Breast cancer
(Ellence)
Idarubicin Acute myelogenous leukemia
(Idamycin)
Anthracenediones Mitoxantrone Acute myelogenous leukemia
(Novantrone) Prostate cancer
Epipodophyllotoxins Etoposide Small-cell lung cancer
(VePesid Testicular cancer
Toposarm
Etopophos)
Antimicrotubule Taxanes Disrupt microtubule dynamics by Paclitaxel Solid tumors
agents reducing the critical tubulin (Taxol,
concentration required for Onxol)
microtubule assembly and produce Docetaxel Breast cancer
similar disruptive effects on the (Taxotere) Gastric cancer
mitotic spindle apparatus and the Head and neck cancer
mitotic process, induce a mitosis Prostate cancer
block at the metaphase/anaphase Non–small cell lung cancer
transition Ovarian cancer
Vinca alkaloids Bind rapidly and reversibly to sites Vincristine Lymphoma
on tubulin (Oncovin, Vincasar PFS) Acute leukemia,
Neuroblastoma
Rhabdomyosarcoma
AIDS-related Kaposi's sarcoma
Multiple myeloma
Testicular cancer
Vinblastine Hodgkin's and non-Hodgkin's lymphoma
(Velban) Kaposi's sarcoma
Breast cancer
Testicular cancer
Bladder cancer
 Prostate cancer
Renal cell cancer
Vinorelbine Non–small cell lung cancer
(Navelbine) Breast cancer
Cervical cancer
Ovarian cancer
Antitumor Inhibit DNA /RNA synthesis Bleomycin Testicular cancer
antibiotics (Blenoxane) Head and neck cancers
Lymphomas
Mitomycin C Gastric cancer
(Mutamycin) Pancreatic cancer
Molecular Tyrosine kinase Interfere with products of Imatinib Chronic myelogenous leukemia
targeted agents inhibitors oncogenes and tumor-suppressor (Gleevec) Non small cell lung cancer
genes, regulators of cell death Dasatinib Renal cell carcinoma
pathways or other substrates (Sprycel) Gastrointestinal stromal tumors
responsible for tumor growth Nilotinib
(Tasigna)
Sunitinib
(Sutent)
Sorafenib
(Nexavar)
Lapatinib
(Tykerb)

Proteasome inhibitors Bortezomib Multiple myeloma

(Velcade) Non Hodgkins lymphoma

Histone deacetylase Vorinostat Cutaneous T cell lymphoma

inhibitors (Zolinza)
Romidepsin
(Istodax)
Differentiating agents ATRA Leukemia
(Vesanoid, Tretinoin)
Arsenic trioxide Promyelocitic leukemia
(Trisenox)
 Antibodies Rituximab Non Hodgkins lymphoma
(Rituxan) Metastatic breast cancer
Trastuzumab Acute myelogenous leukemia
(Herceptin) Chronic lymphocytic leukemia
Gemtuzumab Head/neck cancer
(Mylotarg) Colorectal cancer
Alemtuzumab Non small cell lung cancer
(Campath)
Cetuximab
(Erbitux)
Bevacizumab
(Avastin)

Miscellaneous Biologic response Stimulates the activity of natural Interferon alfa Melanoma
agents modifiers killer cells and macrophages, and (Intron) Renal cell cancer
enhance the recognition of foreign
cells by increasing antigen
presentation to T cells

Modulates immune response to Interleukin 2 Renal cell cancer

cancer (Proleukin)

Hormones Activity against hormonally Anastrozole Breast cancer

responsive tumors (Arimidex)
Exemestane
(Aromasin)
Letrozole
(Femara)
Tamoxifen
(Nolvadex)
Inhibitors of a serine/threonine Everolimus Brain cancer
protein kinase (regulatory protein (Afinitor Breast cancer
involved in cell-cycle progression, Zortress) Pancreatic cancer
proliferation, and angiogenesis) Renal cell cancer
Temsirolimus Renal cell carcinoma
(Toricel)
Direct cytotoxicity and modulation Lenalinomide Multiple myeloma
of the immune response (alters (Revlimid)
cytokine production, regulating T
cell co stimulation and augments
the non killer cell cytotoxicity)
Table 2

Combination Chemotherapy Components Steroids

Abbreviation
A-CMF Doxorubicin, cyclophosphamide, methotrexate, 5-
fluorouracil

ABVD Bleomycin, doxorubicin, vinblastine, dacarbazine

BEP Bleomycin, etoposide, cisplatin
BEACOPP Bleomycin, etoposide, vincristine, Prednisone
cyclophosphamide, vincristine, procarbazine
CAPP Cyclophosphamide, doxorubicin, cisplatin Prednisone
CAPOX Capecitabine, oxaliplatin;
CHOP ± rituximaba Cyclosphosphamide, doxorubicin, vincristine Prednisone
CHOEP ± Cyclosphosphamide, doxorubicin, etoposide, Prednisone
rituximaba vincristine
CHOP-Bleo Cyclosphosphamide, doxorubicin, vincristine, Prednisone
bleomycin
DHAP Cisplatin, cytarabine Dexamethasone
ESHAP Cisplatin, cytarabine, etoposide Methylprednisolone
FAC 5-Fluorouracil, cyclophosphamide, doxorubicin
FEC 5-Fluorouracil, cyclophosphamide, epirubicin
FOLFIRI 5-Fluorouracil, irinotecan, leucovorin
FOLFOX 5-Fluorouracil, leucovorin, oxaliplatin
hyper-CVAD Course A: cyclophosphamide, doxorubicin, Dexamethasone
methotrexate, vincristine (± MESNA)
Course B: cytarabine, leucovorin, methotrexate
M-VAC Methotrexate, vinblastine, doxorubicin, cisplatin

R-CHOP Rituximab + CHOP

TAC Cyclophosphamide, docetaxel, doxorubicin
TCG Paclitaxel, cisplatin, gemcitabine
VAD Doxorubicin, vincristine Dexamethasone
VIM Etoposide, ifosfamide, methotrexate
VIP Etoposide, ifosfamide, cisplatin, MESNA

Table 2. Common chemotherapy regimens (Adapted with permission from Sahai SK et al. Med
Clin North Am. 2010 Mar;94(2):403-19)
Table 3

Drug Incidence Onset Duration Signs and symptoms

Busulfan 2% (cardiac 3-9 years Unknown Heart failure, palpitations,
tamponade) (endocardial cardiac tamponade,
fibrosis) pericardial effusion, EKG
changes

Cyclophospham 7- 28% in adults 1-10 days after 1-6 days Heart failure, chest pain,
ide the first dose pleural and pericardial
5% in children䚈 effusions, loss of QRS
voltage on EKG

Ifosfamide 17% Acute onset-6- 4-7 days Heart failure, pleural

23 days after effusions, ventricular
the first dose tachycardia, EKG
changes

Cisplatin Rare Within hours of Unknown Chest pain, hypotension,

completion of arrhythmias,
infusion atrioventricular block,
myocardial infarction,
ST-T changes

Methotrexate Rare Hours after Hours after Syncope, myocardial

intravenous discontinu infarction,
infusion ation supraventricular and
ventricular arrhythmias

Months after Days after

oral use discontinu
ation

5 Fluorouracil 1.2-7.6% 2-5 days into 48 hours Angina, myocardial

(ischemia) first course infarction, hypotension,
cardiogenic shock, EKG
Up to 23% changes
(arrhythmias)

Cytarabine Unknown 3-28 days Several Pericarditis, heart failure,

following hours pleural effusion
 initiation

Capecitabine 3-9% 4-17 days after Within Angina, arrhythmias,

initiation days of myocardial infarction,
stopping sudden death

Doxorubicin Acute or subacute Within a week Unknown EKG changes, sinus

Daunorubicin after䚈 a single tachycardia, arrhythmias,
20- 30% (EKG dose or a course pericarditis, myocarditis
changes)

0.5–3%
(arrhythmias)

Early onset 0-231 days Heart failure

chronic (within a year)

7%

Late onset 4-15 years after Heart failure

chronic completion

8-65%

Epirubicin Unknown 0.5-71.6 months Unknown Heart failure

Idarubicin 5-7% Unknown Unknown Heart failure,
arrhythmias, angina,
myocardial infarction

Mitoxantrone 2.2-15% Weeks Unknown Arrhythmias, heart

failure, myocardial
infarction, EKG changes

Etoposide 1-2% During the Several Hypotension, myocardial

infusion in the 䚈 hours infarction, EKG changes
first or (chest
subsequent pain)
 courses

Paclitaxel 0.5-5% Within 1 hour 48-72 h, as Sinus bradycardia, atrial

into infusion to short as 4 and ventricular
14 days hours after arrhythmias, myocardial
following discontinu infarction,
paclitaxel ation of supraventricular
therapy therapy tachycardia,
atrioventricular or left
bundle branch block

Docetaxel 2.8% During infusion Resolve Hypotension,

after dysrhythmias, unstable
infusion angina, pulmonary
discontinu edema, and hypertension
ation

Rarely Unknown Unknown Heart failure

Vinca alkaloids 25% (10% clinical Hours to 3 days 2-24 hours Myocardial infarction,
manifestations) EKG changes, atrial
fibrillation, hypertension

Bleomycin <1% Unknown Resolve Pericardititis

after Myocardial ischemia
treatment
discontinu
ation
Mitomycin C 10% After a median Unknown Heart failure
of 3 cycles

Imatinib 0.5-2.3% Months after Unknown Heart failure

therapy

Nilotinib Unknown During oral Resolves QT prolongation

therapy cycles after
therapy
discontinu
ation
Dasatinib 2-4% Unknown Unknown Heart failure
QT prolongation
Sunitinib 47% 22-435 days Resolves Hypertension
after therapy after
initiation therapy
discontinu
ation
8-28% Weeks to Heart failure
months
after
therapy
discontinu
ation
Sorafenib 19% 2-28 weeks Resolves Hypertension
after
therapy
discontinu
ation
2% Weeks to Heart failure
months Cardiac ischemia
after
therapy
discontinu
ation
Lapatinib 0.2-7.7% Median 79 days Resolves Heart failure
after treatment weeks to
initiation (9->25 months
weeks) after
therapy
discontinu
aton
Bortezomib 5% Within weeks Mostly Heart failure
of therapy reversible Cardiac arrest
initiation after Death
therapy
discontinu
ation
Vorinostat Unknown During Unknown QT prolongation
chemotherapy
cycles
Romidepsin 2-63% During Resolve at EKG changes,
chemotherapy therapy arrhythmias
cycles discontinu
ation
ATRA 25% 2 to 21 days Resolves Differentiation syndrome-
after initiation with hypotension
of treatment steroids (as well as fever,
 within 12- dyspnea, weight gain)
24h
5%
mortality
Arsenic trioxide 26-93% With the first Resolves QTc prolongation
treatment after
treatment
in most
cases, but
can persist
for months
after due to
accumulati
on in the
tissue
25-40% 2 to 21 days Resolves Differentiation syndrome-
after initiation with hypotension
of treatment steroids (as well as fever,
within 12- dyspnea, weight gain)
24h
5%
mortality
Rituximab <1% During Resolve Arrhythmias, angina
intravenous after
administration infusion
12% Death Hypertension
<0.1%
10% Hypotension
Trastuzumab 3-27% During Usually Heart failure
treatment cycles resolves 1-
3 months
after
therapy
discontinu
ation
Alemtuzumab 10% During or few Resolves Hypotension
(hypertension) days after after Arrhythmias
infusion infusion
Days to weeks May Heart failure
after therapy resolve in Hypertension
initiation days to
weeks
Cetuximab 2-3% During infusion Resolves Hypotension
after
infusion
discontinu
 ation
2-3% 23-42 days after Sudden cardiac death
therapy
initiation
Bevacizumab 4-5% During Arterial thrombosis
treatment cycles (transient ischemic
attacks, strokes, angina,
and myocardial
infarction)

1.6% Unknown May Heart failure

resolve
with
treatment
23.6% During Resolves Hypertension
treatment cycles after
therapy
discontinu
ation
Interferon alfa Up to 20% Weeks after Resolves Myocardial ischemia and
(arrhythmias) therapy (median within infarction, atrial and
5 weeks) days for ventricular arrhythmias,
arrhythmia cardiomyopathy
s, weeks to
months for
cardiomyo
pathy
Interleukin 2 100% During infusion Within Capillary leak syndrome
days after
therapy
discontinu
ation
14-21% Within days Reversible Arrhythmias, elevated
after within creatine phosphokinase
administration days of
therapy
discontinu
ation

Table 3. Cardiotoxicity of common chemotherapy agents (Adapted with permission

from Pai VB et al. Drug Saf. 2000 Apr;22(4):263-302)
Table 4

Drug class/name Arrhythmias Long QTc Systolic dysfunction Hypertension Myocardial ischemia Thromboembolism
Anthracyclines
Daunorubicin ++/+++ 䩨 + − − −
Doxorubicin +/++ 䩨 ++/+++ − − 䩨
Doxorubicin + 䩨 − − +/++/+++ −
(liposomal)
Epirubicin − 䩨 +/++ − − 䩨
Idarubicin ++/+++ 䩨 ++/+++ − − 䩨
Mitoxantrone ++/+++ 䩨 ++/+++ ++ ++ −
Alkylating agents
Cisplatin 䩨 䩨 䩨 䩨 䩨 ++
Cyclophosphamide − − 䩨 − − +
Ifosfamide 䩨 − +++ − − +
Antimicrotubule agents
Docetaxel +/++ 䩨 ++ ++ ++ 䩨
Paclitaxel ++ 䩨 + − + −
Antimetabolites
Capecitabine 䩨 䩨 䩨 − ++ +/++
5-Fluorouracil 䩨 䩨 + − ++/+++ 䩨
Hormones
Anastrozole − − − ++/+++ ++ ++
Exemestane − − − ++ ++ +
Letrozole − − − ++ ++/+++ ++
Tamoxifen − 䩨 − ++/+++ ++ ++
Monoclonal antibodies
Bevacizumab ++ 䩨 +/++ ++/+++ +/++ ++/+++
Brentuximab − − − − + ++
Cetuximab ++ 䩨 ++ 䩨 +/++
Ipilimumab − − − − − −
Panitumumab 䩨 − − ++ ++ +
Pertuzumab − − ++ − − −
Rituximab 䩨 − − ++ ++ ++/+++
Trastuzumab ++ − ++/+++ ++ − +/++
Proteasome inhibitors
Bortezomib + − +/++ + + +
Tyrosine kinase inhibitors
 Dasatinib ++/+++ +/++ ++ ++ ++ +/++
Erlotinib 䩨 − − − ++ ++
Gefitinib 䩨 䩨 − − +/++ 䩨
Imatinib − − +/++ − +++ +
Lapatinib 䩨 +++ ++ − − −
Nilotinib ++ ++ ++ ++ 䩨 +
Pazopanib − − + +++ +/++ ++
Sorafenib + 䩨 + +++ ++ ++
Sunitinib + + ++/+++ +++ ++ +/++
Miscellaneous agents
Everolimus − − ++ ++ − +
Lenalidomide +/++ + ++ ++ ++ ++/+++
Temsirolimus − 䩨 − ++ +++ ++

Table 4. Summary of common antineoplastic agents and relevant cardiotoxicities (Adapted with permission from Truong J et al. Can J
Cardiol. 2014 Aug;30(8):869-78)

+++ > 10%; ++ represents 1%-10%; + represents < 1% or rare; 䩨represents observed but precise incidence not well established; and - represents
not well recognized complication with no/minimal data.
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Figure 3