Evidence Based Management

of Cancers in India

Guidelines for
Cardio Oncology

(PART A)
Editors
Dr. Aruna Alahari Dhir, MD
Professor & Head Dept. of Medicine

Dr. Sheela P. Sawant, MD DNB

Associate Professor & Assistant Physician

Published by
Tata Memorial Centre
Mumbai
Tata Memorial Hospital
Dr. Ernest Borges Road, Parel
Mumbai 400 012. INDIA.
Tel.: +91-22-2417 7000
Fax: +91-22-2414 6937
Email: crs@tmc.gov.in
Website: http: //tmc.gov.in

Evidence Based Management of Cancers in India

Vol. XIV
Three Parts
Set ISBN: 978-93-82963-06-6
Guidelines for Modern Radiation Oncology Practice
Part A ISBN: 978-93-82963-07-3
Guidelines for Cytogenetic and Molecular Testing
in Myeloid Malignancies
Part B ISBN: 978-93-82963-08-0
Guidelines for Cardio Oncology
Part C ISBN: 978-93-82963-09-7

Published by the Tata Memorial Hospital, Mumbai

Printed at the Sundaram Art Printing Press, Mumbai
© 2015 Tata Memorial Hospital, Mumbai
All rights reserved.
 Dedicated to
all our patients at
The Tata Memorial Hospital
Contributors

Dept. of Medicine
Dr Aruna Alahari Dhir
Dr Sheela Sawant
Dr Anuprita Daddi
Dr Prakruthi J
Dept. of Paediatric Oncology
Dr Purna Kurkure
Dr Maya Prasad
DMG- Breast
Dr Ashwini Budrukkar
Dr Jaya Ghosh
Dr Lavanya G
DMG- Genitourinary
Dr Kumar Prabhash
Dr Vanita Noronha
Dr Amit Joshi
Dept. of Nuclear Medicine
Dr Venkatesh Rangrajan
Dept. of Radiology
Dr Shashikant Juvekar
DMG- Haematolymphoid Malignancies
Dr Siddartha Laskar
Dr Shirley Lewis
Contents

1. Cancer Therapy Induced Cardiotoxicity - 1

Overview
2. Anthracycline Induced Cardiotoxicty 10
3. Cardiotoxicity with HER 2 Targeted 25
Therapy
4. Tyrosine Kinase Inhibitor Induced 43
Cardiotoxicities
5. Role of Echocardiography in 57
Chemotherapy Induced Cardiotoxicity
6. Scintigraphy Techniques for Early 67
Detection of Cancer Treatment Induced
Cardio-toxicity
7. Role of Cardiac MRI in Early Detection 83
of Chemotherapy Induced Cardio toxicity
8. Role of Cardiac Biomarkers in early 91
Detection of Cardiotoxicity
9. Late Cardiotoxicity in Survivors of 105
Childhood Cancers
10. Radiation Induced Heart Disease. 130
11. Cardiac Effects of Radiation Therapy in 146
Women with Breast Cancer
Preface

This year marks the 13 th “Evidence-Based

Management” meeting at Tata Memorial Centre.
Evidence-based medicine (EBM) has been defined as
the use of current best evidence to make informed
clinical decisions for individual patients. The Tata
Memorial Centre has pioneered the concept of EBM
in oncology in India and has been conducting the
annual meeting on EBM in common cancers for the
past 12 years.
Cardio-oncology (cardiovascular care of cancer
patients) has emerged as a new discipline in clinical
medicine. The goals of anti-cancer therapies are to
prevent recurrence, prolong life, and provide cure.
Advances in cancer management has substantially
improved the prognosis of cancer patients.The
population of cancer survivors is large and growing.
However, cancer treatment-related cardiotoxicity is
the leading cause of treatment-associated mortality
in survivors of pediatric and adolescent cancers, after
recurrence and second or subsequent malignancies.
It is one of the most common post-treatment issues
among five- to ten-year survivors of adult cancer.
Surviving cancer at the cost of developing
cardiotoxicity does not seem to be the most optimal
outcome. In addition, cancer patients may receive
suboptimal therapy due to concern about potential
cardiotoxicity, resulting in increased disease
progression and mortality. The scientific knowledge
gaps on cancer treatment-related cardiotoxicity are
numerous spanning basic and clinical science.
Cardio-oncology is not limited to cardiologists, but
also includes medical oncologists, radiation
oncologists, internists ,surgical oncologists, and all
others who are interested in caring for cancer patients
with cardiac problems . The two particular challenges
that this discipline is dealing with are: number one,
to help patients with known cardiovascular disease
undergo the most aggressive forms of cancer therapy
safely; and, number two, to optimally manage
patients who develop cardiovascular disease as a
consequence of cancer therapy. Early detection of
cardiotoxicity is crucial for applying preventive and
supportive therapeutic strategies. Important issues
in the diagnosis and management of cancer therapy
induced cardiotoxicity will be discussed in this book.

R A Badwe
February 2015 Director,
Mumbai Tata Memorial Centre
Cancer Therapy Induced
Cardiotoxicity - Overview

Life expectancy after the diagnosis and treatment of cancer

has increased significantly in the past 2 decades1. Cancer
therapy induced cardiotoxicity is responsible for
considerable morbidity and mortality. Developing and
understanding optimal prevention, early detection and
treatment strategies for cancer therapy induced
cardiotoxicity is a critical aspect of cancer patient care,
and may have a significant impact on the overall prognosis
and survival of cancer patients.
A wide range of chemotherapy agents have been
associated with cardiotoxicity [Table 1]. The most frequent
cardiotoxicity is asymptomatic or symptomatic left
ventricular dysfunction2 .Other cardiotoxic effects include
hypertension 3, thromboembolic disease 4, pericardial
disease5, arrhythmias 6and myocardial ischemia7. Radiation
therapy can also lead to coronary artery disease and fibrotic
changes of the valves, pericardium and myocardium.

1
Table 1- Chemotherapy induced cardiotoxic effects2-10.

Cardiotoxic Effect Chemotherapy Agent (incidence)

Left ventricular Anthracyclines/analogues -
dysfunction Doxorubicin (3%-26%), Epirubicin
(0.9-3.3.%) Mitoxantrone(5%)
Alkylating agents-Cyclophosphamide
(7%-28%),Ifosfamide( 17%)
Antimicrotubule agents-Docetaxel
(2.3%-8%)
HER 2 inhibitor- Trastuzumab
(2%-28%),
VEGF inhibitors- Bevacizumab
(1.7%-3%), Sunitinib (2.7-11%)
Proteasome inhibitor-Bortezomib
(2-5%)
Myocardial Ischemia Pyrimidine analogue-Capecitabine
(3-9%),5 Flurouracil(1-68%)
Antimicrotubule agents- Paclitaxel
(<1%-5%),Docetaxel ( 1.7%)
Alkylating agents-Cisplatin
VEGF inhibitors-Bevacizumab
(2.3%),Erlotinib( 2.3%)
Hypertension VEGF inhibitors-Bevacizumab
(4%-35%), Sunitinib(5-47%),
Sorafenib (17-43%),Pazopanib(47%)
Hypotension Antimicrotubule agents-Paclitaxel
Etoposide

(Contd...)

2
(Contd...)
Venous Alkylating agents-Cisplatin ( 8.5%)
thromboembolism Angiogenesis inhibitors-
Thalidomide(14-26%),Lenalinomide
VEGF inhibitors-Bevacizumab(6.8-
19.9%)
Bradycardia Antimicrotubule agents- Paclitaxel
(<0.1%-31%)
Angiogenesis inhibitors-Thalidomide(
0.12-55%)
QT prolongation Arsenic trioxide (26-93%)
HER2 inhibitor-Lapatinib (15%)

Cardiac Review and Evaluation Committee proposed the

following definition of chemotherapy induced
cardiomyopathy as part of its oversight of clinical trials of
the monoclonal antibody trastuzumab 10
The diagnosis of chemotherapy induced cardiomyopathy
can be established when at least one of the following
elements is present:
1) Cardiomyopathy characterized by a decrease in
cardiac LVEF that was either global or more severe
in the septum.
2) Symptoms of congestive heart failure.
3) Associated signs of congestive heart failure,
including but not limited to S3 gallop, tachycardia,
or both.
4) Decline in LVEF of at least 5% to less than 55%
with accompanying signs or symptoms of

3
 congestive heart failure, or a decline in LVEF of at
least 10% to below 55% without accompanying
signs or symptoms.

Cardiac dysfunction can occur early (within 1 year) or late

(particularly among children). For several decades, cancer
therapy-induced cardiomyopathy was almost exclusively
associated with the use of cumulative doses of
anthracyclines, which cause permanent damage at the
cellular level. However, newer targeted therapies can
induce transient reversible myocyte dysfunction which is
unrelated to the dose used.
Antineoplastic drugs are classified as type I agents, which
cause irreversible damage, or type II, in which there is
reversible cardiac dysfunction (Table 2). Type II agents can
be used for years before signs of cardiac injury appear
and may be reintroduced after cardiac recovery with an
acceptable level of risk. Combined anticancer therapy with
class I and II agents is associated with a higher than
expected incidence of cardiac dysfunction.
Hypertension is a class effect of Vascular Endothelial
Growth Factor (VEGF) signaling pathway (VEGF) inhibitors3.
These drugs can worsen prexisting hypertension or cause
de novo hypertension to develop. HTN may be a surrogate
for the activity of VEGF inhibitors.12
Coronary vasospasm is an important effect of cancer
therapy that leads to myocardial ischemia and/or infarction.
Myocardial ischemia, and occasionally myocardial
infarction (MI) is caused by 5-fluorouracil (5-FU) and
capecitabine7 . Underlying coronary artery disease increases

4
 Table 2: Classification of Chemotherapy related cardiac dysfunction

Chemotherapy Type I Type II

related cardiac
dysfunction
Manifestation Cardiomyopathy/heart failure,
myocardial infarction, thrombosis
Diagnosis Injury marker release
Progressive contractile dysfunction
Cardiac remodelling
Temporary contractile dysfunction,
Vasospastic angina, arterial hypertension
No injury marker release
Reversible contractile dysfunction
Reversible arterial hypertension

5
Dose relation Cumulative, dose related Not dose related
Pathophysiology Cell loss(necrosis/apoptosis) Cellular dysfunction (mitochondrial/
protein dysfunction)
Drugs Anthracycline and non anthracycline HER2 inhibitors, VEGF inhibitors
analogues, alkyating agents,
pyrimidine analogue

Cancer drugs and the heart: importance and management T.M. Suter and M.S. Ewer ,Eur H J 2012
the risk of coronary artery spasm, but patients with normal
coronaries may also develop myocardial ischemia while
being treated with these drugs. Vinca alkaloids have also
been associated with the development of myocardial
ischemia13 .
Conventional chemotherapeutics, signalling inhibitors, and
endocrine cancer therapies can increase risk of venous or
arterial thromboembolism. 14 Rhythm disturbances
associated with anti-cancer treatment are typically transient
.QT prolongation is associated with arsenic trioxide and
some new drugs like vandetanib,nilotinib and
dasatinib.15,16
Late cardiovascular effects are frequently found following
radiotherapy. Pericardial disease is frequently associated
with radiotherapy, but other disorders can appear months
or years after treatment, including myocardial fibrosis and
cardiomyopathy, accelerated coronary disease, conduction
disturbances and valve dysfunction17.
All patient undergoing chemotherapy with drugs with
potential cardiovascular side effects should undergo a
detailed cardiac evaluation. Patients co morbidities should
be optimally managed both before and during treatment.
Early detection of potential cardiovascular injury, accurate
diagnosis of cardio toxic events and implementation of
appropriate monitoring plans are essential in patients with
cancer. Detection of cardiac injury is crucial since it may
facilitate early therapeutic measures
Echocardiography and multiple gated acquisition are the
non-invasive imaging tools commonly used in cancer
patients for baseline evaluation and monitoring of cardiac

6
function during cancer therapy18. These tests have limited
accuracy for risk stratification. Other methods for early
detection of cardiotoxicity have therefore been explored.
These include newer echocardiographic modalities, such
as tissue Doppler and strain techniques; cardiac MRI and
cardiac biomarkers like troponins which can detect cardiac
dysfunction earlier than conventional echocardiography19.
With modern cancer chemotherapeutics, cancer survivors
are living longer and being exposed to potential
comorbidities related to non-cancer side effects of anti
cancer treatments. There is a growing need in identifying
patients who are at risk of cardiotoxicity prior to becoming
symptomatic or developing cardiotoxicity that may
compromise anticancer treatment completion .

References
1. Jemal A,Bray F,Center MM,et al . Global cancer
statistics. CA Cancer J Clin. 2011; 61:69-90
2. Ewer MS, Ewer SM. Cardiotoxicity of anticancer
treatments:what the cardiologist needs to know. Nat
Rev Cardiol. 2010; 7 : 564-75.
3. Maitland ML, Bakris GL, Black HR, et al. Initial
assessment, surveillance, and management of blood
pressure in patients receiving vascular endothelial
growth factor signaling pathway inhibitors. J Natl
Cancer Inst 2010;102:596–604
4. Khorana AA, Francis CW, Culakova E, et al.
Thromboembolismis a leading cause of death in
cancer patients receiving outpatient chemotherapy. J
Thromb Haemost. 2007;5:632

7
5. Lestuzzi C. Neoplastic pericardial disease: old and
current strategies for diagnosis and management.
World J ardiol.2010;2:270-9.
6. Barbey JT, Soignet S. Prolongation of the QT interval
andventricular tachycardia in patients treated with
arsenic trioxidefor acute promyelocytic leukemia. Ann
Intern Med.2001;135:842-3.
7. López Medrano F, Sánchez Munoz A, Sánchez
Sánchez V, et al.Cardiotoxicity of 5-fluorouracil:
ischemia or myocardial toxicity?Rev Clin Esp.
2001;201:106-7.
8. Yeh ET, Tong AT, Lenihan DJ, et al: Cardiovascular
complications of cancer therapy: Diagnosis,
pathogenesis, and management. Circulation 2004
109:3122-3131.
9. Swain SM, Whaley FS, Ewer MS: Congestive heart
failure in patients treated with doxorubicin: A
retrospective analysis of three trials. Cancer 2003,
97:2869-2879.
10. Seidman A, Hudis C, Pierri MK, et al. Cardiac
dysfunction in the trastuzumab clinical trials
experience. J Clin Oncol.2002;20:1215-21.
11. Ewer MS, Lippman SM. Type II chemotherapy related
cardiac dysfunction: time to recognize a new entity. J
Clin Oncol. 2005 May 1~ 23(13):29002.
12. Mir O, Ropert S, Alexandre J, Goldwasser F.
Hypertension as a surrogate marker for the activity of
anti-VEGF agents. Ann Oncol 2009;20:967–970.
13. Lejonc JL et al. (1980) Myocardial infarction following
vinblastine treatment. Lancet 2: 692.

8
14. Moore RA, Adel N, Riedel E et al . High incidence of
thromboembolic events in patients treated with
cisplatin-based chemotherapy: a large retrospective
analysis. J Clin Oncol 2011;29:3466–3473.
15. Soignet SL, Frankel SR, Douer D, et al. United States
multicenter study of arsenic trioxide in relapsed acute
promyelocytic leukemia. J Clin Oncol 2001;19:3852–
3860
16. Wells SA, Gosnell JE, Gagel RF et al . Vandetanib for
the treatment of patients with locally advanced or
metastatic hereditary medullary thyroid cancer. J Clin
Oncol 2010;28:767–772
17. Yusuf SW, Sami S, Daher IN. Radiation-induced heart
disease a clinical update. Cardiol Res Pract.
2011;2011:317659.
18. Carver JR, Schuster SJ, Glick JH. Doxorubicin
cardiotoxicity in the elderly: old drugs and new
opportunities. J Clin Oncol 2008;26:3122–3124
19. Altena R, Perik PJ, van Veldhuisen DJ, et al.
Cardiovascular toxicity caused by cancer treatment:
strategies for early detection. Lancet Oncol.
2009;10:391—9.
20. Cancer drugs and the heart: importance and
management T.M. Suter and M.S. Ewer ,Eur H J 2012.

9
Anthracycline Induced
Cardiotoxicity

Anthracyclines (AC) are chemotherapeutic agents which

include naturally occurring agents derived from
Streptomyces bacteria such as doxorubicin and
daunorubicin, along with synthetic epirubicin and
idarubicin and are used in a wide range of both
hematologic and solid cancers such as lymphoma,
leukemia, and breast cancer. Cardiotoxicity is a serious side
effect of AC. Cardiac dysfunction resulting from exposure
to cancer therapeutics was first recognized in the sixties
with use of anthracyclines.

Incidence
In 2003, heart failure incidences of 5%, 16%, and 26%
were estimated for cumulative doxorubicin doses of 400,
500, and 550 mg/m2, respectively.1
A meta analysis of 55 published RCTs 2concluded that
 significantly greater risk of clinical cardiotoxicity was
found with anthracycline compared with non-
anthracycline regimens (OR 5.43 95% CI: 2.34-12.62),

10
 bolus versus continuous anthracycline infusions
(OR 4.13 95% CI: 1.75-9.72).
 Risk of clinical cardiotoxicity was significantly lower
with epirubicin versus doxorubicin (OR 0.39 95%
CI: 0.20-0.78),
 liposomal versus non-liposomal doxorubicin (OR 0.18
95% CI: 0.08-0.38) and with a concomitant
cardioprotective agent (OR 0.21 95% CI: 0.13- 0.33)

Types of Anthracycline Induced

cardiotoxicity (AIC)
AIC can be divided into acute/subacute and late/chronic:
(Table 1)
Acute/subacute cardiovascular complications can arise
any time from the initiation of therapy to several weeks
after treatment termination.
Chronic cardiotoxicity, which is typically manifested as
clinical heart failure or subclinical decline in myocardial
function, may present early, within one year after
termination of chemotherapy, or late-delayed, becoming
evident beyond one year post treatment.

Mechanisms of cardiotoxicity.
Mechanism of AIC is multifactorial. Anthracyclines induce
multiple forms of cellular injury by free radical production.
In addition, anthracyclines alter nucleic acid biology by
intercalation into DNA and modulate intracellular
signaling, leading to cell death and the disruption of
homeostatic processes such as sarcomere maintenance.
Recent data indicates that in cancer cells, doxorubicin’s
cellular target is the enzyme topoisomerase-II (Top2).3

11
 Table 1 - Types of anthracycline induced cardiotoxicity (AIC)
Type Definition. Incidence
Acute Occurs within 24 hrs <1%
Rare
ECG changes, myocardial dysfunction, pericarditis,
arrythmias
Early onset Occurs within first year after treatment 1.6-2.1%
chronic progressive Most common and clinically recognized
form of cardiotoxicity

12
Late onset chronic Can occur after 1 year upto 10-30 years 1.6-5%
progressive Seen in survivors of childhood malignancy and
other adult cancers
Doxorubicin binds both Top2 and DNA to form the ternary
Top2-doxorubicin-DNA cleavage complex, which triggers
cell death. There are two Top2 enzymes, Top2-alpha and
Top2-beta. Top2-alpha is a known marker of cellular
proliferation and over expressed in tumors but not in
quiescent tissues; it is thought to represent the molecular
basis of doxorubicin antitumor activity.4In contrast, Top2b
is present in all quiescent cells, including cardiomyocytes.
Top2 inhibition by anthracycline causes double-stranded
breaks in DNA, which can lead to cardiomyocyte death 5
AIC is irreversible and is classified as type I cardiotoxicity.
(refer chapter 1)

Risk factors for AIC

1. Cumulative dose greater than 450 mg/m2
2. Dose scheduling,time of drug infusion
Infusional administration of anthracyclines over six
hours or more may lower the incidence of
cardiotoxicity compared to bolus therapy 6. In children
infusion is not protective over bolus dose. 7
3. Mediastinal radiotherapy
Previous radiotherapy to the mediastinum has been
described as a risk factor.8,9Irradiation may increase
the susceptibility to AIC by inducing endothelial cell
damage and compromising coronary artery blood
flow. This risk of cardiotoxicity is particularly important
in women who have received prior chest wall
irradiation for left-sided breast cancer. The magnitude
of the increased risk may depend upon the
anthracycline dose.Use of other concomitant agents
such as cyclophosphamide, trastuzumab, paclitaxel,

13
 that also cause cardiotoxicity may result in synergistic
toxicity when anthracyclines are given concurrently.
4. Extremes of age(<4yrs,>70 )10
Age extremes predispose to cardiotoxicity at lower
cumulative anthracycline doses 11Children are more
susceptible to AIC, which is consistently observed at
lower cumulative doses than in adults.12
5. Underlying cardiovascular disease
In older patients, preexisting heart disease (including
hypertension) is a risk factor for AIC. However, it is
not clear whether pre-existing heart disease increases
susceptibility to anthracycline-induced damage, or
whether there is less functional reserve to tolerate
additional myocardial damage.
6. Genetic predisposition
Significant interindividual variability in susceptibility
to AIC suggests that inherited factors might influence
risk. These data require prospective confirmation.
7. Time elapsed since therapy administration
Longer duration of survival is also a risk factor for
cardiac toxicity, emphasizing the importance of
monitoring for long-term effects in the growing
population of cancer survivors.13
8. Bone marrow transplantation (BMT)
Myocardial damage can be caused by combination
of cyclophosphamide and total body radiation prior
to BMT. In BMT patients with prior anthracycline
treatment or mediastinal radiation, the risks of
developing cardiotoxicity at the time of bone marrow
transplantation are even greater.14

14
 Table 2 - Cardiovascular evaluation before
anticancer treatment with anthracyclines15
(ESMO guidlines 2012)
Baseline evaluation Evidence level
Careful clinical evaluation and IA
assessment of CV risk factors and
comorbidities (CAD & HT)
Patients should be considered at risk for IA
cardiac toxicity in case they have history
of exposure to any of the following
cumulative doses of anthracyclines as
specified below.
• Doxorubicin >500 mg/m2
• Liposomal doxorubicin >900 mg/m2
• Epirubicin >720 mg/m2
• Mitoxantrone >120 mg/m2
• Idarubicin >90 mg/m2
LVEF assessment is mandatory for basal IA
evaluation cardiac function before
potential cardiotoxic cancer
treatment (2D echo, MUGA)*
A standard 12-lead ECG,QTc should be IB
calculated (QTc =QT/”RR)
Assessment of LV diastolic function and IA
LV end diastolic diameter
Cardiac Biomarkers (troponin, BNP) IIIB
Treatment optimization of pre-existent IA
cardiopathies: Beta blockers and an
giotensin converting enzyme inhibitors
(ACE inhibitors) where appropriate,
maximize medical therapy for patients
with coronary artery disease, coronary
revascularization if clinically appropriate.

15
 Baseline evaluation Evidence level

To minimize cardiotoxicity, the use of IIIB

liposome-encapsulated doxorubicin and
the use of an appropriate cardioprotectant
regimen (as dexrazoxane, beta blockers,
ACE-inhibitors, angiotensin receptor
blockers (ARB) should be considered and
planned in all patients at high risk of
cardiotoxicity
* Echocardiography is the standard procedure for basal
assessment of cardiac structure, performance and
hemodynamics. Multiple gated acquisition (MUGA) scan can
reduce interobserver variability with the disadvantages of
including the exposure to radioactivity and the limited information
than can be obtained on cardiac structure and diastolic function.

Table 3- Monitoring during anti cancer treatment

with anthracyclines.15
Patients receiving adjuvant chemotherapy:
- Serial monitoring of cardiac function at IA
baseline, 3, 6 and 9 months during
treatment, and then at 12 and
18 months after the initiation of
treatment.
- Monitoring should be repeated during
or following treatment as clinically
indicated.
- Increased vigilance recommended for
patients >60 yrs old.
Patients treated for metastatic disease: IIA
LVEF should be monitored at baseline
and then infrequently in the absence
of symptoms

16
Assessment of cardiac function is IIB
recommended 4 and 10 years after
anthracycline therapy in patients with
cumulative dose of doxorubicin of
>240 mg/m2 or epirubicin >360 mg/m2
Performing baseline assessment of IIIB
biomarker (Troponin I or BNP)
concentrations and periodic measurements
during therapy (every each cycle) may
identify patients who need further
cardiac assessment
LVEF reduction of ≥ 15% from baseline IIB
with normal function (LVEF ≥ 50%) -
to continue anthracyclines.
LVEF decline to <50% during
anthracyclines containing regimens -
reassessment of LVEF after 3 weeks.
If confirmed, hold chemotherapy, consider
therapy for LVD* and further frequent
clinical and echocardiographic monitoring.
LVEF decline to <40%-stop chemotherapy,
discuss alternatives and treat LV systolic
dysfunction(LVSD)
Aggressive medical treatment of those
patients, even asymptomatic, who are
detected to have LVSD in 2DEcho after
anthracycline therapy is mandatory,
especially if the cancer could have a
long-term survival; it consists of ACE
inhibitors and beta blockers and the
earlier heart failure therapy is begun
(within 2 months from the end of
anthracycline therapy), the better the
therapeutic response

17
 Fig 1 - Algorithm for the management of cardiotoxicity in patients receiving anthracyclines15

18
Treatment of LV dysfunction induced by
anticancer treatment15
In patients with subclinical cardiotoxicity II A
induced by Type I agents, identified also
by increase in cardiac troponin, a treatment
with ACE inhibitors (enalapril) may prevent
LVEF reduction and associated cardiac events
Patients who develop LVD should be treated II A
with standard guideline-based HF therapy21
just as any other HF patient

PREVENTION
Identifying high-risk patient presents an opportunity for
targeted preventive measures.The development of
cardiotoxicity, even asymptomatic, negatively impacts
patients cardiac outcome and also limits their therapeutic
options ,when they present with relapse and require further
chemotherapy.Intensive monitoring of myocardial function
during treatment has been used to detect the earliest
evidence of cardiotoxicity and prevent the development
of more severe heart failure.

Recommendations
1. Limiting the cumulative dose to 450 mg/m2
2. Infusion protocols — Anthracyclines given as an
infusion over six hours or more may lower the
incidence of cardiotoxicity compared to bolus
therapy.In a meta-analysis of four randomized trials
comparing infusional versus bolus schedules of
epirubicin or doxorubicin, bolus administration
significantly increased the risk of clinical cardiotoxicity
(OR 4.13, 95% CI 1.75-9.72).16

19
3. Use of structural analogs Epirubicin,liposomal
doxyrubicin –
Use of epirubicin significantly decreased the risks of
both clinical (OR 0.39, 95% CI 0.2-0.78) and
subclinical cardiotoxicity (OR 0.30, 95% CI 0.16-
0.57)16. Maximal cumulative dose of epirubicin be
limited to 900 mg/m 2 to minimize the risk of
myocardial dysfunction.
Liposomal encapsulation of doxorubicin , modifies
pharmacokinetics and tissue distribution without
compromising antitumor efficacy. Liposomal
compared to conventional doxorubicin significantly
decreased the risk of clinical (OR 0.18, 95% CI 0.08-
0.38), and subclinical cardiotoxicity (RR 0.31, 95% CI
0.20-0.48)16.
4. Dexrazoxane
Dexrazoxane is the only FDA approved cardio-
protective agent for AIC.The American Society of
Clinical Oncology (ASCO) has published detailed
guidelines for the adjunctive use of dexrazoxane in
patients with breast cancer17 and other malignancies
and for monitoring therapy, which were updated in
2008 .
Key points from these guidelines that apply to adults
include the following:
a) Initial use of dexrazoxane in patients with
metastatic breast cancer (MBC) is not
recommended in patients receiving initial
doxorubicin-based chemotherapy
b) Dexrazoxane can be considered for patients
being treated for MBC who have received a

20
 cumulative dose of doxorubicin e”300 mg/
m 2 and may benefit from continued
treatment.Patients receiving dexrazoxane with an
anthracycline require continued close
monitoring. Anthracycline treatment should be
discontinued if there is a decline in LVEF to below
institutional normal limits or evidence of clinical
heart failure.
c) The use of dexrazoxane in patients with breast
cancer in the adjuvant setting is not suggested
outside a clinical trial.
d) In adult patients with other malignancies use of
dexrazoxane can be considered in those who
have received more than 300 mg/m 2 of
doxorubicin-based therapy; caution should be
exercised in the use of dexrazoxane in settings in
which doxorubicin-based therapy has been
shown to improve survival .
e) There is insufficient evidence to make a
recommendation for the use of dexrazoxane in
the treatment of pediatric malignancies.
f) Guidelines are not available for dexrazoxane use
in patients with cardiac risk factors.
5. Role of beta-blockers, ACE inhibitors, or ARBs in
primary prevention-
In a small single-center prospective study, angiotensin-
converting-enzyme inhibitor have been shown to
prevent a decline in LV ejection fraction and cardiac
events in cancer patients treated with high-dose
anthracyclines.19 At present role of beta-blockers, ACE
inhibitors, or ARBs for primary prevention is

21
 uncertain.Despite the lack of data in high-risk patients
(elderly, hypertension, receiving doxorubicin doses
≥ 50 mg/m2 per cycle, concurrent trastuzumab)
some authors suggest use of beta blocker such as
carvedilol before starting therapy (Grade 2C).20

References:
1. Swain SM, et al ,Congestive heart failure in patients
treated with doxorubicin:a retrospective analysis of
three trials. Cancer 2003;97:2869–79.
2. Lesley A Smith, et al,Cardiotoxicity of anthracycline
agents for the treatment of cancer: Systematic review
and meta-analysis of randomised controlled trials
3. Tewey KM, Rowe TC, Yang L, et al. Adriamycin-induced
DNA damage mediated by mammalian DNA
topoisomerase II. Science 1984; 226:466.
4. Lyu YL, Lin CP, et al. Role of topoisomerase IIbeta in
the expression of developmentally regulated genes.
Mol Cell Biol 2006; 26:7929.
5. Zhang S, et al. Identificationof the molecular basis of
doxorubicininducedcardiotoxicity. Nat Med
2012;18:1639–42.
6 Smith LA, , et al. Cardiotoxicity of anthracycline agents
for the treatment of cancer: systematic review and
meta-analysis of randomised controlled trials. BMC
Cancer 2010; 10:337.
7. Lipshultz SE, Miller TL, , et al Continuous versus bolus
infusion of doxorubicin in children with ALL: long-
term cardiac outcomes.Pediatrics 2012;130:1003–11.
8. Bristow MR, Mason JW, , et al: Doxorubicin
cardiomyopathy: Evaluation by phonocardiography,

22
 endomyocardial biopsy and cardiac catheterization.
Ann Intern Med 88:168-175, 1978
9. Billingham ME, Bristow MR, Glatstein E, et al:
Adriamycin cardiotoxicity: Endomyocardial biopsy
evidence of enhancement by irradiation. Am J Surg
Pathol 1:17-23, 1977
10. Von Hoff DD, Layard MW, Basa P et al. Risk factors
for doxorubicin-induced congestive heart failure. Ann
Intern Med 1979;91:710–17.
11. Swain SM, Whaley FS, Ewer MS. Congestive heart
failure in patients treated with doxorubicin: a
retrospective analysis of three trials. Cancer 2003;
97:2869.
12. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac
effects of doxorubicin therapy for acute lymphoblastic
leukemia in childhood. N Engl J Med 1991; 324:808.
13. Carver JR, Shapiro CL, Ng A, et al. American Society
of Clinical Oncology clinical evidence review on the
ongoing care of adult cancer survivors: cardiac and
pulmonary late effects. J Clin Oncol 2007; 25:3991
14. Armenian SH, Sun CL, Francisco L, et al. Late
congestive heart failure after hematopoietic cell
transplantation. J Clin Oncol 2008; 26:5537.
15. G. Curigliano, D. Cardinale, T. Suter, etal. Cardio-
vascular toxicity induced by chemotherapy, targeted
agents and radiotherapy: ESMO Clinical Practice
Guidelines Annals of Oncology 23 (Supplement 7): :
vii155–vii166, 2012
16. Smith LA, Cornelius VR, Plummer CJ, et al.
Cardiotoxicity of anthracycline agents for the
treatment of cancer: systematic review and meta-

23
 analysis of randomised controlled trials. BMC Cancer
2010; 10:337.
17. Hensley ML, Hagerty KL, Kewalramani T, et al.
American Society of Clinical Oncology 2008 clinical
practice guideline update: use of chemotherapy and
radiation therapy protectants. J Clin Oncol 2009;
27:127.
18. Kalay N, Basar E, Ozdogru I, et al. Protective effects
of carvedilol against anthracycline-induced
cardiomyopathy. J Am Coll Cardiol 2006; 48:2258.
19. Cardinale D, Colombo A, Sandri MT, et al. Prevention
of high-dose chemotherapy-induced cardiotoxicity in
high-risk patients by angiotensin-converting enzyme
inhibition. Circulation 2006; 114:2474.
20. Floyd J, Morgan J P et al .(2014) Cardiotoxicity of
anthracycline-like chemotherapy agents. UpToDate.
21. Clyde W. Yancy et al . 2013 ACCF/AHA Guideline for
the Management of Heart Failure: A Report of the
American College of Cardiology foundation/American
Heart Association Task Force on Practice guidelines .
Circulation 2013

24
Cardiotoxicity with HER 2
Targeted Therapy

HER2 is a member of the human epidermal growth factor

receptor (HER/EGFR/ERBB2) family. Amplification or
overexpression of HER2 has been shown to play an
important role in the development and progression of
certain aggressive types of breast cancer. In recent years
the protein has become an important biomarker and
target of therapy for approximately 30% of breast
cancer patients. HER2 are transmembrane receptors; they
have an extracellular binding component, a
transmembrane component and an intracellular tyrosine
kinase component. HER2 inhibitors are either tyrosine
kinase inhibitors or monoclonal antibodies that slow down
or stop cell growth.
Trastuzumab is a humanized IgG1 kappa monoclonal
antibody that selectively binds with high affinity to
the extracellular domain of HER2.Trastuzumab improves
survival in patients with metastatic breast cancer and
prolongs disease-free survival and overall survival in
patients with early-stage breast cancer (1,2). Trastuzumab
is also used in treatment of some HER2 overexpressing

25
metastatic gastric and gastroesophageal junction
adenocarcinomas. Cardiac dysfunction due to trastuzumab
has been reported particularly with concurrent
anthracyclines (1). Cardiac dysfunction of trastuzumab is
typically manifested by an asymptomatic decrease in left
ventricular ejection fraction and sometimes by clinical heart
failure. Lapatinib, a dual kinase inhibitor of HER2 and EGFR,
and pertuzumab, a newer anti-HER2 monoclonal antibody
that recognizes an epitope distant from that of
trastuzumab, appear to be only rarely associated with
clinically-relevant cardiotoxicity.

TRASTUZUMAB CARDIOTOXICITY
Cardiac Review and Evaluation Committee criteria for the
diagnosis of cardiac Dysfunction(3).
1. Cardiomyopathy characterized by a decrease in LVEF
or changes of contraction most apparent in the
interventricular septum
2. Heart failure symptoms
3. Signs associated with heart failure
4. Decline in initial LVEF of at least 5% to less than 55%
with signs and symptoms of heart failure or
asymptomatic decrease in LVEF of at least 10% to
less than 55%
Incidence-
In the initial trials of trastuzumab in metastatic breast
cancer, the incidence of cardiac toxicity was variable, with
rates for patients who received trastuzumab alone,
trastuzumab and paclitaxel, and trastuzumab plus an
anthracycline and cyclophosphamide of 3 to 7, 13, and
27 percent, respectively (1,3).
26
Individual studies and meta-analysis have been undertaken
to assess risk-benefit analysis, especially in patients with
low-risk disease(4-6). In 2012 Cochrane review, Moja et al
summarized findings from eight major randomized clinical
trials that evaluated the efficacy of trastuzumab for patients
with early and locally advanced breast cancer, including
the B31, BCIRG006, Buzdar, FinHer, HERA, N9831, NOAH,
and PACS-04 trials (4). It included 11,991 women ; 7,020
women were exposed to a trastuzumab-containing
regimen and 4,971 women to a treatment without
trastuzumab. The relative risk of developing congestive
heart failure (CHF), and LVEF decline was 5.11 (90% CI
3.00 to 8.72, P < 0.00001) and 1.83 (90% CI 1.36 to
2.47, P = 0.0008) respectively. The absolute numbers were
135 cases (2.5%) of CHF out of 5471 patients in the
trastuzumab group and 20 cases (0.4%) out of 4810 in
the control group.

Risk factors for trastuzumab cardiotoxicity

(1,7-11)
- previous or concurrent anthracycline use, especially
if the cumulative doxorubicin dose is >300 mg/m2
- age greater than 50 years
- preexisting cardiac dysfunction (ie, decreased LVEF),
- high body mass index,
- antihypertensive therapy
(Concurrent treatment with trastuzumab and adjuvant
radiation therapy, diabetes, valvular heart disease, and
coronary artery disease does not significantly increase risk.)

27
Mechanisms of HER2 inhibitor cardiotoxicity-
In animal models, HER2 signaling is important for
embryonic cardiac development and myocyte survival as
well as protection from potential cardiotoxins (13).
Evidence from both in vivo and in vitro studies indicate
the importance of the epidermal growth factor signaling
system in the normal heart and suggest that cardiotoxicity
associated with trastuzumab is directly related to HER2
blockade (12). Cardiotoxicity caused by trastuzumab is
most likely secondary to inhibition of cardiomyocyte human
ErbB2 signaling, thereby interfering with normal growth,
repair, and survival of cardiomyocytes (14,15). In response
to oxidative stress, neuregulin activates compensatory
mechanisms via HER2 receptors; in the presence of
trastuzumab, HER2/HER2 and HER2/HER4 dimers are
blocked and the compensatory mechanisms are
inactivated, leading to apoptosis and heart failure(16).
There may also be a mechanism of cardiotoxicity
independent of ErbB2 signaling, since both lapatinib and
trastuzumab inhibit ErbB2, but with different incidences
of HF. Other mechanisms include drug– drug interactions,
effect on cardiac stem cells and immune-mediated
destruction of cardiomyocytes (17,18).The mechanism
underlying the synergistic cardiotoxicity seen with
anthracyclines and trastuzumab is unclear, but
upregulation of HER2 expression by anthracyclines may
contribute. (19)

Clinical presentation
Trastuzumab-induced cardiotoxicity presents with a range
of severity from asymptomatic decline in left ventricular
ejection fraction (LVEF) to symptomatic heart failure(20)
and does not appear to be related to either dose or
duration (21).Withdrawal or discontinuation of the drug

28
can reverse the effects with the support of standard
treatment for heart failure (22), including initiation of
β blockers and angiotensin-converting enzyme inhibitors
(ACEIs) (23). This has led to the classification of
trastuzumab-related cardiac dysfunction as Type II
chemotherapy related cardiac dysfunction, as opposed to
the irreversible changes associated with anthracyclines
(Type I chemotherapy related cardiac dysfunction )(22).
Rechallenge with trastuzumab following discontinuation
of trastuzumab and treatment of cardiac symptoms has
been reported to be well-tolerated (22)

Baseline Evaluation and Monitoring

When trastuzumab therapy is planned for patients in the
adjuvant or metastatic setting, the patient’s risk for
trastuzumab-related cardiotoxicity should be carefully
assessed 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. In the metastatic setting, the decision is
more complex, given the clinical benefit provided by
trastuzumab The United Kingdom National Cancer
Research Institute guidelines (Jones et al 2010)(26) and
the European Society for Medical Oncology guidelines
(Curigliano et al 2012)(25), are the recent guidelines
regarding the cardiac monitoring of patients proposed to
receive trastuzumab

Pretreatment baseline evaluation –

Patients receiving chemotherapy may be considered to be
at increased risk of developing cardiac dysfunction – Stage
A heart failure in ACC/AHA guidelines (24).

29
Cardiovascular evaluation before anticancer
treatment with potential nonreversible (Type I)
or reversible (type II) cardiotoxicity (25).
Baseline evaluation Level of
recommendation
Careful clinical evaluation and IA
assessment of cardiovascular risk factors
and comorbidities(coronary artery
disease and hypertension)
Patients should be considered at risk for IA
cardiac toxicity in case they have history
of exposure to any of the following
cumulative doses of anthracyclines as
specified below.*
• Doxorubicin >500 mg/m2
• Liposomal doxorubicin >900 mg/m2
• Epirubicin >720 mg/m2
• Mitoxantrone >120 mg/m2
• Idarubicin >90 mg/m2
LVEF assessment is mandatory for IA
baseline of evaluation of cardiac function
before potential cardiotoxic cancer
treatment
Echocardiography is the standard IA
procedure for basal assessment of
cardiac structure, performance and
hemodynamics **
A standard 12-lead ECG IB

30
 Baseline evaluation Level of
recommendation
Echocardiography
2D or 3D images to be obtained in the IA
left ventricular parasternal long- and
short-axis views and in the apical four-
and two-chamber long-axis views.
Assessment of diastolic function,
by (E/A ratio, the deceleration time of
the early peak flow,isovolumic
relaxation time
Left ventricular end-diastolic diameter
to be measured for LV dilatation
Treatment optimization of pre-existent IA
cardiopathies: Beta Blockers and
ACE inhibitors where appropriate,
maximize medical therapy for patients
with coronary artery disease, coronary
revascularization if clinically appropriate
* Some patients may have a significant decrease in LVEF after
anthracyclines.These patients are not eligible to commence
trastuzumab and should be started on an ACE inhibitor and
referred to a cardiologist. Repeat assessment of cardiac
function should take place after 3 months(26)
** Multiple gated acquisition (MUGA) scan can reduce
interobserver variability with the disadvantages of including
the exposure to radioactivity and the limited information
than can be obtained on cardiac structure and diastolic
function. Magnetic resonance imaging (MRI) is another
method used to evaluate myocardial function. Its spatial
resolution is higher than that of echocardiography, but its
temporal resolution is lower.

31
Cardiac monitoring during and after treatment:
There is variation in the recommended frequency of
monitoring cardiac function during adjuvant treatment in
different guidelines (25,).

ESMO guidelines(25)
Adjuvant treatment-
Serial monitoring of cardiac function at baseline, 3, 6
and 9 months during treatment, and then at 12 and
18 months after the initiation of treatment.
Monitoring should be repeated during or following
treatment as clinically indicated.
Increased vigilance is recommended for patients >60
years old.
Patients treated for metastatic disease –
LVEF should be monitored at baseline and then
infrequently in the absence of symptoms, IIA (25).

Updated United Kingdom National Cancer

Research Institute recommendations for early and
metastatic breast cancer (26)
Routine LVEF monitoring is recommended at baseline
and 4 and 8 months. A further assessment at the end
of treatment is recommended for patients requiring
cardiovascular intervention during treatment

Role of biomarkers in monitoring -Cardiac biomarkers such

as the troponins and brain natriuretic peptides (BNP), and
neutrophil glucosaminidase associated lipocalin as a
marker of renal injury, may be expected to be elevated

32
with significant cardiotoxicity. The NCCTG N9831 adjuvant
trastuzumab trial included the measurement of eight
cardiac biomarkers, including Tn and BNP, and an
assessment of their relationship with EF(27). Cardinale et
al identified a subgroup of patients treated with
trastuzumab who exhibit elevations in serum TnI who were
more likely to develop trastuzumab cardiotoxicity and less
likely to recover, even when treated for cardiac
dysfunction(28). Although it is not yet established whether
their routine monitoring is useful in predicting
cardiotoxicity, and this needs to be examined in future
studies(25).

Management of trastuzumab cardiotoxicity(25)

Patients who have received both anthracyclines and anti-
HER2 agents who develop cardiac failure should be treated
and monitored as patients with an irreversible cardiac
toxicity. Those who develop cardiac dysfunction during or
following treatment with type II agents in the absence of
anthracyclines can be observed if they remain
asymptomatic and LVEF remains >40%.
Management of trastuzumab-related cardiotoxicity has
two distinct aspects: withdrawal of trastuzumab therapy
and treatment of cardiac dysfunction. The ‘stopping/
restarting’ rules, recommendations for a cardiology consult
or treatment of cardiac dysfunction (or both) are shown
in fig 1.(25)

33
 Fig 1- algorithm for continuation and discontinuation of trastuzumab based on LVEF assessments.
(ESMO guidelines 2012)

34
Treatment of Trastuzumab induced LV
dysfunction-
ESMO has made the following recommendations(25)
Symptomatic LVD must be treated with HF treatment:
• All patients with HF and an LVEF <40% should be
treated with an ACE-I in combination with a beta
blocker (BB) unless a specific contraindication exists
[I, A].
• To prevent further degradation of LVEF or the
development of clinical HF, an ACE-I should be
considered if the patient’s LVEF is between 40%
and 50%.
Asymptomatic LVD should be treated:
• ACE-Is should be used in all asymptomatic patients
with LVD and an ejection fraction <40% [IA for
ejection fraction <35%; IB for ejection fraction
35%–40%].
• Also, an ACE-I should be considered if LVEF is
<50%.
• BB should be considered in all patients with
asymptomatic LVD and an LVEF <40% [if prior
myocardial infarction I, B; if no myocardial
infarction II, C].
Prevention of trastuzumab cardiotoxicity:
There is ongoing research to assess the use of ARBs, BB,
or their combination to prevent the development of left
ventricular dysfunction in patients receiving standard
adjuvant treatment for early breast cancer.Currently there
are no recommendations for prevention of trastuzumab
cardiotoxicity.

35
Novel HER2-targeted therapies
LAPATINIB
Lapatinib, an oral dual kinase inhibitor of epidermal growth
factor receptor (EGFR) and HER2. In a pooled analysis of
3689 patients enrolled in clinical trials only 60 (1.6 percent)
patients exposed to lapatinib had a cardiac event; 53 were
asymptomatic declines in LVEF and seven (0.2 percent)
had symptoms of a decline in cardiac function.Out of 552
patients previously treated with anthracyclines, 12 (2.2
percent) had a decreased LVEF while on lapatinib and 14
(1.7 percent) of the 826 patients previously exposed to
trastuzumab. The decrease in LVEF was rarely severe; the
mean nadir was 43 percent. 88 percent had partial or full
recovery regardless of whether or not lapatinib was
continued (29).
Guidelines for management — The FDA-approved
manufacturer’s package insert recommends that a normal
LVEF be confirmed prior to starting treatment with lapatinib
and periodically during treatment. They advise
discontinuation of lapatinib for a drop in the LVEF to <50
percent, and for any patients who develop clinical heart
failure during therapy(23)]. Dose reduction is
recommended if the LVEF recovers to normal after a
minimum of two weeks and the patient is asymptomatic.
ADO-TRASTUZUMAB EMTANSINE — Ado-trastuzumab
emtansine (also known as T-DM1) is an antibody-drug
conjugate composed of trastuzumab, a thioether linker,
and a derivative of the antimitotic agent, maytansine
Guidelines for management — The US FDA-approved
prescribing information recommends that all patients
treated with T-DM1 have LVEF assessed at treatment
36
initiation and at regular intervals (eg, every three months)
during treatment (31). At least temporary discontinuation
of therapy is recommended if the LVEF falls to <40 percent
or is 40 to 45 percent with a ≥10 percent absolute decrease
below the pretreatment value.
PERTUZUMAB — Pertuzumab is a monoclonal antibody
that binds to a different epitope of the HER2 extracellular
domain than trastuzumab, and it prevents HER2 homo-
and heterodimerization with other HER-family receptors
The phase III Cleopatra trial randomly assigned 808 patients
with HER2-positive breast cancer to first-line treatment
with trastuzumab and docetaxel plus either pertuzumab
or placebo (32). Combined therapy with pertuzumab and
trastuzumab was not associated with significantly worse
cardiotoxicity. Among patients in whom LVEF was assessed
after the baseline assessment, a decline of ≥10% that
resulted in a LVEF of <50 percent occurred in 3.8 percent
of the pertuzumab group versus 6.6 percent of the control
group. Notably, 72 percent of patients on the placebo
arm and 87 percent of those on the pertuzumab arm
recovered to a value of ≥50 percent.
Guidelines for management — The US FDA-approved
prescribing information recommends that all patients
treated with pertuzumab have LVEF assessed at treatment
initiation and at regular intervals (eg, every three months
in the metastatic setting and every 6 weeks in the
neoadjuvant setting) during treatment. If LVEF is <45
percent, or is 45 to 49 percent with a ≥10 percent absolute
decrease below the pretreatment value, withhold both
pertuzumab and trastuzumab and repeat LVEF assessment
within approximately 3 weeks. Discontinue pertuzumab
and trastuzumab if the LVEF has not improved or has

37
declined further, unless the benefits for the individual
patient outweigh the risks.

References
1. Slamon DJ, Leyland-Jones B, Shak S, et al:Use of
chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overexpresses
HER2. N Engl J Med 344:783-792,2001.
2. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et
al: Trastuzumab after adjuvant chemotherapy in HER2-
positive breast cancer. N Engl J Med 353:1659-1672,
2005.
3. Seidman A, Hudis C, Pierri MK, et al. Cardiac
dysfunction in the trastuzumab clinical trials
experience. J Clin Oncol 2002; 20:1215.
4. Moja L, Tagliabue L, Balduzzi S, Parmelli E et al.
Trastuzumab containing regimens for early breast
cancer. Cochrane Database of Systematic Reviews.
2012. 4: p. CD006243.
5. Chen T, Xu T, Li Y, Liang C, Chen J et al. (2011). Risk of
cardiac dysfunction with trastuzumab in breast cancer
patients: a meta-analysis. Cancer treatment reviews,
37(4), 312-320.
6. Romond EH, Jeong J-H, Rastogi P, Swain SM et al:
Seven-year follow-up assessment of cardiac function
in NSABP B-31, a randomized trial comparing
doxorubicin and cyclophosphamide followed 25by
paclitaxel (ACP) with ACP plus trastuzumab as
adjuvant therapy for patients with node-positive,
human epidermal growth factor receptor 2–positive
breast cancer. J Clin Oncol 2012;30:3792-3799

38
7. Chen J, Long JB, Hurria A, Owusu C, Steingart RM,
Gross CP.Incidence of heart failure or cardiomyopathy
after adjuvant trastuzumab therapy for breast cancer.J
Am Coll Cardiol. 2012;60(24):2504.
8. Russell SD, Blackwell KL, Lawrence J, Pippen JE Jr, Roe
MT, Wood F, Paton V, Holmgren E, Mahaffey KW.
Independent adjudication of symptomatic heart
failure with the use of doxorubicin and
cyclophosphamide followed by trastuzumab adjuvant
therapy: a combined review of cardiac data from the
National Surgical Adjuvant breast and Bowel Project
B-31 and the North Central Cancer Treatment Group
N9831 clinical trials. J Clin Oncol. 2010;28(21):3416.
9. Rastogi P, Jeong J, Geyer CE, et al. Five-year update of
cardiac dysfunction on NSABP B-31, a randomized
trial of sequential doxorubicin/cyclophosphamide
(AC)-paclitaxel compared to AC-T with trastuzumab
(abstract). J Clin Oncol 2007; 25:6s.
10. Halyard MY, Pisansky TM, Dueck AC, et al.
Radiotherapy and adjuvant trastuzumab in operable
breast cancer: tolerability and adverse event data from
the NCCTG Phase III Trial N9831. J Clin Oncol 2009;
27:2638.
11. Smith I, Procter M, Gelber RD, et al. 2-year follow-up
of trastuzumab after adjuvant chemotherapy in HER2-
positive breast cancer: a randomised controlled trial.
Lancet 2007; 369:29.
12. Cote GM, Sawyer DB, Chabner BA.ERBB2 inhibition
and heart failure.N Engl J Med. 2012 ;367(22):
2150-3.
13. Mackey JR, Kaufman B, Clemens M, et al. Trastuzumab
prolongs progression-free survival in hormone-
dependent and HER2-positive metastatic breast

39
 cancer (abstract). Data presented at the 29th annual
San Antonio Breast Cancer Symposium, December 14,
2006.
14. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in
the prevention of dilated cardiomyopathy. Nature
Medicine 2002;8:459–65.
15. Guglin M, Cutro R, Mishkin JD. Trastuzumab-induced
cardiomyopathy. Journal of Cardiac Failure
2008;14:437–44.
16. Lemmens K, Doggen K, de Keulenaer GW. Role of
neuregulin-1/ErbB signaling in cardiovascular
physiology and disease: implications for therapy of
heart failure. Circulation.j2007;116:954—60.
17. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus
capecitabine for HER2-positive advanced breast
cancer. N EnglJ Med. 2006;355:2733—43.
18. Sliwkowski MX, Lofgren JA, Lewis GD, et al.
Nonclinical studies addressing the mechanism of
action of trastuzumab (herceptin).Semin Oncol.
1999;26:60—70.
19. Chien KR. Herceptin and the heart—a molecular
modifier of cardiac failure. N Engl J Med.
2006;354(8):789.
20. Chien AJ, Rugo HS. The cardiac safety of trastuzumab
in the treatment of breast cancer. Expert Opin Drug
Saf. 2010 Mar;9(2):335-46.
21. Tripathy D, Slamon DJ, Cobleigh M, Arnold
A, Saleh M, Mortimer JE, Murphy M, Stewart SJ.
Safety of treatment of metastatic breast cancer with
trastuzumab beyond disease progression. J Clin
Oncol. 2004 Mar 15;22(6):1063-70.

40
22. Ewer MS, Lippman SM. Type II chemotherapy-related
cardiac dysfunction: time to recognize a new entity. J
Clin Oncol 2005; 23:2900.
23. Perez, E. and Morgan, J. (2013) Cardiotoxicity of
trastuzumab and other HER2-targeted
agents. UpToDate.
24. Bonow RO, Bennett S, Casey Jr DE, Ganiats TG, Hlatky
MA, Konstam MA,Lambrew CT, Normand S-LT, Pina
IL, Radford MJ, Smith AL, Warner Stevenson L (2005)
ACC/AHA Clinical Performance Measures for Adults
with Chronic Heart Failure: a report of the American
College of Cardiology/American Heart Association Task
Force on Performance Measures (Writing Committee
to Develop Heart Failure Clinical Performance
Measures): endorsed by the Heart Failure Society of
America. Circulation 112: 1853–1887
25. Curigliano, D. Cardinale, T. Suter, etal. Cardiovascular
toxicity induced by chemotherapy,targeted agents and
radiotherapy: ESMO Clinical Practice Guidelines Annals
of Oncology 23 (Supplement 7): : vii155–vii166, 2012
26. Jones AL, Barlow M, Barrett-Lee PJ et al. Management
of cardiac health in trastuzumab-treated patients with
breast cancer: updated United Kingdom National
Cancer Research Institute recommendations for
monitoring. Br J Cancer. 2009; 100: 684–692.
27. Kutteh LA, Hobday T, Jaffe A, LaPlant B, Hillman D,
Kaufman P et al, North Central Cancer Treatment
Group. A correlativestudy of cardiac biomarkers and
left ventricular ejection fraction (LVEF) from N9831,
a phase III randomized trial of chemotherapy and
trastuzumab as adjuvant therapy for HER2-positive
breast cancer. J Clin Oncol 2007;25(suppl 18S):579.
41
28. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli
M, Salvatici M, Lamantia G, Colombo N, Cortinovis S,
Dessanai MA, Nole‘ F, Veglia F, Cipolla CM.
Trastuzumab-induced cardiotoxicity: clinical and
prognostic implications of troponin I evaluation. J Clin
Oncol 2010;28:3910–3916.
29. Perez EA, Koehler M, Byrne J, et al. Cardiac safety
of lapatinib: pooled analysis of 3689 patients enrolled
in clinical trials. Mayo Clin Proc 2008;83:679-686.
30. US Food and Drug Administration (FDA)-approved
prescribing information for trastuzumab emtansine
available at http://www.accessdata.fda.gov/
drugsatfda_docs
31. Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes
J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez
EA Phase II randomized study of trastuzumab
emtansine versus trastuzumab plus docetaxel in
patients with human epidermal growth factor
receptor 2-positive metastatic breast cancer. J Clin
Oncol. 2013;31(9):1157
32. Baselga J, Gelmon KA, Verma S, Wardley A, Conte P,
Miles D, Bianchi G, Cortes J, McNally VA, Ross GA,
Fumoleau P, Gianni L Phase II trial of pertuzumab and
trastuzumab in patients with human epidermal
growth factor receptor 2-positive metastatic breast
cancer that progressed during prior trastuzumab
therapy. J Clin Oncol. 2010 Mar;28(7):1138-44.

42
Tyrosine Kinase Inhibitor Induced
Cardiotoxicities

INTRODUCTION
Cancer treatment has made significant advances in recent
years with the development of targeted therapies which
has substantially improved the prognosis of cancer
patients. Tyrosine kinases (TK) are proteins which on
activation phosphorylates key structures in the cell.
Mutations of TK in cancer cells leads to increased cell
proliferation, angiogenesis and inhibition of apoptosis
which ultimately transforms normal cells into malignant
subtype. Tyrosine kinase inhibitors (TKIs) are the drug which
acts by inhibiting the kinase activity. This targeted approach
by inhibition of tyrosine kinase activity, has significantly
changed the management and subsequently outcome of
chronic myeloid leukemia (CML), gastrointestinal stromal
tumor (GIST), colon cancer, breast cancer and renal cell
carcinoma (RCC)1,2,3. Principal behind the use of targeted
therapy is to improve the outcome of cancer treatment
without increasing the toxicities which is common with
use of conventional chemotherapies. TKIs inhibit tyrosine

43
kinase in both cancerous and noncancerous cells. Inhibition
of tyrosine kinase in normal cells particularly in skin and
GI mucosa leads to the usual side effects of skin rash and
diarrhoea. Several recent studies have also revealed some
unanticipated cardiac side effects of targeted therapies
which include hypertension, left ventricular (LV)
dysfunction, acute coronary syndrome, symptomatic heart
failure and prolongation of QTc interval4,5. Cardiac toxicities
of TKIs are less frequent but it is more serious and it is
difficult to diagnose at initial stages of treatment.
Different TKIs exert varying degree of toxicity on the cardio-
myocytes. Cardio toxicity of TKIs does not correlate with
expression of tyrosine kinase on cardio-myocytes. Functions
of the specific TK when inhibited by TKIs seems to be the
determining factor for developing cardio toxicity.

INCIDENCE
Dasatinib: Reported incidence of heart failure with
dasatinib therapy ranges from 2% to 4%.However Grade
3 or 4 HF occurred only in up to 2% of patients6.
Lapatinib: In a pooled analysis of 3689 patients enrolled
for various phase I to III trials in breast cancer patients7,
60 (1.6%) experienced a cardiac event in which 53 patients
(1.4%) had asymptomatic cardiac events and 7(0.2%)
patients had symptomatic events.
Imatinib mesylate: In a retrospective review of clinical trials
conducted by Novartis showed that incidence of HF was
0.5% in patients treated with imatinib monotherapy8.
Similarly patients received Imatinib at MDACC in various
trials showed HF incidence of 1.7%9.

44
Sunitinib: Clinical trials involving patients with
gastrointestinal stromal tumor and metastatic renal cell
cancer have shown LVD (left ventricular dysfunction) in
range between 4% to 11% of patients10. Chu et al11
retrospectively reviewed all cardiovascular events in
imatinib resistant metastatic gastrointestinal stromal tumor
patients receiving sunitinib for there disease and found
that 11% had a cardiac event, with 8% having New York
Heart Association functional class III to IV HF. In another
retrospective review in RCC patients which showed that
2.7% sunitinib-treated patients developed HF10.
Sorafenib: Sorafenib can cause acute coronary symptoms
including myocardial infarction in 2.9% of patients12.
Hypertension was observed in 5 to 11% of the treated
patients in four phase I trials of sorafinib in various
malignancies13 . Escudier et al in their study reported
hypertension in 17% of the patients14.
Gefitinib and Erlotinib : No increased cardiovascular
toxicities has been reported with the use of these agents
in treatment of lung cancer.

PATHOPHYSIOLOGY
Based on their study, Suter and Ewer15 have proposed a
system to identify drugs leading to cardiac damage. Type
I are the drugs that have the potential to cause irreversible
damage and includes conventional chemotherapeutic
agents while type II are drugs that predominantly induce
reversible dysfunction and comprises of monoclonal
antibodies and TKIs and can be used for prolonged times
before signs and symptoms of cardiac injury appears and
can be rechallenged after improvement in cardiac function
with acceptable risk.
45
 Table-1 TKI Cardiotoxicity
Agent Targets Indications Cardiac toxicity
Imatinib Bcr-Abl, c-kit, CML, PhALL, CHF, LVEF
PDGFR-a GIST depression
and b
Dasatinib Bcr-Abl, c-kit, CML QT prolongation,
PDGFR-aandb, Peripheral
Src Family oedema,
pericardial
effusion
Nilotinib Bcr-Abl, c-kit, CML QT prolongation
PDGFR-a
and b
Sunitinib VEGFR 1-3, RCC, GIST Hypertension,
RET, PDGFR-a LVEF
and b, c-kit, depression, CHF,
FLT3, CSF1R MI
Sorafenib VEGFR 2&3, RCC, HCC Acute coronary
c-kit, PDGFR b, syndrome, MI,
FLT3, RAF1, Hypertension
BRAF
Lapatinib EGFR, ERBB2 Breast Ca Asymptomatic
LVEF depression

Following are probable mechanisms leading to cardiac

injury by use of TKIs:
1. Mitochondrial toxicity
2. Inhibition of AMP-Activated Protein Kinase
3. PDGFR Inhibition
4. Effects of Kinase Inhibitors on the Vasculature

46
5. Ion Channel Inhibition
6. Interactions with Adenosine Receptors

DIAGNOSIS
Left ventricular dysfunction (LVD), heart failure and
prolongation of QTc are the most common manifestations
of cardio toxicity seen after the use of TKIs.
The definition of LVD has been laid down by the Cardiac
Review and Evaluation Committee supervising trastuzumab
clinical trial (Table-1)17.
Table-3 Criteria to confirm or revise a preliminary
diagnosis of cardiac dysfunction.
(1) Cardiomyopathy characterized by a decrease in LVEF that
was either global or more severe in the septum
(2) Symptoms of CHF
(3) Associated signs of CHF, including S3 gallop, tachycardia,
or both
(4) Decline in LVEF of at least 5% to less than 55% with signs
or symptoms of CHF, or a decline in LVEF of at least 10% to
below 55% without signs or symptoms

Baseline evaluation of all patient planned for TKIs includes;

history of cardiac co morbidity, previous use of cardio toxic
drugs and any concurrent medications for HT, DM or CAD.
Most commonly used modality for detecting cardio toxicity
is the regular measurement of LVEF by using either
echocardiography or multigated acquisition scanning
(MUGA). But there are no consensus guidelines on how
often, by what means, or how long cardiac function should
be monitored during and after cancer treatment for
detecting TKIs induced cardiac dysfunction18.

47
Cardiac biomarkers, particularly troponins has proven to
be a more sensitive and more specific tool for early, real-
time identification, assessment and monitoring of drug
induced cardiac injury 19 . It detects anticancer drug
induced-cardiotoxicity in its earliest phase, long before any
reduction in LVEF has occurred. It has been studied
extensively in bone marrow transplant setting as it allows
for the early diagnosis of risk of developing cardiac
dysfunction and gives an opportunity to plan preventive
therapy in selected high-risk patients 20.It is still an
experimental tool and in process of validation, hence not
routinely indicated.

MONITORING AND MANAGEMENT OF LVD

and HF
Baseline assessment of LVEF by echocardiogram or MUGA
scan and an ECG are suggested variably by the
manufacturers of the different agents. Caution and close
serial monitoring of LVEF is warranted during therapy
with VEGFR TKIs. For older adult patients and for those
with a history of poorly-controlled hypertension, heart
disease, or anthracycline exposure frequent cardiac
examination is advised. The clinical significance of
asymptomatic increases in cardiac enzymes or ECG changes
to detect myocardial ischemia remains undefined. A low
threshold should be maintained for cardiac evaluation in
symptomatic patients.
SUNITINIB: The FDA-approved manufacturer’s labeling
recommends discontinuation in the presence of clinical
manifestations of heart failure, and interruption of therapy
or dose reduction in patients without clinical evidence of

48
heart failure, but with an ejection fraction <50
percent and/or >20 percent below baseline21.
SORAFENIB: The FDA manufacturer’s labeling information
recommends temporary or permanent discontinuation of
the drug in any patient who develops cardiac
ischemia and/or infarction22.
PONATINIB: Labeling information suggests discontinuation
of the drug in any patient who develops “serious” heart
failure.
IMATINIB: Guidelines for management of imatinib toxicity
from the National Comprehensive Cancer Network suggest
only that patients with cardiac disease or risk factors for
heart failure who are receiving imatinib be monitored
carefully, and that any patient with signs or symptoms
consistent with heart failure be evaluated and treated23.
LAPATINIB: The FDA-approved manufacturer’s package
insert recommends that the drug should be discontinued
for a drop in the LVEF to <50 percent, for those whose
LVEF drops below the institution’s lower limit of normal,
and for any patients who develops clinical heart failure
during therapy24. Dose reduction is recommended if the
LVEF recovers to normal after a minimum of two weeks
and the patient is asymptomatic25.
All patients with HF and an LVEF <40% should be treated
with an ACE-inhibitors in combination with a beta blockers
unless a specific contraindication exists.
In general, if the cardiac event was not major and the
patient recovered, restarting therapy is warranted if there
was evidence of clinical benefit in their primary disease.
Some patients who recover from LV dysfunction may

49
tolerate the same drug on re-exposure for long periods of
time. For patients who develop frank heart failure during
treatment, best to switch to an alternative, less cardio-
toxic anti-VEGF agent.

Hypertension:
High blood pressure (BP) is associated with increased risk
of cardiovascular complications, including stroke,
myocardial infarction, and heart failure26 . It has been
established that TKIs, especially those that interfere with
the vascular endothelial growth factor (VEGF) signaling
pathways (VSPs; VSP inhibitors), have a class effect of
raising BP significantly, and that effect correlates with
CV(cardiovascular) adverse effects. Hypertension is an
important consideration when treating patients with small-
molecule TKIs (sunitinib, sorafenib, pazopanib, vandetanib,
and cabozantinib). Incidence of Grade III hypertension with
these agents varies between 2 to 13%27.
Management of HT: The angiogenesis task force of the
NCI investigational drug steering committee26 has issued
the following recommendations for the prevention and
management of hypertension in patients receiving TKIs
inhibitors:
1. Minimum of two standardized BP measurements to
be done before starting TKIs. A thorough patient
history and assessment of CV risk factors to be done
before starting TKIs.
2. Goal of BP 140/90 mmHg for most patients is to be
set for all adults. Higher-risk patients, including those
with diabetes and/or chronic kidney disease, should
achieve a lower BP goal (e.g., 130/80 mmHg).

50
3. BP should be monitored weekly during the first cycle
of TKIs therapy and then at least every 2–3 weeks for
the duration of treatment.
4. Adherence to prescribed anti-hypertensive drug is to
be ensured in patient with known hypertension. In
newly diagnosed patients with hypertension, anti-
hypertensive therapy is to be initiated and titrated to
effective dose, before initiating TKIs therapy.
5. Blood pressure is to be effectively managed to avoid
the development of complications associated with
prolonged BP increase.
6. If BP cannot be controlled with effective
antihypertensive therapy than dose reduction or
discontinuation of TKI therapy may be considered.
TKI therapy should be reinstituted at the same or lower
dose once the desired BP is achieved, to achieve
maximum efficacy on the tumor. Thiazide diuretics,
beta blockers, calcium channel blockers, angiotensin-
converting enzyme inhibitors, angiotensin- receptor
blockers are routinely used in patients for control of
blood pressure.
QT Prolongation
Use of many TKIs (nilotinib, dasatinib, sunitinib ,sorafinib
and cabazotinib ) has been associated with prolongation
of QTc interval and subsequent increased risk “torsades
de pointes” and sudden cardiac death. The International
Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICHTR)
considers QTc prolongation >500ms (and QTc change
from baseline of >60 ms) to be of particular concern
because torsades de pointes rarely occurs when QTc is <
500 ms28.
51
Monitoring and prevention of tyrosine kinase inhibitor-
associated prolonged QT intervals
In patients receiving certain TKIs concomitant treatment
with QT-prolonging drugs, including certain
antiarrhythmic, antibiotic, and antifungal agents, should
be avoided. Patient is to be advised to stop all nonessential
medications, such as dietary and herbal supplements. In
patients with excessive corrected QT interval prolongation
(> 500 ms) treatment with TKIs should not be started.
Monitoring with ECG is to be done for QT intervals at
baseline and frequently thereafter as advised by the drug’s
prescribing information. QT prolongation can occur with
diarrhea due to the resulting electrolyte imbalance
particularly potassium and magnesium .Hence electrolytes
should be monitored and diarrhea to be managed
appropriately. In patients with impaired renal and hepatic
function, tyrosine kinase inhibitor dosage should be
modified or reduced following the drug’s prescribing
information to avoid increased drug exposure and
subsequently increased QTc29.

References
1. Demetri GD, van Oosterom AT, Garrett CR et al.Efficacy
and safety of sunitinib in patients with advanced
gastrointestinal stromal tumour after failure of
imatinib: a randomised controlled trial. Lancet.
2006;368:1329 –1338.
2. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus
interferon alfa in metastatic renal-cell carcinoma.N
Engl J Med. 2007;356:115–124.

52
3. Sherbenou DW, Druker BJ. Applying the discovery of
the Philadelphia chromosome.J Clin Invest.
2007;117:2067–2074.
4. Chu T, Rupnick MA, Kerkela R, et al. Cardiotoxicity
associated with the tyrosine kinase inhibitor sunitinib.
Lancet. 2007;270:2011–2019.
5. Kerkela R, Grazette L, Yacobi R,et al. Cardiotoxicity of
the cancer therapeutic agent imatinib mesylate. Nat
Med. 2006;12:908 –916.
6. Talpaz M, Shah N, Kantarjian H, Donato N, Nicoll J,
Paquette R, et al. Dasatinib in imatinib-resistant
Philadelphia chromosome-positive leukemias. N Engl
J Med 2006;/ 354:/2531-41.
7. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E,
Ewer MS. Cardiac safety of lapatinib: pooled analysis
of 3689 patients enrolled in clinical trials. Mayo Clin
Proc 2008;83:679 – 86.
8. Hatfield A, Owen S, Pilot PR. In reply to ’Cardiotoxicity
of the cancer therapeutic agent imatinib mesylate’.
Nat Med 2007;13:13, author reply 15– 6.
9. Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive
heart failure is a rare event in patients receiving
imatinib therapy. Blood 2007;110:1233–7.
10. Khakoo AY, Kassiotis CM, Tannir N, et al. Heart failure
associated with sunitinib malate: a multitargeted
receptor tyrosine kinase inhibitor. Cancer
2008;112:2500 – 8.
11. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity
associated with tyrosine kinase inhibitor sunitinib.
Lancet 2007;370:2011–9.

53
12. Bayer Pharmaceuticals. Nexavar (sorafenib) prescribing
information: 2009.
Available from: http://www.univgraph.com/bayer/
inserts/nexavar.pdf
13. Strumberg D, Clark JW, Awada A, Moore MJ, Richly
H, Hendlisz A, et al. Safety, pharmacokinetics, and
preliminary antitumor activity of sorafenib: A review
of four phase I trials in patients with advanced
refractory solid tumors. Oncologist 2007;/12:/42637.
14. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard
S, Siebels M, et al. Sorafenib in advanced clear-cell
renal-cell carcinoma. N Engl J Med 2007;/356:/12534.
15. Suter TM, Ewer MS. Cancer drugs and the heart:
importance and management. Eur Heart J. 2012.
[Epub ahead of print].
16. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility
of trastuzumab-related cardiotoxicity: new insights
based on clinical course and response to medical
treatment. J Clin Oncol. 2005;23:7820-6
17. Seidman A, Hudis C, Pierri MK, et al. Cardiac
dysfunction in the trastuzumab clinical trials
experience. J Clin Oncol.2002;20:1215-21.
18. Eschenhagen T, Force T, Ewer M et al. Cardiovascular
side effects of cancer therapies: a position statement
from the Heart Failure Association of the European
Society of Cardiology. Eur J Heart Fail. 2011; 13: 1–
10.
19. Cardinale D, Sandri MT, Colombo A et al. Prognostic
value of Troponin I in cardiac risk stratification of
cancer patients undergoing high-dose chemotherapy.
Circulation. 2004; 109: 2749–2754.

54
20. Cardinale D, Sandri MT, Martinoni A et al. Left
ventricular dysfunction predicted by early troponin I
release after high-dose chemotherapy. J Am Coll
Cardiol.2000; 36: 517–522
21. Sutent [package insert]. New York, NY: Pfizer Inc;
2012. Available at: http://www.pfizer.com.
22. Nexavar [package insert]. Wayne, NJ: Bayer HealthCare
Pharmaceuticals Inc.; 2011. Available at: http://
www.bayer.com.
23. National Comprehensive Cancer Network (NCCN).
NCCN Clinical practice guidelines in oncology.
http://www.nccn.org/professionals/physician_gls/
f_guidelines.asp (Accessed on April 01, 2014).
24. Storniolo AM, Koehler M, Preston A, et al. Cardiac
safety in patients with metastatic breast cance treated
with lapatinib and trastuzumab (abstract). J Clin Oncol
2007; 25:6s.
25. Tykerb [package insert]. Research Triangle Park, NC:
GlaxoSmithKline; 2012. Available at: http://
www.gsk.com/.
26. Maitland ML, Bakris GL, Black HR et al. Initial
assessment, surveillance, and management of blood
pressure in patients receiving vascular endothelial
growth factor signaling pathway inhibitors. J Natl
Cancer Inst 2010;102:596 –604.
27. Daniel J. Leniman et al. Overview and Management
of Cardiac Adverse Events Associated With Tyrosine
Kinase Inhibitors.TheOncologist 2013;18:900–908.
28. Strevel EL, Ing DJ, Siu LL. Molecularly targeted
oncology therapeutics and prolongation of the QT
interval. J Clin Oncol 2007;25:3362–3371.
55
29. Drew BJ, Califf RM, FunkMet al. Practice standards
for electrocardiographic monitoring in hospital
settings: An American Heart Association scientific
statement from the Councils on Cardiovascular
Nursing, Clinical Cardiology, and Cardiovascular
Disease in the Young: Endorsed by the International
Society of Computerized Electrocardiology and the
American Association of Critical-Care Nurses
Circulation 2004;110:2721–2746.

56
Role of Echocardiography in
Chemotherapy Induced
Cardiotoxicity

The Cardiac Review and Evaluation Committee (CREC)

defined that the diagnosis of chemotherapy related cardiac
dysfunction can be established when at least one of the
following elements is present:
1) Cardiomyopathy characterized by a decrease in
cardiac left ventricular ejection fraction (LVEF) that
was either global or more severe in the septum;
2) Symptoms of congestive heart failure;
3) Associated signs of congestive heart failure, including
but not limited to S3 gallop, tachycardia, or both
4) Decline in LVEF of at least 5% to less than 55% with
accompanying signs or symptoms of congestive heart
failure, or a decline in LVEF of at least 10% to below
55% without accompanying signs or symptoms.
Early diagnosis during follow-up is of paramount
importance, and careful surveillance is recommended.
Currently, the most widely used method in clinical practice

57
for monitoring the potential of cardiotoxicity is calculation
of left ventricular ejection fraction ( LVEF).
Echocardiography is the cornerstone in the cardiac imaging
evaluation of patients before, during and after cancer
therapy. It is widely available, easily repeatable, there is
lack of radiation exposure and safe in patients with
concomitant renal disease. In addition to the evaluation
of left ventricle(LV) and right ventricular (RV) dimensions,
systolic and diastolic function at rest and during stress,
echocardiography also allows a comprehensive evaluation
of cardiac valves, the aorta, and the pericardium.

I. LV systolic function
LV ejection fraction (LVEF) has been validated as a measure
of LV systolic function.Accurate calculation of LVEF should
be done with the best method available in the
echocardiography laboratory.

Two dimensional echocardiography ( 2DE)

When using 2DE, the modified biplane Simpson’s
technique is the method of choice. It requires manual or
semi automated tracing of the endocardial border in four
and two chamber views at end-diastole and end systole,
and volumetric calculation is based on the geometric
assumption of stacked elliptical disks characterizing the
LV shape.
LVEF should be combined with the calculation of wall
motion score index.

58
 Modified biplane Simpson’s technique : This method
is currently recommended method of choice for
estimation of LVEF. The principle of this method is that
the total left ventricular volume is calculated from the
summation of a stack of elliptical discs. The height of
each disc is calculated as a fraction of the left
ventricular long axis based on the longer of the two
lengths from the two- and four-chamber views.
Normal values of left ventricular ejection fraction are
≥ 55% for both genders (Lang et al 2006)

Limitations
1. Image quality can reduce the precision of endocardial
border definition and limit measurement accuracy.
The use of contrast often has the potential to
overcome this limitation. Contrast allows enhanced
accuracy, reduced interobserver variability, and
improved correlation with magnetic resonance
imaging measurement of LVEF.
2. Dependence on loading conditions that can vary
among studies, resulting in changes in the calculated
LVEF and, therefore, the perceived LV systolic
function.The use of LV systolic function to determine
whether to continue or discontinue the use of
chemotherapeutic agents also is limited as decrease
in LVEF frequently occurs late and can be irreversible.
3. LVEF assessed by 2DE often fails to detect small
changes in LV contractility
Despite all these identified limitations of LVEF, it is time
tested and the measure most used in clinical practice today.

59
Three dimensional echocardiography (3DE)
The complexity of geometric assumptions used in
calculating biplane LV volumes has been overcome by
three-dimensional imaging. 3DE volume calculation is
reliable, lowers the probability of chamber foreshortening,
and has proved to be an accurate modality for serial
measurements of systolic function. 3DE is the preferred
technique for monitoring LV function and detecting cardiac
dysfunction in patients with cancer.
Strengths : Better accuracy in detecting LVEF below the
lower limit of normal, better reproducibility and lower
temporal variability compared with 2DE in patients of
cancer treated with chemotherapy.
Limitations : High costs, non availability, high reliance
on image quality and need for training of operators
currently limit the wide application of 3DE.

Stress echocardiography
Stress echocardiography was proposed as a method to
identify early systolic dysfunction due to chemotherapy.
However, data are very poor and the results derived from
small studies have been conflicting.

II. Diastolic dysfunction

Diastolic dysfunction early after chemotherapy occurs
frequently and independent of symptoms or changes in
systolic function. This finding is limited by the observation
that abnormal myocardial relaxation is the most common
diastolic pattern identified in clinical practice.
Chemotherapy-related diastolic dysfunction can occur at
any time, acute and transient 1 hour after the

60
administration of doxorubicin. Additionally, impaired
diastolic parameters have been described weeks to months
after anthracycline therapy in the absence of reduced LVEF,
and the same subtle diastolic abnormalities can be
associated with normal LVEF several years after
chemotherapy completion. Alterations in LV diastolic
function (as evaluated by Doppler indices of mitral inflow
and e’ by pulsed Doppler tissue imaging (DTI ) precede
alterations in systolic function. However the evidence does
not support the role of these indices for the prediction of
later chemotherapy related systolic dysfunction.

III. Global longitudinal Strain

A number of peer-reviewed studies have reported the
sensitivity of measuring deformation indices (strain, strain
rate, and twist) in the detection of sub-clinical LV
dysfunction in patients treated for cancer. The decrease in
deformation indices preceded the decrease in LVEF and
persisted during the subsequent cancer treatment. Early
decreases in radial and longitudinal strain and strain rate
were noted using DTI and speckle tracking
echocardiography (STE) and have been confirmed in
patients treated with anthracyclines (in some studies in
association with taxanes and trastuzumab), with or
without later decreases in LVEF.
STE has been validated as a more accurate tool for the
evaluation of myocardial deformation. STE is based on
the analysis of discrete areas of the myocardial wall,
referred to as speckles.Any modification of each speckle
can be tracked, frame by frame, in any direction of the
imaging plane, and parameters of velocity, strain, and strain
rate can be evaluated. A significant reduction of

61
longitudinal strain (>10% from baseline) after 3 months
is reported to predict a future reduction in LVEF (after 6
months) with sensitivity of 78%to 79% and specificity of
79% to 82%. Global longitudinal strain has been shown
in some small studies to have some potential as an early
predictor of late LV systolic dysfunction.
Myocardial deformation (strain) can be measured
using DTI or 2D STE. STE is favoured because of a lack
of angle dependency.
Global longitudinal strain (GLS ) is the optimal
parameter of deformation for the early detection of
sub-clinical LV dysfunction.
Ideally, the measurements during chemotherapy
should be compared with the baseline value. In
patients with available baseline strain measurements,
a relative percentage reduction of GLS of <8% from
baseline appears not to be meaningful, and those
>15% from baseline are very likely to be abnormal.
When applying STE for the longitudinal follow-up of
patients with cancer, the same vendor-specific
ultrasound machine should be used.

62
Current recommendations for baseline evaluation and cardiac
monitoring during and after cancer treatment with potential
reversible or non reversible cardiotoxicity.(ESMO guidelines 2012)
LVEF assessment is mandatory for basal evaluation IA
cardiac function before potential cardiotoxic
cancer treatment(2D echo, MUGA, cardiac MRI).
2D or 3D images to be obtained in the left
ventricular parasternal long- and short-axis views
and in the apical four- and two-chamber long-axis
views. Assessment of diastolic function,
by (E/A ratio, the deceleration time of the early
peak flow,isovolumic relaxation time), Left
ventricular end-diastolic diameter to be measured
for LV dilatation
Assessment of LV diastolic function and LV end IA
diastolic diameter
Patients receiving anthracyclines /or trastuzumab
In the adjuvant setting: perform serial monitoring IA
of cardiac function at baseline, 3, 6 and 9 months
during treatment, and then at 12 and 18 months
after the initiation of treatment. Monitoring
should be repeated during or following treatment
as clinically indicated.
In metastatic disease: LVEF should be monitored IIA
at baseline and then infrequently in the absence
of symptoms
Assessment of cardiac function is recommended IIB
4 and 10 years after anthracycline therapy in
patients with cumulative dose of doxorubicin of
>240 mg/m2 or epirubicin >360 mg/m2

63
 LVEF reduction of ≥15% from baseline with IIB
normal function (LVEF ≥ 50%) is an indication to
continue anthracyclines/or trastuzumab.
LVEF decline to <50% during anthracyclines
containing regimens necessitate reassessment
after 3 weeks. If confirmed, hold chemotherapy,
consider therapy for left ventricular dysfunction
(LVD) and further frequent clinical and
echocardiographic checks. In case of LVEF decline
to <40% stop chemotherapy, discuss alternatives
and treat LVD
LVEF decline to <50% during trastuzumab
therapy (post-anthracyclines) necessitate
reassessment after 3 weeks. If confirmed,
continue trastuzumab and consider therapy
for LVD and further frequent clinical and
echocardiographic checks. In case of LVEF decline
to <40% stop trastuzumab and treat LVD IA

References and suggested reading:

1. J C Plana et al Expert consensus for multimodality
imaging evaluation of adult patients during and after
cancer therapy: a report from the American Society
of Echocardiography and the European Association
of Cardiovascular Imaging. European Heart Journal –
Cardiovascular Imaging (2014)15, 1063–1093.
2. Schwartz RG, McKenzie WB, Alexander J, et al.
Congestive heart failure and left ventricular
dysfunction complicating doxorubicin therapy. Seven-
year experience using serialradionuclide
angiocardiography. Am J Med 1987;82:1109-18.
3. Seidman A, Hudis C, Pierri MK, et al. Cardiac
dysfunction in the trastuzumab clinical trials
experience. J Clin Oncol.2002;20:121521.
64
4. Kerkhove D, Fontaine C, Droogmans S, et al. How to
monitor cardiac toxicity of chemotherapy: time is
muscle! Heart. 2014;100:1208-17.
5. Maiello M, Sharma RK, Ciccone MM, Reddy HR,
Palmiero P. Early diagnosis of cardiac toxicity related
to antineoplastic treatment. J Cancer Ther
2011;2:161-6.
6. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh
JK, Smiseth OA, et al. Recommendations for the
evaluation of left ventricular diastolic
7. StoddardMF, Seeger J, Liddell NE, Hadley TJ, Sullivan
DM, Kupersmith J. Prolongation of isovolumetric
relaxation time as assessed by Doppler
echocardiography predicts doxorubicin-induced
systolic dysfunction in humans. J Am Coll Cardiol
1992;20:62-9.
8. Ho E, Brown A, Barrett P, Morgan RB, King G,
KennedyMJ, et al. Subclinical anthracycline- and
trastuzumab induced cardiotoxicity in the longterm
follow-up of asymptomatic breast cancer survivors: a
speckle tracking echocardiographic study. Heart
2010;96:701-7.
9. Appel JM, Sogaard P, Mortensen CE, Skagen K, Nielsen
DL. Tissue-Doppler assessment of cardiac left
ventricular function during short-term adjuvant
epirubicin therapy for breast cancer. JAm Soc
Echocardiogr 2011;24: 200-6.
10. Poterucha JT, Kutty S, Lindquist RK, Li L, Eidem BW.
Changes in left ventricular longitudinal strain with
anthracycline chemotherapy in adolescents precede
subsequent decreased left ventricular ejection fraction.
J Am Soc Echocardiogr 2012;25:733-40.

65
11. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan
TC, et al. Assessment of echocardiography and
biomarkers for the extended prediction of
cardiotoxicity in patients treated with anthracyclines,
taxanes and trastuzumab. Circ Cardiovasc Imaging.
In press.
12. Ewer MS, Lippman SM. Type II chemotherapy-related
cardiac dysfunction: time to recognize a new entity. J
Clin Oncol 2005;23:2900-2.
13. Hoffmann R, von Bardeleben S, ten Cate F, Borges
AC, Kasprzak J, Firschke C, et al. Assessment of systolic
left ventricular function: a multicentre comparison of
cineventriculography, cardiac magnetic resonance
imaging, unenhanced and contrast-enhanced
echocardiography. Eur Heart J 2005;26:607-16.
14. Sugeng L, Mor-Avi V, Weinert L, Niel J, Ebner C,
SteringerMascherbauer R, et al. Quantitative
assessment of left ventricular size and function: side-
by-side comparison of real-time three-dimensional
echocardiography and computed tomography with
magnetic resonance reference. Circulation
2006;114:654-61.
15. Stapleton GE, Stapleton SL, Martinez A, Ayres NA,
Kovalchin JP, Bezold LI, et al. Evaluation of longitudinal
ventricular function with tissue Doppler
echocardiography in children treated with
anthracyclines. J Am Soc Echocardiogr 2007;20:
492-7.
16. Curigliano, D. Cardinale, T. Suter, etal. Cardiovascular
toxicity induced by chemotherapy,targeted agents and
radiotherapy: ESMO Clinical Practice Guidelines Annals
of Oncology 23 (Supplement 7): : vii155–vii166, 2012
66
Scintigraphy Techniques for Early
Detection of Cancer Treatment
Induced Cardiotoxicity.

A: Role of imaging in diagnosis of

cardiotoxicity:
Detection of myocardial injury before irreversible functional
impairment is the most logical approach for the prevention
of treatment induced cardiotoxicity. The rationale behind
early detection of cardio toxicity are as follows;
1. Early identification will reduce morbidity and mortality.
2. To plan alternative treatment strategies by
incorporating other less toxic anti-cancer agents, like
replacing sequential doxorubicin and trastuzumab
with docetaxel, carboplatin and trastuzumab which
have similar efficacy.
3. To initiate cardio-protective drugs like angiotensin
blockers in early phase to prevent cardiac
deterioration.

67
Non Invasive imaging of cardiotoxicity:
Over the years, several imaging modalities have been
developed that vary considerably in precision, ease of use,
availability, and costs. LVEF may be measured by planar
multigated radionuclide angiography (MUGA),
quantitative gated blood-pool SPECT (GBPS), 2- and
3-dimensional echocardiography, radiographic contrast
angiography, or cardiac MRI.
Together echocardiography and MUGA are the most widely
accepted methods to assess patients’ LVEF during cancer
treatment. Lack of radiation, portability, increased
availability and easy to use makes echocardiography most
commonly used modality for serial monitoring in
susceptible patients. However poor specificity, low
sensitivity to measure decline in LVEF, lower feasibility in
patients with obesity and emphysema, high inter-observer
variability, gain dependent edge identification and
transducers positioning artifacts are some of its
disadvantages. 3D echo and contrast echo can be
reasonably expected to improve the accuracy of blinded
echocardiographic EF measurements by avoiding
underestimation of LV volumes by 2D echocardiography,
as reviewed by the American Society of Echocardiography.
However larger clinical studies are required.

68
 Table 1: Traditional and Novel Scintigraphy
techniques for early detection of cardiotoxicity.
Technique Radiopharmaceuticals
Calculation of LVEF 99mTc-MUGA, or blood
pool SPECT
Neuronal imaging 123I- MIBG
Imaging cell necrosis/death 111In- Antimyosin
Imaging apoptosis 99mTc-Annexin
Fatty acid metabolism 123I-BMIPP
Endogenous neurotransmitters 18F-6-Fluorodopamine
(PET tracer)
Endogenous neurotransmitters 11C-Epinephrine
(PET tracer)

Table 2: Advantages of individual scintigraphy

techniques
Technique Advantages
99mTc- MUGA 1. Highly sensitive and specific
modality for serial assessment
of systolic and diastolic
function
2. Cost effective.
3. Highly reproducible.
4. Largest clinical experience/
evidence
99mTc-Blood pool SPECT 1. Good correlation with MUGA
2. Can calculate right
ventricular ejection fraction.
3. Software mediated assessment
of wall motion analysis.

69
 Technique Advantages
123I-MIBG 1. Detects myocardial injury
before irreversible damage,
potentially earlier than with
MUGA.
2. Strong prognostic value
3. No Gating errors/can be used
in arrhythmias
111In-Tc-Antimyosin/ 1. High sensitivity
99mTc-Annexin 2. No Gating errors/can be used
in arrhythmias

Table 3: Limitations of individual scintigraphic techniques:

Technique Limitations
99mTc- MUGA 1. LVEF at rest correlates poorly
with early myocardial damage
seen in endo-myocardial
biopsy
2. May not be feasible in
patients with arrhythmias
99mTc-Blood pool SPECT 1. Underestimate LVEF
2. Less feasible in patients with
normal small cavities.
3. Lack of large scale data
supporting its clinical use
123I-MIBG 1. Lack large scale clinical data
supporting clinical use.
2. Availability of 123-I
3. Correction for Age required
as uptake of 123I-MIBG
physiologically reduced
99mTc-annexin/ 1. Low specificity
111In-Anti-myosin 2. Availability issues

70
A) MUGA:
Serial MUGA is still regarded as the noninvasive gold
standard for identifying subclinical left ventricular
dysfunction in adult patients treated with cardiotoxic
agents. MUGA, also called radionuclide ventriculography
is a noninvasive technique that makes use of 99mTc-
labelled RBC’s. The labeling (3 techniques, in-vitro, in-vivo
and modified in-vivo) technique makes use of the binding
of the radionuclide 99mTc to erythrocytes facilitated by
stannous chloride, which dilutes the 99mTc and prevents
it from leaking out of the red blood cells during the
procedure. Most commonly done is the in vivo labeling
procedure which consists of intravenous injection of 0.5
to 1.0 mg of stannous ion, frequently as stannous
pyrophosphate. After allowing the tin ion to equilibrate
in the blood for 20 minutes, about 20 mCi (740 MBq) of
99mTc-pertechnetate is injected. With the tin acting as a
complexing agent, a sufficient number of red blood cells
are tagged in vivo to allow for labeling of the intravascular
space.Cardiac blood pool is visualized using a gamma
camera. As the images are acquired, the simultaneously
registered patient’s heartbeat is used to gate the
acquisition. Gating means that the heart cycle is split into
16 or 32 time bins based on the electrocardiography. Then,
the image information obtained in every respective time
bin of all heart actions is summarized to obtain a favorable
image quality. The final result is a series of images of the
heart, 1 at each stage of the cardiac cycle. Fourier analysis
provides a functional image (a parametric map of
sequential contractions, or phase imaging), which permits
precise quantification of left ventricular volume and
dyssynchrony, with high reproducibility. A major strength

71
of this technique is that the quantitative computation of
ejection fraction and chamber volumes does not depend
on mathematic assumptions of ventricular geometry.

B) Guidelines for monitoring anthracyline

cardiotoxicity using MUGA:
Guidelines for monitoring patients receiving doxorubicin
therapy and avoiding CHF based on the analysis of CHF
outcomes in this high risk group of patients are listed in
Table 4 .Those patients whose management was not strictly
concordant with these guidelines despite serial monitoring
of quantitative LVEF had significantly higher incidence of
CHF. Severity of CHF was also higher in those patients not
managed in accordance with the recommended
guidelines. In summary, monitoring resting LVEF with serial
ERNA is associated with a low incidence, benign course,
and reversible degree of CHF. In a population at high risk
of developing anthracycline cardiotoxicity, who were
monitored with serial ERNA, strict adherence to the specific
guidelines for timing of studies and termination of
chemotherapy which were developed over seven years and
subsequently validated in clinical practice over three
decades, reduces the incidence and severity of CHF.

72
 Table 4: Guidelines for serial MUGA based
monitoring of cardio toxicity:
Baseline evaluation performed at rest to determine LVEF before
initiation of doxorubicin treatment or before 100mg/m2
Subsequent evaluations performed 3 weeks after the last
indicated dose and before the next dose at the following
intervals
1. Patients with baseline LVEF = or > 50%
a: Second study after 250-300mg/m2
b: Repeat study after 400mg/m2 in patients with risk
factors* or after 450mg/m2 in absence of risk factors.
Discontinue doxorubicin if decrease in the absolute
LVEF > or = 10% or to a level <50%
2. Patient with abnormal baseline LVEF (<50%)
a: Do not start doxorubicin if baseline LVEF < 30%
b: For LVEF between 30-50%, perform study with each
dose
Discontinue doxorubicin if decrease in the absolute
LVEF > or = 10% or to a level <30%
 Risk factors- Known heart disease, hypertension,
abnormal ECG, cyclophosphamide, history of radiation
therapy

73
C) Evidence and Appropriate use score for
MUGA/ERNA in monitoring doxorubicin
cardiotoxicity.
Table 5: Level of evidence
Indication Test Class Level of evidence
Baseline and serial Rest MUGA I A
monitoring of
LV function during
therapy with
cardio-toxic drugs
(e.g. doxorubicin)
Reference- ACC/AHA/ASNC guidelines for clinical use of
radionuclide imaging, 2003
Table 6: Appropriate use criteria for radionuclide
imaging in monitoring cardiotoxicity
Indication Test Appropriate score
 Serial assessment of Rest ERNA A(9)
LV function with
radionuclide angiogram
 Baseline and serial
measures after key
therapeutic
milestones or evidence
of toxicity
Reference: ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM,
2009 appropriate use criteria for radionuclide imaging.

74
Selected abstracts:
1. BMC Cancer. 2010 Jun 29;10:337. doi:
10.1186/1471-2407-10-337.
Cardiotoxicity of anthracycline agents for the treatment
of cancer: systematic review and meta-analysis of
randomised controlled trials.
Smith LA(1), Cornelius VR, Plummer CJ, Levitt G, Verrill M,
Canney P, Jones A.
BACKGROUND: The authors conducted a systematic
review and meta-analysis to clarify the risk of early and
late cardiotoxicity of anthracycline agents in patients
treated for breast or ovarian cancer, lymphoma, myeloma
or sarcoma.
METHODS: Randomized controlled trials were sought
using comprehensive searches of electronic databases in
June 2008. Reference lists of retrieved articles were also
scanned for additional articles. Outcomes investigated
were early or late clinical and sub-clinical cardiotoxicity.
Trial quality was assessed, and data were pooled through
meta-analysis where appropriate.
RESULTS: Fifty-five published RCTs were included; the
majority were on women with advanced breast cancer. A
significantly greater risk of clinical cardiotoxicity was found
with anthracycline compared with non-anthracycline
regimens (OR 5.43 95% confidence interval: 2.34, 12.62),
anthracycline versus mitoxantrone (OR 2.88 95%
confidence interval: 1.29, 6.44), and bolus versus
continuous anthracycline infusions (OR 4.13 95%
confidence interval: 1.75, 9.72). Risk of clinical
cardiotoxicity was significantly lower with epirubicin versus

75
doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78),
liposomal versus non-liposomal doxorubicin (OR 0.18 95%
confidence interval: 0.08, 0.38) and with a concomitant
cardioprotective agent (OR 0.21 95% confidence interval:
0.13, 0.33). No statistical heterogeneity was found for
these pooled analyses. A similar pattern of results were
found for subclinical cardiotoxicity; with risk significantly
greater with anthracycline containing regimens and bolus
administration; and significantly lower risk with epirubicin,
liposomal doxorubicin versus doxorubicin but not
epirubicin, and with concomitant use of a cardioprotective
agent. Low to moderate statistical heterogeneity was
found for two of the five pooled analyses, perhaps due to
the different criteria used for reduction in Left Ventricular
Ejection Fraction. Meta-analyses of any cardiotoxicity
(clinical and subclinical) showed moderate to high
statistical heterogeneity for four of five pooled analyses;
criteria for any cardiotoxic event differed between studies.
Nonetheless the pattern of results was similar to those for
clinical or subclinical cardiotoxicity described above.
CONCLUSIONS: Evidence is not sufficiently robust to
support clear evidence-based recommendations on
different anthracycline treatment regimens, or for routine
use of cardiac protective agents or liposomal formulations.
There is a need to improve cardiac monitoring in oncology
trials.
PMCID: PMC2907344 PMID: 20587042

2. Am J Med. 1987 Jun;82(6):1109-18.

Congestive heart failure and left ventricular dysfunction
complicating doxorubicin therapy. Seven-year experience
using serial radionuclide angiocardiography.

76
Schwartz RG, McKenzie WB, Alexander J, Sager P, D’Souza
A, Manatunga A, Schwartz PE, Berger HJ, Setaro J, Surkin
L, et al.
To impact on the development of clinical congestive heart
failure as a complication of doxorubicin therapy, left
ventricular ejection fraction was monitored with serial
resting radionuclide angiocardiography in 1,487 patients
with cancer over a seven-year period in both university
and community hospital environments. A high-risk subset
of 282 patients was selected for retrospective analysis of
their clinical outcome. High-risk patients were identified
by one or two of the following three criteria: decline of
10 percent or more in absolute left ventricular ejection
fraction from a normal baseline to 50 percent or less; high
cumulative dose of doxorubicin (more than 450 mg/m2);
abnormal baseline left ventricular ejection fraction (less
than 50 percent). Clinical congestive heart failure occurred
in 46 (16 percent) during the treatment period, and in an
additional three patients (1.3 percent) at last follow-up
examination 11.8 +/- 14.2 months following
discontinuation of doxorubicin. Total cumulative dosages
of doxorubicin that precipitated congestive heart failure
(75 to 1,095 mg/m2) and those that did not (30 to 880
mg/m2) varied widely. Decline of 10 percent or more in
absolute left ventricular ejection fraction to a value of 50
percent or less preceded administration of the final dose
of doxorubicin that precipitated clinical congestive heart
failure in the majority of patients in whom congestive heart
failure developed. Clinical congestive heart failure improved
in 87 percent given routine therapy with digitalis, diuretics,
and/or vasodilators. Criteria for monitoring left ventricular
ejection fraction and discontinuing doxorubicin were

77
formulated. The occurrence of clinical congestive heart
failure was compared in those patients whose
management was concordant with proposed criteria
(Group A) and in those whose management was not
(Group B). Group A had a lower incidence of congestive
heart failure compared with Group B (2.9 percent versus
20.8 percent, p less than 0.001) and had only mild
congestive heart failure that resolved with treatment (n =
2) and no deaths due to congestive heart failure.
Multivariate analysis with proportional-hazards regression
(Cox’s model) demonstrated a fourfold reduction in the
incidence of congestive heart failure independent of other
clinical predictor variables in those patients whose
management was concordant with proposed guideline
criteria. The incidence, persistence, late development,
predictability, and reversibility of clinical congestive heart
failure were comparable in university and community
hospital settings.
PMID: 3605130

3. J Nucl Cardiol. 2003 Mar-Apr;10(2):132-9.

Doxorubicin cardiotoxicity: prevention of congestive heart
failure with serial cardiac function monitoring with
equilibrium radionuclide angiocardiography in the current
era.
Mitani I(1), Jain D, Joska TM, Burtness B, Zaret BL.
BACKGROUND: Congestive heart failure (CHF) is among
the most serious toxicities of doxorubicin, a potent cancer
chemotherapeutic agent. Serial left ventricular ejection
fraction (LVEF) monitoring during doxorubicin therapy for
preventing CHF was proposed over 20 years ago. The

78
current utility and cost-effectiveness of this approach in
the present era are not known.
METHODS AND RESULTS: Clinical and follow-up data
of 265 patients with cancer
(age, 53 +/- 14 years; 76% women) undergoing
doxorubicin chemotherapy with serial equilibrium
radionuclide angiocardiography (ERNA) monitoring (> or
=2 studies) were analyzed retrospectively. Patients with a
normal baseline LVEF (> or =50%) and a 10% or greater
point fall in LVEF to a final value of less than 50% during
doxorubicin therapy were considered “at risk” for CHF
(n = 41). Over 679 +/- 426 days of follow-up, 7 patients
(2.6%) had CHF develop and 90 (34%) died (all cancer-
related deaths, with none due to CHF). A comparison of
“at-risk” (n = 41[15%]) and “low-risk” (n = 224 [85%])
groups showed a higher incidence of CHF (12% vs 0.9%,
P <.0001), lower baseline LVEF (58% +/- 8% vs 64% +/-
8%, P <.0001), lower value for the lowest LVEF (42% +/
- 8% vs 57% +/- 7%, P <.0001), and higher rate of cancer-
related deaths (59% vs 29%, P =.0003) in the former
despite similar cumulative doxorubicin dose (304 +/- 124
mg/m(2) vs 284 +/- 110 mg/m(2), P = not significant).
There were no differences in age, gender, cancer type,
and co-morbidity. Cost analysis showed the overall cost of
ERNA studies to be lower than the 1-year cost of caring
for additional cases of CHF that would potentially be
prevented by routine LVEF monitoring.
CONCLUSIONS: An incipient fall in LVEF detected on serial
ERNA during doxorubicin therapy provides an appropriate
and cost-effective approach for predicting and preventing
impending CHF. Use of this approach was associated with

79
a low incidence of CHF (2.6%) and no CHF-related mortality
in this study.
PMID: 12673177

4. Br J Cancer. 2002 Jan 21;86(2):226-32.

Clinical and economic impact of multiple gated acquisition
scan monitoring during anthracycline therapy.
Shureiqi I(1), Cantor SB, Lippman SM, Brenner DE, Chernew
ME, Fendrick AM.
The clinical and economic impacts of monitoring cardiac
function in patients given doxorubicin have yet to be
determined, especially in relation to patient age, cumulative
doxorubicin dose, and the relative efficacies of doxorubicin-
based vs alternative regimens. We developed a decision
analysis model that includes these factors to estimate the
incremental survival benefit and cost-effectiveness of using
multiple gated acquisition scans to measure left-ventricular
ejection fraction before and during doxorubicin
chemotherapy. Probability distributions for the incidences
of abnormal left-ventricular ejection fraction findings and
congestive heart failure were derived from a retrospective
review of 227 consecutive cases at The University of
Michigan Medical Center and published findings. Multiple
gated acquisition-scan monitoring minimally improved the
probability of 5-year survival (<1.5% in the base—case
scenario). For patients who received up to 350 mg m(-2)
of doxorubicin, multiple gated acquisition-scan screening
had an incremental cost of $425 402 per life saved for
patients between the ages of 15—39. This incremental
cost markedly decreased to $138 191, for patients between
the ages of 40—59, and to $86 829 for patients older

80
than 60 years. The small gain in 5-year survival probability
secondary to multiple gated acquisition scan monitoring
doubled for all age groups when the average cumulative
dose for doxorubicin reached 500 mg m(-2).Variations in
the cure rate differences between the doxorubicin and
alternative regimens had insignificant effects on the
improvement in 5-year survival rates from multiple gated
acquisition-scan screening. The use of multiple gated
acquisition scans for pretreatment screening appears to
be more cost effective for patients who are 40 years or
older, when cumulative doxorubicin dose is 350 mg m(-2)
or less.
PMCID: PMC2375190

References:
1. De Geus-Oei LF, Mavinkurve-Groothuis AM, Bellersen
L, Gotthardt M, Oyen WJ, Kapusta L, van Laarhoven
HW. Scintigraphic techniques for early detection of
cancer treatment-induced cardiotoxicity. J Nucl Med
Technol. 2013 Sep;41(3):170-81. doi: 10.2967/
jnumed.110.082784. Epub 2013 Aug 8. Review.
PubMed PMID: 23929800.
2. Schwartz RG, Jain D, Storozynsky E. Traditional and
novel methods to assess and prevent chemotherapy-
related cardiac dysfunction noninvasively. J Nucl
Cardiol. 2013 Jun;20(3):443-64. doi: 10.1007/
s12350-013-9707-1. Review. PubMed PMID:
23572315.
3. Schwartz RG, McKenzie WB, Alexander J, Sager P,
D’Souza A, Manatunga A, et al. Congestive heart
failure and left ventricular dysfunction complicating

81
 doxorubicin therapy: A seven year experience using
serial radionuclide angiocardiography. Am J Med
1987;82:1109-18.
4. Wakasugi S, Fischman AJ, Babich JW, Aretz HT,
Callahan RJ, Nakaki M, et al. Metaiodobenzyl-
guanidine: evaluation of its potential as a tracer for
monitoring doxorubicin cardiomyopathy. J Nucl Med
1993;34:1283-6.
5. Lautamaki R, Tipre D, Bengel FM. Cardiac sympathetic
neuronal imaging using PET. Eur J Nucl Med Mol
Imaging. 2007;34(suppl 1):S74–S85.

82
Role of Cardiac MRI in Early
Detection of Chemotherapy
Induced Cardiotoxicity

Introduction:
In addition to 2D Echocardiography and radionuclide
ventriculography, presently there are newer investigations
in the imaging armamentarium like 3D echocardiography
and myocardial strain imaging and cardiac magnetic
resonance imaging (CMR) and there are other sensitive
biochemical tools like troponin and brain natriuretic
peptide (BNP), which serve as cardiac biomarkers for
predicting cardiac dysfunction.
CMR is a well established tool for the structural assessment
of cardiac anomalies and is often preferred to
echocardiography and nuclear imaging for its wide field
of view ,flexible scanning planes and lack of ionizing
radiation.Only recently multiple studies are being
conducted to assess the role of CMR in detecting both
acute and chronic complications of cardiotoxic
chemotherapy on cardiac function.

83
The most commonly used definition of cardio toxicity is
greater than 5% decrease in left ventricular ejection fraction
to less than 55% in patients with symptoms of heart failure
and greater than 10% decrease in left ventricular ejection
to less than 55% in asymptomatic patients, however it
must be remembered that left ventricular ejection fraction
measurements may be normal in presence of subclinical
changes in cardiac function.Increase in left ventricular end
systolic volume and increase in left ventricular mass and
early relative myocardial gadolinium enhancement and
myocardial edema are considered as markers of early
cardiac injury.

Cardiac Magnetic Resonance Imaging:

The usefulness of cardiac MRI is that it can be used to
evaluate the performance of ventricles and characterization
of myocardium. It is reproducible and non-operator
dependent as compared to 2D echocardiography.
The requirement for performing cardiac MRI is an
equipment of 1.5 Tesla magnet (Tesla being a measure of
magnetic field strength) with strong and fast gradients
and dedicated multi element cardiac phased array RF coil.
The dedicated coil provides better spatial resolution and
image quality and fast imaging times because of parallel
imaging.
The cardiac and respiratory motions need to be overcome
as they produce artifacts. This is done by breath hold
imaging for respiratory motion. ECG gating for cardiac
motion allows for acquiring data during specified portion
of cardiac cycle and images are created from images
obtained over several cardiac cycles (R –R intervals) after
placing MR compatible ECG leads over patients left chest
wall, the leads are positioned to accentuate R waves.

84
Cardiac MRI is performed using a variety of pulse
sequences, generally labelled as black blood (Spin Echo)
techniques and white blood(Gradient Echo)
techniques.Gradient echo sequences are fast imaging
sequences and could be referred to as workhorse of cardiac
imaging, they are used for ventricular function assessment,
myocardial perfusion studies and delayed enhanced
imaging and are used for blood flow and velocity
measurements.
Cine Cardiac MRI is gold standard for accurate and
reproducible assessment of left ventricular and right
ventricularvolume measurements and ejection fraction
measurements. Normalized tables for Cardiac MRI are
available, that corrected for age, sex and body surface
area and these can be used to assess subtle
dysfunctions.The pulse sequence used for cine cardiac MR
imaging is Steady state free precession(SSFP), it is a
modified gradient echo imaging which has high temporal
resolution and produces excellent contrast between bright
blood within the heart and myocardium, because of which
it is good pulse sequence for global/regional wall motion
evaluation and volumetric measurement.
Inversion Recovery (IR) nulls signal from desired tissue to
highlight pathology, Turbo Spin Echo(TSE) T2 weighted
with black blood preparation and fat suppression with
Short Tau Inversion Recovery (STIR) is a sequence that
suppresses signal from flowing blood and fat and high
lights fluid when long T2 relaxation times are used, it useful
for delineation of myocardial edema/infiltration.Phase
Sensitive Inversion recovery (PSIR) sequence is a new
automated version, which obviates the use of scout

85
inversion time series. The common use of this sequence is
during delayed enhancement imaging.
Contrast enhanced Cardiac MRI is performed for evaluation
of myocardial perfusion (First pass imaging) useful for
assessment of cardiomyopathy related perfusion defects
and delayed-enhancement imaging and to differentiate
between intra cardiac mass lesions and for MR
Angiography (MRA). The contrast used are gadolinium
chelates
Delayed-enhancement imaging is performed
approximately 10 to 20 minutes after injection of
intravenous contrast with an IR sequence. The basis for
delayed-enhancement cardiac imaging is that in normal
myocardium contrast quickly washes in and out, while
there is delayed washout in injured myocardium and
delayed enhancement is seen in acute as well as chronic
injury and it can pick up even minor myocardial injury.
The dose of gadolinium is 0.1mmol/kg that is 0.2cc/kg;
majority of gadolinium preparations are (0.5mmol/cc). The
doses used for cardiac MR perfusion and delayed-
enhancement studies are 0.15cc/kg and 0.3cc/kg body
weight of contrast material.The pattern of delayed-
enhancement helps in pin pointing the cause of myocardial
dysfunction.

Strengths:
1. No ionizing radiation.
2. Absence of acoustic window limitations
3. The ability of delayed-enhancement imaging to detect
subtle myocardial injury is one of its major strengths
together with its ability to non-invasively diagnose

86
 myocarditis and detect fibrosis related to
chemotherapy induced cardiomyopathy.
4. CMR is considered the reference standard for
measurement of ventricular volumes and function and
hence it makes it ideally suited for assessment of
cardiotoxicity.
5. Allows for the early recognition of cardiac injury and
provides a unique means of noninvasive biopsy of
the underlying histopathological myocardial changes
Limitations :
1. Metallic implants and pacemaker are absolute
contraindication, while clinical instability and
claustrophobia are relative contraindications.
2. The possibility of developing Nephrogenic Systemic
Fibrosis (NSF) in patients with GFR of < 30ml/min if
gadolinium is administered should be borne in mind.
3. The low availability of MRI scanners and cost are still
an issue
4. Anesthesia may be required for young children during
MRI examination.

Applications of CMR
1. Contrast enhanced CMR provides information about
epicardial rim of viable tissue that cannot be provided
by any other non-invasive imaging technique. Delayed
myocardial enhancement has good diagnostic and
prognostic value in cardiovascular disease; however
there is limited, inconclusive data on its incidence and
prognostic significance in patients evaluated for cardio
toxicity cancer therapy.

87
2. Early enhancement of myocardium in contrast
(gadolinium) enhanced CMR using T1-weighted fast-
spin echo sequences is suggestive of myocardial injury
in patients with myocarditis.
3. A technique known as myocardial tagging, which
quantifies myocardial deformation, contraction and
relaxation in radial circumferential and longitudinal
directions is also used for assessing ventricular wall
motion and pericardial disease.
4. The ability of cardiac MRI in detecting myocardial
fibrosis can help in early detection of therapy related
cardiomyopathy.
5. For non-invasive assessment of left ventricular function
and evaluation cardiac volumes cardiac MRI is
considered the gold standard .Cardiac MRI is accurate
in assessing cardiac chamber volumes with little or
no intra or inter observer variability.
6. Cardiac MRI has a role to play in monitoring response
to therapy in established cardiomyopathy and may
play an important in clinical trials of prophylactic
cardioprotective drugs in patients receiving anti-
cancer therapy.
Currently the existing data on the applications of
cardiac MRI suggest the following uses:
(1) detection of early cardiac injury,
(2) identification of cardiotoxicity during or <1 year of
treatment,
(3) detection of late consequence of therapy (>1 year
post-treatment), and
(4) monitoring response to cardioprotective therapy

88
 Though presently there is lack of high level of evidence
for use of Cardiac MRI with gadolinium enhancement
for evaluation of cancer therapy related cardio toxicity
(Level of evidence 4 [case series]), in years to come its
use for detecting and monitoring cardio toxicity will
increase due to its robustness and reproducibility.

References and Suggested Reading:

1. Chen J, Long JB, Hurria A, Owusu C, Steingart RM,
Gross CP. Incidence of heart failure or cardiomyopathy
after adjuvant trastuzumab therapy for breast cancer.
J Am Coll Cardiol. 2012;60:2504–2512.
2. Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg
TD. Cardiovascular disease competes with breast
cancer as the leading cause of death for older females
diagnosed with breast cancer: a retrospective cohort
study. Breast Cancer Res. 2011;13:R64.
3. Yeh ET, Bickford CL. Cardiovascular complications of
cancer therapy: incidence, pathogenesis, diagnosis,
and management. J Am Coll Cardiol. 2009;53:2231–
2247.
4. Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang
T, Ahmadie R, Walker JR, Lister D, Arora RC, Barac I,
Morris A, Jassal DS. Trastuzumab mediated
cardiotoxicity in the setting of adjuvant chemotherapy
for breast cancer: a retrospective study. Breast Cancer
Res Treat. 2009;117:357–364.
5. Vasu S, Hundley WG. Understanding cardiovascular
injury after treatment for cancer: an overview of
current uses and future directions of cardiovascular

89
 magnetic resonance. J Cardiovasc Magn Reson.
2013;15:66.
6. Bristow MR, Thompson PD, Martin RP, Mason JW,
Billingham ME, Harrison DC. Early anthracycline
cardiotoxicity. Am J Med. 1978;65:823–832.
7. Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal
DS. Delayed contrast enhancement cardiac magnetic
resonance imaging in trastuzumab induced
cardiomyopathy. J Cardiovasc Magn Reson.
2008;10:5.
8. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang
G, Alakija P, Cooper LT, et al. Cardiovascular Magnetic
Resonance in Myocarditis:A JACC White Paper. J Am
Coll Cardiol. 2009 April 28,2009;53(17):1475-87.
9. Cardinale D, Sandri MT. Role of Biomarkers in
Chemotherapy- Induced Cardiotoxicity. Prog
Cardiovasc Dis 2010; 53(2):121-9.
10. Altena R 1 , Perik PJ, van Veldhuisen DJ,et al
Cardiovascular toxicity caused by cancer treatment:
strategies for early detection Lancet Oncol. 2009
Apr;10(4):391-9. doi: 10.1016/S1470-2045(09)
70042-7.

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Role of Cardiac Biomarkers in
Early Detection of Cardiotoxicity

The most common way to prevent the immediate

chemotherapy- induced cardiotoxicity from leading to
irreversible congestive heart failure (CHF) is to monitor
cardiac function during and following treatment by
estimating left ventricular ejection fraction (LVEF) using
echocardiography or radionuclide ventriculography
.However, this approach shows low sensitivity for the early
prediction of cardiomyopathy when the possibilities of
appropriate management could still improve the patient’s
outcome.1
Cardiac biomarkers are upcoming modality of assessment
of cardiac function to detect early changes that can predict
the risk of developing chemotherapy related
cardiotoxicity.2The biomarkers known to predict heart
failure could be divided into six categories according to
their origin or effects (inflammation, oxidative stress,
extracellular matrix remodelling, neurohormones, myocyte
injury, myocyte stress) 3. Heart failure, including in
cardiotoxicity, appears to result from a complex interplay
among genetic, neurohormonal, inflammatory, and

91
biochemical changes acting on cardiac myocytes, the
cardiac interstitium, or both.
Studies have consistently reported that, on theoretical
basis, it is possible to use troponin and cardiac peptides in
the detection of cardiotoxicity following administration
of chemotherapy.

TROPONINS:
Cardiac troponins are the gold standard markers for
myocardial injury.Both troponin I and T have been used in
different studies. The evidence emerging from these studies
is that the percentage of patients with positive troponin
values ranges from 15 to 34 %. Thus, the increase in
troponin concentrations in the blood underlines the
occurrence of irreversible myocardial cell injury in patients
treated with potentially cardiotoxic Chemotherapy. 4-9
Clinical Studies on Cardiac Troponin as a Marker
of Chemotherapy-Induced Cardiotoxicity
Author/Year Population studied No. (%) Troponin Cut off
Troponin+ type (mcg/L)
Sandri et al, Advanced 179 (32) I >0.08
2003 neoplasia
treated with HDC*
Auner et al, Blood cancers 78 (15) T >0.03
2003
Cardinale et al, Advanced 703 (30) I >0.08
46 2004 neoplasia
treated with HDC
Lipshultz et al, Acute 76(32) T >0.03
2004 lymphoblastic
leukemia in
children

92
 Author/Year Population studied No. (%) Troponin Cut off
Troponin+ type (mcg/L)

Kilickap et al, Advanced 41 (34) T >0.01

2005 neoplasia treated
with HDC

*HDC- high dose chemotherapy

Dolci A, DominiciR,Cardinale D, Sandri MTet al Biochemical Markers for
Prediction of Chemotherapy-Induced Cardiotoxicity. Am J
ClinPathol2008;130:688-695
The role of cardiac troponin determination to stratify the
risk of cardiotoxicity is currently based on strong evidence
clearly suggesting the routine use of this biomarker10.
Clinical evidence derived from various published studies
was summarized by Cardinale D et al as follows:10
(1) Troponin determination is able to predict, at least 3
months in advance, the occurrence of a clinically
significant dysfunction of the left ventricle.
(2) The early increase of the troponin concentrations also
predicts the degree and severity of future left
ventricular dysfunction.
(3) Among patients with positive troponin values,
persistence of the increase 1 month after the last
chemotherapy administration is related to an 85%
probability of major cardiac events within the first
year of follow-up.
(4) A persistently negative troponin test result can identify,
with a predictive negative value of 99%, patients with
the lowest cardiotoxicity risk, who will, most likely,
never encounter cardiac complications, at least within
the first year after the end of chemotherapy.

93
Cardiac troponins have been incorporated into the National
Cancer Institute (NCI) classification of cardiotoxicity of
anticancer therapy (Common Terminology Criteria for
Adverse Events, CTCAE) 11
Evaluation of troponin levels during high-dose
chemotherapy allows for the early identification of patients
at risk of developing cardiac dysfunction, the stratification
of risk of cardiac events after chemotherapy and the
opportunity for a preventive therapy in selected high-risk
patients 8,12,13.
In patients treated with trastuzumab, troponin might help
us to distinguish between reversible and irreversible cardiac
injury by identifying myocardial cell necrosis 14.
The measurement of troponin immediately before and
immediately after each cycle of cancer therapy seems to
be effective enough, and is also transferable from clinical
research to clinical practice.15

NATRIURETIC PEPTIDES:
Brain natriuretic peptide (BNP),is a hormone produced by
the mammalian heart atria. These peptides are involved in
the maintenance of extracellular fluid volume and blood
pressure.16
BNP is released by the myocardium in response to wall
strain, and to volume and pressure overload.17 Pre-
prohormone BNP is synthesized in the myocytes and it is
cleaved to prohormone BNP . Prohormone is released
during hemodynamic stress like- dilatation of ventricle,
hypertrophy or increased wall tension. The Prohormone
BNP is cleaved into two polypeptides, inactive NT-pro-BNP

94
 Clinical Studies on B-Type Natriuretic Peptides as Markers of
Chemotherapy-Induced Cardiotoxicity
Author/ Year Population studied No. (%) NP evaluated Cut off Conclusions
NP+
Poutanen et al, Paediatric cancers 39 (?) BNP Not defined No clinical
2003 usefulness
Daugaard et al, Advanced 107(?) BNP Not defined Not useful to
2005 neoplasia replace
treated with HDC* estimation
of LVEF

95
Sandri et al, Advanced neoplasia 52(69) NT-proBNP Male, Persistent
2005 treated with HDC >88 ng/L increase
(≤50 y); associated with
>227 ng/L development of
(>50 y); cardiac
female, dysfunction
>153 ng/L
(≤50 y),
>334 ng/L
(>50 y)
 Author/ Year Population studied No. (%) NP evaluated Cut off Conclusions
NP+
Horacek et al Acute myeloid 15(?) NT-proBNP Not defined Concentrations
2005 leukemia increased after
treatment
Pichon et al, Breast cancer 79(49) BNP 51.3 ng/L To predict
2005 development of
CHF, sensitivity,
83.3% (CI, 52%
-97%); specificity,

96
90.2%
(CI, 86%-94%)
Soker and Blood cancers 31(?) NT-proBNP Not defined Concentrations
Kervancioglu, increased in
2005 patients with
ventricular
dysfunction
*HDC- high dose chemotherapy
Dolci A, DominiciR,Cardinale D, Sandri M T et al Biochemical Markers for Prediction of Chemotherapy-
Induced Cardiotoxicity. Am J ClinPathol2008;130:688-695
and bioactive peptide BNP.BNP causes arterial vasodilation,
diuresis, and natriuresis, and reduces the activities of the
renin–angiotensin–aldosterone system and the
sympathetic nervous system.The natriuretic peptides are
excreted by the kidneys, and the hypervolemia and
hypertension characteristically associated with renal failure
enhance the secretion and is associated with elevated levels
of BNP, especially theNT-pro-BNP10.
Overall, studies were unable to confirm definitively the
clinical usefulness of natriuretic peptides as cardiotoxicity
biomarkers. New prospective studies on large cohorts of
patients using validated, commercially available assays and
comparing natriuretic peptides with well-established
markers of cardiotoxicity are needed.11
In the last decade, a new approach, based on the use
of cardiac biomarkers, in particular troponins, has
emerged, and has proven to be a more sensitive and
more specific tool for early, real-time identification,
assessment and monitoring of anticancer drug induced
cardiac injury 8,12 Measurement of cardiospecific
biomarkers has proven to have higher prognostic value
than imaging modalities18

STUDIES UNDER PROGRESS:

Effectiveness of Using Biomarkers to Detect and Identify
Cardiotoxicity and Describe Treatment (PREDICT) trial was
started in 2009 and is being regularly updated. The last
update was of the trial was in July 2014.The trial uses
Cardiac Biomarkers, B-type Natriuretic Peptide (BNP) and
Troponin I (TnI), for Detecting Cardiotoxicity in Patients
Undergoing Anthracycline-based Chemotherapy.BNP

97
greater than 200 pg/ml is considered abnormal. Troponin
I greater than 0.4 ng/ml is also considered abnormal.
Patients having at least one abnormal evaluation preceding
cardiotoxicity for either biomarker (i.e., one abnormal
troponin or one abnormal BNP assessments) classified as
having an abnormal test.

FDA regulatory acceptance19

- No current existing FDA guidelines for biomarker
usage in myocardial toxicity
Use of Biomarkers in Clinical practice.
Cardiospecific biomarkers, such as cardiac troponins,
show high diagnostic efficacy in the early subclinical
phase of the disease, before the clinical onset of
cardiomyopathy. The increase in their concentrations
correlates with disease severity and may predict the
occurrence of major cardiac events during follow-up.
Negative troponin concentrations may identify patients
with a low risk of cardiomyopathy. The role of cardiac
troponin determination to stratify the risk of
cardiotoxicity is currently based on strong evidence
suggesting the routine use of this biomarker.

Natriuretic peptides have been investigated in

detection of Chemotherapy-induced cardiotoxicity.
Definitive evidence of their diagnostic and prognostic
role in early detection of cardiotoxicity is still lacking
and natriuretic peptides have not been routinely used
for monitoring of cardiotoxicity in clinical practice

98
 20
Clinical recommendation Evidence rating
Troponin I or BNP concentrations seem to IIIB
identify patients at risk of cardiotoxicity,
specifically in case of administration of
type I agents (such as anthracyclines).
Performing baseline assessment of
biomarker concentrations and periodic
measurements during therapy
(every each cycle) may identify patients
who need further cardiac assessment

References
1. Scully, R. &Lipshultz, E. (2007). Anthracycline-
cardiotoxicity in long-term survivorsofchildhood
cancer. Cardiovascular Toxicology, Vol. 7, No. 2, (Apr
2007), pp. 122-128.
2. BNP Predicts Chemotherapy-Related Cardiotoxicity
and Death: Comparison with Gated Equilibrium
RadionuclideVentriculography, DortheSkovgaard,
Philip Hasbak, AndreasKjaer. PLOS ONE, May 2014 |
Volume 9 | Issue 5
3. Braunwald E. (2008). Biomarkers in heart failure. The
New England Journal of Medicine, Vol.358, No. 20,
(May 2008), pp. 2148-2159, ISSN 0028-4793.
4. Cardinale D, Sandri MT, Martinoni A, et al. Left
ventricular dysfunction predicted by early troponin I
release after high-dose chemotherapy. J Am
CollCardiol. 2000;36:517-522.
5. Cardinale D, Sandri MT, Martinoni A, et al. Myocardial
injury revealed by plasma troponin I in breast cancer
treated with high-dose chemotherapy. Ann Oncol.
2002;13:710-715.

99
6. Sandri MT, Cardinale D, Zorzino L, et al. Minor
increases in plasma troponin I predict decreased left
ventricular ejection fraction after high-dose
chemotherapy. Clin Chem. 2003;49:248-252.
7. Auner HW, Tinchon C, Linkesch W, et al. Prolonged
monitoring of troponin T for the detection of
anthracyclinecardiotoxicity in adults with
hematological malignancies. Ann Hematol.
2003;82:218-222.
8. Cardinale D, Sandri MT, Colombo A, et al. Prognostic
value of troponin I in cardiac risk stratification of
cancer patients undergoing high-dose chemotherapy.
Circulation. 2004;109:2749-2754.
9. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful
marker for early detection of anthracycline-
cardiotoxicity. Ann Oncol. 2005;16:798-804.
10. Dolci A, DominiciR,Cardinale D, Sandri MTet al
Biochemical Markers for Prediction of Chemotherapy-
Induced CardiotoxicitySystematic Review of the
Literature and Recommendations for Use. Am J
ClinPathol2008;130:688-695
11. Horáèek JM, Mathonová M, Tichý M, et al.[Evaluation
of cardiotoxicity of oncology treatment – comparison
of WHO and NCI classification]. Voj zdrav Listy 2009;
78: 129-134.
12. Pichon MF, Cvitkovic F, Hacene K et al. Drug-induced
cardiotoxicity studied by longitudinal B-type natriuretic
peptide assays and radionuclide ventriculography. In
Vivo. 2005; 19: 567–576.
13. Braverman AC, Antin JH, Plappert MT et al.
Cyclophosphamide cardiotoxicity in bone marrow

100
 transplantation: a prospective evaluation of new
dosing regimens. J Clin Oncol. 1991; 9: 1215–1223.
14. Cardinale D, Colombo A, Torrisi R et al. Trastuzumab-
induced cardiotoxicity: clinical and prognostic
implications of troponin I evaluation. J Clin Oncol.
2010;28: 3910–3916.
15. Curigliano, D. Cardinale, T. Suter, etal. Cardiovascular
toxicity induced by chemotherapy,targeted agents and
radiotherapy: ESMO Clinical Practice Guidelines Annals
of Oncology 23 (Supplement 7): : vii155–vii166, 2012
16. Tsuneo Ogawa and Adolfo J de Bold, The heart as an
endocrine organ. Endocrine Connections (2014) 3,
R31–R44.
17. Biomarkers and early detection of cardiotoxicity. Maria
Teresa Sandri Unit of Laboratory Medicine European
Institute of Oncology, Milan. 25 September 2009
18. Alessandro Colombo & Daniela Cardinale. Using
cardiac biomarkers and treating cardiotoxicity in
cancer. Future Cardiology [2013, 9(1):105-118]
Review Article
19. Kendall B. Wallace , Elizabeth Murphy , I.Y. Rosenblum,
Gene Herman et al. NCSS Fact Finding Cardiotoxicity
Expert Working Group. http://www.fda.gov/ohrm

Selected abstracts.
1. Circulation. 2004 Jun 8;109(22):2749-54. Epub 2004
May 17.
Prognostic value of troponin I in cardiac risk stratification
of cancer patients undergoing high-dose chemotherapy.
Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M,
Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini
C, Cipolla CM.
101
BACKGROUND:
In patients with aggressive malignancies who are
undergoing high-dose chemotherapy, even minimal
elevation of troponin I (TnI) is associated with late left
ventricular dysfunction. The time course of the subclinical
myocardial damage and its impact on the clinical outcome
have never been investigated previously.

METHODS AND RESULTS:

In 703 cancer patients, we measured TnI soon after
chemotherapy (early TnI) and 1 month later (late TnI).
Troponin was considered positive for values > or =0.08
ng/mL. Clinical and left ventricular ejection fraction
evaluation (echocardiography) were performed before
chemotherapy, 1, 3, 6, and 12 months after the end of
the treatment, and again every 6 months afterward. Three
different TnI patterns were identified, and patients were
grouped accordingly. In 495 patients, both early and late
TnI values were <0.08 ng/mL (TnI-/- group); in 145, there
was only an early increase (TnI+/- group); and in 63
patients, both values increased (TnI+/+ group). In the
TnI-/- group, no significant reduction in ejection fraction
was observed during the follow-up, and there was a very
low incidence of cardiac events (1%). In contrast, a greater
incidence of cardiac events occurred in TnI-positive
patients, particularly in the TnI(+/+) group (84% versus
37% in the TnI+/- group; P<0.001).

CONCLUSIONS:
TnI release pattern after high-dose chemotherapy identifies
patients at different risks of cardiac events in the 3 years
thereafter. This stratification allows us to differentiate the

102
monitoring program and to plan, in selected patients,
preventive strategies aimed at improving clinical outcome.
2. Circulation. 2006 Dec 5;114(23):2474-81. Epub 2006
Nov 13.
Prevention of high-dose chemotherapy-induced
cardiotoxicity in high-risk patients by angiotensin-
converting enzyme inhibition.
Cardinale D1, Colombo A, Sandri MT, Lamantia G, Colombo
N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla
CM.

BACKGROUND:
An increase in troponin I soon after high-dose
chemotherapy (HDC) is a strong predictor of poor
cardiological outcome in cancer patients. This finding has
important clinical implications and provides a rationale
for the development of prophylactic strategies for
preventing cardiotoxicity. Angiotensin-converting enzyme
inhibitors slow the progression of left ventricular
dysfunction in different clinical settings, but their role in
the prevention of cardiotoxicity has never been
investigated.

METHODS AND RESULTS:

Of the 473 cancer patients evaluated, 114 (72 women;
mean age, 45+/-12 years) who showed a troponin I
increase soon after HDC were randomized to receive
(angiotensin-converting enzyme inhibitor group; 20 mg/
d; n=56) or not to receive (control subjects; n=58)
enalapril. Treatment was started 1 month after HDC and
continued for 1 year. Cardiological evaluation was

103
performed at baseline and at 1, 3, 6, and 12 months after
HDC. The primary end point was an absolute decrease
>10 percent units in left ventricular ejection fraction, with
a decline below the normal limit value. A significant
reduction in left ventricular ejection fraction and an
increase in end-diastolic and end-systolic volumes were
observed only in untreated patients. According to the
Kaplan-Meier analysis, the incidence of the primary end
point was significantly higher in control subjects than in
the angiotensin-converting enzyme inhibitor group (43%
versus 0%; P<0.001).

CONCLUSIONS:
In high-risk, HDC-treated patients, defined by an increased
troponin I value, early treatment with enalapril seems to
prevent the development of late cardiotoxicity.

104
Late Cardiotoxicity in Survivors
of Childhood Cancers

INTRODUCTION:
Advances in all fields of Oncology have led to an increase
in outcomes – In the majority of paediatric malignancies,
five – year survival rates approach 80%1.
This has resulted in an increasing focus on the late effects
of therapy and quality of life in the growing population of
childhood cancer survivors (CCS).Approximately 2 of every
3 CCS will experience 1 late effect, and 40% may develop
a severe, disabling, or life-threatening condition 30 years
after cancer diagnosis2.Of these, cardiovascular toxicity of
therapy is the leading cause of morbidity and mortality
after cancer recurrence and secondary malignancies inthese
survivors 2.By the age of 45 years, the cumulative
incidence of coronary artery disease, heart failure,valvular
disease and arrhythmia among survivors is 5.3, 4.8, 1.5
and 1.3%, respectively, whereas the cumulative incidence
for each among siblings is much lower: 0.9, 0.3, 0.1 and
0.4%, respectively 3.

105
The factors most causally related to late cardiovascular
complications in CCS are treatment with anthracyclines,
and irradiation to fields involving the heart. Around 60%
of children with cancer receive anthracyclines as part of
the treatment, and roughly 20% of the children will get
irradiation involving the heart region (i.e., total body
irradiation, left or whole abdominal irradiation, spinal
irradiation and thoracic irradiation)4.

Mechanism of Anthracycline induced

cardiotoxicity:
Anthracyclines such as doxorubicin, daunorubicin,
idarubicin and epirubicin are among the most effective
drugs used in the treatment of paediatricmalignancies,
and are widely used to treat solid tumours and leukaemia.
The exact mechanism by which anthracyclines cause
cardiotoxicity is still not fully known. The most commonly
accepted hypothesis relates to increased oxidative stress
5,7. According to this hypothesis, anthracyclines form

complexes with intracellular iron,resulting in free radical

formation, and leading to lipid peroxidation and DNA
damage5,7 . The heart is particularly vulnerable to oxidative
stress due to (a) an abundance of mitochondria in
cardiomyocytes (b) high concentrations of
cardiolipin,which results in increases passive entry and
accumulation of anthracyclines in the cardiomyocytes (c)
reduced ability to scavenge free radicals due to low
concentrations of catalase and glutathione peroxidase in
the presence of anthracyclines. These free radicals damage
the DNA of cardiac myocytes, sarcomere and myofilaments,
in turn leading to left ventricular (LV) diastolic dysfunction
with impaired contractility 5,6 . Traditionally, the factors
that have been found to cause higher risk of anthracycline-
106
induced cardiotoxicity are young age (<5 years) at
exposure, female gender, combination therapy with other
agents (cyclophosphamide, bleomycin, vincristine)or
mediastinal radiation,pre-existing cardiac disease (coronary,
valvular, or myocardial) and longer duration of follow-
up8.Haematopoietic cell transplantation (HCT) survivors are
at increased risk for developing congestive heart failure
(CHF), primarily due to pre-HCT exposure to anthracyclines9.
Certain genetic polymorphisms have been implicated in
the pathogenesis of anthracycline – induced cardiac
toxicity, and have been found to predict susceptibility 9-11.

Mechanisms of Radiotherapy-Induced Cardiotoxicity:

Any radiation in which the heart was in the field of
treatment (mediastinal, thoracic, spinal, left or whole
abdominal, Total Body Irradiation) can lead to late
cardiovascular toxicity, especially when used in conjunction
with anthracyclines. Radiotherapy can cause myocardial
fibrosis,cardiomyopathy, early coronary disease, valvular
disease andarrhythmias7,12. Cardiovascular side effects of
radiotherapy result from acute microvascular injury and
inflammation leading to long-term (interstitial) myocardial
fibrosis 6. Like anthracyclines, radiation also induces dose-
dependent cardiotoxicity, and correlates with the area of
the heart exposed and the radiological technique used, as
well as the patient’s age, witha greater incidence in
younger patients. Patients receiving more than 1,500–
3,500 cGy show an increased risk for cardiac disease7,12.

Clinical Presentation:
Cardiotoxicity may manifest as cardiomyopathy,
pericarditis, congestive heart failure, valvular heart disease,
or premature coronary artery disease.

107
Three distinct forms of anthracycline-induced cardiotoxicity
have been described 8 : acute, early onset chronic
progressive ,and late onset chronic progressive.
a. Acute changes: occur within a week of infusion; range
from minor abnormalities to fatal ventricular
arrhythmias, but LV systolic dysfunction is usually
transient.
b. Early-onset chronic progressive: appears after 1 week
and within 1 year after completion of therapy.
c. Late-onset chronic progressive cardiotoxicity: occurs
after the first year, but may occur as long as 2 decades
after therapy has been completed. The risk of
developing heart failure remains a lifelong threat.
Radiation cardiotoxicity tends to have a gradual onset and
usually manifests after a decade or more 8.
Cardiovascular side effects in CCS may be either subclinical
(cardiac abnormalities, diagnosed with different diagnostic
methods in patients without symptoms )or clinical(
symptoms of clinical heart failure that are confirmed by
an abnormal diagnostic test). In the end stage of clinical
heart failure, heart transplantation is the only remaining
treatment option.
In children, the prevalence of subclinical heart failure at a
median of 6.4 years after treatment has been reported to
be more than 57% 13and the incidence of clinical heart
failure is as high as 16% 0.9 to 4.8 years after treatment14.
CCS are also at higher risk to develop cardiometabolic Risk
Factors for Premature Atherosclerosis. They are at a higher
risk of developing obesity, atherosclerosis and non –
atherosclerotic vascular disease, lipid abnormalities

108
(and metabolic syndrome), hypertension, endocrine
abnormalities (Growth hormone deficiency and Diabetes
Mellitus) and risky health behaviour, all of which can lead
to an increased risk of premature coronary vascular
disease8.

DIAGNOSIS AND MONITORING of

CARDIAC DYSFUNCTION AFTER THERAPY:
Monitoring of cardiac status during treatmenthelps to
identify early signs of potentially reversible disease, and
also provides baseline values for follow-up. Long-term
monitoring of CCS should be aimed at early, preclinical
detection, when interventions can be expected to have
the greatest benefit. There are no evidence based
guidelines for the monitoring of cardiac function in children
undergoing treatment for cancer or in CCS.
Parameters commonly assessed include (a) LV systolic
function and heart valve function by echocardiography,
(b) QTc and rhythm abnormalities by ECG, and (c) comorbid
conditions influencing cardiovascular health (blood
pressure, Lipid profile etc)8.
Echocardiography continues to be the mainstay of
monitoring due to convenience and availability. However,
the commonly measured parameters of LV shortening and
ejection fractions may not detect early cardiac dysfunction.
Other load-independent measures of systolic function
(end-systolic wall stress and velocity of circumferential fibre
shortening), diastolic function, tissue Doppler imaging,
global function (myocardial performance index), and
measures of cardiac mechanics (2-dimensional strain and
strain rate) are being evaluated 8. Cardiac MRI is a versatile

109
imaging modality ,with increasing potential application
in cardiac monitoring of CCS.
The most commonly accepted definition for anthracycline
induced cardiac dysfunction (during treatment) was laid
down in 1992 by Steinherz et al8. A clinically important
deterioration in function is defined as (1) a 10% absolute
decrease in LV FS, (2) an LV FS with an absolute value
<29% as measured by echocardiography, (3) a 10%
decrease in LV EF, or (4) a LV EF with an absolute value
<55%. The guidelines recommend discontinuing
anthracycline therapy if deterioration is found on 2
successive tests and obtaining a myocardial biopsy, if
possible. However, these guidelines are not evidence- based
and there is no evidence that screening using these
guidelines predicted either early or late adverse cardiac
toxicity 8.
Several cardiac biomarkers have been studied15-17 in those
who have already developed cardiotoxicity, or as predictors
of future cardiotoxicity. These studies support N-terminal
probrain natriuretic peptide (NT-proBNP) as one of the
best available biochemical markers of late anthracycline
cardiotoxicity; other markers such as cardiac troponin T,
studies and high-sensitivity C-reactive protein are yet to
show promise.
The frequency of screening depends on the CCS’s history
and physical examination, age at treatment, time from
treatment,and specific exposures and their cumulative
doses. There are several guidelines for screening in
CCS18-22 , and they are described later in this write-up.
Although cerebral vascular disease is reported with
increasing frequency in CCS, routine surveillance for this

110
complication is unsupported by evidence8. High Risk or
symptomatic patients will need evaluation with dedicated
vascular imaging such as magnetic resonance angiography.

GUIDELINES FOR MONITORING :

Four of the major childhood cancer collaborative groups
have proposed guidelines for the monitoring and
management of late cardiac effects due to treatment.1821.
These guidelines have been largely based on expert opinion
rather than being evidence- based. There have been a few
Cochrane reviews on this topic, as have already been
described earlier.
The North American Children’s Oncology group ( COG)
guidelines 18 were laid down by the COG Guideline
Taskforce on Cardiovascular Complications . These
advocate monitoring for cardiovascular disease in CCS who
have received anthracyclines, mediastinal irradiation and
neck irradiation. Amongst survivors who had received
anthracyclines, the high risk category was those who
received a cumulative anthracycline dose of > 550 mg/
m2 ( >300 mg/m2 if age <18 y at time of treatment), any
anthracycline dose in infants; or concomitant chest
radiation of30 Gy. Mediastinal irradiation of 40 Gy (30Gy
in those received concomitant anthracyclines) were also
considered high risk. These high risk CCS were advised (a)
Annual history and physical examination (b) Baseline
echocardiography or multiple gated acquisition (MUGA)
scan, then periodically, with frequency (ranging from yearly
to every 5 years) based on age at treatment, radiation
dose, and cumulative anthracycline dose. (c) Baseline
electrocardiogram for evaluation of QTc. Additionally, those
who received mediastinal radiation were advised to do
111
Fasting glucose and lipid profile every 3–5 years. CCS who
received Neck radiation of > 40 Gy were advised to
monitor for Carotid and subclavian artery disease with (a)
Annual history and physical examination (b) Doppler
ultrasound as clinically Indicated and
The Dutch Children’s Oncology group (DCOG LATER)
guidelines20 also recommend risk-based screening for
asymptomatic cardiac dysfunction in 5-year CCS. DCOG
recommends screening for asymptomatic cardiac
dysfunction in all CCS treated with potentially cardiotoxic
cancer treatment (anthracyclines, cardiac radiotherapy and
mitoxantrone), with more frequent follow-up for survivors
treated with anthracycline dose > 300 mg/m2 , mediastinal
> 30 Gy, or a combination of the two (any dose). DCOG
also recommends extra screening for female survivors in
the third trimester of pregnancy. The recommended
duration of follow-up is once every 5 years for lower risk
patients, and every 2/3 years for the higher risk groups,
and lifelong follow-up . The recommended modality for
monitoring is echocardiography , with parameters being
a decreased EF and/or FS ; borderline abnormal values were
defined as FS 25% –29% and EF 45%–49%) and clearly
abnormal cardiac function defined as FS < 25%, EF <
45%. Asymptomatic diastolic dysfunction and other
abnormal echocardiographic findings have not been
considered as significant parameters for asymptomatic
cardiac dysfunction in CCS. ACE Inhibitors have been
recommended after weighing the risk/benefit ratio, and
with careful monitoring for toxicity.
The Scottish Intercollegiate Network (SIGN) guidelines19
are similar to the above recommendations: CCS who have
received anthracyclines or radiation to a field that includes

112
the heart are advised long term monitoring for cardiac
dysfunction using echocardiography of EF and FS. CCS
detected to have asymptomatic left ventricular dysfunction
require long term echocardiographic monitoring. The
frequency of echocardiographic surveillance should be
individualized to the risk of anthracycline induced
cardiotoxicity : As with the DCOG guidelines, the
recommended duration of follow-up is once every 5 years
for lower risk patients( cumulative anthracycline doses less
than 250 mg/m2) and every 2/3 years in higher risk patients
(cumulative anthracycline doses greater than 250 mg/m2
,or who have also received radiotherapy to a field that
includes the heart) .Serum markers of cardiac injury are
not recommended as part of routine monitoring. CCS who
develop heart failure should be treated according to
evidence based guidelines for heart failure therapy.
The guidelines of the United Kingdom Children’s Cancer
Study Group Late Effects Group ( UK CCLG)21 are more
brief and concise, and also different from the other groups.
CCLG recommends monitoring for CCS who have received
Anthracyclines and related drugs, with/without
Radiotherapy to field including thorax, thoracic spine or
mediastinum. If the echocardiogram done at the end of
treatment is normal, monitoring should be repeated either
5 years after completion of treatment or at end of pubertal
growth spurt. CCS who have not had an echocardiogram
within the first 6 months after last anthracycline dose
should undergo echocardiography 3 yearly if repeatedly
normal. Abnormal echocardiogram defined as shortening
fraction of less than 28%. High risk CCS need more
frequent monitoring, and these include CCS previously
treated for early anthracycline cardiotoxicity, cumulative

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anthracycline dose >250 mg/m2, those who received
concomitant radiotherapy ,those who perform strenuous
exercise , pregnant CCS ,those on growth hormone /sex
steroid replacement therapy, and CCS with congenital heart
disease.
All the above guidelines also advocate health education;
CCS need education regarding the importance of a healthy
lifestyle, paying particular attention to smoking behaviour,
exercise and avoidance of overweight or obesity. CCS also
need monitoring for Cardiovascular risk factors such as
obesity, diabetes mellitus, hypertension and hyper-
lipidaemia .
The recommendations made by the first three groups have
many similarities, especially in the broad definition of High
Risk CCS, frequency and modality of monitoring and
management of asymptomatic cardiac dysfunction. The
COG guidelines summarize the levels of consensus, while
the DCOG guidelines summarize the methodological
quality and the level of evidence. The other two groups
do not clearly mention either methodology or levels of
evidence used in these recommendations.
Recently, The International Late Effects of Childhood Cancer
Guideline Harmonization Group 22 (IGHG; a worldwide
collaboration between several national guideline groups
and the Cochrane Childhood Cancer Group, and the
European PanCareSurFup Consortium) has proposed
Cardiomyopathy Surveillance Recommendations for
CCS.This international collaboration in guideline
development aims to reduce duplication of effort, optimize
the quality of care, and improve quality of life for
childhood, adolescent, and young adult cancer survivors.

114
The IGHG guidelines draw from the above-mentioned
major guidelines and the latest in literature, and are in the
process of publication. Asymptomatic cardiomyopathy is
defined as decline in LV systolic function (abnormal EF, SF,
wall stress) or diastolic function (abnormal E/A, prolonged
IVRT) in the context of preserved EF, without corresponding
symptoms of heart failure . Heart failure (HF) is defined as
symptomatic cardiomyopathy with evidence of cardiac
dysfunction on imaging studies (as defined by American
Heart Association). CCS at ‘High Risk’ of cardiac
dysfunction are those who have received > 250mg/m2 of
Anthracyclines, > 35 Gy of mediastinal radiation or
e”100mg/m2 of Anthracycline and e” 15 Gy mediastinal
radiation. Moderate risk is defined as Anthracycline dosage
between 100mg/m2 and 250mg/m2, and mediastinal
radiation between 15 to 35 mg/m2. CCS at low risk are
those who have received less than 100mg/m 2 .
Echocardiography is recommended as the primary
cardiomyopathy surveillance modality for assessment of
cardiac function .Radionuclide angiography or cardiac
magnetic resonance imaging (CMR) may be reasonable in
CCS for whom echocardiography is not technically feasible.
Assessment of cardiac blood biomarkers is not
recommended as the only strategy for surveillance, but
may be reasonable in conjunction with imaging studies
may be reasonable in instances where symptomatic
cardiomyopathy is strongly suspected. Surveillance is
recommended for High Risk survivors to begin no later
than 2 years after completion of cardiotoxic therapy,
repeated at 5 years after diagnosis and continued every 5
years thereafter. More frequent, and lifelong
cardiomyopathy surveillance is reasonable for High Risk
survivors. A similar strategy is reasonable in moderate/low

115
risk survivors. Cardiomyopathy surveillance is reasonable
prior to pregnancy or in the first trimester for all female
CCS treated with anthracyclines and/or chest radiation.
Cardiology consultation is recommended for CCS with
asymptomatic cardiomyopathy following treatment with
anthracyclines and/or chest radiation. The IGHG guidelines
also recommend regular exercise in CCS who have normal
cardiac function. CCS with asymptomatic cardiomyopathy
are recommended to consult a cardiologist before exercise.
Screening for modifiable CV risk factors (hypertension,
diabetes, dyslipidaemia, obesity) is also recommended for
all CCS so that necessary interventions can be initiated to
help avert the risk of symptomatic cardiomyopathy.

PREVENTION OF CARDIAC LATE EFFECTS

IN CCS :
So far, there is limited and suboptimal therapy for
anthracycline or radiation -induced cardiomyopathy in CCS
, and prevention of these late effects should be the aim.
In view of this known late effect, clinicians need to weigh
the risks and benefits while treating a child with cancer.
Some of the strategies to reduce/ avoid cardiovascular side
effects are as below
a. Dose reduction: Current treatment regimens now
utilize lower cumulative anthracycline doses and
reduced doses and fields of mediastinal irradiation ,
or completely avoid them altogether. Earlier
guidelines 8 considered a higher cumulative
anthracycline dose of 550mg/m2 as being risky, but
recent guidelines22 consider even doses of 250mg/
m2 to be high risk for late effects. A recent Cochrane
review 23 found a significantly higher survival with

116
 Anthracyclines in Wilms tumour and Ewings sarcoma
(metanalysis) ,and in a few individual studies of Acute
Lymphoblastic Leukaemia and Acute Myeloid
Leukaemia, but not in other tumours.
b. Structural modification of drugs: Several less
cardiotoxic anthracycline analogues have been
developed, including liposomal anthracyclines. These
drugs achieve higher concentrations in tumours and
lower concentrations in the heart 24, enabling higher
cumulative doses and causing less cardiac side effects.
However, these findings are yet to be confirmed in
children24,25 .
c. Lengthening the duration of infusion : Although adult
studies have found that continuous infusion of
anthracyclines results in lower cardiovascular side
effects than bolus doses, this finding was not
replicated in children 26,27.
d. Cardioprotective agents: There has been extensive
research devoted to the identification of agents
capable of preventing or ameliorating the toxicity.
— Dexrazoxane : Clinical trials 28,29 of dexrazoxane
(an iron-chelating agent that reduces the
formation of iron-anthracycline complexes ) have
been conducted in children, with encouraging
evidence of short-term cardioprotection and no
adverse effects on antitumor activity.A recent
Cochrane meta-analysis 29 showed a statistically
significant benefit in favour of dexrazoxane for
the occurrence of heart failure, with no difference
in response rate or survival between the
dexrazoxane. There was no significant difference
in the occurrence of secondary malignancies,

117
 although evidence regarding other side effects
was ambiguous. The Cochrane cancer group30
suggests that if treatmentwith anthracyclines is
necessary, then treatment with dexrazoxane
should beconsidered.
— Other cardioprotective agents such as ACE
inhibitor Carvedilol, antioxidants Coenzyme Q,L
–Carnitine ,Glutathione, N-acetylcysteine ,
vitamins E and C were found to be effective in
preclinical studies or isolated clinical studies, but
high quality evidence is lacking31.

MANAGEMENT OF LATE CARDIOTOXICITY

IN CCS :
Medical management of heart failure in CCS is as per
guidelines for the general population. Description of these
is beyond the scope of this write- up, but those interested
are referred to the comprehensive guidelines published
by the American Heart Association 8,32,33.
A recent Cochrane review 34 compared the effect of medical
interventions on anthracycline-induced cardiotoxicity in
childhood cancer patients or survivors withthe effect of
placebo, other medical interventions or no treatment.One
RCT comparing enalapril with placebo in childhood cancer
survivors with asymptomaticcardiac dysfunction showed
no statistically significant differences in overall survival,
mortality due to heart failure, development of clinical heart
failure or quality of life between treatment and control
group. Although enalapril temporarily improved left
ventricular end systolic wall stress , it was associated with
a high risk of complications such as hypotension and
dizziness. Another RCT comparing a two-week treatment

118
of phosphocreatine with a control treatment (vitamin C,
ATP, vitamin E, oral coenzyme Q10) in leukaemia patients
with anthracycline-induced cardiotoxicity found no
differences in overall survival, mortality due to heart failure,
echocardiographic cardiac function or adverse events
between treatment and control group. The authors
recommend higher quality studies before any conclusions
can be drawn .

Dietary and Exercise Recommendations for CCS :

Adult survivors of childhood cancer have an increased
prevalence of obesity and insulin resistance and may be at
risk of developing diabetes, dyslipidaemia, and metabolic
syndrome, all of which are potent risk factors for premature
cardiovascular disease 8. Thus monitoring for these
complications, and prevention/ management remains
crucial in CCS35-39. Lifestyle modifications in the form of
structured diet and exercise have been found useful in
promoting cardiovascular health in CCS 39-41 .Health
information and educational material for CCS in late effects
clinics, through peer-support groups and on the internet42-
44helps in promoting awareness and healthy lifestyles.

CONCLUSIONS AND FUTURE DIRECTIONS :

Improved survival in paediatric cancers highlights the
burden of late toxicities; cardiotoxicity is a major cause of
morbidity and mortality. Evidence-based monitoring and
screening of those at risk is essential in decreasing the
prevalence of this complication. The way forward appears
to be focussed Translational research and high quality
clinical trials , development of international collaborative
evidence- based guidelinesand validation of these
guidelines in the clinical setting.
119
 BOX SUMMARY WITH LEVEL OF EVIDENCE :
Level of Evidence Recommendation with Grade
Candidates for Surveillance:
Survivors treated with high dose Level 1 A Grade A
anthracyclines
Survivors treated with high dose Level 1 B Grade A
chest radiation
Survivors treated with anthracyclines Level 1 B Grade A
AND chest radiation

120
Survivors treated at a younger age (<5y) Level 2A Grade B
Female Survivors -symptomatic cardiac Level 1 B Grade A
dysfunction
Modality for cardiac surveillance in survivors :
Echocardiography No evidence Consensus : Recommended
Modality
Radionuclide angiography/ No conclusive Consensus: Not Recommended
Cardiac biomarkers evidence in isolation.
 Level of Evidence Recommendation with Grade
Frequency of Surveillance :
High Risk survivors * Level 1B** Consensus: Surveillance to begin
2 years after completion of
cardiotoxic therapy
Survivors who received Anthracyclines Level 1B** Consensus : <300mg/m2 –
every 5 years
>300 mg/m2- every 2/3years
Radiotherapy involving the heart No evidence Consensus : <30 Gy- every 5 years

121
>30Gy- 2/3 years
Anthracycline and Radiotherapy Level 2A Consensus : Regardless of dose,
every 2-3 years
Pregnant survivors Level 3 Consensus : Once in 3rd trimester
Duration of Screening No evidence Consensus : Lifelong
Management of Asymptomatic and Symptomatic Cardiac Dysfunction :
ACE inhibitors in asymptomatic anthracycline Level 2 Recommended when EF< 50%
induced cardiac dysfunction and FS< 30%, with monitoring
for side effects.
 Level of Evidence Recommendation with Grade
Other cardiovascular medication in No conclusive Consensus : Not recommended
asymptomatic cardiac dysfunction evidence
Cardiology consultation in asymptomatic Consensus: Recommended
and symptomatic cardiac dysfunction
Regular exercise Consensus : Recommended
Screening for modifiable CV risk factors Consensus : Recommended
(hypertension, diabetes, dyslipidemia,
obesity) in all survivors.

122
 * High Risk as defined in text
 ** Although evidence regarding late cardiotoxicity in these groups is of level 1B, there are no
evidence based guidelines regarding frequency of monitoring.
 Most guidelines for screening are based on expert consensus.
References :
1. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER
Cancer Statistics Review, 1975-2011, National Cancer
Institute. Bethesda, MD, http://seer.cancer.gov/csr/
1975_2011/ , based on November 2013 SEER data
submission, posted to the SEER web site, April 2014
2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic
health conditions in adult survivors of childhood
cancer. N Engl J Med. 2006;355(15):1572–1582
3. Armstrong GT, Oeffinger KC, Chen Yet al: Modifiable
risk factors and major cardiac events among adult
survivors of childhood cancer. J ClinOncol 2013; 31:
3673–3680
4. Van der Pal HJ, Van Dalen EC, Van Delden E, et al.
High Risk of Symptomatic Cardiac Events in
ChildhoodCancer Survivors. Journal of Clinical
Oncology 2012;30:1429-37.
5. Diamond M, Franco V: Preventing and treating
anthracycline-related cardiotoxicity in survivors of
childhood cancer. Curr Cancer Ther Rev 2012; 8: 141–
151.
6. Franco VI, Henkel JM, Miller TL, et al: Cardiovascular
effects in childhood cancer survivors treated with
anthracyclines. Cardiol Res Pract 2011;2011: 134679.
7. Lipshultz S.E., Sambatakos P, Maguire M, et al.
Cardiotoxicity and Cardioprotection in Childhood
Cancer ActaHaematol 2014;132:391–399
8. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term
cardiovascular toxicity in children, adolescents, and
young adults who receive cancer therapy:

123
 pathophysiology, course, monitoring, management,
prevention, and research directions: a scientific
statement from the American Heart
Association. Circulation. 2013;128:1927-1995
9. Armenian, S. H., Ding, Y., Mills, G., et al Genetic
susceptibility to anthracycline-related congestive heart
failure in survivors of haematopoietic cell
transplantation. British Journal of Haematology
(2013), 163: 205–213.
10. Blanco JG, Sun CL, Landier W, et al.: Anthracycline-
related cardiomyopathy after childhood cancer: role
of polymorphisms in carbonyl reductase genes—a
report from the Children’s Oncology Group. J
ClinOncol 30 (13): 1415-21, 2012
11. Visscher H, Ross CJ, Rassekh SR, et al.:
Pharmacogenomic prediction of anthracycline-
induced cardiotoxicity in children. J ClinOncol 30 (13):
1422-8, 2012.
12. Dillenburg RF, Nathan P, Mertens L: Educational paper:
decreasing the burden of cardiovascular disease in
childhood cancer survivors: an update for the -
pediatrician. Eur J Pediatr 2013; 172: 1149–1160.
13. Kremer LCM, van der Pal HJH, Offringa M, e t
al. Frequency and risk factors of subclinical
cardiotoxicity after anthracycline therapy in children:
a systematic review. Annals of Oncology
2002;13:819-29.
14. Kremer LCM, van Dalen EC, Offringa M, Voute
PA. Frequency and risk factors of anthracycline-
induced heart failure in children: a systematic
review. Annals of Oncology 2002;13:503-12.

124
15. Lipshultz SE, Miller TL, Scully RE, et al. Changes in
cardiac biomarkers during doxorubicin treatment of
pediatric patients with high-risk acute lymphoblastic
leukemia: associations with longterm
echocardiographic outcomes. J ClinOncol 2012; 30:
1042–1049
16. Mavinkurve Groothuis, Annelies, et al. “Abnormal NT
pro BNP levels in asymptomatic long term survivors
of childhood cancer treated with
anthracyclines.” Pediatric blood & cancer 52.5
(2009): 631-636.
17. Mladosievicova B, Urbanova D, Radvanska E, et al.
Role of NT-proBNP in detection of myocardial damage
in childhood leukemia survivors treated with and
without anthracyclines. J ExpClin Cancer
Res. 2012;31:86
18. Shankar SM, Marina N, Hudson MM, et al.:
Monitoring for cardiovascular disease in survivors of
childhood cancer: report from the Cardiovascular
Disease Task Force of the Children’s Oncology Group.
Pediatrics 121 (2): e387-96, 2008.
19. Scottish Intercollegiate Guidelines Network (SIGN).
Long term follow up of survivors of childhood cancer.
Edinburgh: SIGN; 2013. (SIGN publication no. 132).
[March 2013] accessible online http://
www.sign.ac.uk/pdf/sign132.pdf
20. E. Sieswerda, A. Postma,E. C. van Dalen, et al. The
Dutch Childhood Oncology Group guideline for
follow-up of asymptomatic cardiac dysfunction in
childhood cancer survivorsAnnOncol (2012) 23 (8):
2191-2198

125
21. United Kingdom Children’s Cancer Study Group
(2005) Therapy based long-term follow-up. In A
practice statementSkinner R, Wallace WH, Levitt GA
(eds) 2nd Edition United Kingdom children’s cancer
study group, Late effects group: UK
22. International Late Effects of Childhood Cancer
Guideline Hormonizatino Group (and Pan Care SurFup
Consortium) Harmonising Cardiomyopathy
Surveillance Recommendations After Treatment of
Childhood Cancer, presented at European Symposium
on Late Complications after Childhood Cancer
September 15, 2014. (Used with permission)
23. Va n D a l e n E C , R a p h a ë l M F, C a r o n H N , e t
a l . Treatment including anthracyclines versus
treatment not including anthracyclines for childhood
cancer. Cochrane Database Syst Rev 2009; 1.
24. Sieswerda E, Kremer LC, Caron HN, et al. The use of
liposomal anthracycline analogues for childhood
malignancies: a systematic review. Eur J Cancer 2011;
47: 2000– 2008
25. van Dalen EC, Michiels EMC, Caron HN, et al. Different
anthracyclinederivates for reducing cardiotoxicity in
cancer patients. Cochrane Database of Systematic
Reviews 2010, Issue 5. Art. No.: CD005006
26. Lipshultz SE, Miller TL, LipsitzSR,et al . Dana-Farber
Cancer Institute Acute Lymphoblastic Leukemia
Consortium: Continuous versus bolus infusion of
doxorubicin in children with ALL: long-term cardiac
outcomes. Pediatrics 2012; 130: 1003–1011.
27. van Dalen EC, van der Pal HJH, Caron HN, et al.
Different dosage schedules for reducing cardiotoxicity
in cancer patients receiving anthracycline

126
 chemotherapy. Cochrane Database of Systematic
Reviews 2009, Issue 4
28. Lipshultz SE, Rifai N, Dalton V,et al. The effect of
dexrazoxane on myocardial injury in doxorubicin-
treated children with acute lymphoblastic
leukemia.NEngl J Med 2004; 351: 145–153.
29. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment
of dexrazoxane as a cardioprotectant in doxorubicin-
treated children with high-risk acute lymphoblastic
leukaemia: long-term follow-up of a prospective,
randomised, multicenter trial. Lancet Oncol 2010; 11:
950–961.
30. van Dalen E.C., van den Berg H., Raphael M.F., et
al. Should anthracyclines and dexrazoxane be used
for children with cancer? (2011) The Lancet
Oncology, 12 (1) , pp. 12-13
31. van Dalen EC, Caron HN, Dickinson HO, et al.
Cardioprotective interventions for cancer patients
receiving anthracyclines. Cochrane Database of
Systematic Reviews 2008, Issue 2.
32. Hsu DT, Pearson GD. Heart failure in children: Part II:
Diagnosis, treatment, and future directions. Circ Heart
Fail 2009;2:490-8.
33. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/
AHA Guideline for the Management of Heart
Failure:Executive Summary: A Report of the American
College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J Am
CollCardiol 2013;62:1495-539
34. Sieswerda E, Van Dalen EC, PostmaAet al. Medical
interventions for treating anthracycline-induced

127
 symptomatic and asymptomatic cardiotoxicity during
and after treatment for childhood cancer. Cochrane
Database of Systematic Reviews 2011, Issue 9.
35. Akanji AO, Smith RJ. The insulin-like growth factor
system, metabolic syndrome, and cardiovascular
disease risk. MetabSyndrRelatDisord 2012;10:3-13.
36. Smith, W. A., Li, C., Nottage, K. A., et al. Lifestyle and
metabolic syndrome in adult survivors of childhood
cancer: A report from the St. Jude Lifetime Cohort
Study. Cancer, (2014), 120: 2742–2750
37. van Waas M, Neggers S. J. C. M. M., Pieters R, et al
.Components of metabolic syndrome in 500 adult
long-term survivors of childhood cancer Ann Oncol
(2010) 21;5:1121-1126
38. Claire Oudin, Marie-Claude Simeoni, Nicolas Sirvent,
et al. Prevalence and risk factors of the metabolic
syndrome in adult survivors of childhood
leukemiaBlood Apr 2011,117(17)4442-4448
39. Nuver, J The metabolic syndrome in long-term cancer
survivors, and important target for secondary
preventive measures.Cancer Treatment Reviews ,
Volume 28 , Issue 4 , 195 – 214
40. Järvelä, L. S., Kemppainen, J., Niinikoski, H , et
al.Effects of a home-based exercise program on
metabolic risk factors and fitness in long-term
survivors of childhood acute lymphoblastic leukemia.
Pediatr. Blood Cancer, (2012), 59: 155–160
41. Armstrong GT, Oeffinger KC, Chen Y, et al.: Modifiable
risk factors and major cardiac events among adult
survivors of childhood cancer. J ClinOncol 31 (29):
3673-80, 2013.

128
42. Childrens Oncology Group. Staying healthy through
diet and physical activity. http://
www.survivorshipguidelines.org/pdf/Dietand
PhysicalActivity.pdf. Health Links. Accessed November
12,2014.
43. CureSearch for Children’s Cancer Heart Problems
http://www.curesearch.org/Heart-Problems Accessed
November 12,2014.
44. Children’s Cancer and Leukaemia Group (CCLG) The
Heart http://www.cclg.org.uk/dynamic_files/CCLG-
AfterCure-Heart.pdf Accessed November 12,2014.

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Radiation Induced Heart Disease

Introduction
Radiation therapy is one of the mainstay of current
multimodality treatment for various cancer types. More
than 50% of patients with cancer are treated with
radiotherapy. The outcomes of cancer therapy have
changed over a last few decades with the use combined
modality treatment leading to increase in cancer
survivorship. Many childhood and adolescent tumors have
excellent cure rates. With improving cure rates the focus
shifts from disease control to long term effects of treatment
and quality of life (QOL). Prevention & management of
cardiac complications is a major challenge for clinicians
amongst various other late adverse effects of cancer
therapy. Amongst survivors of Hodgkin lymphoma (HL),
who have received radiation, cardiovascular disease (CVD)
is one of the most common non-malignant cause of death.
It is usually seen decades after treatment. The spectrum
of radiation induced heart disease is broad and includes
Coronary Artery Disease, Valvular Heart Disease, Congestive
Heart Failure, Pericardial Disease and Sudden Death.

130
Incidence
The patients cured of HL are at significantly increased risk
of death from CVD. The relative risk of cardiac mortality
ranges from 2.2 to 12.7 and absolute risk is 9.3 to more
than 28 of 10,000 person years of follow-up.(1)(2)(3)
About 88% of patients show asymptomatic cardiac
abnormalities. (4)The relative risk of death from a fatal
myocardial infarction in patients treated with mediastinal
RTis increased from 1.5 to 3.0 times that of un-irradiated
patients. There is also increase in cardiovascular morbidity
with increased need for interventions in the form
ofcoronary artery bypass grafting (CABG) (3.2-fold),
percutaneous coronary intervention (PCI) (1.6-fold),
implantable cardioverter defibrillator (ICD) or pacemaker
(1.9-fold), valve surgery (9.2-fold), pericardial surgery
(12.9-fold), and heartfailure (4.9-fold).(5)(6) This was seen
in the era when patients were treated with large fields of
radiation and with higher dose.With improvement in
radiation techniques and reduction in dose of radiation
the risk has decreased. However long term incidence of
cardiac morbidities using modern radiotherapy techniques
and reduced dose & volumes of radiation are currently
not clearly understood.Further long term follow up is
needed to see the patterns and prevalence of radiation
induced heart disease.

Pathophysiology of Radiation Induced

Cardiac Injury
Radiation damage to the heart can involve any part of
heart with pericardium, myocardium, valves, and coronary
vessels with pericardium being most frequently
involved.Radiation damages the endothelium by

131
generation of reactive oxygen species leading to endothelial
dysfunction, stimulation of growth factors and eventually
collagen deposition and fibrosis. The pathologic hallmark
of radiation induced heart disease is diffuse fibrosis of
myocardium and arterial lumen narrowing.
The spectrum of radiation induced heart disease includes:
(1) Radiation-induced atherosclerosis
(a) Symptomatic
(b) Asymptomatic
(2) Pericardial disease
(a) Acute pericarditis
(b) Delayed pericarditis
(c) Pericardial effusion
(d) Constrictive pericarditis
(3) Myocardial and Endocardial disease
(a) Pancarditis- myocardial fibrosis/ scar
(b) Restrictive Cardiomyopathy
(c) Heart failure- systolic or diastolic dysfunction.
(4) Valvular disease- mitral and aortic stenosis and
insufficiency.
(5) Conduction disturbances
(a) RBBB
(b) Atrioventricular nodal block

Coronary Artery Disease: There is increased capillary wall

permeability, intimal proliferation with collagen deposition
and fibrosis leading to stenosis of the artery. There is
formation of more fibrous atheromatous plaques. Ostial

132
stenosis is characteristic with high incidence of left main
disease followed by right coronary artery and left anterior
descending artery correlating with location of RT portals.
Pericarditis is usually self-limiting and effusions are
associated with dense fibrous adhesions. The fibrous
adhesions and fusion between the parietal and visceral
layers of pericardium are responsible for the constrictive
pericarditis. Diffuse interstitial fibrosis of the myocardium
alters its compliance leads to systolic and diastolic
dysfunction. Radiation can also damage the valves leading
to fibrotic thickening, valvular retraction, and late
calcification.
Bundle branch block is thought to be due to ventricular
injury affecting purkinje branches from high dose to the
epicardium. Right bundle branch block is more common
due to high dose to right ventricle owing to its anterior
location.

Clinical Presentation
The effect of radiation on the heart is evident about 2-3
decades intervals ranging from 3 to 29 years post
treatment.Acute pericarditis may develop during or after
mediastinal radiation, is usually transient and self-limiting.
Patients present with chest pain which is usually pleuritic
in character and on auscultation a friction rub is heard.
Chest X ray shows enlarged globular cardiac silhouette
and electrocardiogram shows diffuse ST segment elevation
in early phase and T wave inversion in late stages. It may
be complicated by tamponade if associated with effusion
and presents with dyspnea. Echocardiography helps to
establish the diagnosis.

133
Pericardial effusion is usually asymptomatic however
routine follow up chest X ray shows increase in heart size.
Constrictive pericarditis may present with exertional
dyspnea and pleural effusions or present as biventricular
failure with dyspnea, peripheral edema, hepatomegaly and
tamponade. Echocardiography, CT or MRI show thickening
of the pericardium without change in ventricular size.
Cardiac ischemia secondary to coronary artery disease may
be clinically silent or present with angina or exertional
dyspnea. Conduction defects present with BBB or
prolonged PR interval on ECG may develop AV block and
may require pacemakers.
Valvular heart disease is usually asymptomatic and during
routine follow up examination, auscultation reveals cardiac
murmurs suggestive of mitral or tricuspid valvular
insufficiency. Echocardiography is considered to document
extent of valvular insufficiency and need for interventions.

Risk Factors
The age at which patients are irradiated is an important
factor with higher risk in patients treated before the age
of 40 years. Treatment at a younger age conferred a higher
relative risk of MI than older age however the absolute
risk of death increases with increasing age of irradiation.
The risk of MI is higher in patients who receive mediastinal
radiation after 60 years.Risk is higher in patients who
receive repeated course of mediastinal radiation for
recurrent disease.
Patients treated with large field sizes as in “Mantle Field RT”
are conferred a higher risk.High dose per fraction (>2 Gy/
fraction) and Dose delivery via “anterior mediastinal field

134
alone”or “anteriorly weighted fields alone” also increase
the risk of cardiac complications. RT techniques using
“subcarinal blocking” tends to limit the dose to
myocardium to 30-35Gy and reduces the risk of myocardial
disease.Patients with classical risk factors like hypertension,
smoking, hypercholesterolemia, obesity and family history
are at increased risk of radiation-related cardiovascular
complications.
Table 1: Risk factors of Radiation Induced
Cardiotoxicity
Total dose more than 30–35 Gy
Higher dose/fraction >2 Gy/day
Field size (Volume of heart irradiated)
Relative field weighting (anterior/posterior positioning)
Presence of tumor next to the heart
Younger age at exposure
Cardiotoxic chemotherapy (e.g., anthracycline,
trastuzumab)
Other cardiovascular risk factors (e.g., diabetes, smoking,
hypertension)
Technique (reduced with conformal RT techniques)

Radiation Therapy Related Factors:

The dose threshold for risk of pericardial injury is 40 Gy if
more than 60% of the heart is included in the radiation
field and 55-60 Gy if less than 15% of the heart is
irradiated. The risk of early pericarditis is 20% in absence
of shielding, 7% with shielding of left ventricle and 2.5%
with both left ventricular shield and subcarinal block with
dose to ventricles limited to 30 Gy. There is no defined
dose effect criteria for development of coronary vascular
disease and 30 Gy is thought to be a relatively safe dose.

135
However with concurrent chemotherapy, it is appropriate
to keep dose to entire heart limited to 15 Gy with field
reductions. (7)The relationship between dose volume
parameters and valvular heart disease is also unclear due
to long latency and small number of events.

Treatment of Radiation Induced

Cardiotoxicity
Acute pericarditis is generally treated with non-steroidal
anti-inflammatory agents and in severe and refractory cases
steroids may be used. Pericardiocentesis is usually needed
to relieve tamponade. Small pericardial effusions usually
subside without any intervention. Constrictive pericarditis
usually needs pericardiectomy. Significant valvular
insufficiency may need corrective surgery.

Cardiac Evaluation and Screening

Prior to commencing radiation, a through baseline
evaluation includes cardiovascular history, cardiac
examination, documentation of risk factors and
echocardiography (include both systolic and diastolic
function). Medical management of risk factors should be
initiated.Rest and exercise echocardiography and
radionuclide scintigraphy is usually used to document
cardiovascular dysfunction in lymphoma survivors at
routine follow ups.The optimal frequency and method of
screening in post radiation patients is unclear. Exercise
echocardiography and radionuclide perfusion imaging are
used to screen the lymphoma survivors for occult coronary
artery disease and silent ischemia. Perfusion imaging with
MIBI shows stress related perfusion defects.
Echocardiography shows diastolic dysfunction with

136
decreased left ventricular mass and decreased left
ventricular ejection fraction. Rest and stress
echocardiography is used to assess LV systolic function,
diastolic function, valvular function, pericardial integrity,
and regional wall abnormalities.
Cardiac MRI is a sensitive test to assess arrhythmias,
cardiomyopathy. The American college of Radiology and
NCCN recommends a baseline stress echocardiogram at 5
to 10 years and 10 years, with 1 to 3 yearly glucose and
lipid profile review. (8)(9)The Children’s Oncology Group
has developed guidelines for the surveillance of pediatric
patients. They recommend second yearly transthoracic
echocardiograms for those below 5 years of age at
treatment (once yearly if concomitant anthracycline
therapy). For children >5 years at age of treatment,
recommendationswere based on radiation dose. Children
exposed to <30 Gy will require 5 yearly echocardiograms
however for those exposed to >30 Gy, a second yearly
echocardiogram (once yearly if moderate-dose
anthracyclines were needed). (10)Cardiac screening should
commence as early as 5 years post-cessation of radiation
treatment or after the age of 30, whichever occurs first.
Biomarkers: B type natriuretic peptide (BNP) and troponin
serve as useful serum biomarkers of early myocardial injury.
It should be done at 5 years and then annually. It may
help identify high risk patients.
In addition serum glucose and lipid profiles should be
monitored annually. Annual ECG is rather a simple
investigation to identify conduction anomalies. (11)

137
Prevention of Radiation Induced Cardiac
Injury
Subclinical damage occurs in more than 50% of the
survivors treated with radiation. The modern techniques
to reduce cardiac exposure mainly entails either
modification of the radiation portal (Involved field, involved
node and involved site RT), cardiac shielding (with lead
blocks or MLC), reduced fraction size (<2 Gy/day), reduced
total dose of radiation (<30 Gy/day), and relative field
weighting (aimed to minimize overexposure to the anterior
mediastinum). Newer promising techniques to further
reduce cardiac dose are under investigation and include
3-dimensional treatment planning, intensity modulated
RT, image-guided therapy and respiratory gating.
Patients who have already received mediastinal radiation
should undergo periodic assessment of known cardiac risk
factors and optimal medical management of lipids, glucose
intolerance and hypertension should be done. Efforts
should be aimed for tobacco cessation.Periodic screening
with stress tests and imaging studies may reduce the risk
of acute MI or sudden death.
In the earliest era of treatment of HL, heart was thought
to be radio-resistant. The earliest reports of radiation
induced heart disease emerged from Stanford in patients
treated with mantle field. The large population based
studies spanning 3 decades from 1970’s documented the
cardiac effects ranging from acute pericarditis, chronic
constrictive pericarditis, valvular heart disease and
premature coronary artery disease. The use of subcarinal
heart blocking, combined modality treatment with
chemotherapy and reduced volumes of radiation virtually

138
eliminated the risks of constrictive pericarditis and
pancarditis in patients with hodgkins’s lymphoma.
Myrehaug et al evaluated the risk of hospital admission
for cardiac disease in 1190 Hodgkin lymphoma survivors.
Pre-existing cardiac disease was the strongest predictor
for post-Hodgkin lymphoma therapy cardiac
hospitalization. Among patients with pre-existing cardiac
disease, mediastinal radiotherapy plus doxorubicin was
associated with a significantly higher risk of cardiac
hospitalization compared with doxorubicin-based
chemotherapy alone (p=0.036), and mediastinal
radiotherapy alone was associated with a significantly
higher risk than chemotherapy alone (p= 0.025)(12)
Galper et al assessed the risk of cardiac disease among
1279 Hodgkin lymphoma patients treated with mediastinal
irradiation at one of four Harvard-affiliated hospitals. At a
median follow-up of 15 years, the 5-, 10-, 15-, and 20-
year cumulative incidence rates of cardiac events were
2.2%, 4.5%, 9.6%, and 16%. Younger age at diagnosis
had an excess risk of cardiac events with radiation
therapy.(5)
Castellino et al conducted a multi-institutional retrospective
cohort study among 2742 survivors of HL in the Childhood
Cancer Survivor Study diagnosed from 1970 to 1986. A
substantial excess absolute risk (EAR) of mortality per
10,000 person-years was identified and about 13.1 was
attributed to cardiovascular disease.(3)

Cardiac Devices and Radiation

With increase in cardiovascular diseases, there is an increase
in patients with in situ pacemakers requiring radiation

139
treatments. The electromagnetic interferences can affect
working of the pacemaker. The use of radiation to the site
of implanted pacemaker can lead to failure or malfunction
due to ionizing effect or electromagnetic interferences.
The reasons for the damage to the pacemaker are 1)
destruction of electrical components (due to direct
irradiation) 2) effects on the random access memory (most
often secondary to scatter radiation or electromagnetic
irradiation. 3) Loading of the silicon dioxide insulator with
excess of electron-hole pairs which may persist to
accumulate a net positive charge on the insulator. All these
lead to temporary or permanent change in pacemaker
function. A permanent change will require either
reprogramming or replacement. (13)Ferrara et al studied
the effect of radiation on in-situ pacemakers(PM) in 45
patients requiring radiotherapy treatment and observed
no dysfunctions in any PM. The average maximum dose
received by PM was 2.5 Gy for head and neck and 1.8 Gy
for the thoracic region. The threshold tolerance dose of
PM was estimated from in-vitro studies and the maximum
safe dose rate is 20cGy/min. Hence no PM should never
be directly irradiated during treatment. (14)
American Association of Physicists in Medicine (AAPM)
issued guidelines in 1994(15):
a. Patients with implanted pacemaker should not be
treated with a betatron.
b. Pacemakers should not be in direct line of radiotherapy
beam.
c. The absorbed dose to be received by the pacemaker
should be estimated before treatment.
d. Pacemaker function should be checked if the total
estimated dose to the pacemaker might exceed 2Gy.

140
e. Most of the studies till dated have dealt with linear
accelerators, betatrons, and cobalt irradiators only.
The interaction of pacemakers with other units should
be evaluated on an individual basis and approached
with caution.
In 1997 Last et al reviewed the damage to pacemakers
from ionizing radiation.(16) The recommendations are as
follows:
a. Discuss actively with cardiologist regarding pacemaker
dependence.
b. It is reasonable to assume a 2 Gy threshold for
absorbed dose tolerance.
c. If possible, a 3 cm margin should be kept from the
radiation field edge.
d. Consider TLD or diode measurement on day one of
radiation therapy.
e. Do high-level monitoring if dose >2 Gy or pacemaker
dependent patient.
f. If cumulative dose >10 Gy, consider repositioning
the pacemaker.
Hurkman et al have proposed new guidelines for patients
with Cardiac Implantable Electronic Devices (CIED) as an
initiative by the Dutch Society of Radiotherapy
andOncology.(17)The CIED patients receiving radiotherapy
should be categorised based on the chance of device failure
and the clinical consequences in case of failure.
Low Risk: Patients receiving a dose of less than 2 Gy
to their CIED are categorised as low risk.
No extra measures are advised for this group.

141
 Medium Risk: Between 2 and 10 Gy, all patients are
categorised as medium risk. This also i n c l u d e s
patients who receive less than 2 Gy and are pacing
dependent. These patients can be safely treated
with additional monitoring. The precautions needed
are weekly CIED check by a pacemaker technician
and ECG-monitor and ‘crash cart’ including
defibrillator or AED present during each fraction. In
case of an emergency, external pacing equipment (e.g.
external pacemaker), personnel trained in
resuscitation and a pacemaker technologist and/or
cardiologist must be able to reach the patient within
10 minutes of a request in case of an emergency.
High Risk: Every patient receiving above 10Gy is
categorised as high risk. The benefit of
treatment should be weighed against the risk and
atleast the measures of medium risk must be
taken. ECG monitoring during each treatment can
be observed and CIED must be checked within
24 hours of treatment by pacemaker technician.

References:
1. Aleman BMP, van den Belt-Dusebout AW, Klokman
WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE. Long-
term cause-specific mortality of patients treated for
Hodgkin’s disease. Journal of clinical oncology/ :
official journal of the American Society of Clinical
Oncology. 2003 Oct 15;21(18):3431–9. PMID:
12885835
2. Swerdlow AJ, Higgins CD, Smith P, Cunningham D,
Hancock BW, Horwich A, et al. Myocardial infarction
mortality risk after treatment for Hodgkin disease: a

142
 collaborative British cohort study. Journal of the
National Cancer Institute. 2007 Mar 7;99(3):206–14.
PMID: 17284715
3. Castellino SM, Geiger AM, Mertens AC, Leisenring
WM, Tooze JA, Goodman P, et al. Morbidity and
mortality in long-term survivors of Hodgkin
lymphoma/ : a report from the Childhood Cancer
Survivor Study. Blood. 2011;117(6):1806–17.
4. Carver JR, Szalda D, Ky B. Asyptomatic Cardiac toxicity
in Long-term Cancer survivors: Defining the
population and Recommendations for surveillance.
Seminars in Oncology. 2013;40(2):229–38.
5. Galper SL, Yu JB, Mauch PM, Strasser JF, Silver B,
Lacasce A, et al. Clinically significant cardiac disease
in patients with Hodgkin lymphoma treated with
mediastinal irradiation. Blood. 2011;117(2):412–9.
6. Aleman BMP, Belt-dusebout AWVD, Bruin MLD, Veer
MBV, Baaijens MHA, Boer JPD, et al. Late cardiotoxicity
after treatment for Hodgkin lymphoma. Blood.
2007;109(5):1878–87.
7. Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce
LJ, Allen AM, et al. Radiation dose-volume effects in
the heart. International journal of radiation oncology,
biology, physics. 2010 Mar 1 [cited 2015 Jan 6];76(3
Suppl):S77–85. PMID: 20171522
8. Ng A, Constine LS, Advani R, Das P, Flowers C,
Friedberg J, et al. ACR Appropriateness Criteria: follow-
up of Hodgkin’s lymphoma. Current problems in
cancer. Elsevier Inc.; 2010 [cited 2015 Jan
31];34(3):211–27. PMID: 20541059

143
9. National Comprehensive Cancer Network (NCCN):
Clinical Practice Guidelines in Oncology. 2010.
Available at: http://www.nccn.org/professionals/
physician_gls/pdf/hodgkins.pdf.
10. Group CsO. Long-Term Follow-Up Guidelines for
Survivors of Childhood, Adolescent, and Young Adult
Cancers. Available at: http://survivorship-
guidelines.org/pdf/LTFUGuidelines.pdf.
11. Jaworski C, Mariani J a, Wheeler G, Kaye DM. Cardiac
complications of thoracic irradiation. Journal of the
American College of Cardiology. 2013 Jun 11 [cited
2015 Jan 13];61(23):2319–28. PMID: 23583253
12. Myrehaug S, Pintilie M, Yun L, Crump M, Tsang RW,
Meyer RM, et al. A population-based study of cardiac
morbidity among Hodgkin lymphoma patients with
preexisting heart disease.Blood. 2010;116(13):2237–
41.
13. Munshi A, Agarwal JP, Pandey KC. Cancer patients
with cardiac pacemakers needing radiation treatment:
a systematic review. Journal of cancer research and
therapeutics. 2013 [cited 2015 Jan 31];9(2):193–8.
PMID: 23771357
14. Ferrara T, Baiotto B, Malinverni G, Caria N, Garibaldi
E, Barboni G, et al. Irradiation of pacemakers and
cardio- defibrillators in patients submitted to
radiotherapy/ : a clinical experience. Tumori. 2010;76–
83.
15. Marbach JR, Sontag MR, Van Dyk J, Wolbarst AB.
Management of radiation oncology patients with
implanted cardiac pacemakers: report of AAPM Task
Group No. 34. American Association of Physicists in
Medicine.Medical physics. 1994;21(1):85–90.
144
16. Last A. Radiotherapy in patients with cardiac
pacemakers. Br J Radiol. Department of Radiotherapy,
Royal Marsden Hospital, London, UK.;
1998;71(841):4–10.
17. Hurkmans CW, Knegjens JL, Oei BS, Maas AJJ,
Uiterwaal GJ, van der Borden AJ, et al. Management
of radiation oncology patients with a pacemaker or
ICD: a new comprehensive practical guideline in The
Netherlands. Dutch Society of Radiotherapy and
Oncology (NVRO). Radiation Oncology; 2012
Jan;7(1):198. PMID: 3528416

145
Cardiac Effects of Radiation
Therapy in Women with
Breast Cancer

Introduction
Radiotherapy (RT) has a vital role in the treatment of breast
cancer in the adjuvant setting, both after mastectomy &
breast conserving surgery (BCS) (1). However there have
always been concerns regarding toxicity of RT with respect
to normal structures such as heart and lung (1, 2). The
therapeutic index has been hampered due to cardiac dose
of RT which has impact both on morbidity as well as
mortality (3). In view of close proximity to the heart, the
left sided breast cancers may be at a higher risk of
developing cardiac effects (4).

History & evolution of data

Heart was considered as a radioresistant organ till 1950’s
when the data concerning cardiac mortality started to
emerge from the Hodgkin’s lymphoma studies where
patients were primarily treated with radiation (5). The doses
of more than 30 Gy were considered detrimental (5, 6).
146
However data from the atomic bomb survivors showed
that doses as low as 0-4 Gy leads to clinically significant
cardiotoxicity & mortality (7, 8).
In 1987, Cuzick et al, reported the detrimental effect of
radiotherapy on survival in the adjuvant setting &
concluded that radiation was associated with more risks
(9). Later, Cuzick et al in 1994 conducted an individual
patient meta-analysis of 8 randomised trials started before
1975 in which patients were randomised to radiotherapy
vs no radiotherapy after mastectomy (2). This study also
showed 62% increase in cardiac mortality rates with RT
which was statistically significant (p < 0.001). However it
was observed that the breast cancer associated deaths
were significantly less in patients who received
radiotherapy & that the cardiac mortality rates were less
in patients treated with newer techniques.
The Early Breast Cancer Trialist Collaborative Group
(EBCTCG) in their initial publication of 1995 evaluated the
impact of RT in 28,405 women with breast cancer enrolled
in 36 randomised trials (10). They observed 3 times
reduction in the rate of recurrence with addition of RT to
surgery. However there was statistically significant increase
in the non-cancer mortality in the women receiving RT
(p=0.002) which resulted in similar overall survival with
or without RT.
The reported literature were mainly of the pre-linear
accelerator era where the radiotherapy techniques were
older & delivery was with orthovoltage X Rays with wider
fields, often encompassing the internal mammary chain.
Also, a practice of treating the chestwall with a direct
anterior portal was more common. Another important

147
factor is that in some of the older studies, the chestwall
was not irradiated which diluted the beneficial results. With
the improvement in radiotherapy planning, uniform
treatment of chestwall in all the patients & the advent of
computed tomography for planning purpose, the results
are definitely expected to be less detrimental.
The next oxford overview of the 40 randomised trials by
the EBCTCG group evaluated the causes of mortality in
patients treated with radiotherapy(11). The overview
reported that there was 2/3rd reduction in loco-regional
recurrence rates with RT. This resulted in statistically
significant improvement in breast cancer mortality
(2p=0.0001). It was observed that there was around 30%
increase in cardiovascular related deaths (2p= 0.0003).
The most common cause of non-cancer mortality was due
to circulatory cause followed by heart diseases. This
resulted in a modest 2-4% improvement in overall survival
which was not statistically significant. This overview has
been criticized as it included both earlier & newer trials
and a mix of older & newer techniques.
Hence, there was a need to address the issue of risk benefit
ratio of adjuvant radiotherapy with modern techniques.
Patt et al, analysed approximately 16,000 patients of the
SEER database to evaluate the cardiac morbidity in breast
cancer patients treated in the megavoltage era (3).The
authors reported that there was no significant increase in
cardiovascular morbidities in patients treated with adjuvant
radiotherapy compared to non-irradiated patients. The
main strength of this study was that the authors reported
the incidence of various manifestations of heart diseases
such as ischemic heart disease, vascular heart diseases,

148
and conduction abnormalities in patients with a follow
up of more than 10 years. Another observation was the
insignificant difference between the morbidity based on
the laterality of the cancer. The report of morbidity might
have been under reported as the patients with minor
defects may be overlooked since patients who were
hospitalised only were taken into account. This is one of
the first studies which evaluated the causes of cardiac
morbidity.
Finally in 2005, the EBCTCG update of 78 randomized
trials confirmed the improvement in the overall survival
with addition of RT. They concluded that for every 4 local
recurrence reduction, there is a benefit of avoiding 1 breast
cancer death. This means that the decrease in 5-year local
recurrence risk by 20% would reduce the 15-year breast
cancer mortality by 5% approximately (SE 0·8, 2p;
0·00001). The main cause of non breast cancer mortality
even in this publication was cardiovascular events (1).
Giordano et al analysed 12 registry SEER dataset to analyse
the risk of mortality due to ischaemic heart disease in
patients treated with adjuvant radiotherapy over different
time periods & also to evaluate the results of left sided vs
right sided breast cancers. It was observed that pre-1980’s
treated patients were at a higher risk of developing
ischaemic heart disease associated mortality. There was a
significant increase in ischaemic heart disease related
mortality in left sided cancers as compared to right sided
cancers. This difference was significantly higher in patients
who were treated in 1970’s with 15 year mortality rate of
13.6% vs 10.2% in left vs right side cancers. The authors
reported a decrease in death risk from 13% to 5.5% for
those treated in 1970s as compared to those treated

149
between1985-1989.During the later period the difference
in the mortality between the right & left sided cancers
reduced significantly (4). This again can be attributed to
the improvement in techniques, & the decline in the use
of IMC irradiation.
Darby et al, reported the results of a prospective analysis
of heart related mortality in patients treated between
1973-2001 in which patients were analysed depending
on the era of treatment. It was observed that in patients
treated prior to 1983, the mortality risk ratio was 1.58 at
15 year follow up, 1.42 at 10 year follow up & 1.2 at less
than 10 year follow up. In patients treated between 1983-
1992, cardiac mortality ratio was 1.27 at 10 or more years
follow up & 1.04 at less than 10 year follow up. Patients
treated between 1993-2001, there was a reduction in
cardiac mortality which was 0.96 in patients with less than
10 year follow up (12). This again confirmed reduction in
the cardiac damage with improved techniques.
Hooning et al, provided with various important conclusions
in their report of mortality in long term survivors of breast
cancer patients treated with radiotherapy (13). The
detrimental effect of IMC radiation was clearly obtained
in patients with a follow up of two decades. With lesser
use of IMC radiation in 1980’s, though the risk of
myocardial infarction was reduced, there was an increase
in deaths due to congestive cardiac failure. Risk factors
such as use of anthracycline based chemotherapy increased
the risk of congestive cardiac failure, Smoking,
hypertension & hypercholesterolemia are synergistic factors
for the development of myocardial infarction and
congestive cardiac failure significantly.

150
All the above studies have clearly stated the benefit of
radiotherapy with decrease in cardiac related events over
the years. However, it is prudent to know that radiotherapy
has a cardiotoxic effect & every attempt to reduce cardiac
doses should be practised with vigour since a small
reduction in heart doses can reduce further morbidities.

Pathophysiology
Various mechanisms of damage due radiation have been
described (14):
Diffuse myocardial interstitial fibrosis
Microcirculatory damage leading to ischemia and fibrosis
Pericardial fibrosis, valvular fibrosis
Atherosclerosis.

Clinical situations
The damage to cardiac structures results in various clinical
manifestations which are as follows:
Coronary artery disease
Pericarditis
Cardiomyopathy
Valvular pericarditis
Valvular heart disease
Perfusion defects (Left sided breast cancers) due to
microvascular damage
In addition to the above, conduction abnormalities in the
form of arrhythmias also have been reported.
Coronary artery disease is the most common manifestation
after RT with patients developing accelerated atherosclerosis
151
resulting in the increased incidence of myocardial
infarction. The time period to the development of the
above manifestations varies from a few weeks in case of
pericarditis to more than 10 years for cardiomyopathies
(14). Most commonly, radiation induced heart disease is a
late sequelae, with the first manifestation after 2-3 years
of RT. Attempts have been made to understand the
pathophysiology of changes in patients treated with newer
techniques where ejection fraction & myocardial perfusion
changes have been studied (15). It has been noted that
perfusion defects start after 6 months after RT & the left
ventricular volume irradiated plays an important role. Even
a 5% inclusion of left ventricular volume can also have
major implications. The recent EBCTCG update reported
an increase in 3% of the cardiac related death with every
increase in 1 Gray.
Symptoms vary from patients being asymptomatic to
sudden cardiac death. Hence, it is crucial to identify the
patients and take appropriate measures to reduce these.
Pathophysiology Clinical Features
Pericardium Fibrosis & Pericarditis
fluid accumulation Pericardial effusion
Myocardium Interstitial Fibrosis Myocarditis
Capillary damage Congestive cardiac failure
Endocardium Stenosis & Fibrosis Regurgitation
Coronary Stenosis Premature CAD
Vessels Atherosclerosis Pulmonary hypertension
Conduction Fibrosis Valvular heart disease
& Valves Arrhythmias

152
Risk factors
In addition to radiation, presence of various other risk
factors have been associated with the increased risk of
cardiac mortality. Smoking has been shown to increase
fatal myocardial infarction as compared to non-smoking
patients with a hazard ratio (HR) of 3.04 (16). Similarly,
hypertension & left sided breast cancer patients have higher
mortality rates (HR: 11.4 vs no hypertension and no RT)
(16, 17).
Age is also an important risk factor with younger individuals
at a greater risk in view of higher fraction of cells being in
the dividing phase (18). The SEER results when analysed
with respect to age and the development of fatal
myocardial infarction, it was observed that the likelihood
of developing fatal myocardial infarction was higher in
patients with less than 60 years of age at the time of
presentation (16). With the increase in younger women
developing breast cancer, this is a major concern.
Framingham risk score (FRS) is a tool to assess the 10 year
cardiovascular risks & it would be advisable to categorise
the risk factors into modifiable & non modifiable.
Prophylactic treatments should be initiated in patients with
a higher risk of developing cardiac disease.

Radiation dose relationships

Though heart had been considered as a radioresistant
organ conventionally, radiobiological studies & clinical
reports have shown that radiation induced changes are
significant & need to be addressed in the clinical setting.
Although the tolerance of heart is assumed to be 30 Gy
with conventional fractionation in the past there have also

153
been reports where dose as low as 5Gy have caused
morbidity (19).
Maximum heart distance (MHD) & mean heart distances
have been traditionally used to estimate the dose to heart.
For every 1 cm increase in MHD, it was observed that mean
heart doses increased by 2.9% on average.
The French society of radiation oncology have reported
that heart doses should kept below 35 Gy. However, it is
important to note that the volume & the area of heart
irradiated is more crucial. The Danish breast cancer co-
operative group (DBCG) have proposed V20Gy of 10% &
V40 of 5% in patients treated with conventional dose
fractionation.
Lind et al, correlated the short term perfusion changes
with the percentage of left ventricle receiving > 25 Gy
whereas Correa et al, correlated the mean lung doses to
to the development of cardiac toxicity (20, 21).
Gagliardi et al, evaluated the volume co-relation to the
development of toxicities & concluded that maximum heart
distance is a poor indicator of the heart doses received
(22). Factors such as organ motion & the need of three
dimensional imaging has been emphasised. The literature
co-relating the dose-volume histograms to the
development of cardiac toxicities are not mature enough
to be clinically meaningful.
The risk of developing cardiac morbidity mainly ischaemic
heart diseases in patients treated with adjuvant
radiotherapy was evaluated by Darby et al. It was observed
that coronary diseases increase in a linear fashion with
the increase in the mean dose to the heart by 7.4% per

154
gray. The mean doses to the heart was 4.9 Gy in this study.
An important observation in this study was that there was
no threshold for the development of cardiac toxicities
contrary to the old school of thought of acceptance of
heart doses of 30 Gy. The presence of co-morbid conditions
such as diabetes, circulatory disorders, smoking prior to
RT had a higher incidence of cardiac events. When women
were grouped according to the mean radiation dose to
the heart of less than 2 Gy, 2 to 4 Gy, 5 to 9 Gy, or 10 or
more Gy, the percentage increase in the major coronary
effects were 10%, 30%, 40%, and116% respectively as
compared with the estimated percentage risk if heart did
not receive any dose (19).
Hence it is important to reduce the cardiac dose during
irradiation as much as possible. Small doses such as 5Gy
can also have detrimental effect. Hence complete shielding
of the heart should be considered where ever feasible.

Methods for detection

There are various investigations to detect the changes in
the heart & the vasculature.
Perfusion defects are commonly seen after 6 months which
may extend upto 5 years. Single photon emission
computed tomography (SPECT) is used for this purpose
(23). Pre and post RT SPECT have shown perfusion changes
which depend on the volume of the left ventricle irradiated
with more than 5% of left ventricle irradiated, more than
half of the patients developed perfusion defects. However,
the clinical relevance of perfusion studies in the
development of late sequelae such as myocardial infarction
or congestive cardiac failure are still uncertain.

155
Blood investigations for cardiac markers such as troponins
& brain natriuretic peptide (BNP) are useful in detecting
abnormalities especially when the patients have received
cardiotoxic chemotherapy. Hyperlipidemic changes are
observed after 2 years which can be evaluated by
conducting lipid profile tests at regular intervals in patients
with high risk.
Electrocardiography & 2D Echocardiography are the other
investigations used (24). Left ventricular ejection fraction
(LVEF) monitoring is done by 2D Echo. Newer techniques
such as strain rate imaging with Doppler Echo can detect
myocardial dysfunction at an earlier stage (25). Chest X
Ray is also valuable in detecting pericardial effusions.
Various studies have reported an increase late effects in
left sided breast cancer patients in the form of abnormal
stress tests and the increase need of cardiac catheterisation
which have shown coronary artery stenoses, with left
anterior descending artery developing stenosis in more
than three fourths of the patients (21, 26). It has been
observed that the distal part of the left anterior descending
artery receives a higher dose as compared to the proximal
part.
The timing of conducting the tests & the exact predictive
values are not conclusive since there are reversible changes
such as perfusion defects which normalise over years. Also,
there are no specific tests to diagnose RT induced heart
damage. Gene expression profile studies are still in the
experimental phase.
Awareness amongst the treating oncologists is essential
to anticipate the toxicities & conduct appropriate tests &
recognise the defects clinically in order to avoid mortality.

156
Current radiotherapy techniques
The main difference in the present day radiotherapy
practice compared to the older era is the use of tangential
portals & doses which are practised uniformly on an
average. The use of wide & deep tangents has reduced
drastically. Also, the use of internal mammary irradiation
has become very much less, though there is still a
significant group of radiation oncologists practising IMC
irradiation However, the techniques of practising IMC
irradiation also has undergone many changes with most
of the clinicians practising photon electron combination
therapy for IMC. Heart is also shielded completely or
partially with blocks even with conventional techniques.
These changes lead to a significant reduction in the doses
received to the heart & coronary vessels.
Improvisations can be done with the use of conformal
blocks which help in better dose distributions to the tumor
bed. The use of 3DCRT & IMRT techniques help in better
sparing of heart as compared to conventional techniques
especially in left sided cancers (27).
With the advent of respiratory gating, this can be achieved
with various methods such as deep inspiratory breath hold
technique, active breathing control, & gating (28, 29). The
disadvantage is that it is time consuming, however needs
to be implemented in suitable patients. For example, in a
patient with left sided tumour with hypertension or other
cardiac co-morbidities & receiving trastuzumab which
increases the risk of developing late toxicities which may
be fatal would be an ideal candidate for these techniques
under image guidance.

157
Factors such as treatment position have also shown great
difference in the volume of the heart being exposed to
the RT fields. In a study, it was reported that the heart
volume increased by 70% when the position was changed
from T-bar to 90 degree arm position (30).The position of
the tumour is also an important determining factor for
the volume of the heart irradiated with the inner quadrant
tumors receiving higher heart doses (31). Prone position
technique propagated by the MSKCC group have shown
to reduce the heart dose. Other positions like lateral
decubitus has been used by the French group.
The use of IMRT helps in achieving better dose
homogeneity, reducing the hot spots & mean heart doses
due to the steep dose gradient (27). Techniques such as
field in field forward IMRT technique have been used &
dosimetric studies have shown superior heart sparing as
compared to 2 dimensional & 3DCRT techniques (32).
Image guidance provides with the additional advantage
of visualisation of the respiratory movements & further
scope of reducing toxicities by incorporating respiratory
gating (33).
Another important area which needs to be addressed in
the present day is the use of hypofractionated RT after
breast conserving surgery. The START A & B trials have
shown comparable local control rates as that of
conventional fractionation (34).The increased dose of the
heart & its implications in long term are yet to be addressed
& hence the need of meticulous planning & delivery of
treatment is needed. It is important to be cautious when
heart is within the field & also when treating patients with
co-morbidities such as hypertension, diabetes and obesity.

158
At present it would be advisable to avoid hypofractionation
in these situations. The newer radiation techniques ensures
a promise to reduce the cardiac effects but the clinical
translation of the same to be witnessed would require
atleast a follow up of 15-20 years. The volume of heart
receiving higher doses should be monitored during plan
evaluation & methods to reduce this by tailoring the RT
portals, use of beam modifying devices optimally should
be implemented.
The use of anthracylines & taxanes combined with
radiotherapy enhances the effects of RT on the heart (35,
36). The cardiac manifestation of anthracycline is mainly
in the form congestive cardiac failure which is irreversible
as compared to trastuzumab which is reversible & rarely
fatal if drug is stopped. The interplay of all the three
modalities & the resulting effects need to be evaluated.
Magne et al reported that there was no significant increase
in cardiac toxicities in patients treated with anthracyclines
and sequential RT (36). However, long term data is not
available at present.

References:
1. Clarke M, Collins R, Darby S, Davies C, Elphinstone P,
Evans E, et al. Effects of radiotherapy and of
differences in the extent of surgery for early breast
cancer on local recurrence and 15-year survival: an
overview of the randomised trials. Lancet. 2005 Dec
17;366(9503):2087-106.
2. Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards
R, Redmond C, et al. Cause-specific mortality in long-
term survivors of breast cancer who participated in

159
 trials of radiotherapy. J Clin Oncol. 1994
Mar;12(3):447-53.
3. Patt DA, Goodwin JS, Kuo YF, Freeman JL, Zhang DD,
Buchholz TA, et al. Cardiac morbidity of adjuvant
radiotherapy for breast cancer. J Clin Oncol. 2005 Oct
20;23(30):7475-82.
4. Giordano SH, Kuo YF, Freeman JL, Buchholz TA,
Hortobagyi GN, Goodwin JS. Risk of cardiac death
after adjuvant radiotherapy for breast cancer. J Natl
Cancer Inst. 2005 Mar 16;97(6):419-24.
5. Hancock SL, Tucker MA, Hoppe RT. Factors affecting
late mortality from heart disease after treatment of
Hodgkin’s disease. JAMA. 1993 Oct
27;270(16):1949-55.
6. Gagliardi G, Lax I, Soderstrom S, Gyenes G, Rutqvist
LE. Prediction of excess risk of long-term cardiac
mortality after radiotherapy of stage I breast cancer.
Radiother Oncol. 1998 Jan;46(1):63-71.
7. Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki
G. Noncancer disease incidence in atomic bomb
survivors, 1958-1998. Radiat Res. 2004
Jun;161(6):622-32.
8. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi
K. Studies of mortality of atomic bomb survivors.
Report 13: Solid cancer and noncancer disease
mortality: 1950-1997. Radiat Res. 2003
Oct;160(4):381-407.
9. Cuzick J, Stewart H, Peto R, Baum M, Fisher B, Host
H, et al. Overview of randomized trials of
postoperative adjuvant radiotherapy in breast cancer.
Cancer Treat Rep. 1987 Jan;71(1):15-29.

160
10. Effects of radiotherapy and surgery in early breast
cancer. An overview of the randomized trials. Early
Breast Cancer Trialists’ Collaborative Group. N Engl J
Med. 1995 Nov 30;333(22):1444-55.
11. Favourable and unfavourable effects on long-term
survival of radiotherapy for early breast cancer: an
overview of the randomised trials. Early Breast Cancer
Trialists’ Collaborative Group. Lancet. 2000 May
20;355(9217):1757-70.
12. Darby SC, McGale P, Taylor CW, Peto R. Long-term
mortality from heart disease and lung cancer after
radiotherapy for early breast cancer: prospective
cohort study of about 300,000 women in US SEER
cancer registries. Lancet Oncol. 2005 Aug;6(8):557-
65.
13. Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen
MA, Klijn JG, van Leeuwen FE. Cause-specific mortality
in long-term survivors of breast cancer: A 25-year
follow-up study. Int J Radiat Oncol Biol Phys. 2006
Mar 15;64(4):1081-91.
14. Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo
LF, Kodama K, et al. Radiation-related heart disease:
current knowledge and future prospects. Int J Radiat
Oncol Biol Phys. Mar 1;76(3):656-65.
15. Yu X, Prosnitz RR, Zhou S, Hardenberg PH, Tisch A,
Blazing MA, et al. Symptomatic cardiac events
following radiation therapy for left-sided breast
cancer: possible association with radiation therapy-
induced changes in regional perfusion. Clin Breast
Cancer. 2003 Aug;4(3):193-7.

161
16. Hooning MJ, Botma A, Aleman BM, Baaijens MH,
Bartelink H, Klijn JG, et al. Long-term risk of
cardiovascular disease in 10-year survivors of breast
cancer. J Natl Cancer Inst. 2007 Mar 7;99(5):365-75.
17. Kannel WB. Hypertension as a risk factor for cardiac
events—epidemiologic results of long-term studies. J
Cardiovasc Pharmacol. 1993;21 Suppl 2:S27-37.
18. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease
following treatment of Hodgkin’s disease in children
and adolescents. J Clin Oncol. 1993 Jul;11(7):1208-
15.
19. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-
Goldman U, Bronnum D, et al. Risk of ischemic heart
disease in women after radiotherapy for breast cancer.
N Engl J Med. 2013 Mar 14;368(11):987-98.
20. Lind PA, Pagnanelli R, Marks LB, Borges-Neto S, Hu
C, Zhou SM, et al. Myocardial perfusion changes in
patients irradiated for left-sided breast cancer and
correlation with coronary artery distribution. Int J
Radiat Oncol Biol Phys. 2003 Mar 15;55(4):914-20.
21. Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ,
Harris EE. Coronary artery findings after left-sided
compared with right-sided radiation treatment for
early-stage breast cancer. J Clin Oncol. 2007 Jul
20;25(21):3031-7.
22. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-
term cardiac mortality after radiotherapy of breast
cancer—application of the relative seriality model. Br
J Radiol. 1996 Sep;69(825):839-46.

162
23. Prosnitz RG, Hubbs JL, Evans ES, Zhou SM, Yu X,
Blazing MA, et al. Prospective assessment of
radiotherapy-associated cardiac toxicity in breast
cancer patients: analysis of data 3 to 6 years after
treatment. Cancer. 2007 Oct 15;110(8):1840-50.
24. Lindahl J, Strender LE, Larsson LE, Unsgaard A.
Electrocardiographic changes after radiation therapy
for carcinoma of the breast. Incidence and functional
significance. Acta Radiol Oncol. 1983;22(6):433-40.
25. Nikitin NP, Cleland JG. [Use of myocardial tissue
Doppler imaging in cardiology]. Kardiologiia.
2002;42(3):66-79.
26. Erven K, Florian A, Slagmolen P, Sweldens C, Jurcut
R, Wildiers H, et al. Subclinical cardiotoxicity detected
by strain rate imaging up to 14 months after breast
radiation therapy. Int J Radiat Oncol Biol Phys. Apr
1;85(5):1172-8.
27. Landau D, Adams EJ, Webb S, Ross G. Cardiac
avoidance in breast radiotherapy: a comparison of
simple shielding techniques with intensity-modulated
radiotherapy. Radiother Oncol. 2001 Sep;60(3):247-
55.
28. Mulliez T, Veldeman L, Speleers B, Mahjoubi K,
Remouchamps V, Van Greveling A, et al. Heart dose
reduction by prone deep inspiration breath hold in
left-sided breast irradiation. Radiother Oncol. Dec 9.
29. Korreman SS, Pedersen AN, Nottrup TJ, Specht L,
Nystrom H. Breathing adapted radiotherapy for breast
cancer: comparison of free breathing gating with the
breath-hold technique. Radiother Oncol. 2005
Sep;76(3):311-8.

163
30. Taylor CW, Nisbet A, McGale P, Darby SC. Cardiac
exposures in breast cancer radiotherapy: 1950s-
1990s. Int J Radiat Oncol Biol Phys. 2007 Dec
1;69(5):1484-95.
31. Bouchardy C, Rapiti E, Usel M, Majno SB, Vlastos G,
Benhamou S, et al. Excess of cardiovascular mortality
among node-negative breast cancer patients
irradiated for inner-quadrant tumors. Ann Oncol.
Mar;21(3):459-65.
32. Stillie AL, Kron T, Herschtal A, Hornby C, Cramb J,
Sullivan K, et al. Does inverse-planned intensity-
modulated radiation therapy have a role in the
treatment of patients with left-sided breast cancer? J
Med Imaging Radiat Oncol. Jun;55(3):311-9.
33. Lemanski C, Thariat J, Ampil FL, Bose S, Vock J, Davis
R, et al. Image-guided radiotherapy for cardiac sparing
in patients with left-sided breast cancer. Front
Oncol.4:257.
34. Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett
J, Barrett-Lee PJ, et al. The UK Standardisation of Breast
Radiotherapy (START) trials of radiotherapy
hypofractionation for treatment of early breast cancer:
10-year follow-up results of two randomised
controlled trials. Lancet Oncol. Oct;14(11):1086-94.
35. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond
C, Margolese RG, et al. Two months of doxorubicin-
cyclophosphamide with and without interval
reinduction therapy compared with 6 months of
cyclophosphamide, methotrexate, and fluorouracil in
positive-node breast cancer patients with tamoxifen-
nonresponsive tumors: results from the National

164
 Surgical Adjuvant Breast and Bowel Project B-15. J
Clin Oncol. 1990 Sep;8(9):1483-96.
36. Magne N, Castadot P, Chargari C, Di Leo A, Philippson
C, Van Houtte P. Special focus on cardiac toxicity of
different sequences of adjuvant doxorubicin/
docetaxel/CMF regimens combined with radiotherapy
in breast cancer patients. Radiother Oncol. 2009
Jan;90(1):116-21.

165