Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer

Department of Pediatrics, Leonard M Miller School of Medicine, University of Miami, Holtz Children's Hospital of the University of Miami/Jackson Memorial Medical Center, Miami, FL 33101, USA.
Heart (British Cardiac Society) (Impact Factor: 5.6). 05/2008; 94(4):525-33. DOI: 10.1136/hrt.2007.136093
Source: PubMed

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Available from: Rebecca Elizabeth Scully, Jan 20, 2016
CLINICAL PHARMACOLOGY
Anthracycline associated
cardiotoxicity in survivors of
childhood cancer
Steven E Lipshultz,
1
Jorge A Alvarez,
2
Rebecca E Scully
2
1
Department of Pediatrics,
Leonard M Miller School of
Medicine, University of Miami,
Holtz Children’s Hospital of the
University of Miami/Jackson
Memorial Medical Center, and
the University of Miami
Sylvester Comprehensive Cancer
Center, Miami, Florida, USA;
2
Department of Pediatrics,
Division of Clinical Research,
University of Miami Miller
School of Medicine, Miami,
Florida, USA
Correspondence to:
Steven E Lipshultz, MD,
Department of Pediatrics,
Leonard M Miller School of
Medicine, University of Miami,
Holtz Children’s Hospital of the
University of Miami/Jackson
Memorial Medical Center and
The University of Miami
Sylvester Comprehensive Cancer
Center, PO Box 016820 (D820),
Miami, FL 33101, USA;
slipshultz@med.miami.edu
The development of effective antineoplastic thera-
pies for childhood cancer is a great success in
modern medicine. Five year survival rates of
children diagnosed with cancer in the USA and
Western Europe in excess of 70% make long term
survivors of childhood cancer a steadily increasing
population. Although there is much to celebrate,
new challenges lie ahead in treating the systemic
sequelae of chemotherapy.
1
Results from the
Childhood Cancer Survivor Study (CCSS) showed
that 30 years after treatment, the cumulative
incidence of chronic health conditions in long term
survivors reaches 73%, with a cumulative incidence
of 42% for severe, disabling, or life threatening
conditions or death.
2
Severe conditions, that are
significantly more common in childhood cancer
survivors than in their siblings, include: major joint
replacement (relative risk (RR) 54.0), congestive
heart failure (RR 15.1), second malignant neoplasm
(RR 14.8), severe cognitive dysfunction (RR 10.5),
coronary artery disease (RR 10.4), cerebrovascular
accident (RR 9.3), and renal failure (RR 8.9).
2
Previous CCSS results found that patients who
had survived at least 5 years after diagnosis had
10.8-fold increased rates of all cause mortality.
3
The standardised mortality ratio for cardiac causes
was 8.2 times higher than expected and the
cumulative probability of cardiac death increased
15–25 years after cancer diagnosis. A similar study
in a large Nordic cohort documented a standardised
mortality ratio of 5.8 for cardiac death and elevated
rates of sudden, presumed arrhythmic, deaths.
4
Chief among adverse late effects is the
cardiovascular toxicity of anthracyclines.
5–11
Unfortunately, despite well documented dose
related toxicity, the superior disease-free survival
rates of regimens including anthracyclines leave
limited viable treatment alternatives and the
majority of long term paediatric cancer survivors
in the Pediatric Oncology Group received an
anthracycline during treatment.
12
NATURAL HISTORY OF ANTHRACYCLINE
CARDIOTOXICITY
Mechanism of cardiotoxicity
Several cytotoxic biochemical changes follow
anthracycline exposure in cellular studies and
animal models, and cardiac dysfunction after in
vivo exposure is likely to be the cumulative result
of several insults.
9111314
A major pathogenic pathway links the genera-
tion of radical oxygen species (ROS) and lipid
peroxidation of the cell membrane to cardiomyo-
cyte injury acquired during anthracycline exposure.
Anthracyclines can induce ROS generation both
enzymatically and through the formation of
anthracycline–iron complexes.
9111314
The anthra-
cycline’s quinone moiety can be reduced to
semiquinone by cytosolic enzymes and then read-
ily donate an electron to oxygen, generating
superoxide anions. The superoxide anions can
cause subcellular damage directly, or they can be
further converted to hydrogen peroxide and the
highly reactive hydroxyl radical. These agents are
highly toxic and react with lipids, proteins and
nucleic acids, resulting in lipid peroxidation, deple-
tion of sulfhydryl-containing peptides, and damage
to DNA. Cardiac myocytes have low levels of free
radical scavenging systems, such as catalase and
glutathione peroxidase, which may sensitise these
cells to ROS induced injury.
9111314
Cardiolipin is a polyunsaturated, fatty acid-rich
phospholipid with a high affinity for anthracy-
clines found in elevated concentrations in the inner
mitochondrial membrane. Anthracyclines are
thought to enter mitochondria and to inhibit the
respiratory chain by binding to cardiolipin or by
interacting with mitochondrial DNA. The high
concentrations of cardiolipin within the mitochon-
dria may also increase the susceptibility of cardiac
cells to anthracycline damage.
9111314
Anthracyclines decrease ATP production by
disrupting the cardiac muscle specific gene expres-
sion of enzymes critical in energy production, as
well as by disrupting structural gene products (for
example, cardiac troponins, myosin light chains,
and creatine kinase). They may also downregulate
mRNA expression for sarcoplasmic reticulum Ca
2+
-
ATPase, which in turn decreases cardiac contrac-
tility. Energy depletion reduces the ability of
cardiac myocytes to contract effectively and, if
severe enough, can lead to cell death. A cycle of
interconnected mitochondrial DNA and respira-
tory chain insults can continue after the end of
treatment and in the absence of anthracyclines.
These insults may, in part, account for the delayed
manifestation of cardiomyopathy.
9111314
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Although the oxidative effects of anthracyclines
may not be limited to cardiac cells, rapidly dividing
cells may be able to replace those lost to apoptosis or
necrosis. Cardiomyocytes—which divide very
slowly, if at all—cannot sufficiently replace cells
damaged during treatment. Myocardial histology
suggests that surviving myocytes compensate to
maintain normal cardiac structure via hypertrophy.
5–
7
These findings suggest that the characteristically
delayed manifestation of symptomatic cardiotoxicity
after anthracycline exposure may be related to the
eventual failure of a reduced number of unhealthy
cardiomyocytes to maintain normal functions.
5–7
Presentation of disease
The cardiac effects of anthracycline chemotherapy
are variable and include asymptomatic electrocar-
diographic abnormalities, mild hypotension,
arrhythmias, myocarditis, pericarditis, acute myo-
cardial infarction, heart failure, and long term
cardiomyopathy. Anthracycline induced cardio-
toxicity is classified into three categories: (1) acute,
(2) early onset chronic progressive, and (3) late
onset chronic progressive (table 1). There are some
differences in time of onset, clinical characteristics,
and associated risk factors.
8–11
Acute anthracycline cardiotoxicity often pre-
sents as a reversible episode of myocardial dysfunc-
tion during therapy. The estimated incidence of
acute clinically symptomatic toxicity on frontline
protocols is less than 1%.
912
Within a week of the
initial dose, cardiotoxicity manifests as transient
clinical symptoms suggesting heart failure.
Electrocardiographic abnormalities, including non-
specific ST segment and T wave changes, decreased
QRS amplitude, and prolonged QTc interval, are
infrequently seen; however, sinus tachycardia is
most often present and may represent autonomic
dysfunction. Symptoms usually resolve when
therapy is discontinued.
Early onset chronic progressive cardiomyopathy
occurs within 1 year after anthracycline treat-
ment.
8–12 15
Electrophysiological changes, left ven-
tricular (LV) dysfunction, decreased exercise
capacity, and clinical heart failure may develop.
Late onset chronic progressive cardiomyopathy
occurs more than 1 year after anthracycline treat-
ment.
8–11 15
Cardiac function begins to deteriorate
and is associated with myocyte loss, which leads to
LV wall thinning and in some cases progressive LV
dilation.
5–7
Echocardiographic abnormalities may
include decreased LV fractional shortening, end
diastolic posterior wall thickness, mass, contrac-
tility, and increased LV afterload. Left ventricular
dimension may be increased, normal, or decreased.
In 115 survivors of childhood acute lymphoblastic
leukaemia (ALL), we found that 6 years after
anthracycline treatment nearly 65% had abnormal
LV structure or function.
5
Although adults typically develop chronic
dilated cardiomyopathy after anthracycline che-
motherapy, children at the end of anthracycline
treatment have a dilated cardiomyopathy, which
may then progress to a restrictive cardiomyo-
pathy.
7
Afterload increases, in spite of normal-to-
reduced blood pressure caused by decreased LV
wall thickness and mass.
5–7
Thus, the decline in LV
function is related more to elevated LV afterload
than reduced LV systolic performance.
5–7
Heart
failure with preserved LV ejection fraction (LVEF)
is increasingly recognised in this exposed popula-
tion with long term follow-up. In patients without
cancer survival rates have remained unchanged
over a similar period, whereas in patients with
heart failure associated with decreased LVEF,
outcomes have improved.
111
These findings under-
score the need to develop treatments specific to
this type of cardiac dysfunction.
10 11 14 16
EFFECT OF ANTHRACYCLINES ON CHILDREN’S
HEARTS
The degree and progression of anthracycline-
related toxicity varies widely between individuals,
suggesting that genetic predisposition and modifi-
able and non-modifiable risk factors are present.
Several risk factors for cardiotoxicity have been
identified (table 2, fig 1). Some risk factors,
including cumulative dose, dose rate, dosing
schedule, and concomitant treatment, are poten-
tially modifiable.
5–12 15
The accumulation of risk
factors leads to a substantial increase in relative
risk for early anthracycline cardiotoxicity.
12
Understanding these risk factors will allow clin-
icians to identify high risk patients and to tailor
monitoring and treatment to individual patients.
11
Table 1 Characteristics of the different types of anthracycline associated cardiotoxicity
Characteristic Acute cardiotoxicity Early onset, chronic progressive cardiotoxicity Late onset, chronic progressive cardiotoxicity
Onset Within the first week of anthracycline treatment ,1 year after the completion of anthracycline
treatment
.1 year after the completion of anthracycline
treatment
Risk factor
dependence
Unknown Yes Yes
Clinical features in
adults
Transient depression of myocardial contractility;
myocardial necrosis (cTnT elevation); arrhythmia
Dilated cardiomyopathy; arrhythmia Dilated cardiomyopathy; arrhythmia
Clinical features in
children
Transient depression of myocardial contractility;
myocardial necrosis (cTnT elevation); arrhythmia
Restrictive cardiomyopathy and/or dilated
cardiomyopathy; arrhythmia
Restrictive cardiomyopathy and/or dilated
cardiomyopathy; arrhythmia
Course Usually reversible on discontinuation of
anthracycline
Can be progressive Can be progressive
Adapted with permission from Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood
Cancer 2005;44:600–6. Copyright Wiley-Liss, Inc.
15
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526 Heart 2008;94:525–533. doi:10.1136/hrt.2007.136093
Page 2
Non-modifiable cardiotoxicity risk factors
Age at treatment
Patients treated at a younger age appear to be more
vulnerable to anthracycline induced cardiotoxi-
city.
5–7 9
We found that treatment before age
4 years was a significant risk factor for later cardiac
dysfunction.
7
Length of follow-up
The importance of continuing to follow children
with, or at risk for, premature symptomatic
cardiovascular disease cannot be overemphasised.
With longer follow up after anthracycline treat-
ment, the prevalence and severity of cardiac
abnormalities increase.
5–7
This increase may relate
to the emergence of new cases of late onset cardiac
toxicity and to the worsening of previously
detected early onset chronic progressive cardio-
myopathy.
In children with ALL, LV contractility is
substantially depressed immediately after doxo-
rubicin treatment (negative Z score) but returns to
normal over the next 6 years.
7
From 6 to 14 years
later, however, LV contractility declines notably
(fig 2). Thus, the importance of lifetime follow-up
cannot be overstated and preventing late cardio-
toxicity must be a research priority,
717
particularly
as the number of asymptomatic cancer survivors at
risk for cardiac dysfunction later in life increases.
More than 6 years of follow-up is necessary to
identify those long term survivors at risk for
cardiac dysfunction.
7
Sex
Girls are at significantly greater risk than boys for
late depressed contractility, even when receiving
the same cumulative dose of doxorubicin.
67
Though the underlying cause of this difference is
not yet known, differences in sex specific body fat
percentage may be involved.
6
Genetic factors
High inter-patient variability in development and
progression of cardiac toxicity after anthracycline
use suggests that genetic factors (natural geno-
types or induced changes) may affect anthracycline
processing and eventual toxic effects.
11
Mutations
effecting iron metabolism are particularly impli-
cated. Mice with hereditary haemochromatosis, a
genetic disorder involving excess iron uptake and
storage, are significantly more sensitive to the
cardiotoxic effects of anthracyclines, than are wild
type mice. Anthracycline associated cardiac mito-
chondrial DNA (mtDNA) mutations have also
been implicated in susceptibility to cardiotoxicity.
11
Whether these mutations are inherent or induced is
not yet known.
Modifiable cardiovascular risk factors
The long term risk of anthracycline exposure can
be reduced by modifying risk factors that minimise
initial cardiac damage.
Table 2 Risk factors for anthracycline cardiotoxicity
Risk factor Aspects References
Cumulative
anthracycline
dose
Cumulative doses .500 mg/m
2
associated with significantly elevated long
term risk
Lipshultz et al 1991
5
; Krischer et al
1997
12
; Lipshultz et al 1995
6
; Lipshultz
et al 2005
7
Length of post-
therapy interval
Incidence of clinically significant
cardiotoxicity increases progressively
post-therapy
Lipshultz et al 1991
5
; Lipshultz et al
1995
6
; Lipshultz et al 2005
7
Rate of
anthracycline
administration
Prolonged administration to minimise
circulating dose volume may decrease
toxicity; results are mixed
Lipshultz et al 2002
23
Individual
anthracycline
dose
Higher individual anthracycline doses are
associated with increased late
cardiotoxicity, even when cumulative
doses are limited
Lipshultz et al 1995
6
; Lipshultz et al
2005
7
Type of
anthracycline
Liposomal encapsulated preparations may
reduce cardiotoxicity. Conflicting data
exist about anthracycline analogues and
cardiotoxicity differences
Wouters et al 2005
14
; Barry et al
2007
11
; Van Dalen et al 2006
20
Radiation therapy Cumulative radiation dose .30 Gy; prior
or concomitant anthracycline treatment
Giantris et al 1998
9
; Adams et al 2005
15
Concomitant
therapy
Trastuzumab, cyclophosphamide,
bleomycin, vincristine, amsacrine, and
mitoxantrone may increase susceptibility/
toxicity. Others are implicated as well
Giantris et al 1998
9
; Barry et al 2007
11
Pre-existing
cardiac risk
factors
Hypertension; ischaemic, myocardial, and
valvular heart disease; prior cardiotoxic
treatment
Barry et al 2007
11
Comorbidities Diabetes, obesity, renal dysfunction,
pulmonary disease, endocrinopathies,
electrolyte and metabolic abnormalities,
sepsis, infection, pregnancy
Barry et al 2007
11
Age Both young and advanced age at
treatment are associated with elevated
risk
Lipshultz et al 1991
5
; Lipshultz et al
1995
6
Sex Females are at greater risk than males Lipshultz et al 1995
6
Additional factors Trisomy 21; African American ancestry Krischer et al 1997
12
Figure 1 Demographic and clinical characteristics associated with cardiac and non-
cardiac findings in long term survivors of childhood cancer treated with anthracycline
therapy. Summary of significant associations of multivariable analyses of risk of reduced
left ventricular fractional shortening 8 years after anthracycline (doxorubicin) treatment
for childhood acute lymphoblastic leukaemia or osteosarcoma.
6
Reproduced with
permission from Wouters KA, Kremer LCM, Miller TL, et al. Protecting against
anthracycline-induced myocardial damage: a review of the most promising strategies. Br
J Haematol 2005;131:561–78. Copyrightß Blackwell Publishing 2005.
14
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Heart 2008;94:525–533. doi:10.1136/hrt.2007.136093 527
Page 3
Cumulative dose
A high cumulative anthracycline dose is a well
recognised risk factor for cardiac damage and
remains the best predictor of eventual cardiac
dysfunction, including increased afterload and
decreased contractility.
5–11 14 18–20
The risk of cardio-
toxicity with 550 mg/m
2
or more is five times
higher than that of lower cumulative doses.
12
A
cumulative doxorubicin dose above 300 mg/m
2
is a
significant risk factor for decreased cardiac func-
tion 8 years after therapy.
21
However, there is no
absolutely safe dose of anthracycline; even the
lowest clinically relevant doses can cause subse-
quent cardiac dysfunction.
7
Although lowering cumulative dose might
appear to be a straightforward solution to reducing
cardiotoxicity, cardioprotection must be balanced
with oncologic efficacy.
71622
Fortunately, the ratio
of increasing cumulative dose to increasing treat-
ment efficacy begins to plateau at higher doses and
the greatest gains in antineoplastic activity occur
within a range of slowly increasing cardiac risk.
16 22
In this case, the optimal cumulative anthracycline
dose is determined by taking both competing risks
into account.
Rate of administration
Peak serum concentrations of anthracyclines can
be controlled in part by altering the rate of
doxorubicin administration. Prolonged infusion
therapy has been recommended to reduce anthra-
cycline cardiotoxicity.
10 11 14 16 18–20 23 24
This practice
became standard before confirmation by rando-
mised trials and subsequent studies have ques-
tioned its efficacy to reduce long term
cardiotoxicity. Our blinded, randomised trial in
children with newly diagnosed ALL comparing
bolus administration of doxorubicin given over
,1 h to 48 h infusion for each of 12 dosages found
no significant benefit.
23
After a median 1.5 years of
follow-up, multiple echocardiographic measure-
ments showed abnormalities in both groups,
including a significant decrease in median LV
fractional shortening (LVFS) and LV contractility,
and a significant increase in LV peak systolic wall
stress. In children with ALL randomly assigned to
receive anthracyclines by bolus or by 6 h contin-
uous infusion after subclinical abnormal cardiac
function, continuous infusion did not significantly
reduce toxicity.
24
Furthermore, prolonged infusions
require additional hospitalisation and costs, possi-
bly increase morbidity, and may create additional
stress to patients and families.
23
Concomitant radiation and other chemotherapy agents
Radiation therapy (RT) is frequently combined
with chemotherapy in children with cancer.
Radiation may worsen the cardiotoxic effects of
anthracyclines, but whether this effect is additive
or synergistic is unclear.
1 8–11 14 15
Other antineo-
plastic drugs, including mitoxantrone, high dose
cyclophosphamide, amsacrine, bleomycin, vincris-
tine and trastuzumab, may also augment doxo-
rubicin cardiotoxicity.
1 8–12 14 15 18–20
Figure 2 Z scores of left ventricular contractility (panel A) and left ventricular mass (panel B) from 115 long term survivors of acute lymphoblastic
leukaemia treated with doxorubicin, by time since diagnosis. A model of follow-up data for all children is given. The solid line is the overall group mean.
A Z score of zero indicates the normal population mean. The dashed lines are the upper and lower 95th centile confidence bounds from the predicted
mean. Reproduced from Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood
acute lymphoblastic leukemia. J Clin Oncol 2005;23:2629–36. Reprinted with permission from the American Society of Clinical Oncology.
7
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CURRENT MONITORING, PREVENTIVE, AND
TREATMENT PRACTICES
Monitoring cardiac function may be useful during
and after anthracycline treatment.
1 8–12 14 15 22 25
Without evidence based guidelines for monitoring
of cardiac function during treatment, monitoring
schedules and methods vary widely in both
protocol and practice.
1 8–12 14 15 22 25
For children
receiving cardiotoxic treatment, the American
Heart Association’s class I recommendation is
serial monitoring by echocardiography, including
Doppler analysis, M mode echocardiography, two
dimensional transthoracic echocardiography, and,
when indicated, transoesophageal echocardio-
graphy, at baseline and with recurrent re-evalua-
tions.
11
Suggested guidelines for stopping
anthracycline treatment are neither codified nor
sufficient.
1 8–12 14 15 22 25
Serological evaluation of cardiac function may also
be useful during treatment, although the relationship
between short term changes and late cardiotoxicity
remains to be determined.
110111314152627
Elevated
serum cardiac troponins—proteins mostly of the
cardiac myocyte sarcomere released after cellular
damage—appear to be directly related to the
degree of cardiac damage when clearance is
normal.
1101113152627
N-terminal pro B type natriure-
tic peptide (NT-proBNP), a biomarker of unhealthy
heart muscle, and high sensitivity C reactive protein
(HsCRP), a marker of generalised inflammation, may
also help to assess cardiac status during and after
treatment in children with cancer.
11
NT-proBNP is an
independent predictor of cardiovascular events and
mortality in populations with chronic heart failure
(CHF), acute coronary syndromes, prior myocardial
infarction, vascular disease, elevated coronary risk,
and in community based samples. Preliminary results
suggest that NT-proBNP may also help to identify
cardiac stress before irreversible damage in children
receiving anthracyclines.
11
HsCRP is also an indepen-
dent predictor of outcome in some studies of adults
with ischaemic and non-ischaemic cardiomyopathy
and may be an important indicator of overall
cardiovascular health during and after treatment.
11
Preventing cardiotoxicity and cardiovascular
disease
Although the symptomatic treatment of cardio-
vascular disease in childhood cancer survivors is
important, available treatments can often only
delay the progression of cardiac dysfunction.
16 28 29
The most effective way to reduce late cardiotoxi-
city is to prevent initial damage
16 26 27
(see also
recent reviews).
110111418
Cardioprotectants: the case for dexrazoxane
The primary way to attenuate cardiotoxicity is
during anthracycline exposure. Several compounds
have been tested for their ability to reduce
cardiovascular toxicity, specifically by controlling
free radical oxidative stress (table 3).
8 13 14 18–20 26 27
Most have had only limited success.
Currently, the most promising cardioprotectant
for use in children is dexrazoxane.
8 13 14 18–20 26 27
A
member of the bisdioxopiperazine family similar to
ethylene diamine tetra-acetic acid (EDTA), it
chelates intracellular iron. Dexrazoxane scavenges
free iron as well as transferrin and ferritin bound
iron, thereby inhibiting the formation of the
anthracycline–iron complexes responsible for gen-
erating myocardiocyte damaging ROS.
8 13 14 18–20 26 27
The reduction in cardiotoxicity from high doses of
doxorubicin by dexrazoxane has been
reviewed.
11011141518192627
Dexrazoxane was approved in 2002 by the US
Food and Drug Administration for reducing the
incidence and severity of cardiomyopathy asso-
ciated with doxorubicin administration in women
with metastatic breast cancer who had received a
cumulative doxorubicin dose of at least 300 mg/m
2
and would continue to receive anthracycline
treatment to maintain tumour control.
11
Dexrazoxane is currently recommended by the
American Society of Clinical Oncology for this
indication.
25
Clinical trials with dexrazoxane in children have
been encouraging. In a randomised trial of children
diagnosed with ALL treated at the Dana Farber
Cancer Institute ALL Consortium, children who
Table 3 Strategies evaluated for cardioprotective
potential in the presence of anthracyclines
Class Example
Antihistamines Chlorpheniramine
Ketotifen
Disodium cromoglycate
Antioxidants N acetyl cysteine
a tocopherol
Carvedilol
Coenzyme Q10
Resveratrol
Chelating agents Dexrazoxane
Cytokines Erythropoietin
Granulocyte stimulating factor
Thrombopoietin
Energy regulators Adenosine
Carnitine
Enzyme inhibitors COX 2 inhibitors
Digoxin
Amrinone
Exercise
Hormones Oestrogen
Inhibitors of mediator release Cromolyn
Ion regulators Calcium channel blockers
a and b adrenergic antagonists
Membrane stabilisers Steroids
Taurine
Metabolic agents Probucol
Lovastatin
Miscellaneous agents Bismuth
Zinc
Cadmium
Uptake inhibitors Tetracyclines
COX, cyclo-oxygenase.
Reproduced with permission from Barry E, Alvarez JA, Scully RE, et al.
Anthracycline-induced cardiotoxicity: course, pathophysiology,
prevention and management. Expert Opin Pharmacother 2007;8:1039–58.
Copyright Ingentia.
11
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Heart 2008;94:525–533. doi:10.1136/hrt.2007.136093 529
Page 5
received dexrazoxane before doxorubicin were
significantly less likely to have cardiac injury
during treatment as measured by elevated serum
levels of cardiac troponin T (cTnT) (fig 3).
13 26 27
Dexrazoxane is the only proven cardioprotectant
in cancer patients receiving anthracycline chemo-
therapy.
10 11 14 18 19
Although dexrazoxane may
decrease the antineoplastic activity of doxorubicin,
no convincing evidence shows that it impairs
survival after doxorubicin treatment or that it
has any new or clinically relevant sequelae (infec-
tion, haemorrhage, deaths, or necessity for change
of dosage).
10 11 14 18 19
Of 16 clinical trials performed
in seven countries over the past 10 years involving
more than 1500 patients, only one reported that
dexrazoxane lowered the response rate, but it did
not affect survival.
10 11 14 18 19
Thus, where evidence
shows that it may be beneficial, dexrazoxane has
been recommended for use in paediatric research
protocols to evaluate the long term balance of
cardioprotection and the possible effect on anti-
tumour efficacy.
10 11 14 18 19
Pharmacologic options for treating anthracycline
associated cardiotoxicity
Treating of anthracycline induced heart disease in
childhood cancer survivors is of critical clinical
importance.
Angiotensin converting enzyme inhibitors
Angiotensin converting enzyme (ACE) inhibitors
reduce LV afterload and tend to slow the progres-
sion of LV dysfunction. Thus, they may be useful
in treating long term cancer survivors who often
develop symptomatic LV dysfunction. The success
of ACE inhibitors in adults
11 14
led to their
evaluation in children.
19
In a study of the long
term effect of ACE inhibitors in childhood cancer
survivors with anthracycline induced cardiac dys-
function, enalapril initially significantly improved
LV dimension, afterload, fractional shortening, and
mass.
19
However, these gains were lost after 6–
10 years on enalapril. Furthermore, LV wall thick-
ness deteriorated throughout the study, as did LV
contractility and systolic blood pressure. After
6 years of treatment, all patients who had started
with CHF had progressed to cardiac transplanta-
tion or cardiac death. Although ACE inhibitors did
not prevent progression of LV dysfunction and
thinning of LV walls, they did provide some respite
in the form of afterload reduction.
Growth hormone therapy
Growth hormone (GH) may act indirectly on the
heart through the action of insulin-like growth factor
1 (IGF-1) to maintain adequate LV mass.
29
For
survivors of childhood cancer, GH deficiency is a
common problem.
29
When GH is insufficient, thin
LV walls and decreased LV contractility are believed
to lead to increased LV afterload and LV dysfunction.
Growth hormone deficiency also increases cardiac
related mortality and dyslipidaemia.
29
Although
small pilot studies in adults with impaired LV
structure and function found improved cardiac
function and exercise performance, as well as an
increased cardiac mass after GH therapy, several
randomised trials have found no clinical benefits of
GH treatment, despite the increase in LV mass.
29
In anthracycline treated survivors of childhood
cancer with reduced LV wall thickness and func-
tion, GH therapy temporarily improved wall
thickness.
29
This improvement was lost after
treatment was discontinued.
29
A similar group of
untreated controls showed no changes in wall
thickness. Growth hormone therapy did not affect
progressive LV dysfunction.
29
Secondary prevention: the heart healthy life
For childhood cancer survivors unable to
benefit from cardioprotective strategies during
Figure 3 Percentage of patients with at least one elevated serum cardiac troponin T level overall, before and during treatment with doxorubicin. An
elevated level of serum cardiac troponin T was defined as one that exceeded 0.01 ng/ml. The number of patients in whom serum cardiac troponin T
was measured at least once during the specified intervals is shown in each bar. Reproduced with permission from Lipshultz SE, Rifai N, Dalton VM, et
al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145–53.
Copyrightß 2004, Massachusetts Medical Society. All rights reserved.
27
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530 Heart 2008;94:525–533. doi:10.1136/hrt.2007.136093
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chemotherapy who sustained cardiotoxicity, sec-
ondary prevention of cardiac disease should not be
dismissed. All patients should be educated about
the cardiotoxic risks of their treatments and about
the need for lifelong monitoring of heart function
and coronary artery disease risks.
110111415172530
Integral to education is a concerted effort to
making heart healthy decisions.
Diet, obesity, and drugs
A heart healthy diet low in saturated fat is
recommended for these patients, and salt intake
should be restricted to 2.5 g/day. However, scien-
tific evidence on the effects of a modified diet and
lifestyle in patients exposed to anthracyclines is
limited.
10
Ideal body weight should be maintained.
Obesity is associated with increased cardiovascular
morbidity and mortality and is a major preventable
coronary risk factor. Its prevalence is increased in
survivors of childhood cancer, especially in those
with ALL. Other risk factors for preventing
cardiovascular disease should be minimised in these
patients, who are at increased risk for premature
symptomatic cardiovascular disease. These risk
factors include diabetes, hypertension, and endo-
crinopathies. These patients should also be con-
sidered higher risk during anaesthesia, pregnancy,
severe infections, or other conditions of cardiovas-
cular stress. The impact of obesity on anthracy-
cline induced cardiomyopathy is not known.
Alcohol consumption, illicit drug use—especially
cocaine or other stimulants—and cigarette smok-
ing should be discouraged in patients at risk for
cardiomyopathy, especially in patients with LV
dysfunction, because these habits may further
impair LV function.
25
Exercise
Aerobic exercise can be beneficial, but patients
should undergo maximal or submaximal exercise
testing to ensure that they have stable cardiovas-
cular function before exercise programmes are
recommended. Isotonic exercise, such as weight
lifting, should be pursued only under the direct
supervision of a cardiologist and exercise physiol-
ogist.
10 30
Concomitant trastuzumab treatment increases
susceptibility to anthracycline cardiotoxicity.
11 14
Neuregulin, a ligand for the erbB4/erbB2 receptor
complex targeted by trastuzumab, may be impor-
tant in cardioprotection.
11
In rats, exercise training
before combination chemotherapy appears to be
cardioprotective through endogenous upregulation
of neuregulin or other cardioselective signalling
pathways.
11
Clinical studies have not yet investi-
gated this claim.
One pilot study that examined exercise in
children with chronic illnesses included two
paediatric cancer survivors treated with anthracy-
clines.
30
Both had substantially depressed LV
function and were treated in a paediatric cardiac
rehabilitation centre with a 12 week, hospital
based physical activity programme.
30
The interven-
tion notably reduced their body fat and improved
their strength. Other risk factors for premature
cardiovascular disease also improved.
30
The importance of assessing the impact of an
intervention on total cardiac risk, not just risk for
heart failure, is also illustrated in the above
study.
10 11 30
Improvement was sustained for at
least 1 year.
30
However, in one child, although LV
contractility improved, LV afterload increased,
leading to a more dilated and thinner LV.
30
The
overall effects of exercise may be highly beneficial
in some survivors, but harmful in others, making
close monitoring of these patients imperative when
using exercise as a therapeutic modality.
30
CONCLUSION
Anthracycline chemotherapy can lead to a broad
range of cardiovascular abnormalities, many of
which are progressive and of late onset. Although
more children will continue to benefit from
Anthracycline associated cardiotoxicity: key
points
c Cardiotoxicity is a primary limiting factor in the
use of anthracycline chemotherapy.
c Late cardiotoxicity in children and young adults
may be related to acute damage during
treatment.
c The potentially long latency and high cumulative
incidence of chronic cardiac dysfunction related
to cancer treatment indicates that long term
monitoring of asymptomatic individuals is
essential.
c Risk factors have helped identify patients at high
risk for late cardiomyopathy and heart failure.
c Lifestyle changes may reduce long term risk.
You can get CPD/CME credits for Education in Heart
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you need to answer the accompanying multiple choice questions (MCQs). To
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Education in Heart
Heart 2008;94:525–533. doi:10.1136/hrt.2007.136093 531
Page 7
anthracyclines and become cancer survivors, it is
clear that there is no ‘‘safe dose’’ free from
potential cardiovascular damage. Cumulative dose
and length of follow-up after anthracycline expo-
sure both effect the development of late cardio-
toxicity; in group analyses, cardiotoxicity in long
term survivors is progressive regardless of dose.
5–7 11
Survivors should be counselled about the presence
of cardiac risk, encouraged to follow a preventive
heart healthy lifestyle, and monitored lifelong with
appropriate tests to identify subclinical cardiovas-
cular disease. With regard to preserving cardiac
function without compromising anti-tumour effi-
cacy, recent clinical data from paediatric and adult
oncology trials support the use of dexrazoxane
during treatment on research protocols. With the
increased success of paediatric cancer treatment,
cardiac care providers must assume their role in the
prevention, diagnosis, and management of treat-
ment related cardiovascular disease.
Acknowledgements: Our thanks to Drs Rudolf Steiner, Eugene
Herman, and James Speyer for their review and editorial insight.
Funding: This paper has been supported in part by grants from the
National Cancer Institute (CA68484-SL, CA34183-SL, CA79060-SL,
CA06516-SL, CA127642-SL), National Heart, Lung, and Blood
Institute (HL69800-SL, HL53392-SL, HL59837-SL, HL53392-SL), the
Lance Armstrong Foundation (SL), the Children’s Cardiomyopathy
Foundation (SL), and the Women’s Cancer Association (SL).
Competing interests: In compliance with EBAC/EACCME guide-
lines, all authors participating in Education in Heart have disclosed
potential conflicts of interest that might cause a bias in the article. Dr
Lipshultz has investigator-initiated research grants from Pfizer and
Novartis and has been a consultant to Chiron, all of whom
manufacture dexrazoxane. The other authors indicated no potential
financial conflicts of interest.
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  • Source
    • "A major limitation of anthracycline is the risk of cardiotoxicity, manifested as asymptomatic cardiac dysfunction in up to 57% [2, 3] and cardiomyopathy with subsequent clinical heart failure in up to 16% [4]. Subclinical cardiac abnormalities are persistent and progressive after anthracycline therapy and can lead to significant clinical symptoms [5]. Early and accurate diagnosis of ventricular dysfunction in asymptomatic cardiac patients may permit a prompt onset of therapy of subclinical cardiotoxicity before the development of life-threatening complication [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background. Childhood cancer survivors treated with anthracyclines and mediastinal irradiation are at risk for late onset cardiotoxicity. Aims of the Study. To assess the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) and tissue Doppler imaging (TDI) as early predictors of late onset cardiotoxicity in asymptomatic survivors of childhood cancer treated with doxorubicin with or without mediastinal irradiation. Methods. A cross-sectional study on 58 asymptomatic survivors of childhood cancer who received doxorubicin in their treatment protocols and 32 asymptomatic Hodgkin's lymphoma survivors who received anthracycline and mediastinal irradiation. Levels of NT-proBNP, TDI, and conventional echocardiography were determined. Thirty percent of survivors had abnormal NT-proBNP levels. It was significantly related to age at diagnosis, duration of follow-up, and cumulative dose of doxorubicin. TDI detected myocardial affection in 20% more than conventional echocardiography. Furthermore, abnormalities in TDI and NT-pro-BNP levels were more common in Hodgkin lymphoma survivors receiving both chemotherapy and radiotherapy. Conclusions. TDI could detect early cardiac dysfunction even in those with normal conventional echocardiography. Measurement of NT-proBNP represents an interesting strategy for detecting subclinical cardiotoxicity. We recommend prospective and multicenter studies to validate the role of NT-proBNP as an early marker for late onset doxorubicin-induced cardiotoxicity.
    Full-text · Article · May 2015 · Disease markers
  • Source
    • "Cardiotoxicity is one of the most serious long-term complications after cancer therapy mainly due to anthracycline chemotherapy and mediastinal irradiation12345. Guidelines for cardiovascular monitoring after cancer treatment are available but the appropriate underlying evidence is often missing. "
    [Show abstract] [Hide abstract] ABSTRACT: Cardiotoxicity is one of the most serious long-term complications in childhood cancer survivors. Measurement of the left ventricular ejection and shortening fraction remains the most common screening tool for cardiac systolic dysfunction. However, M-mode echocardiography can be viewed as a crude approach as refined strategies are now available. The aim of this prospective study was to determine the role of cardiac MRI in the detection of subclinical left or right ventricular dysfunction as well as the prevalence of myocardial scaring in patients undergoing cancer treatments. Eighty-one children were enrolled in a pre-chemotherapy and then in a yearly protocol including a: (i) clinical evaluation; (ii) laboratory evaluation; (iii) electrocardiogram; (iv) echocardiogram; and (v) a cardiac magnetic resonance imaging (cMRI). Early left ventricular systolic dysfunction was only detected in two patients. The entire cohort presented a significant increase of the left atrial volume as measured by cMRI. This finding correlated with the total cumulative dose of anthracyclines (r = 0.34; P < 0.05) and the mean left ventricular radiation dose (r = 0.86; P < 0.05). We also observed a mild increase of myocardial scaring, similarly correlated to the radiation dose (r = 0.85; P < 0.05). Screening tools for late-onset cardiomyopathy secondary to cancer treatment are lacking. Our findings support the use of cMRI for the evaluation of the left atrial volume, as an early marker of diastolic dysfunction, and myocardial delayed enhancement, as a marker of myocardial fibrosis and scaring. Longer follow-up and larger studies are still needed to better define the role of cMRI in the evaluation of childhood cancer survivors. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2015 · Pediatric Blood & Cancer
  • Source
    • "The adverse effects of chemotherapy can be acute toxicity or may develop gradually as a result of cumulative and chronic toxicity. Acute toxicity can result in pericarditis , myocarditis, valvular heart disease or congestive heart failure, whereas chronic toxicity can result in cardiomyopathy or premature coronary artery disease [2, 15, 16, 28]. Because of the gradual increase in the risk of cardiotoxicity after discontinuation of chemotherapy, periodic cardiac evaluation is mandatory. "
    [Show abstract] [Hide abstract] ABSTRACT: Improvement in long-term survival in patients with acute childhood leukemia has led to the need for monitorization of chemotherapy-related morbidity and mortality. This study included 60 patients with acute lymphoblastic leukemia that were in remission for at least 2 years and 30 healthy controls. Systolic and diastolic function of myocardium was evaluated using conventional echocardiography and tissue Doppler imaging of the left ventricle, interventricular septum and right ventricle. Median age of patients was 11.7 years (range 10–14.9 years), and the median duration of remission was 4 years (range 2.5–5 years). All patients were treated with a low cumulative dose of adriamycin (100 mg/m2) according to the St. Jude Total-XIIIA protocol. The ejection fraction (EF) and fractional shortening were normal in the patient and control groups, even though EF values were significantly lower in the patients (69.5 ± 2.3 vs. 72.7 ± 3 %, P < 0.01). Myocardial systole (S m), early diastole (E m) and late diastole (A m) velocities in all segments of the myocardium were significantly lower in the patient group (P < 0.01 for all segments). Cardiotoxicity was noted in all segments of the myocardium in the patient group, despite the fact that they were all treated with a low cumulative dose of adriamycin. Based on these findings, we think that there is no safe dose for anthracyclines and periodic echocardiographic evaluation of both the left and right ventricles must be performed in all patients treated with anthracyclines, even at low doses.
    Full-text · Article · Jan 2015 · Pediatric Cardiology
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