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Anthracycline-induced cardiotoxicity during and after treatment
for childhoodcancer : long-term risk, risk factors and
prevention
van Dalen, E.C.
Publication date2007Document VersionFinal published version
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Citation for published version (APA):van Dalen, E. C. (2007).
Anthracycline-induced cardiotoxicity during and after treatment
forchildhood cancer : long-term risk, risk factors and
prevention.
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Anthracycline-induced cardiotoxicity
during and after treatment for childhood cancer
Long-term risk, risk factors and prevention
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The research in this thesis was financially supported by the
Foundation of Pediatric Cancer Research (Stichting
Kindergeneeskundig Kankeronderzoek), the Jacques H de Jong
Foundation, Knowledge and Research Center for Alternative Medicine,
Danish Cancer Society, and Stichting Steun Emma Kinderziekenhuis
AMC. Printed by: Van Marle Drukkerij B.V., Moerkapelle ISBN:
978-90-9021404-7 © E.C. van As – van Dalen No part of this thesis
may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopy, recording or
otherwise without permission of the author.
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Anthracycline-induced cardiotoxicity during and after treatment
for childhood
cancer
Long-term risk, risk factors and prevention
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit van
Amsterdam op gezag van de Rector Magnificus
prof. dr. J.W. Zwemmer ten overstaan van een door het college
voor promoties
ingestelde commissie, in het openbaar te verdedigen in de Aula
der Universiteit
op woensdag 4 april 2007, te 12:00 uur
door
Elvira Caroline van Dalen
geboren te Rotterdam
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Promotiecommissie Promotor: Prof. dr. H.N. Caron Co-promotor:
Dr. L.C.M. Kremer Overige leden: Prof. dr. F. Doz Dr. J.A. Gietema
Prof. dr. W.A. Helbing Prof. dr. H.S.A. Heymans Prof. dr. F.E. van
Leeuwen Prof. dr. M. Offringa Faculteit der Geneeskunde Financial
support by the Netherlands Heart Foundation for the publication of
this thesis is gratefully acknowledged.
-
Voor Jorrit
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Contents 1 Introduction and outline of the thesis. 9 2 Clinical
heart failure in a cohort of children treated with anthracyclines:
25 a long-term follow-up study. European Journal of Cancer 2006;
42: 3191-3198. 3 Clinical heart failure during pregnancy and
delivery in a cohort of female 43 childhood cancer survivors
treated with anthracyclines. European Journal of Cancer 2006; 42:
2549-2553. 4 Cumulative incidence and risk factors of
mitoxantrone-induced 55 cardiotoxicity in children: a systematic
review. European Journal of Cancer 2004; 40: 643-652. 5
Cardioprotective interventions for cancer patients receiving
anthracyclines: 73
a Cochrane systematic review. Cochrane Database of Systematic
Reviews 2005; 1: CD003917.
6 Different anthracycline derivates for reducing cardiotoxicity
in cancer patients: 105 a Cochrane systematic review. Cochrane
Database of Systematic Reviews 2006; 4: CD005006. 7 Different
dosage schedules for reducing cardiotoxicity in cancer patients
161
receiving anthracycline chemotherapy: a Cochrane systematic
review. Cochrane Database of Systematic Reviews 2006; 4:
CD005008.
8 Anthracycline-induced cardiotoxicity: comparison of
recommendations for 191
monitoring cardiac function during therapy in paediatric
oncology trials. European Journal of Cancer 2006; 42:
3199-3205.
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9 Management of asymptomatic anthracycline-induced cardiac
damage after 205 treatment for childhood cancer: a postal survey
among Dutch adult and paediatric cardiologists. Journal of
Pediatric Hematology Oncology 2005; 27: 319-322.
10 General discussion and recommendations for future research
and implications 215
for clinical practice. A manuscript based on part of the
discussion (Prevention of anthracycline- induced cardiotoxicity in
children: the evidence) is accepted for publication in the European
Journal of Cancer.
11 Summary 243 12 Samenvatting 249 13 Dankwoord 255 14
Publications 259
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1
Introduction and outline of the thesis
-
Introduction
11
Anthracyclines have gained widespread use in the treatment of
numerous solid tumours and haematological malignancies in both
adult and paediatric patients. Nearly 60% of children diagnosed
with a malignancy receive anthracyclines as part of their
treatment. Its anti-tumour activity is the result of irreversible
damage to DNA of cancer cells, but the exact mechanisms of
anthracycline activity remain a matter of controversy [1, 2]. The
introduction of anthracyclines, together with other improvements in
childhood cancer treatment, has contributed to the improvement in
cancer survival, particularly among children, where survival rates
have increased from 30% in the 1960s to 70% nowadays [3, 4]. As a
result, a rapidly growing number of children will have survived
childhood cancer. In the Netherlands, at the moment, approximately
1 out of every 750 to 800 young adults has survived childhood
cancer [5]. Unfortunately, the use of anthracyclines is limited by
the occurrence of cardiotoxicity, which has been known since its
introduction [6].
Types of anthracycline-induced cardiotoxicity
Anthracycline-induced cardiotoxicity can become manifest in
patients as either clinical heart failure [7] or asymptomatic
cardiac dysfunction [8], which encloses various cardiac
abnormalities diagnosed with different diagnostic methods, like
echocardiography, nuclear angiography, cardiac biopsy or cardiac
markers, in asymptomatic patients. According to the time of
presentation, anthracycline-induced cardiotoxicity can be divided
into early and late cardiotoxicity [9, 10]. Early cardiotoxicity
refers to cardiac damage that develops during anthracycline therapy
or in the first year after its completion, and late cardiotoxicity
manifests itself thereafter [9]. However, although widely used,
this distinction between is probably artificial because the damage
caused by anthracyclines begins with the first dose of the drug;
anthracycline-induced cardiotoxicity is therefore described more
accurately as progressive from the first dose [11].
Pathophysiology To date, the precise mechanism underlying
anthracycline-induced cardiotoxicity is not fully understood. The
majority of evidence shows that it involves the generation of free
radicals, through an enzymatic mechanism using the mitochondrial
respiratory chain, as well as through a non-enzymatic pathway,
incorporating iron. Both free radicals and iron can damage cells.
Compared with cells of other organs, cardiac cells are more
vulnerable to free radical damage because of their highly oxidative
metabolism and relatively poor antioxidant defences, like the
presence of protective enzymes such as superoxide dismutase,
catalase, glutathione peroxidase with cofactor selenium and
glutathione transferases. Additionally, anthracyclines have a very
high affinity for cardiolipin, a phospholipid in the inner
mitochondrial membrane of cardiomyocytes, resulting in accumulation
of anthracyclines inside cardiac cells [1, 11-14].
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Chapter 1
12
The free radicals may continue to be generated after
anthracycline treatment has ceased and could account for the late
manifestation of cardiotoxicity [1]. Cardiomyocytes that have been
damaged cannot be repaired or replaced and, consequently,
anthracycline-induced cardiac damage is irreversible and has a
negative effect on cardiac function. Loss of cardiomyocytes leads
to progressive left ventricular dilatation, left ventricular wall
thinning and decreased contractility (i.e. dilated cardiomyopathy).
As contractility diminishes over time, the ventricle dilates
further to maintain cardiac output. These changes eventually
increase left ventricular wall stress, promoting further left
ventricular compromise, however, eventually the heart will be
unable to compensate further when demands increase [15, 16]. As a
result, in time, the overall function of the left ventricle will be
depressed [1]. In children, an additional factor is important,
namely the fact that cardiomyocytes rarely proliferate after 6
months of age. Virtually all myocardial growth after this time
results from increasing cardiomyocyte size. When there is
cardiomyocyte loss due to anthracycline therapy, the surviving
cardiomyocytes compensate by hypertrophy even more than usual
resulting in a restrictive cardiomyopathy. As opposed to adults,
who typically have purely dilated disease, childhood cancer
survivors tend to have a combination of dilated and restrictive
cardiomyopathy [15]. Late anthracycline-induced cardiotoxicity may
be the result of damage caused during anthracycline therapy which
was not serious enough to cause symptoms immediately. When the
surviving cardiomyocytes are unable to keep pace with the demands
placed on the heart by normal body growth, pregnancy and other
cardiac stresses, the cardiac dysfunction becomes evident [15].
Cumulative incidence Anthracycline-induced cardiotoxicity is a
widely prevalent problem. Several studies have evaluated the
incidence of anthracycline-induced cardiotoxicity in children [8,
17-21], but the majority of these studies have serious
methodological limitations: small study populations, only subgroups
were described, and/or a short follow-up period. The reported
incidence of anthracycline-induced clinical heart failure varies
widely between 0 and 16% and that of asymptomatic cardiac
dysfunction has been reported to be more than 57%. The incidence of
anthracycline-induced cardiotoxicity, both clinical and
asymptomatic, seems to increase with a longer follow-up period [18,
19, 21]. In one of our earlier studies the estimated risk of
anthracycline-induced clinical heart failure increased with time to
2% at 2 years and 5% at 15 years after the start of treatment
[19].
Risk factors Several risk factors for anthracycline-induced
cardiotoxicity, like a higher cumulative anthracycline dose,
different anthracycline derivates, a higher anthracycline peak
dose,
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Introduction
13
radiation therapy involving the heart region, female sex,
younger age at diagnosis, black race, additional treatment with for
example cyclophosphamide or mitoxantrone and presence of trisomy 21
(even when patients with congenital cardiovascular malformations
were excluded), have been identified [10, 17, 20]. For example, in
a study of patients treated with anthracyclines for acute
lymphoblastic leukaemia or osteosarcoma, female patients had a
significantly greater reduction in ventricular contractility than
males. The higher the cumulative anthracycline dose received, the
greater the difference [22]. Although the reason for the higher
susceptibility of females is not fully understood, differences in
body composition between the two sexes may play a role by altering
the distribution and metabolism of anthracyclines. Girls have more
body fat than boys (with comparable body surface area) and
anthracyclines are poorly absorbed by fat tissue. As a result,
anthracycline clearance is reduced in girls and equivalent doses of
anthracyclines in girls could lead to higher concentrations, for a
longer time, in non-fat tissues, including the heart [10, 16, 23].
Unfortunately, with the exception of the cumulative anthracycline
dose, the results of the evaluations of risk factors for
anthracycline-induced cardiotoxicity are not conclusive in all
studies [10, 17, 20]. Also, as mentioned before, although the
follow-up since anthracycline therapy cannot be controlled as an
independent risk factor, the risk of anthracycline-induced
cardiotoxicity seems to increase with a longer follow-up period
[18, 19, 21]. Finally, the cardiac stress associated with pregnancy
and delivery can trigger the occurrence of cardiotoxicity [24, 25],
as can other sources of cardiovascular stress, such as weight
lifting and surgery [9].
Monitoring Serial monitoring of the cardiac function of children
receiving anthracycline therapy allows early identification of
cardiac damage. During therapy, the anthracycline dosage can then
be adjusted or anthracycline therapy can be even stopped, which,
hopefully, can prevent more cardiac damage to occur. Unfortunately,
at the moment, there is no evidence on the most optimal way to
monitor cardiac function in children treated with anthracyclines
with regard to 1) the diagnostic test(s) and their predictive value
as a surrogate marker for the future development of clinical heart
failure after anthracycline therapy for childhood cancer, 2) time
and frequency of testing, and 3) interventions based on the results
of monitoring in children treated with anthracyclines. For example,
no randomised studies have evaluated the effects of dose
modification based on cardiac test results and therefore any
deviations from protocol are not based on experimental evidence and
could potentially harm the patient [26, 27]. There are many
different methods available to monitor for anthracycline-induced
cardiotoxicity, but one should keep in mind the above mentioned
limitations of monitoring.
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Chapter 1
14
Endomyocardial biopsy Endomyocardial biopsy is considered to be
the ‘gold standard’ for the detection of anthracycline-induced
cardiotoxicity [28]. Billingham et al developed a standardised
grading scale for the degree of damage [29]. The grade of damage is
associated with the cumulative anthracycline dose and has been
shown to be predictive for subsequent asymptomatic
anthracycline-induced cardiac dysfunction and the development of
clinical heart failure [30, 31]. Unfortunately, there are a number
of limitations to using this method. Its use for routine monitoring
is limited by its invasive nature. Also, a considerable amount of
variability may exist in the degree of morphological changes.
Cardiac damage may be underestimated as a result of this so-called
scattering of cardiomyopathic changes. Furthermore, the expertise
needed to perform a biopsy and interpret the results may not be
available in all institutions [32]. Echocardiography Since
echocardiography is both non-invasive and available in most
paediatric oncology centres, the echocardiographic left ventricular
shortening fraction (LVSF) is the most widely used diagnostic
method for detecting anthracycline-induced cardiotoxicity in
children. It measures the left ventricular systolic function, and
anthracyclines primarily cause systolic dysfunction. An advantage
of echocardiography is that it is possible to also evaluate heart
structures, such as the heart valves. A disadvantage is that, as a
result of body habitus, in adults the quality of echocardiography
is rather poor [15]. Also, the echocardiographic LVSF has
limitations. First, it depends on the loading conditions of the
patient which vary considerably [15], especially in children being
treated for a malignancy, since conditions such as fever, anaemia,
renal failure, and malnutrition often complicate chemotherapy and
may significantly alter loading conditions [10, 33]. The value of
the LVSF also depends on the exact methods used to obtain the LVSF
[34]. Moreover, the interpretation of the measurement of the LVSF
can vary considerably between different observers [35]. Finally,
early cardiac changes may not be detected using LVSF. Patients with
substantial cardiac injury may maintain a normal LVSF, because
impairment of the LVSF occurs after a critical number of cells have
been damaged [32]. With echocardiography it is also possible to
measure load-independent parameters: wall stress and contractility
(stress velocity index) [15, 16]. Radionuclide angiography Using
radionuclide angiography (RNA) it is also possible to measure the
left ventricular systolic function. The left ventricular ejection
fraction (LVEF) is more accurate than echocardiography, but also
load dependent and with RNA it is not possible to measure any
load-independent parameters [15]. An advantage of RNA is that it
can also be used in adults, which is important when screening young
adult childhood cancer survivors. However, it is a semi-invasive
method and should be performed in reliable cardiac nuclear
medicine
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Introduction
15
centres [32]. As opposed to echocardiography, with RNA it is not
possible to evaluate heart structures. Again, the LVEF will detect
cardiotoxicity relatively late, because impairment of the LVEF only
occurs after a critical number of cells have been damaged [32].
Other monitoring methods Other possible methods for monitoring of
the cardiac function of children receiving anthracycline therapy
are magnetic resonance imaging (MRI) [36], electrocardiography
(ECG) [28], indium-111-antimyosin scintigraphy [37], exercise
testing [32], and biochemical markers, such as atrial natriuretic
peptide (ANP) [38, 39], brain natriuretic peptide (BNP) [39, 40],
troponin T [41], troponin I [42], and endothelin-1 [43]. It should
be noted that all these possible methods have only been evaluated
in small study groups; they still have to be validated in large
cohort studies.
Consequences The consequences of anthracycline-induced
cardiotoxicity are extensive. Anthracycline-induced damage to the
heart can be the dose-limiting factor in cancer treatment. If
cardiotoxicity could be prevented or at least be reduced, higher
doses of anthracyclines could potentially be used, thereby possibly
further increasing cancer survival [1]. Furthermore, cardiotoxicity
can lead to long-term side effects, causing severe morbidity and
reduced quality of life. It involves long-term treatment and thus
high medical costs and it causes premature death. The excess
mortality due to cardiac disease is 8-fold higher than expected for
long-term survivors of childhood cancer compared to the normal
population [44]. With the current improved cancer survival rates,
the problem of late-onset cardiotoxicity is increasing. The risk of
developing heart failure remains a lifelong threat, especially to
children who have a long life-expectancy after successful
antineoplastic treatment.
Treatment possibilities Irrespective of the presence of
anthracycline-induced clinical heart failure or asymptomatic
cardiac dysfunction, in all childhood cancer survivors treated with
anthracyclines heart-healthy lifestyles should be encouraged in
order to avoid additional risk to the function of the heart [45].
Aerobic activities are encouraged, but performing weight lifting
and other isometric exercise should be limited [15]. A low-fat
diet, no smoking, limited alcohol intake and no illicit drugs
should also be emphasized [1]. Clinical heart failure The current
treatment of anthracycline-induced clinical heart failure consists
mainly of symptomatic treatment. Drug therapy is the same as for
other causes of congestive heart
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Chapter 1
16
failure. It should be targeted to correct the
anthracycline-induced abnormalities that lead to
anthracycline-induced clinical heart failure. Treatment should
include ACE (angiotensin-converting enzyme)-inhibitors (for
afterload reduction), digoxin (for increasing contractility) and
diuretics (for inducing diuresis) [32]. In the end stage of
clinical heart failure, heart transplantation is the only remaining
option to avoid cardiac death. Asymptomatic cardiac dysfunction At
present, the optimal management of a patient with asymptomatic
cardiac dysfunction after anthracycline therapy for childhood
cancer is not clear. In adult patients with asymptomatic cardiac
dysfunction due to causes other than anthracyclines, ACE-inhibitors
have been shown to reduce mortality and cardiac events [46].
However, extrapolation of these data to children with
anthracycline-induced cardiac damage is risky. Pharmacokinetics of
many drugs varies with age and their beneficial and adverse effects
are different in adults and children [47]. Also, the aetiology of
the cardiac damage in the adult study was different. Two studies
have investigated the effect of the ACE-inhibitor enalapril on
anthracycline-induced cardiac damage in childhood cancer survivors
[48, 49]. Although the results of these studies are promising, they
should be interpreted with caution, given their limitations [50,
51]. The study of Lipshultz et al was not a randomised controlled
trial and therefore, bias could not be ruled out. The study of
Silber et al had the following limitations: the follow-up time was
not long enough nor was the study population large enough to
conclude that ACE-inhibitors are not beneficial and the primary end
point (the maximum exercise cardiac index) is not a reliable
surrogate marker for cardiac function. Furthermore, it should be
noted that the study of Lipshultz et al showed that the
enalapril-induced improvement in left ventricular structure and
function is only transient. All parameters deteriorated between 6
and 10 years after the start of enalapril therapy. Also,
ACE-inhibition causes regression of pathologic cardiac hypertrophy
and also impairs physiologic cardiac hypertrophy, but limiting
hypertrophic growth in a growing child may have negative
consequences. Treatment of patients with anthracycline-induced
asymptomatic cardiac dysfunction with beta-blockers has never been
evaluated in a randomised trial. The same is true for growth
hormone therapy. In a non-randomised study of Lipshultz et al [52]
it did not lead to a lasting improvement in cardiac structure and
function. The left ventricular wall thickness increased with growth
hormone therapy, but the effect was lost after therapy was
discontinued.
Prevention An important question regarding the use of any
cardioprotective intervention during anthracycline therapy is
whether this intervention could selectively decrease the cardiac
damage caused by anthracyclines without reducing the anti-tumour
efficacy and without
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Introduction
17
negative effects on toxicities other than cardiac damage, such
as alopecia, nausea, vomiting, stomatitis, diarrhoea, fatigue,
anaemia, leukopenia and thrombocytopenia. Extensive research has
been devoted to the identification of methods or agents capable of
ameliorating anthracycline-induced cardiotoxicity. Unfortunately,
for many of the methods described below, the reported results are
not univocal. The following methods for primary prevention have
been identified: 1) Avoiding the use of anthracyclines in the
treatment of childhood cancer If anthracycline therapy does not
have an added value with regard to tumour response and survival to
treatment without anthracyclines, it should not be used in
treatment protocols for childhood cancer and as a result
anthracycline-induced cardiotoxicity will not be an issue.
Unfortunately, in many treatment protocols for childhood cancer,
anthracyclines have been included without thorough evaluation of
their use in randomised controlled trials. For example, although
ample evidence supports the anti-leukaemic activity of
anthracyclines administered as a single drug, data supporting
anthracycline use in modern multi-drug combinations, which now
constitute the mainstay of current leukaemia treatments, is
lacking. It is unclear if the use of anthracyclines improves
outcome [53]. Currently, in the SIOP-2001 protocol for the
treatment of nephroblastoma, patients with stage II or III
intermediate risk are being randomised to treatment with or without
doxorubicin to evaluate the effect of doxorubicin on treatment
efficacy and anthracycline-induced cardiotoxicity [54]. 2) The use
of possible less cardiotoxic anthracycline analogues and
anthracenediones Numerous possible less cardiotoxic anthracycline
analogues of the first anthracycline drug doxorubicin have been
developed, including daunorubicin, epirubicin, and idarubicin. Also
available are liposomal-encapsulated anthracycline derivates.
Intravenously administrated liposomes cannot escape the vascular
space in sites that have tight capillary junctions, such as the
heart muscle. They do exit the circulatory system in tissues and
organs with cells that are not tightly joined or through areas
where capillaries are disrupted, for example, by tumour growth.
Thus, the changes in tissue distribution of liposomal
anthracyclines lead to less drug exposure in sensitive organs.
Also, the release of the drug is slow, which may avoid high peak
plasma concentrations [1]. Doxorubicin is available as doxil
(caelyx) [55] and myocet [56], daunorubicin as daunoxome [57].
Mitoxantrone is an anthracenedione derivate which is structurally
related to the anthracycline derivates, but possibly with less
cardiotoxicity [58]. 3) Reducing the cumulative dose of
anthracyclines Although there is no absolute safe dose of
anthracycline therapy, most treatment protocols for childhood
cancer have limited the maximum cumulative anthracycline dose
patients will receive.
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Chapter 1
18
4) Reducing the anthracycline peak dose Anthracycline-induced
cardiotoxicity appears to be related to the peak plasma drug
concentration. The anti-tumour activity, however, is dependent on
the tissue concentration over time and not on the peak plasma
concentration [32]. This means that reducing the anthracycline peak
dose could be potentially less cardiotoxic, while anti-tumour
activity is maintained. Reducing the anthracycline peak dose can be
achieved in different ways. First, by reducing the individual
anthracycline dose (for example, instead of 100 mg/m² of
anthracyclines at once, 50 mg/m² on day 1 and another 50 mg/m² on
day 5). Second, by prolonging the infusion duration of
anthracycline therapy (for example, by replacing bolus
administration of anthracyclines with slower infusions, like over 6
or 48 hours). However, despite reductions in anthracycline peak
dose, the associated longer exposure of cardiomyocytes to
anthracyclines with longer infusion durations could lead to greater
myocardial damage [1, 10, 32]. 5) Use of cardioprotective agents
Better understanding of the pathophysiological mechanism of
anthracycline-induced cardiac damage has led to the development of
many different cardioprotective agents, of which dexrazoxane is the
most generally investigated one. Animal studies have suggested that
dexrazoxane protects against cardiotoxicity by binding free iron,
thereby preventing the formation of the anthracycline-iron complex
[59]. Also, dexrazoxane seems to be able to displace iron from the
already formed complexes with anthracyclines [60]. Moreover, it has
been suggested that dexrazoxane decreases anthracycline toxicity by
a mechanism independent from iron complexation. Dexrazoxane is able
to reduce the formation of free radicals by doxorubicin via
inhibition of an NAHD-dependent enzyme which has not been
characterized [60]. The information on pharmacodynamic properties
of dexrazoxane in humans is limited [61]. Other agents of which
cardioprotective effects have been reported are for example vitamin
E [62], n-acetylcysteine [63], superoxide dismutase [64], probucol
[65] and amifostine [66]. Vitamin E traps peroxyl radicals, thereby
adding to cellular defences against free-radical damage.
N-acetylcysteine and amifostine can reduce oxidative stress by
increasing cellular levels of glutathione, which is used by the
antioxidant enzyme glutathione peroxidase. Superoxide dismutase is
an antioxidant enzyme [67]. Probucol is a lipid lowering agent and
a potent antioxidant [65].
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Introduction
19
Outline of the thesis The aim of this thesis is to assess the
cumulative incidence and risk factors of anthracycline-induced
cardiotoxicity during and after treatment for childhood cancer and
to evaluate possibilities to reduce or prevent the occurrence of
cardiac damage in children treated with anthracyclines. Cumulative
incidence and risk factors of anthracycline-induced cardiotoxicity
during and after treatment for childhood cancer In order to
establish adequate follow-up and treatment for children treated
with anthracyclines, it is important to estimate the risk and risk
factors of anthracycline-induced clinical heart failure in those
patients. The current evidence has limitations; for peripartum
anthracycline-induced clinical heart failure only case reports are
available. In chapter 2 the cumulative incidence and risk factors
of anthracycline-induced clinical heart failure are evaluated in a
large cohort of 830 children treated with a mean cumulative
anthracycline dose of 288 mg/m² with a very long and complete
follow-up from the start of anthracycline therapy (mean 8.5 years;
complete for 95.8% of the cohort). Chapter 3 reports on the
evaluation of the cumulative incidence and risk factors of
peripartum anthracycline-induced clinical heart failure in a cohort
of 53 childhood cancer survivors who had delivered one or more
children. Cumulative incidence and risk factors of
mitoxantrone-induced cardiotoxicity during and after treatment for
childhood cancer In order to establish adequate follow-up and
treatment for children treated with mitoxantrone, it is important
to know the cumulative incidence of mitoxantrone-induced
cardiotoxicity and to understand which patients are at greatest
risk to develop mitoxantrone-induced cardiotoxicity. Chapter 4
presents the results of a systematic review on the cumulative
incidence and risk factors of mitoxantrone-induced cardiotoxicity,
both clinical and asymptomatic. Primary prevention of
anthracycline-induced cardiotoxicity In this part, the existing
evidence on different methods to prevent both clinical and
asymptomatic anthracycline-induced cardiotoxicity is reviewed and
analysed in separate systematic reviews. In chapter 5 various
cardioprotective agents are evaluated in a systematic review. In
chapter 6 a systematic review of different anthracycline derivates
is reported. In chapter 7 different anthracycline dosage schedules
(infusion duration and anthracycline peak dose) are compared by
means of a systematic review.
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Chapter 1
20
Monitoring cardiac function during anthracycline therapy in
paediatric oncology trials Serial monitoring of the cardiac
function of children receiving anthracycline therapy allows early
identification of cardiac damage. During therapy, the anthracycline
dosage can then be adjusted or anthracycline therapy can be even
stopped, which, hopefully, can prevent more cardiac damage to
occur. At the moment, it is unclear which monitoring guidelines are
used in the different treatment protocols for childhood cancer. In
chapter 8 an overview of the currently available guidelines for
monitoring anthracycline-induced cardiotoxicity during
anthracycline therapy for childhood cancer and of the monitoring
recommendations currently used in European paediatric oncology
trials is given. Current treatment policies for asymptomatic
anthracycline-induced cardiotoxicity used in the Netherlands The
management of childhood cancer survivors with asymptomatic
anthracycline-induced cardiac dysfunction is still unclear. In
chapter 9 the results of a survey to assess the treatment policy
among Dutch adult and paediatric cardiologists when dealing with
childhood cancer survivors with asymptomatic anthracycline-induced
cardiac dysfunction are described. General discussion and
recommendations for future research and clinical practice In
chapter 10 the results and hypotheses generated in this thesis are
further discussed leading to recommendations for future research
and clinical practice.
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Introduction
21
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-
2
Clinical heart failure in a cohort of children treated with
anthracyclines: a long-term
follow-up study
Elvira C van Dalen1 Helena JH van der Pal2,3
Wouter EM Kok4 Huib N Caron1,2
Leontien CM Kremer1,2
European Journal of Cancer 2006; 42(18): 3191-3198*
1 Department of Pediatric Oncology, Emma Children’s Hospital /
Academic Medical Center; 2 Late Effects Outpatient Clinic (PLEK:
Polikliniek Late Effecten Kindertumoren) and Study
Group, Emma Children’s Hospital / Academic Medical Center; 3
Department of Medical Oncology, Academic Medical Center; 4
Department of Cardiology, Academic Medical Center
(Amsterdam, the Netherlands). (*
http://intl.elsevierhealth.com/journals/ejca/)
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Chapter 2
26
Abstract The cumulative incidence of anthracycline-induced
clinical heart failure (A-CHF) in a large cohort of 830 children
treated with a mean cumulative anthracycline dose of 288 mg/m²
(median 280 mg/m²; range 15 to 900 mg/m²) with a very long and
complete follow-up after the start of anthracycline therapy (mean
8.5 years; median 7.1 years; range 0.01 to 28.4 years) was 2.5%. A
cumulative anthracycline dose of 300 mg/m² or more was the only
independent risk factor (relative risk (RR)=8). The estimated risk
of A-CHF increased with time to 5.5% at 20 years after the start of
anthracycline therapy; 9.8% if treated with 300 mg/m² or more. In
conclusion, 1 in every 10 children treated with a cumulative
anthracycline dose of 300 mg/m² or more will eventually develop
A-CHF. This is an extremely high risk and it reinforces the need of
re-evaluating the cumulative anthracycline dose used in different
treatment protocols and to define strategies to prevent A-CHF which
could be implemented in treatment protocols.
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Clinical heart failure in a cohort of anthracycline-treated
children
27
Introduction Anthracyclines have gained widespread use in the
treatment of numerous childhood malignancies: nearly 60% of
children diagnosed with a malignancy receive anthracyclines. The
introduction of anthracyclines has contributed to the improvement
in survival rates of childhood cancer: from 30% in the 1960s to 70%
nowadays [1, 2]. As a result, a rapidly growing number of children
will have survived childhood cancer. In the Netherlands, nowadays,
approximately 1 out of every 750 to 800 young adults has survived
childhood cancer [3]. Unfortunately, the use of anthracyclines is
limited by the occurrence of cardiotoxicity. It can become manifest
as either clinical heart failure [4] or asymptomatic cardiac
dysfunction [5], which can not only develop during anthracycline
therapy, but also years after the cessation of treatment [6].
Several studies have evaluated the incidence and risk factors for
anthracycline-induced clinical heart failure (A-CHF) in children
[7, 8, 9], but the majority of these studies have serious
methodological limitations: small study populations, only subgroups
were described, and/or a short follow-up period. The reported
incidence of A-CHF varies widely between 0 and 16%. Several risk
factors, like a higher cumulative anthracycline dose, different
anthracycline derivates, peak dose (i.e. maximal dose received in
one week), radiation therapy involving the heart region, female
sex, younger age at diagnosis, black race, additional treatment
with amsacrine, cyclophosphamide, ifosfamide or mitoxantrone and
presence of trisomy 21, have been identified, although not univocal
in all studies [7, 10]. The risk of developing
anthracycline-induced cardiotoxicity remains a lifelong threat. In
one of our earlier studies the estimated risk of A-CHF increased
with time to 2% at 2 years and 5% at 15 years after the start of
treatment [9]. Other studies also reported that the incidence of
cardiac abnormalities increased with time [8, 11]. The consequences
of A-CHF are extensive. It impairs the quality of life in childhood
cancer survivors, it involves long-term treatment and thus high
medical costs and it causes premature death. The excess mortality
due to cardiac disease is 8-fold higher than expected for long-term
survivors of childhood cancer compared to the normal population
[11]. In order to establish adequate follow-up protocols for these
patients, who should have a long life expectancy after successful
antineoplastic treatment, it is important to estimate the risk and
risk factors of A-CHF in those patients. In this study, we
evaluated the cumulative incidence of A-CHF and associated risk
factors in a large cohort of patients with childhood cancer treated
with anthracyclines between 1976 and 2001. Patients treated with
anthracyclines between 1976 and 1996 have been evaluated before
[9], so for this subgroup we are able to give the results of 5
years additional follow-up.
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Chapter 2
28
Patients and methods Patients All children who where treated
with anthracyclines in the Emma Children’s Hospital / Academic
Medical Center (EKZ/AMC) for childhood cancer between January 1st
1976 and December 31st 2000 were eligible for this study. Patients
were identified using the Registry of Childhood Cancer of the
EKZ/AMC. This registry was established in 1966 and contains data on
all children treated for childhood cancer in the EKZ/AMC with
regard to diagnosis, treatment, and follow-up. We decided to
include only patients who received their first treatment with
anthracyclines after 1976, because the chemotherapeutic treatment
was not specified in the early years of the registration. According
to the registry, 831 patients were eligible, including the 609
children treated between 1976 and 1996 who have been evaluated
before [9]. Treatment and follow up data If possible, data were
collected directly from the medical records of the clinical
surveillance of patients at the department of paediatric oncology
and/or the late effects outpatient clinic (PLEK) of the EKZ/AMC by
one of the authors (EVD). For patients whose medical records were
missing, we obtained information by means of the registry charts
kept by the Registry of Childhood Cancer of the EKZ/AMC. Attempts
were made to establish the clinical status of patients lost to
follow-up by sending a questionnaire to their general
practitioners. For each patient the following information was
recorded: (1) date of birth, (2) sex, (3) type of malignancy, (4)
date of tumour diagnosis, (5) chemotherapeutic protocol, including
the cumulative doses of administered anthracycline derivates (i.e.
doxorubicin, daunorubicin, epirubicin and / or idarubicin),
mitoxantrone, ifosfamide, cyclophosphamide, and the
cardioprotectant dexrazoxane, (6) characteristics of the
anthracycline therapy (date of first and last dose of anthracycline
therapy and for each anthracycline derivate: infusion duration,
maximal daily dose, maximal dose received in 1 week (peak dose)),
(7) concurrent radiotherapy (RT) involving the heart region (i.e.
on the mediastinum, left part of the upper abdomen, left part of
the thorax, thoracic spinal cord, and total body irradiation), (8)
last follow-up date, (9) date and cause of death, (10) signs and
symptoms of clinical heart failure and, if that was the case,
aetiology, time of occurrence, treatment and clinical outcome, and
(11) for patients diagnosed with A-CHF the value of
echocardiographic left ventricular shortening fractions (LVSF)
measured at the onset of A-CHF.
Definition of anthracycline-induced clinical heart failure
A case of A-CHF was defined as congestive heart failure, not
attributable to other known causes, such as direct medical effects
of the tumour, septic shock, valvular disease or renal failure. We
defined congestive heart failure as the presence of the following
clinical signs and symptoms: dyspnoea, pulmonary oedema,
peripheral
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Clinical heart failure in a cohort of anthracycline-treated
children
29
oedema, and / or exercise intolerance which were treated with
anticongestive therapy. A cardiologist (WK) confirmed the diagnosis
in patients with cardiac events that may or may not have met this
definition of clinical cardiotoxicity. The cardiologist was unaware
of the cumulative anthracycline dose patients received. The
clinical outcome of A-CHF was either “death”, “alive with
anticongestive treatment” or “clinical recovery without current
requirement for anticongestive therapy, but anticongestive
treatment previously”. Depending on the time of onset, A-CHF was
classified as early A-CHF, i.e. during anthracycline chemotherapy
or within the first year after the end of treatment, or as late
A-CHF, i.e. more than 1 year after the completion of anthracycline
chemotherapy [6]. Statistical analysis The main outcome event was
defined as the occurrence of A-CHF. The 95% confidence interval
(CI) of the cumulative incidence of A-CHF was calculated using the
statistical program Confidence Interval Analysis [12]. If no cases
of anthracycline-induced cardiotoxicity were identified, we used
the “Rule of Three” as described by Hanley and Lippman-Hand [13].
Event-free survival was defined as the time from the start of
anthracycline therapy until the development of A-CHF, or until the
latest follow-up evaluation, or until death. The following risk
factors for A-CHF were evaluated: sex, age at first dose of
anthracycline therapy, cumulative anthracycline dose, additional
treatment with mitoxantrone, ifosfamide, cyclophosphamide, and / or
radiotherapy involving the heart region. The hazard ratio (HR) for
each risk factor was estimated with Cox regression analysis [14].
If the HR for each risk factor did not change over time (i.e. they
fulfilled the proportional hazards assumption), it was allowed to
use the HR as the relative risk (RR). We performed both univariate
and multivariate Cox regression analyses. Statistical significance
(P < 0.05) was determined with the Wald test. The cumulative
risk of A-CHF was estimated as a function of the follow up time
from the first dose of anthracycline therapy by the Kaplan-Meier
method [15]. Survival curves were constructed and confidence
intervals were calculated. Analyses were performed using the
statistical software SPSS for Windows 11.5.1 (release 2003; SPSS,
Inc, Chicago, IL).
Results Study population The study population consisted of 830
out of 831 eligible patients. Data of 817 of 831 children were
collected directly from the medical records. For 13 patients whose
medical records were missing, we obtained information by means of
the registry charts kept by the Registry of Childhood Cancer. No
data were available for 1 child. We succeeded in obtaining
information on the clinical status up to at least January
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Chapter 2
30
2002 (or date of death) for 795 patients (95.8% of the cohort)
including information from general practitioners for 38 patients.
For the other 35 patients (including 20 patients who emigrated or
returned to their home country) we used the data of the last known
follow-up date. The clinical characteristics of the study
population are listed in Table 1. The mean age at the first dose of
anthracycline therapy was 8.8 years (median 8.7 years; range 0.1 to
18.0 years). The mean cumulative dose of anthracyclines was 288
mg/m2 (median 280 mg/m²; range 15 to 900 mg/m2): 435 children
received only doxorubicin (52.4%), 66 children received only
daunorubicin (8.0%), 152 children received only epirubicin (18.3%),
1 child received only idarubicin (0.1%), and 176 children received
a combination of doxorubicin, daunorubicin, epirubicin, and / or
idarubicin (21.2%). The exact cumulative dose of anthracyclines of
19 patients is unknown. Different durations of anthracycline
infusion were used, both bolus and continuous infusion (up till 48
hours). The daily anthracycline dose varied between 13 and 150
mg/m² and the maximal peak dose varied between 15 and 180 mg/m².
Further treatment is described in Table 1. For patients who
received additional treatment with mitoxantrone, ifosfamide and /
or cyclophosphamide, the mean cumulative dose of mitoxantrone was
21.8 mg/m² (median 12 mg/m²; range 12 to 108 mg/m²), the mean
cumulative dose of ifosfamide was 31.3 g/m² (median 18.0 g/m²;
range 1.8 to 132 g/m²), and the mean cumulative dose of
cyclophosphamide was 6.3 g/m² (median 5.8 g/m²; range 0.3 to 73.5
g/m²). The mean follow-up time after the first dose of
anthracycline therapy for the whole group was 8.5 years (median 7.1
years; range 0.01 to 28.4 years). For 272 patients (32.9%), the
follow-up was more than 10 years, for 140 patients (16.9%) it was
more than 15 years and for 51 patients (6.1%) it was more than 20
years. The mean age of the patients at the end of the follow-up was
17.3 years (median 16.7 years; range 0.3 to 42.7 years). At last
contact 297 patients (35.8%) had died: 287 from tumour-related
causes, 4 from other causes (traffic accidents, dengue virus
infection, hepatitis B infection), and there were 6 cases of
cardiac death (5 due to A-CHF and 1 due to pericarditis with
cardiac tamponade). Incidence and outcome of anthracycline-induced
clinical heart failure The cumulative incidence of A-CHF at a mean
follow-up time of 8.5 years (median 7.1 years; range 0.01 to 28.4
years) after the first dose of anthracycline therapy was 2.5% (21
patients; 95% CI 1.6 to 3.8%). The characteristics of the patients
with A-CHF are shown in Table 2. Sixteen cases of A-CHF (76.2%)
occurred during or within the first year of therapy, i.e. early
A-CHF. The mean time between the first dose of anthracycline
therapy and the occurrence of A-CHF was 3.7 years (median 0.84
years; range 0.1 to 20.9 years). For 19 patients an
echocardiographic measurement of the LVSF at the onset of A-CHF was
available: the mean LVSF was 19.4% (median 20.0%; range 5 to
32%).
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Clinical heart failure in a cohort of anthracycline-treated
children
31
Sixteen of the 21 cases of A-CHF were already identified in our
earlier study [9]; after re-evaluation 1 of the 17 patients
diagnosed with A-CHF during pregnancy in that study could not be
confirmed by the cardiologist. The 5 newly diagnosed cases of A-CHF
in this study can be divided in 2 cases of late A-CHF in patients
also included in our earlier study (patient 19 and 20 in Table 2)
and 3 cases of early A-CHF in patients treated with anthracyclines
since 1996 (patients 8, 13 and 14 in Table 2). The mean age of the
patients with A-CHF at the first dose of anthracycline therapy was
8.6 years (median 9.8 years; range 1.3 to 15.9 years). The mean
cumulative anthracycline dose these patients received at the onset
of A-CHF was 434 mg/m² (median 413 mg/m²; range 225 to 810 mg/m²):
13 children received only doxorubicin (61.9%), 3 children received
only epirubicin (14.3%) and 5 children received a combination of
doxorubicin, daunorubicin, and / or epirubicin (23.8%). Different
durations of anthracycline infusion were used, both bolus and
continuous infusion (up till 6 hours). The daily anthracycline dose
varied between 25 and 150 mg/m² and the maximal peak dose varied
between 25 and 180 mg/m². Further treatment is described in Table
2. For patients who received additional treatment with ifosfamide
(7 patients; 33.3%) and cyclophosphamide (9 patients; 42.9%), the
mean cumulative dose of ifosfamide at the onset of A-CHF was 39.9
g/m² (median 42 g/m²; range 12 to 72 g/m²), and the mean cumulative
dose of cyclophosphamide at the onset of A-CHF was 7.3 g/m² (median
7.4 g/m²; range 0.5 to 18.2 g/m²). One patient (4.8%) received
additional treatment with 12 mg/m² mitoxantrone at the onset of
A-CHF. Three patients (14.3%) received RT involving the heart
region. The mean follow-up time after the first dose of
anthracyclines was 7.9 years (median 3.9 years; range 0.5 to 22.1
years). The mean age of the patients at the end of follow-up was
16.6 years (median 15.7 years; range 5.5 to 30.1 years). Five
patients (23.8%) died from A-CHF within 0 to 5.5 years after the
onset of symptoms (mean 1.4 years; median 0.04 years). Nine
patients (42.9%) died from tumour-related causes; all but 1 still
received anticongestive treatment at time of death. Seven patients
(33.3%) are still alive; 3 are still receiving anticongestive
therapy whereas the other 4 are not. One of the patients still
receiving anticongestive treatment at the time of our earlier study
does not at the moment (patient 18 in Table 2), whereas in another
patient the anticongestive therapy was restarted since then
(patient 11 in Table 2). The risk of developing A-CHF as a function
of the follow-up time after the first dose of anthracyclines based
on Kaplan-Meier estimates is shown in Figure 1. The estimated risk
of A-CHF 2 years after the first dose of anthracyclines was 2% (95%
CI 1 to 3%), 5 years after the first dose of anthracyclines it was
2.4% (95% CI 1.3 to 3.5%), 10 years after the first dose of
anthracyclines it was 2.6% (95% CI 1.4 to 3.9%), 15 years after the
first dose of anthracyclines it was 3.7% (95% CI 1.8 to 5.5%), and
20 years after the first dose of anthracyclines it was 5.5% (95% CI
1.5 to 9.5%).
-
Chapter 2
32
Table 1 Clinical characteristics of 830 anthracycline-treated
children Characteristic Number (%) Sex Male Female
476 (57.3) 354 (42.7)
Diagnosis Haematological malignancies Acute lymphoblastic
leukaemia Acute myeloid leukaemia Hodgkin’s disease Non-Hodgkin’s
disease Solid tumours Osteosarcoma Ewing’s sarcoma Wilms’ tumour
Other
169 (20.4) 76 (9.2) 78 (9.4) 170 (20.5) 108 (13.0) 73 (8.8) 54
(6.5) 102 (12.2)
Age at first anthracycline dose (years) < 2 2 – 6 7 – 11 12 –
16 > 16
76 (9.2) 257 (30.9) 224 (27.0) 251 (30.2) 22 (2.7)
Cumulative dose of anthracycline (mg/m²) < 150 150 – 299 300
– 449 450 – 600 > 600 Unknown
101 (12.2) 318 (38.3) 242 (29.1) 135 (16.3) 15 (1.8) 19
(2.3)
Mitoxantrone Any < 40 mg/m² ≥ 40 mg/m² None Unknown
34 (4.1) 29 (85.3) 5 (14.7) 793 (95.5) 3 (0.4)
Ifosfamide Any ≤ 10 g/m² > 10 g/m² Unknown None Unknown
226 (27.2) 54 (23.9) 162 (71.7) 10 (4.4) 601 (72.4) 3 (0.4)
Cyclophosphamide Any ≤ 10 g/m² > 10 g/m² Unknown None
Unknown
456 (55.0) 351 (77.0) 83 (18.2) 22 (4.8) 372 (44.8) 2 (0.2)
Dexrazoxane Any None Unknown
47 (5.7%) 782 (94.2%) 1 (0.1%)
Radiotherapy involving the heart Any None Unknown
176 (21.2%) 653 (78.7%) 1 (0.1%)
-
Table 2 Characteristics, treatment and follow-up of 21 patients
with anthracycline-induced clinical heart failure Pt Sex Tumour Age
at first
anthra dose (years)
Cum anthra dose (mg/m²) ¶
Anthra derivate
Mito- xantrone (mg/m²) ¶
Ifosfa- mide (g/m²) ¶
Cyclo-phos-phamide (g/m²) ¶
RT on heart ¶
Dexra-zoxane ¶
Time to A-CHF after therapy (years)
Outcome of A-CHF
LVSF ¶
1 M NHL 7.1 300 Doxo N N Y (10) N N N During A T * 22% 5 F NHL
3.5 ? Doxo ? ? ? N N During A T * 16% 6 M Osteo 10.6 375 Doxo N Y
(>10) N N N During A No T 20% 7 M Osteo 15.9 450 Doxo N Y
(>10) N N N 0.1 Death 11% 8 F AML 7.9 230 Doxo/
Dauno ? N Y (10) N N 0.1 Death 16% 10 F NHL 10.3 520 Doxo/
Dauno/ Epi
N N Y (10) N N N 0.2 T 9% 12 F NHL 10.1 350 Doxo N N Y (>10)
N N 0.2 No T 18% 13 M Rhabdo 3.4 600 Epi N Y (>10) N N N 0.2 T *
23% 14 F Osteo 11.0 450 Doxo N N N N N 0.2 Death 5% 15 F AML 3.2
570 Doxo/
Dauno N N Y (10) N N N 0.4 T * 21% 17 M AML 12.1 810 Doxo/
Dauno/ Epi
N N Y (10) N N N 6.7 No T ? 19 F NHL 6.2 300 Epi Y (
-
Chapter 2
34
Abbreviations table 2: Pt, patient; M, male; F, female; NHL,
non-Hodgkin lymphoma; AML, acute myeloid leukaemia; osteo,
osteosarcoma; rhabdo, rhabdomyosarcoma; Ewing, Ewing’s sarcoma;
Wilms, Wilms tumour; anthra, anthracycline; cum, cumulative; A-CHF,
anthracycline-induced clinical heart failure; doxo, doxorubicin;
dauno, daunorubicin; epi, epirubicin; N, no; Y, yes; ?, data
missing; RT, radiotherapy; A, anthracycline; LVSF,
echocardiographic left ventricular shortening fraction; T,
anticongestive treatment; no T, no anticongestive treatment at time
of last follow-up, but anticongestive treatment previously; T*,
used anticongestive treatment until time of death (died from tumour
progression or from medical conditions related to tumour treatment
excluding A-CHF); no T*, no anticongestive treatment at time of
death, but anticongestive treatment previously (died from tumour
progression or from medical conditions related to tumour treatment
excluding A-CHF); ¶, at time of diagnosis A-CHF The risk of
developing A-CHF was dose-dependent (see Figure 2). In patients
treated with less than 150 mg/m² of anthracyclines it was 0% (95%
CI 0 to 3%), in patients treated with 150 to 299 mg/m² it was 0.6%
(95% CI 0.1 to 2.3%), in patients treated with 300 to 449 mg/m² it
was 3.3% (95% CI 1.4 to 6.4%), in patients treated with 450 to 600
mg/m² it was 5.9% (95% CI 2.6 to 11.3%) and finally, in patients
treated with more than 600 mg/m² it was 14.3% (95% CI 1.8 to
42.8%). Risk factors for anthracycline-induced clinical heart
failure The results of the univariate Cox regression analyses of
the different risk factors for the occurrence of A-CHF are shown in
Table 3. The univariate analyses showed a statistically significant
increase in the occurrence of A-CHF associated with the cumulative
anthracycline dose: treatment with a cumulative anthracycline dose
of 300 mg/m² or more showed a statistically significant increase in
the occurrence of A-CHF as compared to a cumulative anthracycline
dose of less than 300 mg/m² (RR = 8.66, 95% CI 2.01 to 37.35, P =
0.004). Additional treatment with ifosfamide with a cumulative dose
of more than 10 g/m² also showed a statistically significant
increase in the occurrence of A-CHF as compared to treatment with
no or 10 g/m² or less ifosfamide (RR = 2.67, 95% CI 1.05 to 6.82, P
= 0.04). The other possible risk factors for A-CHF (i.e. female
sex, age at first anthracycline dose 2 years or younger, RT
involving the heart region, additional treatment with mitoxantrone,
and additional treatment with more than 10 g/m² of
cyclophosphamide) were not associated with an increased risk of
A-CHF. Table 3 Risk factors for the occurrence of
anthracycline-induced clinical heart failure (univariate Cox
regression analyses)
Risk factor Relative Risk 95% Confidence Interval P-value Female
sex 1.46 0.62 – 3.43 0.39 Age at first anthracycline dose ≤ 2 years
0.28 0.04 – 2.09 0.22 Cumulative anthracycline dose ≥ 300 mg/m²
8.66 2.01 – 37.35 0.004
Radiotherapy on heart 0.67 0.20 – 2.29 0.53 Treatment with
mitoxantrone 1.38 0.18 – 10.37 0.76 Cumulative ifosfamide > 10
g/m² 2.67 1.05 – 6.82 0.04 Cumulative cyclophosphamide > 10
g/m²
0.73 0.17 – 3.20 0.68
-
Clinical heart failure in a cohort of anthracycline-treated
children
35
In the multivariate Cox regression analysis a cumulative
anthracycline dose of 300 mg/m² or more was the only independent
risk factor (table 4). Since the HR for each risk factor did not
change over time, we present the HR as the RR. Table 4 Risk factors
for the occurrence of anthracycline-induced clinical heart failure
(multivariate Cox regression analyses)
Risk factor Relative Risk 95% Confidence Interval
P-value
Cumulative anthracycline dose ≥ 300 mg/m²
7.78 1.76 – 34.27 0.007
Cumulative ifosfamide > 10 g/m² 1.65 0.64 – 4.26 0.30 The
risk of developing A-CHF as a function of the follow-up time after
the first dose of anthracyclines based on Kaplan-Meier estimates
for patients treated with a cumulative anthracycline dose of less
than 300 mg/m² or 300 mg/m² or more is shown in Figure 3. For
patients treated with a cumulative anthracycline dose of less than
300 mg/m², the estimated risk of A-CHF 2 years after the first dose
of anthracyclines was 0.5% (95% CI 0.0 to 1.23%). This risk did not
increase any further with a longer duration of follow-up. For
patients treated with a cumulative anthracycline dose of 300 mg/m²
or more, the estimated risk of A-CHF 2 years after the first dose
of anthracyclines was 3.3% (95% CI 1.4 to 5.1%), 5 years after the
first dose of anthracyclines it was 4.1% (95% CI 1.9 to 6.2%), 10
years after the first dose of anthracyclines it was 4.5% (95% CI
2.2 to 6.8%), 15 years after the first dose of anthracyclines it
was 6.2% (95% CI 3 to 9.4%), and 20 years after the first dose of
anthracyclines it was 9.8% (95% CI 2.2 to 17.4%).
Discussion This study in a large cohort of patients with a very
long and complete follow-up demonstrates that the risk of A-CHF
increased over time and that it was strongly dose-dependent. The
estimated risk of A-CHF increased from 2% at 2 years after the
start of anthracycline therapy to 5.5% at 20 years. For patients
treated with a cumulative anthracycline dose of 300 mg/m² or more
the estimated risk at 20 years after the start of anthracycline
therapy was nearly 10%. This means that 1 in every 10 children
treated with a cumulative anthracycline dose of 300 mg/m² or more
will eventually develop A-CHF. This is an extremely high risk,
especially considering the fact that presently some treatment
protocols still include 300 mg/m² or more of anthracycline therapy
and that this study describes a young patient population. In the
whole cohort of 830 patients the cumulative incidence of A-CHF
after a mean follow-up of 8.5 years (median 7.1 years; range 0.01
to 28.4 years) after the first dose of
-
Chapter 2
36
Figure 1 Kaplan-Meier plot of the estimated risk of
anthracycline-induced clinical heart failure (A-CHF) as a function
of the follow-up time after the first dose of anthracyclines.
Patients at risk 830 498 386 186 52 10 anthracycline therapy for
childhood cancer was 2.5%. The cumulative incidence of early A-CHF
was 1.9%. An explanation for this high cumulative incidence of
early A-CHF in comparison with the cumulative incidence of late
A-CHF could be that the clinical condition of children during
chemotherapy, when they often suffer from anaemia, acidosis,
cachexia, fever or overhydration from intravenous fluid, possibly
lowers the threshold for A-CHF. The cumulative incidence of late
A-CHF was 0.6%. At the moment, it is unclear what the
Follow-up from first anthracycline dose (years)
302520151050
Ris
k of
A-C
HF
,10
,09
,08
,07
,06
,05
,04
,03
,02
,01
0,00
-
Clinical heart failure in a cohort of anthracycline-treated
children
37
incidence of late A-CHF will be with a follow-up beyond 20
years, but it is seems correct to assume that there will be a
further increase in the incidence of late A-CHF with time. Green
and colleagues [8] reported that the risk of A-CHF increased with a
longer follow-up and several studies have reported an increase in
asymptomatic cardiac dysfunction with longer follow-up [5, 16]. It
is very likely that asymptomatic abnormalities will progress to a
clinically significant impairment of cardiac function. Also, when
the childhood cancer survivors become older, aging of the heart
will become important. A part of this cohort (607 patients, 73%)
has been evaluated before [9] and for this subgroup we now have the
results of 5 years additional follow-up. Therefore, we are able to
present the estimated risk of A-CHF 20 years after the start of
anthracycline therapy, confirming the increase of the risk of A-CHF
beyond 15 years after the start of anthracycline therapy. Two of
the 607 patients developed late A-CHF (respectively at 13.5 and
13.8 years after the cessation of anthracycline therapy) since our
earlier study. Figure 2 Risk of anthracycline-induced clinical
heart failure (A-CHF) according to cumulative anthracycline
dose
0
2
4
6
8
10
12
14
16
600
Ris
k of
A-C
HF
(%)
Cumulative dose of anthracyclines (mg/m2) Mean/ median/ range of
follow-up 7.9/3.8/ 7.7/7.3/ 9.2/8.4/ 10.2/10.3/ 6.1/3.6/ (years)
0.01-26.2 0.06-26.8 0.13-28.4 0.42-25.1 2.0-17.7
-
Chapter 2
38
Figure 3 Kaplan-Meier plot of the estimated risk of
anthracycline-induced clinical heart failure (A-CHF) as a function
of the follow-up time after the first dose of anthracyclines for
patients treated with a cumulative anthracycline dose of less than
300 mg/m² (lower line) or 300 mg/m² or more (upper line).
Follow-up from first anthracycline dose (years)
302520151050
Ris
k of
A-C
HF
,20
,18
,16
,14
,12
,10
,08
,06
,04
,02
0,00
Patients at risk < 300 mg/m² 420 252 123 61 30 7 ≥ 300 mg/m²
391 231 176 100 36 3 As stated in earlier reports, the occurrence
of A-CHF is a dose-dependent phenomenon [4, 7, 8]. This was
confirmed in this study. Even more seriously, for patients treated
with a cumulative anthracycline dose of 300 mg/m² or more an 8-fold
higher risk of A-CHF was
-
Clinical heart failure in a cohort of anthracycline-treated
children
39
found as compared to patients treated with a cumulative
anthracycline dose of less than 300 mg/m² (P=0.007). Only 2 cases
of A-CHF occurred in patients treated with less than 300 mg/m² (225
and 230 mg/m² respectively). For patients treated with a cumulative
anthracycline dose of less than 300 mg/m², the estimated risk of
A-CHF 2 years after the first dose of anthracyclines was 0.5%. This
risk did not increase any further with a longer duration of
follow-up. On the other hand, for patients treated with a
cumulative anthracycline dose of 300 mg/m² or more (47% of our
cohort), the estimated risk of A-CHF 2 years after the first dose
of anthracyclines was 3.3%, and this risk increased to 9.8% 20
years after the first dose of anthracyclines, which is extremely
high. And it is even possible that we underestimated the true
incidence of A-CHF, since we used a very strict definition of
A-CHF, i.e. congestive heart failure treated with anticongestive
therapy not attributable to other known causes including valvular
disease. In contrast with other studies, we could not identify
other risk factors for the development of A-CHF. However, the
identification of risk factors for A-CHF has not been univocal in
the literature [7, 10]. At the moment, many treatment protocols
still include 300 mg/m² or more of anthracycline therapy and many
children diagnosed with a relapse will receive additional
anthracycline therapy. The results of this study reinforce the need
of re-evaluating the cumulative anthracycline dose used in
different treatment protocols. Also, strategies to prevent
anthracycline-induced cardiotoxicity should be implemented in
treatment protocols. For example, even though there is some
suggestion that patients treated with the cardioprotectant
dexrazoxane might have a lower response rate [17], in children who
will receive a cumulative anthracycline dose of 300 mg/m2 or more
it might be justified to use it. Furthermore, it is important not
to forget that, although the risk of A-CHF is significantly
increased with a cumulative anthracycline dose of 300 mg/m² or
more, both A-CHF and asymptomatic cardiac dysfunction can occur
with a lower cumulative anthracycline dose [5]. At present, there
is no effective therapy to prevent further deterioration of
asymptomatic cardiac dysfunction. Both treatment with
ACE-inhibitors [18] and growth hormone therapy [19] did not lead to
a lasting improvement in cardiac structure and function. In
conclusion, the risk of A-CHF 20 years after the start of
anthracycline therapy was estimated to be approximately 10% in
patients treated with a cumulative anthracycline dose of 300 mg/m²
or more. Patients treated with a lower cumulative anthracycline
dose had a relatively low risk of 0.5%. It remains unclear what the
cumulative incidence of A-CHF will be with longer follow-up, but it
is likely to increase even further with time.
Acknowledgements The authors would like to thank MC
Cardous-Ubbink and JH van der Lee for their statistical advice, RC
Heinen for helping identifying all eligible patients, FG
Hakvoort-Cammel (of the Late Effects Outpatient Clinic (LATER),
Sophia Children’s Hospital / Erasmus MC, Rotterdam) and D Bresters
(of the Late Effects Outpatient Clinic (KLEP) of the Leiden
-
Chapter 2
40
University Medical Center, Leiden) for the provision of
additional and follow-up data on patients who went to other
hospitals for their follow-up, and all general practitioners who
returned the questionnaire. This study was supported by the
Foundation of Paediatric Cancer Research (SKK), Amsterdam, the
Netherlands and the Jacques H de Jong Foundation, Nieuwegein, the
Netherlands.
-
Clinical heart failure in a cohort of anthracycline-treated
children
41
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Childhood cancer and the price of cure: studies on late effects of
childhood cancer
treatment. Thesis, University of Amsterdam, Amsterdam 2000. 4.
Von Hoff DD, Layard MW, Basa P, et al. Risk factors for
doxorubicin-induced congestive heart
failure. Ann Intern Med 1979, 91, 710-717. 5. 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, 2629-2636. 6. Shan K, Lincoff AM, Young JB.
Anthracycline-induced cardiotoxicity. Ann Intern Med 1996, 125,
47-58. 7. Kremer LC, van Dalen EC, Offringa M, Voûte PA.
Frequency and risk factors of anthracycline-
induced clinical heart failure in children: a systematic review.
Ann Oncol 2002, 13, 503-512. 8. Green DM, Grigoriev YA, Nan B, et
al. Congestive heart failure after treatment for Wilms' tumor:
a
report from the National Wilms' Tumor Study group. J Clin Oncol
2001, 19, 1926-1934. 9. Kremer LC, van Dalen EC, Offringa M,
Ottenkamp J, Voûte PA. Anthracycline-induced clinical
heart failure in a cohort of 607 children: long-term follow-up
study. J Clin Oncol 2001, 19, 191-196. 10. Simbre II VC, Duffy SA,
Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer
chemotherapy, implications for children. Pediatr Drugs 2005, 7,
187-202. 11. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality
experience in five-year survivors of childhood
and adolescent cancer: the Childhood Cancer Survivor Study. J
Clin Oncol 2001, 19, 3163-3172. 12. Gardner MJ, Altman DG.
Statistics with confidence. BMJ Press, 1989. 13. Hanley JA,
Lippman-Hand A. If nothing goes wrong, is everything alright? JAMA
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1745. 14. Cox DR. Regression models and life-tables. J R Stat
Soc 1972, 34, 187-220. 15. Kaplan EL, Meier P. Nonparametric
estimation from incomplete observations. J Am Stat Assoc
1958, 53, 457-481. 16. Sorensen K, Levitt GA, Bull C, Dorup I,
Sullivan ID. Late anthracycline cardiotoxicity after
childhood cancer, a prospective longitudinal study. Cancer 2003,
97, 1991-1998. 17. Van Dalen EC, Caron HN, Dickinson HO, Kremer
LCM. Cardioprotective interventions for cancer
patients receiving anthracyclines. Cochrane Database Syst Rev
2005, issue 1, Art. No.: CD003917.
18. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Long-term
enalapril therapy for left ventricular dysfunction in
doxorubicin-treated survivors of childhood cancer. J Clin Oncol
2002, 20, 4517-4522.
19. Lipshultz SE, Vlach SA, Lipsitz SR, Sallan SE, Schwartz ML,
Colan SD. Cardiac changes associated with growth hormone therapy
among children treated with anthracyclines. Pediatrics 2005, 115,
1613-1622.
-
3 Clinical heart failure during pregnancy and
delivery in a cohort of female childhood cancer survivors
treated with anthracyclines
Elvira C van Dalen1
Helena JH van der Pal2,3
Cor van den Bos1,2
Wouter EM Kok4
Huib N Caron1
Leontien CM Kremer1,2
European Journal of Cancer 2006; 42(15): 2549-2553*
1 Department of Paediatric Oncology, Emma Children’s Hospital /
Academic Medical Center; 2 Late Effects Outpatient Clinic (PLEK:
Polikliniek Late Effecten Kindertumoren) and Study Group, Emma
Children’s Hospital / Academic Medical Center; 3 Department of
Medical Oncology, Academic Medical Center; 4 Department of
Cardiology, Academic Medical Center (Amsterdam, the
Netherlands).
(* http://intl.elsevierhealth.com/journals/ejca/)
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Chapter 3
44
Abstract The cumulative incidence of peripartum
anthracycline-induced clinical heart failure (A-CHF) was evaluated
in a cohort of 53 childhood cancer survivors who had delivered one
or more children. None of them developed peripartum A-CHF
(cumulative incidence 0%; 95% confidence interval (CI) 0 to 5.7%).
The mean follow-up time after the first administration of
anthracycline therapy was 20.3 years. They received a mean
cumulative anthracycline dose of 267 mg/m2. It is worth noticing
that even 2 patients with A-CHF before pregnancy did not develop
peripartum A-CHF. Since there were no cases of peripartum A-CHF in
our cohort, it was not possible to evaluate associated risk
factors. In conclusion, this study demonstrates a low risk of
developing peripartum A-CHF in childhood cancer survivors. However,
more cohort studies with adequate power and long-term follow-up are
needed to reliably evaluate the cumulative incidence of peripartum
anthracycline-induced cardiotoxicity (both clinical and
asymptomatic) and associated risk factors.
-
Anthracycline-induced clinical heart failure during pregnancy
and delivery
45
Introduction Anthracyclines have gained widespread use in the
treatment of numerous childhood malignancies: nearly 60% of
children diagnosed with a malignancy receive anthracyclines. The
introduction of anthracyclines has contributed to the improvement
in survival rates of childhood cancer: from 30% in the 1960s to 70%
currently [1, 2]. As a result, a rapidly growing number of children
will have survived childhood cancer. In the Netherlands,
approximately 1 out of every 750 to 800 young adults has survived
childhood cancer [3]. Unfortunately, the use of anthracyclines is
limited by the occurrence of cardiotoxicity. Several risk factors,
like a higher cumulative anthracycline dose, a higher anthracycline
peak dose, different anthracycline derivates, radiation therapy
involving the heart region, female sex, younger age at diagnosis,
black race, additional treatment with amsacrine, a longer follow-up
time, and presence of trisomy 21, have been identified, although
not conclusive in all studies [4, 5]. Cardiotoxicity can become
manifest as either clinical heart failure [6] or asymptomatic
cardiac dysfunction [7]. Both can not only develop during
anthracycline therapy, but also years after the cessation of
treatment [8]. In one of our earlier studies the estimated risk of
anthracycline-induced clinical heart failure (A-CHF) increased with
time to 2% at 2 years and 5% at 15 years after the start of
treatment [9]. The frequency of anthracycline-induced asymptomatic
cardiac dysfunction has been reported to be up to 57%; also
increasing with a longer follow-up period [5, 7, 10]. The risk of
developing anthracycline-induced cardiotoxicity thus remains a
lifelong threat. This is especially important in childhood cancer
survivors who have a long life-expectancy after successful
antineoplastic treatment. An increasing number of female childhood
cancer survivors reach the reproductive age and, although
infertility occurs in such women [11], a significant number of them
become pregnant. Pregnancy and delivery are associated with cardiac
stress [12, 13, 14]. The currently accepted estimate of incidence
of peripartum heart failure in the normal population is
approximately 1 case per 3000 to 4000 live births (0.03%) [15].
Female childhood cancer survivors who have been treated with
anthracyclines already have an increased gender-related risk to
develop cardiotoxicity [16, 17, 18] and at the moment, it is
unclear what the exact effect of the cardiac stress during
pregnancy and delivery on the cardiac function of these patients
will be. As described in case reports, it can have significant
clinical implications for these women [19, 20]. The aim of this
study was to evaluate the cumulative incidence of peripartum
anthracycline-induced clinical heart failure and to identify
associated risk factors in a cohort of childhood cancer survivors
treated with anthracyclines between 1966 and 1998.
Patients and methods Patients: All female patients aged 17 years
or older on January 1st, 2003 (or date of death) who survived for
at least five years after the diagnosis of a childhood malignancy
and were
-
Chapter 3
46
treated with anthracyclines at the Emma Children’s Hospital /
Academic Medical Center (EKZ/AMC) between 1966 and 1998 were
included in this study. Patients were identified using the Registry
of Childhood Cancer of the EKZ/AMC. This registry was established
in 1966 and contains data on all children treated for childhood
cancer in the EKZ/AMC with regard to diagnosis, treatment, and
follow-up. According to the registry, 206 patients were eligible.
Treatment and follow up data: In our hospital, patients who
survived at least 5 years after the treatment of a childhood
malignancy, are seen at regular intervals at the Late Effects
Outpatient Clinic (PLEK) [21]. During these visits information on
pregnancy and delivery (including clinical heart failure) is
obtained. Data were collected directly from the medical records.
Attempts were made to es