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Anthracycline-induced cardiotoxicity during and after treatment for childhoodcancer : long-term risk, risk factors and prevention

van Dalen, E.C.

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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

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.

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

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

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.

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

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].

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,

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.

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

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

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

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.

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].

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.

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.

Introduction

21

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31. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978; 88: 168-175.

32. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000; 22: 263-302.

33. Steinherz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the cardiology committee of the Children’s Cancer Study Group. Pediatrics 1992; 89: 942-949.

34. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072-1083.

35. Lipshultz SE, Easley KA, Orav J, et al. Reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function: the prospective P(2)C(2) HIV study. Circulation 2001; 104: 310-316.

36. Wassmuth R, Lentzsch S, Erdbruegger U, et al. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study. Am Heart J 2001; 141: 1007-1013.

37. Kremer LC, Tiel-van Buul MM, Ubbink MC, et al. Indium-111-antimyosin scintigraphy in the early detection of heart damage after anthracycline therapy in children. J Clin Oncol 1999; 17: 1208-1211.

38. Tikanoja T, Riikonen P, Perkkio M, Helenius T. Serum N-terminal atrial natriuretic peptide (NT-ANP) in the cardiac follow-up in children with cancer. Med Pediatr Oncol 1998; 31: 73-78.

39. Hayakawa H, Komada Y, Hirayama M, Hori H, Ito M, Sakurai M. Plasma levels of natriuretic peptides in relation to doxorubicin-induced cardiotoxicity and cardiac function in children with cancer. Med Pediatr Oncol 2001; 37: 4-9.

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40. Germanakis I, Kalmanti M, Parthenakis F, et al. Correlation of plasma N-terminal pro-brain natriuretic peptide levels with left ventricle mass in children treated with anthracyclines. Int J Cardiol 2006; 108: 212-215.

41. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997; 96: 2641-2648.

42. Missov E, Calzolari C, Davy JM, Leclerq F, Rossi M, Pau B. Cardiac troponin I in patients with hematologic malignancies. Coron Artery Dis 1997; 8: 537-541.

43. Yamashita J, Ogawa M, Shirakusa T. Plasma endothelin-1 as a marker for doxorubicin cardiotoxicity. Int J Cancer 1995; 62: 542-547.

44. 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.

45. Simbre II VC, Adams MJ, Deshpande SS, Duffy SA, Miller TL, Lipshultz SE. Cardiomyopathy Caused by Antineoplastic Therapies. Curr Treat Options Cardiovasc Med 2001; 3: 493-505.

46. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-691.

47. Lipshultz SE. Ventricular dysfunction clinical research in infants, children and adolescents. Progr Pediatr Cardiol 2000; 12: 1-28.

48. 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.

49. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 2004; 22: 820-828.

50. Van Dalen EC, Van der Pal HJH, Van den Bos C, et al. Treatment for asymptomatic anthracycline-induced cardiac dysfunction in childhood cancer survivors: the need for evidence. J Clin Oncol 2003; 21: 3377.

51. Lipshultz SE. Cardiovascular trials in long-term survivors of childhood cancer. J Clin Oncol 2004; 22: 769-773.

52. 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.

53. Messinger Y, Uckun FM. A critical risk-benefit assessment argues against the use of anthracyclines in induction regimens for newly diagnosed childhood acute lymphoblastic leukemia. Leuk Lymphoma 1999; 34: 415-432.

54. SIOP-2001 Nephroblastoma clinical trial and study. Protocol December 2001. 55. Rose PG, Blessing JA, Lele S, Abulafia O. Evaluation of pegylated liposomal doxorubicin (Doxil) as

second-line chemotherapy of squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2006; 102: 210-213.

56. Batist G, Ramakrishnan G, Rao CS, et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomised, multicenter trial of metastatic breast cancer. J Clin Oncol 2001; 19: 1444-1454.

57. Lippens RJJ. Liposomal daunorubicin (daunoxome) in children with recurrent or progressive brain tumors. Pediatr Hematol Oncol 1999; 16: 131-139.

58. Shenkenberg TD, Von Hoff DD. Mitoxantrone: a new anticancer drug with significant clinical activity. Ann Intern Med 1986; 105: 67-81.

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59. Lewis C. A review of the use of chemoprotectants in cancer chemotherapy. Drug Saf 1994; 11: 153-162.

60. Weiss G, Loyevsky M, Gordeuk VR. Dexrazoxane (ICRF-187). Gen Pharmac 1999; 32: 155-158. 61. Cvetkovic RS, Scott LJ. Dexrazoxane: a review of its use for cardioprotection during anthracycline

chemotherapy. Drugs 2005; 65: 1005-1024. 62. Wagdi P, Rouvinez G, Fluri M, et al. [Cardioprotection in chemo- and radiotherapy for malignant

diseases: an echocardiographic pilot study]. Schweiz Rundsch Med Prax 1995; 84: 1220-1223. 63. Myers C, Bonow R, Palmeri S, et al. A randomised controlled trial assessing the prevention of

doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983; 10: 53-55. 64. Kawasaki S, Akiyama S, Kurokawa T, et al. Polyoxyethylene-modified superoxide dismutase

reduces side effects of adriamycin and mitomycin C. Jpn J Cancer Res 1992; 83: 899-906. 65. Singal PK, Siveski-Iliskovic N, Hill M, Thomas TP, Li T. Combination therapy with probucol

prevents adriamycin-induced cardiomyopathy. J Mol Cell Cardiol 1995; 27: 1055-1063. 66. Bolaman Z, Cicek C, Kadikoylu G, et al. The protective effects of amifostine on adriamycin-induced

acute cardiotoxicity in rats. Tohoku J Exp Med 2005; 207: 249-253. 67. Simbre VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy:

implications for children. Paediatr Drugs 2005; 7: 187-202.

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/)

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.

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.

Chapter 2

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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


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

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%).


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%).

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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 (

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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


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

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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)

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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

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600

Ris

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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

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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).

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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


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

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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.


41

References 1. Heymans HS, Caron HN. Childhood cancers in the Netherlands (1989-1997). Ned Tijdschr

Geneesk 2001, 145, 1442-1444. 2. Gatta G, Capocaccia R, Coleman MP, Ries LA, Berrino F. Childhood cancer survival in Europe

and the United States. Cancer 2002, 95, 1767-1772. 3. Heikens J. 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 1983, 259, 1743-

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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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

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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

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