Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: An update of the evidence

    Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: An update of the evidence Steven E. Lipshultz, Vivian I. Franco, Stephen E. Sallan, Peter C. Adamson, Rudolf Steiner, Sandra M. Swain, Joseph Gligorov, Giorgio Minotti PII: DOI: Reference:

S1058-9813(14)00008-3 doi: 10.1016/j.ppedcard.2014.09.007 PPC 816

To appear in:

Progress in Pediatric cardiology

Please cite this article as: Lipshultz Steven E., Franco Vivian I., Sallan Stephen E., Adamson Peter C., Steiner Rudolf, Swain Sandra M., Gligorov Joseph, Minotti Giorgio, Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: An update of the evidence, Progress in Pediatric cardiology (2014), doi: 10.1016/j.ppedcard.2014.09.007

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ACCEPTED MANUSCRIPT Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: an update of the evidence

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Steven E. Lipshultz1, Vivian I. Franco1, Stephen E. Sallan2, Peter C. Adamson3,

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Rudolf Steiner4, Sandra M. Swain5, Joseph Gligorov6, Giorgio Minotti7 Department of Pediatrics, Wayne State University School of Medicine and the Children’s

Hospital of Michigan, Detroit, MI, USA; 2Division of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Department of Pediatrics, Harvard Medical 4

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School, Boston, MA, USA; 3The Children's Hospital of Philadelphia, Philadelphia, PA, USA; University of Zurich, Zurich 8006, Switzerland; 5National Surgical Adjuvant Breast and

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Bowel Project and Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, USA; 6Medical Oncology Department, APHP Hôpital Tenon, Paris and UPMC, Institut Universitaire de Cancérologie, Paris, France; 7CIR and Drug Sciences,

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Corresponding author

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University Campus Bio-Medico, Rome, Italy.

Steven E. Lipshultz, MD Department of Pediatrics

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Wayne State University School of Medicine Children’s Hospital of Michigan 3901 Beaubien Boulevard, Suite 1K40 Detroit, MI 48201 Telephone: 313-745-5870 Fax: 313-993-0390 E-mail: [email protected]

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ACCEPTED MANUSCRIPT Abstract Advances in treating childhood cancers over the past 40 years have more than doubled 5-year

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survival rates. More effective use of chemotherapeutic agents has been key to this success.

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However, the increase has come at a price: chronic conditions are significantly more

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prevalent in long-term survivors of childhood cancer than they are in the general population, and managing these survivors can be challenging. In patients receiving anthracyclines, cardiotoxicity is the leading cause of morbidity and mortality after relapse and second

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malignancies. More than 50% of patients exposed to anthracyclines exhibit some form of

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cardiac dysfunction within 20 years after completing chemotherapy, and about 5% develop heart failure. These conditions greatly reduce the quality of life of the individual and also

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consume substantial amounts of healthcare resources. Dexrazoxane has been used to reduce

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anthracycline-related cardiotoxicity in children with cancer, but in 2011, the European Medicines Agency determined, on what it acknowledged were limited data, that dexrazoxane

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was contraindicated in children. Here, we review the evidence for the clinical effects of dexrazoxane in children. Studies published since 2011 have confirmed the efficacy of

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dexrazoxane in preventing or reducing anthracycline-related cardiotoxicity in children with cancer, and no new evidence of increased risks for recurrence of primary or second malignancies, or reductions in antitumor efficacy has been reported. As a result, we believe that dexrazoxane should be available to children with high-risk cancers to reduce the risk of cardiotoxicity associated with high-dose anthracycline treatment.

Keywords: anthracyclines, cancer survivorship, cardioprotection, cardiotoxicity, dexrazoxane, doxorubicin, secondary malignancies.

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ACCEPTED MANUSCRIPT Introduction Advances in cancer treatment have markedly improved oncological outcomes for

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most childhood cancers, to a point where over three-quarters of those treated will still be alive

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in 5 years. However, one repercussion of this success is a marked increase in health problems

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related to anthracycline-induced cardiotoxicity that can present even decades after treatment [1]. After cancer relapse and secondary malignancies, cardiovascular-related problems are the leading cause of morbidity and mortality in childhood cancer survivors [2,3]. Cardiotoxicity

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is a limiting adverse consequence of cancer chemotherapy, and its management is pivotal to

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the survival, overall quality of life, and well-being of these patients. Dexrazoxane has been used to reduce anthracycline-related cardiotoxicity in children

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with cancer. In 2011, the Committee for Medicinal Products for Human Use (CHMP)

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[European Medicines Agency (EMA)] evaluated what it acknowledged were limited data relating the use of dexrazoxane to prevent anthracycline (such as doxorubicin)-induced

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cardiotoxicity in children [4]. This risk-benefit assessment was triggered by early reports suggesting an increase in secondary malignancies, myelosuppression, and infection in

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children treated with dexrazoxane. In particular, the Committee noted that: 

The efficacy of dexrazoxane in children had not been established.

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Acute myeloid leukemia-myelodysplastic syndrome (AML/MDS) was a potential risk of dexrazoxane treatment.

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Second malignant neoplasms (SMNs) were a potential risk of dexrazoxane treatment. The Committee concluded, “the safety and efficacy of dexrazoxane in children have

not been established and that dexrazoxane should therefore not be used in children due to the risk of second malignancies and potentially negative pharmacodynamic interactions with anthracyclines.” On the basis of these findings, the EMA recommended that the use of dexrazoxane in children and adolescents up to 18 years of age be contraindicated.

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ACCEPTED MANUSCRIPT In this literature review we re-evaluate the risk-benefit of dexrazoxane in children and adolescents receiving anthracycline therapy using evidence from studies published after the

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original 2011 EMA appraisal. A MEDLINE search on the use of dexrazoxane in children

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identified 77 articles published between January 1, 2011 and September 12, 2014, 15a of

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which are included in this review. Also included are 10b presentations from major oncology scientific meetings (e.g. American Society of Clinical Oncology [ASCO] and the European

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Society of Medical Oncology [ESMO]) and key articles from earlier literature.

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Childhood cancers and anthracyclines: balancing efficacy with longer-term safety Anthracyclines such as doxorubicin are among common chemotherapeutic drugs used

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to treat solid and hematological malignancies in children [1,5-7]. In a population-based study

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in the UK between 1960 and 1999, 5-year survival increased from 23% to 70% (for leukemias it increased from 6% to 74%), and anthracyclines were administered to 50% of

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children (78% of those with leukemia) [5]. Similar figures have been reported in the US. Since the 1960s, advances in treatment have greatly reduced mortality rates from childhood

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cancers; the 5-year survival rate is now approximately 80% [8] with rates in excess of 90% being reported for diseases such as acute lymphoblastic leukemia (ALL), Hodgkin lymphoma and Wilms tumor [9]. A large proportion of these patients become long-term survivors [10], with an estimated 1 in 530 young adults aged 20- to 39-years-old identified as childhood cancer survivors [8]. The improved longevity of childhood cancer survivors in the US is highlighted by the fact that in the year 2010, 379,112 patients were still alive and, of these, about 70% were 20 years or older [8].

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15 dexrazoxane full references: 1,16-18,22,31,40,43,50,60,70,78,82,83,89

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10 dexrazoxane abstract references: 19,35,45,51,52,59,71-73,79

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ACCEPTED MANUSCRIPT Several long-term studies have focused on the late effects of cancer treatment including anthracycline therapy. Childhood cancer survivors have a significantly higher risk

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of premature death than that of the general population, and a wide range of health problems

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that can reduce their overall well-being and quality of life [1,3,5,11-14]. For example, in the

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Childhood Cancer Survivor Study (Table 1), a retrospective analysis of 10,397 adult survivors of childhood cancer, 62% of patients had at least one chronic condition, and in 28% of these patients the condition was life-threatening (Grade 3 or 4 toxicity) [12].

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Clinical and subclinical cardiovascular damage, heart failure, coronary artery disease,

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and cerebrovascular events are treatment-related health complications in survivors of childhood cancer [3,5,12,15-17]. Cumulative doses of anthracycline of 300 mg/m2 or higher

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increase the risk of cardiomyopathy, valve disorders, and conduction abnormalities over that

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of unexposed survivors; radiotherapy is an added risk factor [18-20]. Heart damage resulting from anthracycline chemotherapy is a serious problem because it reduces quality of life and

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can lead to premature death. This problem is considered in more depth in the section on the cardioprotective effects of dexrazoxane.

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Anthracycline cardiotoxicity

Long-term cardiovascular complications of cancer therapies are a major concern in survivors of childhood cancer. These complications pose a threat to overall quality of life, but more specifically, as it relates to this review, to the cardiotoxicity associated with anthracycline chemotherapy [1,21,22], with or without radiotherapy [2,23,24]. The cardiotoxicity of anthracycline drugs, such as doxorubicin, is a major drawback for physicians treating children with cancer because these drugs are associated with an irreversible and dose-dependent loss of cardiomyocytes. Reported risk factors of cardiotoxicity in childhood cancer survivors include cumulative anthracycline doses greater than 300 mg/m2, combination therapy involving 5

ACCEPTED MANUSCRIPT anthracyclines with other toxic drugs such as the topoisomerase II inhibitors (e.g. etoposide), female sex, cardiovascular history, previous cytotoxic therapy, concomitant mediastinal or

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cranial radiotherapy, younger age at diagnosis, longer follow-up, trisomy 21, and African-

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American race [17]. The correlation between high cumulative doses of anthracyclines and

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cardiotoxicity is well established, but lower doses can also be cardiotoxic, with no safe dose established [18]. This was clearly shown in a study specifically designed to evaluate the effects of low-dose anthracyclines (≤100 mg/m2) on LV function in 91 children after a mean

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of 9.8 years from diagnosis, as a significant proportion demonstrated subclinical

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abnormalities [25].

In 110 children up to 16 years old who were treated with doxorubicin, daunorubicin,

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or both, 15 experienced cardiac dysfunction within a month after treatment and 28 within a

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year [26]. Factors associated with higher incidences of cardiotoxicity included high cumulative dose of doxorubicin, co-treatment with daunorubicin, and AML (which had

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double the risk vs. children with ALL, Hodgkin lymphoma, or non-Hodgkin lymphoma). Seven patients (16%) died from cardiotoxicity in this short-term study, highlighting the need

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for better diagnosis, monitoring, and management, especially because the cardiotoxic effects of anthracyclines tend to be progressive and more cases are likely to occur with time. The interplay between the various factors that can adversely impact the cardiovascular system of children with cancer, and the type of cardiotoxicity they cause is both complex and poorly understood [27]. More thorough evaluation of anticancer therapies, including radiotherapy, and the specific cardiovascular changes they are responsible for may help determine the most appropriate diagnostic and screening procedures for childhood cancer survivors [27].

Epidemiology

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ACCEPTED MANUSCRIPT Formal estimates of the prevalence of cardiotoxicity in children treated with anthracyclines are lacking. Some of the most comprehensive epidemiological data come from

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population-based studies in Europe and the US [3,5,12,15,28,29]. In the US, for example, the

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number of childhood cancer survivors was almost 380,000 in 2010, an increase of 15% from

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the estimated number in 2005 [1,28]. More than 20% had survived for more than 30 years after diagnosis. Survivors of childhood cancer have about a 75% chance of experiencing an eventual treatment-related chronic health problem [12]. Compared with control subjects,

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survivors are:

15 times more likely to have heart failure [12]

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10 times as likely to experience coronary artery disease [12]

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9 times as likely to have a cerebrovascular event [12]

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8 times as likely to die from cardiovascular-related disease [29]

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In addition, 30 years after diagnosis, cardiac-related deaths exceed those caused by

[30].

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cancer recurrence [3], and 45 years after diagnosis 13% of excess deaths are cardiac related

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The Childhood Cancer Survivor Study determined the prevalence of a first occurrence of cardiac disorders [29]. Although the frequency of disorders was low overall, the rates were markedly higher for childhood cancer survivors (Figure 1). Compared to their siblings, survivors had the following hazard ratios: 6.3 for pericardial disease, 5.9 for heart failure, 5.0 for myocardial infarction, and 4.8 for valvular abnormalities. The risks for heart failure, valve disease, and pericardial disease were 2 to 5 times as high in patients treated with anthracyclines, and the cumulative risk appears to continue to increase up to 30 years after diagnosis [31]. In total, more than 50% of patients exposed to anthracyclines show some evidence of cardiac dysfunction within 20 years after chemotherapy, with about 5% experiencing heart failure [29,32].

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Pathogenesis

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Anthracycline-induced cardiotoxicity ranges from acute changes in QT interval

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prolongation and cardiac arrhythmias to longer-term changes in coronary vasomotion,

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myocardial ischemia, myocarditis, pericarditis, contractile dysfunction, cardiomyopathy, and heart failure [33,34]. The pathophysiological mechanisms of chemotherapy-related cardiotoxicity are unclear but appear to be multifactorial [17]. Anthracyclines enter

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cardiomyocytes by passive diffusion, causing myocardial cell damage or loss through

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apoptosis or necrosis [35]. In children with ALL, at a median follow-up of 21 years after doxorubicin treatment, left ventricular (LV) fractional shortening remained decreased, and

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LV dimension adjusted for body-surface area, which was initially elevated, was significantly

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decreased at the last follow-up visit [36]. In later years, the LV thickness-dimension ratio, which was initially reduced, started to increase as a result of wall thickness increasing

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relative to a decreased chamber size (rather than myocardial hypertrophy). The net result of these effects was a progressive reduction in adjusted LV mass and cavity size, which appears

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to be a long-term risk in children treated with high cumulative doses of anthracyclines [36]. The molecular and genetic mechanisms of anthracycline-related cardiotoxicity are not completely understood, but the generation of iron-dependent, reactive free radicals that induce lipid peroxidation with consequent membrane damage is plausible [37]. Other possible contributory mechanisms include effects on topoisomerase directly (mediated through topoisomerase 2β) [38,39], decreased activity of Na+, K+-ATPase, mitochondrial damage, DNA damage, derangement of the calcium current with the inhibition of the sarcoplasmic reticulum, accumulation of tumor suppressor protein, and mitochondrial apoptosis in the heart and cardiomyocytes [17,34,40].

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ACCEPTED MANUSCRIPT Management A major challenge to pediatric oncologists when initially treating children with

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anthracyclines is incurring the risk of dose-related, progressive cardiotoxicity, which can lead

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to reduced LV performance and ultimately to heart failure and possible death [41-44]. For

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example, it was reported that among 3575 patients with Hodgkin lymphoma, after a median follow-up of 22 years since treatment, 1328 had died; 52% from cancer and 15.5% from cardiac disease [45]. The insidious nature of the cardiovascular changes and the fact that

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overt cardiac disease may present many decades after cancer treatment pose an important

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diagnostic dilemma. Waiting for signs or symptoms of cardiotoxicity to appear is clearly unwise because anthracycline-induced cardiomyopathy is associated with a 2-year mortality

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rate as high as 60% [40]. Thus, several organizations, including the Children’s Oncology

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Group (COG) in North America, have created comprehensive surveillance guidelines for these patients which involves periodic lifetime screening based upon age at treatment,

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cumulative anthracycline dosage and whether or not the heart was irradiated [31,42,44,4649]. In addition to taking a medical history, a physical examination for cardiovascular

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symptoms and signs of heart failure, long-term, periodic electrocardiographic and echocardiographic monitoring, especially of LV systolic function, is also recommended. Recently, two research groups independently evaluated the health economic benefits of adhering to the consensus-based COG long-term follow-up guidelines, which advocate lifetime echocardiographic screening for asymptomatic LV dysfunction [47-49]. Using a simulation of life histories and a Markov health states model, applied to 12 risk profiles Wong and colleagues found that compared with no screening, the COG guidelines resulted in an incremental cost-effectiveness ratio of US$ 61,500 and extended life expectancy by 6 months and quality-adjusted life years (QALYs) by 1.6 months, and reduced the cumulative incidence of heart failure by 18% at 30 years after cancer diagnosis [47]. Less frequent

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ACCEPTED MANUSCRIPT screening achieved most of the clinical benefits associated with following the COG guidelines, and proved to be more cost-effective [47]. In contrast, Yeh and colleagues

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categorized patients as low- or high-risk based upon the cumulative anthracycline dosage and

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a cut point of 250 mg/m2 [48]. In this simulation the lifetime risk for systolic heart failure was

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18.8% in 5-year childhood cancer survivors (aged 15 years) without routine cardiac assessment. Routine cardiac follow-up reduced lifetime risk by 2.3% and 8.7% with assessments every 10 years and annually, respectively, and this resulted in incremental cost-

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effectiveness ratios of US$111,600 and US$278,600, respectively. Again, this group found

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that less frequent assessments might be a more cost-effective approach [48]. Apart from imaging techniques, sensitive diagnostic tools as predictors of subclinical

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cardiotoxicity are clearly of interest in treating these patients [50]. Early detection may help

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improve long-term outcomes by prompting early treatment. In this regard, serum biomarkers of myocardial damage, such as elevated concentrations of cardiac troponin T and troponin I,

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which detect acute damage, and of N-terminal pro-brain natriuretic peptide (a marker of increased LV wall stress) to monitor chronic changes, may prove useful [22,31,42].

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Currently, interest is growing in potential genomic predictors of anthracycline cardiotoxicity. Although this research is in its early stages, results suggest that the allele G of the CBR3 gene involved in the carbonyl reductase pathway may be increased in patients with cardiotoxicity [51], and certain plasma microRNAs [52] may be up-regulated after anthracycline administration. Among survivors of childhood high-risk ALL, the risk of doxorubicin-related myocardial injury was nine times as high in carriers, as that of noncarriers, of mutations in the hemochromatosis gene C282Y allele. This mutation is associated with hereditary hemochromatosis, a genetic disorder that leads to cellular iron overload [53]. Since iron binds to doxorubicin to form a free radical complex, having increased iron may result in more free radical formation and associated injury. There is also evidence that low

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ACCEPTED MANUSCRIPT cardiac topoisomerase 2β expression may be predictive of reduced cardiotoxicity and that peripheral blood leukocyte levels might therefore be a useful surrogate marker [39].

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However, prospective studies are required to validate the suitability of these genetic

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biomarkers for clinical application.

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Children determined to be at moderate to high risk of cardiotoxicity are most likely to benefit from three evidence-based specific preventive strategies to reduce the likelihood of cardiotoxicity. These include: (1) limiting the cumulative anthracycline dose: (2) minimizing

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cardiac exposure to radiotherapy: and (3) using a cardioprotectant such as dexrazoxane

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[22,31,44,54]. Other less-cardiotoxic drugs or formulations are also being investigated.

Dexrazoxane and anthracycline-related cardiotoxicity in children and adolescents

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Dexrazoxane is a bisketopiperazine that undergoes stepwise hydrolysis of its two

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piperazine rings to form a one-ring open intermediate; the latter eventually hydrolyses to a

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diacid-diamide that is very similar to ethylenediaminetetraacetic acid (EDTA). The open-ring derivative of dexrazoxane acts as a chelating agent that reduces the number of metal ions that can complex with anthracyclines. As a consequence, it is believed to interfere with iron-

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mediated free radical generation, thereby decreasing tissue damage [33,55]. In animal studies, dexrazoxane reduced or prevented anthracycline-induced cardiotoxicity [56,57]. It also reduced acetaminophen-induced hepatotoxicity, alloxaninduced diabetes, bleomycin pulmonary toxicity, and hyperoxia-induced pulmonary damage. It seems likely that these toxicities involve some form of iron-dependent, oxygen-radical production in the pathogenesis of the cellular damage, lending support to the theory that dexrazoxane acts as a free-radical scavenger [34,57]. There are also data showing that dexrazoxane can change the configuration of topoisomerase 2β, preventing the binding of anthracyclines to the enzyme, and this may also help explain its cardioprotective properties [39,58]. Preclinical studies highlighted irreversible doxorubicin-associated cardiac 11

ACCEPTED MANUSCRIPT mitochondrial dysfunction, which was reflected by an increase in mitochondrial DNA in doxorubicin-treated survivors [57]. Patients treated with dexrazoxane had significantly lower

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mitochondrial DNA copy numbers per cell compared with patients not receiving the

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cardioprotectant [59]. To investigate some of these effects further a pilot placebo-controlled

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study assessing the cardioprotective and antiapoptotic effects of dexrazoxane in children <1year-old undergoing heart surgery has been initiated [60]. This study will evaluate postoperative time to resolution of organ failure, development of low cardiac output

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syndrome, length of cardiac hospitalization, and echocardiographic indices of cardiac

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dysfunction [60].

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Cardioprotective effects

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In the early 1980s, dexrazoxane had shown potential as a cardioprotective agent against anthracycline-related cardiotoxicity in animal models [61] and subsequently in

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women with breast cancer [62,63] and in children with solid tumors or relapsed AML given high cumulative doses of anthracycline (550 to 1150 mg/m2) [64]. After this pediatric study,

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the cardioprotective properties of dexrazoxane have been more formally evaluated in children and adolescents treated with anthracyclines (Table 2) [21,22,65-73]. Studies prior to the EMA evaluation in 2011 provided evidence for less subclinical cardiotoxicity [65], improvement in biomarkers of cardiotoxicity [66], better myocardial responses and LV performance [66-69] and fewer cardiac events [69] in children, adolescents, and young adults treated with dexrazoxane plus doxorubicin compared with those on doxorubicin alone. Data on the cardioprotective effects of dexrazoxane are accumulating steadily. Since the EMA review, clinical studies have reported improvements in predictors of cardiotoxicity such as biomarkers [22], as well as significantly less impact on LV structure and performance, in patients treated with anthracyclines and dexrazoxane compared with those

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ACCEPTED MANUSCRIPT not receiving dexrazoxane (Table 2) [22,70-73]. In early studies of children treated with anthracyclines, the impact of dexrazoxane on clinical outcomes, such as heart failure, could

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not be ascertained due to the limited duration of follow-up and the progressive nature of

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cardiac dysfunction that can take years to develop. However, in a meta-analysis of random

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trials by the Cochrane Group that combined findings from adults and children, heart failure occurred in 11 of 769 patients (1.4%) receiving dexrazoxane plus anthracycline and in 69 of 792 (8.7%) receiving anthracycline alone [16], indicating a clear cardioprotective benefit of

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dexrazoxane [risk ratio (RR), 0.18; 95% CI, 0.10 to 0.32; P <0.001].

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In another meta-analysis that also combined studies of adults and children, similar findings for dexrazoxane were reported [40]. Finally, a review of only children treated with

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anthracyclines indicated that dexrazoxane reduced clinical cardiotoxicity (RR, 0.29; P =

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Clinical response

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0.001) and clinical plus subclinical cardiotoxicity [RR, 0.43; P <0.001] [71].

One early study, from a number of randomized, prospective clinical trials in adults

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with breast cancer, suggested that women treated with dexrazoxane might have lower clinical response rates than those of controls not on dexrazoxane. Interestingly, the time to progression and survival were not significantly different between treatment arms [74]. No other studies in adults or children have confirmed this finding of a reduction in anthracycline antitumor activity, as highlighted in the meta-analysis by the Cochrane group that evaluated response rates (complete and partial remission) and survival times [16]. Of 10 studies involving children and adolescents with a variety of cancers treated with anthracyclines, all 10 found similar response rates and survival times in groups treated with or without dexrazoxane (Table 3) [21, 65,68, 69,75-79]. Mean event-free survival rates (between 5 and 10 years after chemotherapy) ranged from 71% to 87% in dexrazoxane-treated patients and

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ACCEPTED MANUSCRIPT from 73% to 86% in patients treated without dexrazoxane (Table 3). The 5-year, cardiacevent-free survival rates were 69% and 46%, respectively [69]. In a pooled analysis of three

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trials involving children treated with doxorubicin for ALL or Hodgkin lymphoma (low- to

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intermediate-stage or advanced disease), dexrazoxane was not associated with a risk of

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mortality (dexrazoxane+, 12.8% vs. dexrazoxane-, 12.2% at 10 years; HR 1.02, 95% CI 0.721.43) or relapse (10-year cumulative incidence: dexrazoxane +, 15.6% vs. dexrazoxane-,

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Tolerability and second malignancies

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18.8%; HR 0.82, 95% CI 0.60-1.10), nor with differential causes of death [79].

The overall tolerability and safety of dexrazoxane has been extensively reviewed

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[16,80]. Van Dalen et al. reported that dexrazoxane was well tolerated [16]. An earlier review

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had reported that dexrazoxane was associated with a higher incidence of leukopenia (78% vs. 68%; P <0.01), which was dose-related and rapidly reversible [80]. Leukopenia may increase

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the risk of serious infections and should be monitored [4]. Furthermore, the Cochrane review concluded that it could not rule out other undesirable adverse effects for dexrazoxane, given

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the nature of the patient population and the multiple potent therapies that were being administered [16].

The safety of dexrazoxane was formally reviewed by the EMA, which raised concerns about an increased risk of SMNs in children, including those with AML or MDS and solid tumors [4]. These conclusions were largely based on the findings of Tebbi and colleagues from two randomized trials involving 478 patients (<21 years old) treated for Hodgkin lymphoma as part of the Pediatric Oncology Group (POG) series of clinical trials (Table 4) [81]. At a median follow-up of 58 months, SMNs had developed in 10 patients, 8 of whom had received dexrazoxane [81]. The mean (SD) cumulative incidence rate for SMNs was 3.43% (1.2%) in the dexrazoxane group and 0.85% (0.6%) in the doxorubicin control

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ACCEPTED MANUSCRIPT group (P = 0.06). In another POG clinical trial of more than 350 patients (<22 years old) with T-cell ALL who were treated with doxorubicin, with or without dexrazoxane (randomized),

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SMNs developed in only 2.8% of all patients, and no association with dexrazoxane

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administration was apparent [77].

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Tebbi and colleagues published the details of a long-term follow-up of 255 patients (of the original 355 <22 years old at the time of treatment) with Hodgkin lymphoma [78]. In the original study, six SMNs were reported, and the updated analysis documented eight new

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SMNs. Five of the SMNs occurred as first events (three cases of AML, one thyroid

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carcinoma, and one osteosarcoma) and the remaining three occurred after relapse. In the case of the primary SMNs, four were in patients receiving dexrazoxane. The authors attributed

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these four cases to the concomitant administration of three topoisomerase II inhibitors

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(doxorubicin, etoposide, and dexrazoxane) rather than to the effect of any single agent. Since the EMA evaluation was published, several studies have reported no

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statistically or clinically relevant increase in the incidence of SMNs in children or adolescents treated with dexrazoxane (Table 4). Seif and co-workers reported the largest evaluation of

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anthracycline therapy to date, a retrospective analysis of 15,532 cancer patients (30% <5 years old; 70% >3 to <15 years old) from 43 Pediatric Health Information System (PHIS) children’s hospitals [82]. Of these, 1406 received dexrazoxane for cardioprotection. The secondary AML rate was 0.21% in the dexrazoxane group and 0.55% in the non-dexrazoxane group. They found no association between dexrazoxane and the risk of SMNs, but they did find an association between etoposide exposure and secondary AML (OR, 2.36; 95% CI, 1.48 to 3.79; P <0.001). Moreover, in an adjusted model, which included etoposide, dexrazoxane was not significantly associated with secondary AML [82]. These findings are consistent with a pooled analysis by Vrooman and co-workers involving more than 500 children with highor very high-risk ALL who received dexrazoxane. The cumulative incidence for SMNs was

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ACCEPTED MANUSCRIPT 0.24% after 3.8 years [83]. The authors concluded that SMNs were rare in these children and

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recommended the continued use of dexrazoxane in their treatment.

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Discussion

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Over the past 40+ years, oncologists have successfully used anthracyclines to treat several hematological and solid-tumor cancers. This use is possibly best exemplified in pediatric oncology, where 5-year survival rates have more than doubled over this time period.

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Today, more children treated for many different cancers live a relatively normal lifespan, a

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success that brings a different set of problems. The field of cancer survivorship is a rapidly growing medical specialty. Unlike treatments for many other childhood diseases that do not

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affect long-term health and well-being, the delayed effects of chemotherapy and radiotherapy

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often accompany improved survival [84]. The possible longer-term complications of therapy in survivors of childhood cancer may affect multiple organ systems, including the

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cardiovascular, pulmonary, endocrine, renal/urologic, and central nervous systems. In addition, these individuals remain at risk for a relapse of their primary malignancy or a

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second malignancy [85].

After treatment with anthracyclines, the greatest non-cancer-related risk is cardiac toxicity, the severity of which is principally related to cumulative dose, and it can occur from the first administration of drugs such as doxorubicin. Anthracycline-induced cardiotoxicity can be acute (occurring during the first week of therapy), early (<1 year after beginning treatment) or late (>1 year after beginning treatment) [34]. Late-stage cardiotoxicity can be the most challenging because it is progressive and may lead to severe LV contractile dysfunction, cardiomyopathy, and heart failure, and it has a high mortality rate [33,34]. Despite the fact that severe forms of cardiomyopathy are more apparent with higher

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ACCEPTED MANUSCRIPT cumulative-doses of anthracyclines, adverse cardiovascular changes have also been observed at lower dosages, suggesting that there is no safe dose [1,25,31,40].

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Management strategies for children at moderate-to high-risk of cardiotoxicity include

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limiting the cumulative anthracycline dose, substituting a potentially less cardiotoxic drug or

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formulation, minimizing cardiac exposure to radiotherapy, and using a cardioprotective agent such as dexrazoxane before each dose of anthracycline [1,31,40,42]. There is no evidence that administering doxorubicin by continuous intravenous infusion to children provides any

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benefit over bolus infusion in terms of cardioprotection or clinical outcomes [86], and it is

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therefore not recommended because continuous infusion increases the risk of infection, mucositis, and thromboembolic events, requires longer hospital stays, and is more costly

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[40,86].

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In terms of pharmacotherapy, numerous studies have documented the effectiveness of dexrazoxane against anthracycline LV cardiotoxicity, and dexrazoxane is thought to be the

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only cardioprotectant proven to be effective against anthracycline treatment in randomised trials [17]. In a recent review Herrmann and Lerman [87] suggested that certain statins, beta-

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blockers and angiotensin antagonists were as effective as dexrazoxane in preventing anthracycline-induced cardiotoxicity. These conclusions were based upon a meta-analysis [40], which looked mostly at short-term effects and only included one small study for dexrazoxane in childhood cancer from 1996 [65]. We believe that the substantive evidence for dexrazoxane that we have included in this review highlights longer-term cardioprotection that has not been shown for any other agent as yet. Early diagnosis may also be important in optimizing outcomes in long-term survivors of childhood cancer. Apart from research into some of the more traditional surveillance methods based on cardiac performance (echocardiography) or predictive markers of cardiac damage (cardiac troponins T and I and N-terminal pro-brain natriuretic peptide

17

ACCEPTED MANUSCRIPT concentrations), recent research explored genomic predictors of anthracycline cardiotoxicity, such as allele G of the CBR3 gene, which is involved in the carbonyl reductase pathway,

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certain plasma microRNAs, and mutations of the C282Y allele of the hemochromatosis gene

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[51-53].

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The decision to use of dexrazoxane in children and adolescents has been complicated since the EMA contraindicated its use in these age groups [4]. At present, there appears to be a trans-Atlantic polarization of regulatory views about the clinical benefit of dexrazoxane: a

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drug contraindicated in children and adolescents on one side, and in continued use (albeit

MA

very limited, outside of clinical trials) in some US and Canadian children’s hospitals where it is viewed as safe and effective. Indeed, dexrazoxane was recently (August 2014) designated an orphan drug by the FDA for the rare disease “prevention of cardiomyopathy for children

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and adolescents 0 through 16 years of age treated with anthracycline” [88]. Walker and colleagues performed a retrospective cohort study to investigate patterns

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of dexrazoxane usage in pediatric patients with ALL or AML included in the Pediatric Health Information Systems (PHIS) database in the US [89]. Overall, only 2.4% of ALL patients

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(207 of 8733) and 2.0% of AML patients (52 of 2556) received dexrazoxane outside of clinical trials. They found that dexrazoxane administration was limited, and prescribing practices varied widely within and between institutions. The authors suggested that the low off-label usage of dexrazoxane was potentially also related to issues raised by the EMA. During the >3 years since the EMA deemed dexrazoxane to be contraindicated in children, a number of relevant studies have been published that address the EMA’s main concerns: 

Is dexrazoxane an effective cardioprotectant?



Is dexrazoxane associated with an increased risk of SMNs?

18

ACCEPTED MANUSCRIPT 

Does dexrazoxane negatively impact clinical outcomes (response rates or survival times)?

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In this review, we have integrated published new evidence into the existing

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knowledge base of dexrazoxane in pediatric oncology. For all three questions above, the new

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studies summarized in Tables 2 through 4 reinforce earlier findings supporting the cardioprotective properties of dexrazoxane in children and adolescents treated with

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anthracyclines. Furthermore, these new studies, including a systematic review undertaken by the Cochrane group confirm equivalent clinical responses and event-free survival over

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extended follow-up periods, in dexrazoxane-treated patients [16]. A follow-up of the COG studies the EMA cited as concerning for reduced oncologic efficacy has shown reassuring

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results [76]. Finally, no new evidence of an increased risk of SMNs with dexrazoxane has

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been published, and a large retrospective cohort study of 15,532 cancer patients found no

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association between dexrazoxane and risk of SMNs [82]. This analysis did show an association between etoposide exposure and secondary AML, and others have noted that coadministration of etoposide may be an added risk factor in children treated with dexrazoxane

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[83]. These authors reported no SMNs in 487 children with high-risk ALL who were treated with doxorubicin plus dexrazoxane without etoposide, and a single SMN occurred in a veryhigh risk patient who received etoposide. A similar view has been expressed by Tebbi and colleagues [78] in a follow-up to their 2007 study, which was cited in the EMA review of dexrazoxane [4,81]. Tebbi and colleagues more recently concluded that the difference in the number of SMNs in the two treatment groups may have been attributable to the concomitant administration of 3 topoisomerase II inhibitors (doxorubicin, etoposide, and dexrazoxane) rather than the effect of any single agent [78]. They surmised that combining the three drugs could exceed a threshold above which topoisomerase inhibition caused DNA damage in normal tissues. Clearly, further study of the risks associated with concomitant administration 19

ACCEPTED MANUSCRIPT of topoisomerase II inhibitors is needed, though in clinical practice for many pediatric

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cancers such regimens are generally not employed.

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Conclusions

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The 40+ years that anthracyclines have been used in pediatric oncology includes two populations of treated children; those recently diagnosed with cancer, on the one hand, and older patients who received anthracycline therapy as children on the other. For patients who

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have already received high-dose anthracycline chemotherapy, routine monitoring of LV

MA

function and cardiac biomarkers, combined with appropriate symptomatic treatment as necessary, may represent best clinical practice.

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For patients about to be treated with anthracyclines for the first time, several actions

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can help limit future cardiovascular problems, but must be done in a manner that minimizes the risk of compromizing established anti-cancer efficacy. Such actions include employing

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lower cumulative anthracycline doses and using anthracycline analogs or liposomal formulations. However, for children requiring higher doses of anthracyclines to achieve

AC

improved cancer-free survival, cardioprotective therapy is needed and there is now convincing evidence of the cardioprotective effects of dexrazoxane [16,68,72,79]. The DanaFarber Cancer Institute Childhood Acute Lymphoblastic Leukemia Consortium, applying the results from clinical trials, including their own studies, now incorporates dexrazoxane into current and future clinical trial protocols involving anthracycline therapy. Similarly, the Children’s Oncology Group includes administration of dexrazoxane in all its research protocols that require treatment with ≥150 mg/m2 doxorubicin or require anthracycline administration at any dose with planned radiation treatment portals that may impact the heart. As the cardiotoxic effects of anthracyclines can be immediate, and the damage to the

20

ACCEPTED MANUSCRIPT cardiomyocytes irreversible and cumulative, dexrazoxane should be administered before the first anthracycline dose and before each therapy cycle [40,86].

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In sum, the evidence from clinical studies published between 2011 and August 2014

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is now compelling that dexrazoxane is an effective cardioprotectant in children and

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adolescents with cancer receiving anthracycline-based treatment. Collectively, these studies confirm and expand upon the safety and efficacy profile of dexrazoxane in children with cancer. Dexrazoxane-induced leukopenia does not result in treatment delays but should be

NU

monitored. No new evidence supporting the claim that dexrazoxane may interfere with the

MA

antitumor efficacy of chemotherapy or that it increases the incidence of SMNs has been published. Cardiotoxicity was the theme for an International Colloquium held in Rome in

D

March 2014. In several sessions that covered cardioprotection and reviewed all the new

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evidence for the use of dexrazoxane in children, the consensus favored extending its clinical use [90]. We also encourage its use in protocols involving higher-dose (≥150 mg/m2)

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anthracycline-based chemotherapy in treating childhood cancers, such as high-risk ALL, while the search for less-cardiotoxic drugs and more effective prevention and treatment

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strategies continues.

Acknowledgements

We thank Dr. Steve Clissold who provided medical writing services on behalf of Scientific Writing & Publishing Services, Ltd. Vivian Franco is supported by funding from The Michael Garil Fund. Dr. Steven Lipshultz was a paid consultant to The Clinigen Group to help organize the expert panel on cardio-oncology in Newark, NJ in July 2014. Dr. Steven Lipshultz was also supported in part by grants from the National Institutes of Health (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, 21

ACCEPTED MANUSCRIPT HL095127, and HD80002), the Children’s Cardiomyopathy Foundation, the Women’s Cancer Association of the University of Miami, the Lance Armstrong Foundation, the STOP

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Children’s Cancer Foundation, the Scott Howard Fund, and the Michael Garil Fund.

22

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32. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20

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ACCEPTED MANUSCRIPT 36. Lipshultz SE, Scully RE, Stevenson KE, et al. Hearts too small for body size after doxorubicin for childhood ALL: Grinch syndrome. J Clin Oncol 2014;32 (Suppl.

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37. Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against

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38. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of

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Oncol 2005;23:2629-36.

42. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013;128:1927-95. 43. Schlitt A, Jordan K, Vordermark D, Schwamborn J, Langer T, Thomssen C. Cardiotoxicity and oncological treatments. Dtsch Arztebl Int 2014;111:161-8. 44. Truong J, Yan AT, Cramarossa G, Chan KK. Chemotherapy-induced cardiotoxicity: detection, prevention, and management. Can J Cardiol 2014;30:869-78.

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2012;130:1003-11.

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lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of

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patients in the Pediatric Health Information Systems database. Pediatr Blood Cancer

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90. Ewer M, Gianni L, Pane F, et al. Report on the international colloquium on cardiooncology (Rome, 12-14 March 2014). Ecancermedicalscience 2014 May 29;8:433. doi:

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10.3332/ecancer.2014.433.

33

ACCEPTED MANUSCRIPT Table 1. Prevalence and relative risk of selected severe (Grade 3) or life-threatening (Grade 4) health conditions in 10,397 survivors of childhood cancer, compared with their siblings- diagnosed between January 1, 1970 and December 31, 1986 [adapted

Relative risk (95% CI)

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Prevalence, % 1.61

Heart failure

1.24

Second malignant neoplasm

2.38

Severe cognitive dysfunction

0.65

10.5 (2.6 to 43.0)

Coronary artery disease

1.11

10.4 (4.1 to 25.9)

1.56

9.3 (4.1 to 21.2)

0.52

8.9 (2.2 to 36.6)

1.96

6.3 (3.3 to 11.8)

2.92

5.8 (3.5 to 9.5)

2.79

3.5 (2.7 to 5.2)

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Major joint replacement

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Health condition

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from Oeffinger et al. 2006 [12]].

Cerebrovascular events

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Renal failure

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Hearing loss

15.1 (4.8 to 47.9) 14.8 (7.2 to 30.4)

AC

Ovarian failure

CE P

Eye problems

54.0 (7.6 to 386.3)

34

ACCEPTED MANUSCRIPT Table 2. Summary of studies investigating the cardioprotective effects of dexrazoxane (DRZ) in children and adolescents with hematological or solid tumors receiving a chemotherapeutic regimen containing doxorubicin. DOX and DRZ dosage

Results and comments

T

Patients

Wexler et al. 1996 [65]

Sarcoma ≤25 y

DOX 50-70 mg/m2 with (n=18) or without (n=15) DRZ (20:1 dose ratio)

Lipshultz et al. 2004a [21]

ALL <18 y

DOX 30 mg/m2 with (n=105) or without (n=101) DRZ 300 mg/m2

Paiva et al. 2005 [66]

Osteosarcoma <28 y

Untreated control group (n=21) and DOX alone (mean dose 348 mg/m2; n=19) or DOX (mean dose 397 mg/m2; n=18) + DRZ (10:1 dose ratio)

de Matos Neto et al. 2006 [67]

CE P

Reference

Osteosarcoma <21 y

DOX 60-70 mg/m2 with (n=18) or without (n=37) DRZ (20:1 dose ratio)

The cumulative dose of DOX was approximately 15% higher in the DRZ group vs. the non-DRZ group. Systolic dysfunction was similar in the 2 groups, but the DRZ group had significantly (P=0.03) better LV performance as assessed by the mean fractional shortening % at 3 follow-up visits [37.2% vs. 35.7%; 38.5% vs. 35.0%; and 38.2% vs. 35.3%, respectively].

Lipshultz et al. 2010a [68]

ALL <18 y

DOX 30 mg/m2 with (n=68) or without (n=66) DRZ 300 mg/m2

After 5 y, mean LVFS and LVESD Z scores were significantly worse than normal in the DOX group [-0.82 and 0.57, respectively], but not in the DOX + DRZ group [-0.41 and 0.15].

Choi et al. 2010 [69]

Solid tumors ≤14 y

DOX 30 mg/m2 with (n=47) or without (n=42) DRZ (10:1 dose ratio)

There were significantly fewer cardiac events with DOX + DRZ than with DOX (27.7% vs. 52.4%; P=0.02 at mean follow-up of 54 m and 86 m, respectively). DOX + DRZ was also associated with less severe CHF (6.4% vs. 14.3%; P=0.049). 5-y cardiac event-free survival was 69.2% for DOX + DRZ and 45.8% for DOX (P=0.04). DRZ

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Patients who received DRZ were less likely to experience subclinical cardiotoxicity (22% vs. 67%; P<0.01), had a smaller reduction in LVEF per 100 mg/m2 DOX (1.0 vs. 2.7 percentages points; P=0.02), and received a higher median dose of DOX. Elevated troponin T in 55 of 158 pts. Pts on DOX alone were more likely to have elevated troponin T levels (50% vs. 21%; P<0.001) and extremely elevated troponin T levels (32% vs. 10%; P<0.001). Median follow-up was 2.7 y and event-free survival was 83% in both groups Myocardial responses during low-dose dobutamine stress echocardiography in patients treated with DOX + DRZ were similar to those of patients not on chemotherapy and better than those treated with DOX alone. Both ejection fraction (8.3%) and shortening fraction (7.0%) were significantly (P ≤0.02) lower in the DOXonly group vs. the control group (13% and 11%) and DOX + DRZ group (13.2% and 11%). Patients treated with DRZ had better systolic performance than those on DOX alone, suggesting a cardioprotective effect.

35

ACCEPTED MANUSCRIPT reduced the incidence and severity of early and late anthracycline toxicity. ALL (high risk) <18 y

DOX 30 mg/m2 with (n=105) or without (n=100) DRZ 300 mg/m2

Kang et al. 2012 [70]

Children with cancer <18 y

Anthracycline alone (n=123) or combined with DRZ [lowdose, <100 mg/m2, n=85; high-dose, >100 mg/m2, n=50

Shaikh et al. 2014 [71]

Children treated for cancer and with DRZ as a cardiac protectant

Cardiac troponin (CT) levels were increased 47% and 13% (P=0.05) and N-terminal probrain natriuretic peptide (BNP) by 48% and 20% (P=0.07) in the DOX-only and DOX + DRZ groups, respectively. The increases in CT were associated with abnormally reduced LV mass and end-diastolic posterior wall thickness-to-dimension ratio after 4 y (P<0.01). Increases in BNP were related to abnormal LV thickness-to-dimension ratio, suggesting LV remodeling after 4 y (P=0.01). CT and BNP hold promise as biomarkers for anthracycline-induced cardiotoxicity.

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Lipshultz et al. 2012a [22]

During chemotherapy, dose-limiting cardiotoxicity was significantly higher (P=0.006) in the DOX-only group (7.3%) vs. the high- (2.0%) and low-dose (0%) anthracycline groups treated with DRZ. In addition, LVEF and shortening fractions were greater in the low-dose anthracycline + DRZ group vs. the anthracycline only group. Early use of DRZ protects against the development of cardiotoxicity during anthracycline therapy in children with cancer.

Anthracycline alone or combined with DRZ Systematic review limited information

In 2 of 5 RCTs, DRZ was associated with improved shortening fraction Z-score (mean difference 0.61, P=0.002) and thickness dimension Z-score (mean difference 0.66, P<0.001). DRZ was associated with a reduction in clinical cardiotoxicity (relative risk 0.29, P=0.001) and subclinical cardiotoxicity (relative risk 0.43, P<0.001).

Asselin et al. 2012b [72]

ALL (T-cell) ≤21 y

DOX 30 mg/m2 with (n=273) or without (n=264) DRZ 300 mg/m2

After 3 years, Z-scores for LV fractional shortening (-0.05 vs. -0.77), LV wall thickness (-0.13 vs. -0.69) an LV thicknessto-dimension ratio (-0.09 vs. -0.75) were better for the DRZ group vs. the DOX control group. LV fractional shortening remained significantly improved in the DRZ group in a small number of patients after 4-6 y follow-up.

Kopp et al. 2014c [73]

Localized or metastatic osteosarcoma in children and adolescents

In patients with metastatic disease, DOX 375 mg/m2; in patients with localized disease, DOX 450-600 mg/m2. DRZ (10:1 dose ratio) was given for cardioprotection.

None of the 47 patients with metastatic disease evaluated for cardiac effects showed clinical evidence of cardiotoxicity. In 242 patients with localized disease, 1 had a measurable serum troponin-T level and 1 had clinical evidence of cardiotoxicity (grade 3). In this large group of patients with osteosarcoma, DRZ was an effective cardioprotectant.

36

ACCEPTED MANUSCRIPT

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Abbreviations: ALL, acute lymphoblastic leukemia; CHF, congestive heart failure; DOX, doxorubicin; DRZ, dexrazoxane; ESD, end-systolic dimension; LV, left ventricular; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; m, months; RCT, randomized clinical trial; y, years a Protocol Dana-Farber 95-01; b Protocol POG 9404; c Protocol AOST0121 and POG9754

37

ACCEPTED MANUSCRIPT Table 3. Summary of studies investigating oncological outcomes in children and adolescents with hematological or solid tumors treated with a chemotherapy regimen containing doxorubicin, with or without dexrazoxane. Patients Sarcoma ≤25 y

DOX and DRZ dosage DOX 50-70 mg/m2 with (n=18) or without (n=15) DRZ (20:1 dose ratio)

Lipshultz et al. 2004a [21]

ALL <18 y

DOX 30 mg/m2 with (n=105) or without (n=101) DRZ 300 mg/m2

The median follow up was 2.7 y and the event-free survival at 2.5 y was 83% in both groups (P=0.87).

Barry et al. 2008a [75]

ALL (high-risk) <18 y

DOX chemotherapy 30 mg/m2 alone (n=100) or with DRZ (n=105)

Median follow-up 6.2 y, there was no difference between the DOX + DRZ group and the DOX group in terms of clinical outcome: CR 96 vs. 95%; CCR 77 vs. 76%; or relapse 18 vs. 16%.

Schwartz et al. 2009c [76]

Intermediate- and high-risk HD <22 y

DOX 30 mg/m2 with (n=107) or without (n=109) DRZ 300 mg/m2

Choi et al. 2010 [69]

Solid tumors ≤14 y

DOX 30 mg/m2 with (n=47) or without (n=42) DRZ (10:1 dose ratio)

The 5-y cardiac event-free survival rate was 69.2% in the DRZ group and 45.8% in the DOX control group (P=0.04)

ALL <18 y

DOX 30 mg/m2 with (n=68) or without (n=66) DRZ 300 mg/m2

With a median follow-up for recurrence and death of 8.7 y, event-free survival was 76% in the DRZ group and 77% in the DOX control group (P=0.99).

ALL <22 y

DOX with (187) or without (176) DRZ

5- and 10-y event free survival was 74.4% and 73.0%, in the DOX control group and 73.6% and 71.4% in the DRZ group (P=0.85).

Tebbi et al. 2012d [78]

HD (low-risk) ≤21 y

DOX chemotherapy 25 mg/m2 with (n=127) or without (n=128) DRZ 250 mg/m2

Mean (SD) 8-y event-free survival was 86.8% (3.1%) in the DRZ group and 85.7% (3.3) in the DOX control group (P=0.7). 45% of patients achieved CR after 2 cycles of chemotherapy.

Chow et al. 2014e Pooled analysis [79]

ALL (n=537) advanced HD (n=216), low/intermediate HD (n=255)

DOX 100-360 mg/m2 with (n=507) or without DRZ (10:1 dose ratio; n=501).

With a median follow-up of about 8 y, DRZ + DOX and DOX alone produced similar results in terms of overall mortality (12.8% vs. 12.2% at 10 y; hazard ratio, 1.02; 95% CI 0.72-1.43) and relapse (15.6% vs. 18.8% at 10 y; hazard ratio, 0.82; 95% CI 0.60-1.10). The original cancer accounted for 75.8% of all deaths.

Salzer et al. 2010b [77]

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Lipshultz et al. 2010a [68]

Results and comments 81% of the DOX control group achieved objective responses [3 CR and 10 PR in 16 patients] vs. 80% [4 CR and 12 PR in 20 patients] in the DRZ group. There were also no differences in event-free survival, overall survival, and median survival times.

T

Wexler et al. 1996 [65]

Reference

5-y event-free survival was 83% in the DRZ group and 86% in the DOX control group. CR rates after chemotherapy (70 vs. 60%, respectively) and radiation therapy (94 vs. 86%) were not significantly affected by DRZ.

38

ACCEPTED MANUSCRIPT Asselin et al 2012b [72]

ALL (T-cell) ≤21 y

DOX 30 mg/m2 with (n=273) or without (n=264) DRZ 300 mg/m2

No difference in mean (SD) 5-y event-free survival between the DRZ (76.7% [2.7%]) and DOX control (76.5% [2.8%]) groups (P=0.9).

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Abbreviations: ALL, acute lymphoblastic leukemia; CCR, complete continuous response; CI, confidence interval; CR, complete response; DOX, doxorubicin; DRZ, dexrazoxane; HD, Hodgkin’s disease/lymphoma; m, months; PR, partial response; y, years Protocol Dana-Farber 95-01; b Protocol POG 9404; c Protocol POG 9425; d Protocol POG 9426; e Protocols POG 9404, POG9425, and 9429.

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39

ACCEPTED MANUSCRIPT Table 4. Summary of studies investigating the development of second malignant neoplasms in children and adolescents with hematological or solid tumors treated with a chemotherapy regimen containing doxorubicin, with or without dexrazoxane. Patients

DOX and DRZ dosage

Results and comments

T

Reference Tebbi et al. 2007f [81]

HD ≤25 y

DOX 25-30 mg/m2 (ABVE) alone (n=239) or with DRZ 300 mg/m2 (n=239)

Barry et al. 2008a [75]

ALL (high-risk) <18 y

DOX chemotherapy 30 mg/m2 with (n=105) or without (n=100) DRZ

Median follow-up 6.2 y, the 5-y CIR for SMNs was zero for the DOX + DRZ group with no significant difference between the 2 groups. DRZ was not associated with an increased risk for SMNs

Schwartz et al. 2009c [76]

Intermediate- and high-risk HD <22 y

DOX 30 mg/m2 with (n=107) or without (n=109) DRZ 300 mg/m2

SMNs occurred in 3/107 patients in the DRZ group and 1/109 patients in the DOX control group

Salzer et al. 2010b [77]

ALL (T-cell) <22 y

DOX with (173) or without (159) DRZ

The CIR for SMNs after 5 and 10 y, respectively, was 1.3% and 1.3%, in the DOX control group and 2.3% and 4.2% in the DRZ group (p=0.15).

Vrooman et al. 2011g [83]

ALL (high or very-high risk <18 y). Pooled analysis (3 studies including Barry et al 2008)

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Median follow-up 58 m, 4-y CIRs: all SMNs [DOX 0.85 ± 0.6% DOX + DRZ 3.43 ± 1.2% (P=0.06)]; AML/MDS [DOX 0.85 ± 0.6% DOX + DRZ 2.55 ± 1.0% (P=0.16). Adding DRZ to DOX to chemotherapy may increase risk for SMNs

After 3.8 y median follow up (range 0.2 to 13.6 y) mean (SD) overall estimated cumulative incidence of SMNs was 0.24% [0.24%] (95% CI 0.02-1.29%). Thus, in a large population of children with high-risk ALL who received DRZ as a cardioprotectant, the occurrence of SMNs was rare.

HD (low-risk) ≤21 y

DOX 25 mg/m2 with (n=127) or without (n=128) DRZ 250 mg/m2

There were 5 primary SMNs and 3 occurred after relapse. Of the 5 primary SMNs, 4 occurred in the DRZ group and 1 in the DOX control group. The authors attributed the difference to the concomitant use of 3 topoisomerase II inhibitors (including etoposide) rather than to one specific agent.

Seif et al. 2014 [82]

Children with newly diagnosed cancer other than AML in the PHIS database

All children receiving anthracyclines were followed and exposure to DRZ and secondary AML monitored

Of 15,532 children in the cohort exposed to anthracyclines, 1406 received DRZ. The rate for secondary AML was 0.21% in the DRZ group and 0.55% in the group not receiving DRZ. DRZ was not associated with an increased risk of secondary AML.

Chow et al. 2014e [79]

ALL (n=537), advanced HD (n=216), low or intermediate HD (n=255). Pooled analysis [Tebbi et al. 2007, 2012;

DOX 100-360 mg/m2 with (n=507) or without DRZ (10:1 dose ratio; n=501).

With a median follow-up of about 8 y, DRZ + DOX was not associated with an increased risk of second cancers vs. DOX alone (10 vs. 9; hazard ratio, 1.08; 95% CI 0.44-2.67).

Tebbi et al. 2012d [78]

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40

ACCEPTED MANUSCRIPT

Children with cancer treated with DRZ

Kopp et al. 2014h [73]

Localized or metastatic osteosarcoma in children and adolescents

11 SMNs were recorded; 8 in the DRZ group and 3 in the DOX control group (P=0.17). At 5 y the mean cumulative incidences were 0.7 ± 0.5% vs. 0.8 ± 0.5% and at 10 y 1.8 ± 0.9% vs. 1.2 ± 0.7%, respectively. DRZ was not associated with an increased risk of SMNs.

Anthracycline alone or combined with DRZ. Systematic review with limited information.

In 5 RCTs there were16/625 (2.5%) SMNs with DRX vs. 6/619 (1.0%) SMNs without DRZ [P=0.06]. In NRSs, there were 6/860 (0.7%) with DRX vs. 18/1,825 (1.0%) SMNs without DRZ [P=0.06].

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Shaikh et al. 2014 [71]

DOX 30 mg/m2 with (n=273) or without (n=264) DRZ 300 mg/m2

IP

Salzer et al. 2010] ALL (T-cell) ≤21 y

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Asselin et al 2014b [72]

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In patients with metastatic SMNs occurred in 3 of 96 patients with disease, DOX 375 mg/m2, metastatic disease and 2 of 272 patients with and in those with localized localized disease. In all, 5/398 patients disease, DOX 450-600 (1.4%) had SMNs, which compares mg/m2. DRZ (10:1 dose favorably with the historical rate of 1%-2% ratio) was given for in the centers involved in the study cardioprotection. Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CI, confidence interval; CIR, cumulative incidence rate; DOX, doxorubicin; DRZ, dexrazoxane; m, months; MDS, myelodysplastic syndrome; NRSs, non-randomized studies; RCTs, randomized clinical trials; SMN, second malignant neoplasm; y, years a Protocol Dana-Farber 95-01; b Protocol POG 9404; c Protocol POG 9425; d Protocol POG 9426; e Protocols POG 9404, POG9425, and 9429; f Protocol POG 9425 and 9426; g Protocols 95-01, 00-01 and 05-01; h Protocols POG9754 and AOST 0121.

41

ACCEPTED MANUSCRIPT Figure 1. Prevalence of cardiac events among 14,358, 5-year survivors of cancer diagnosed before the age of 21 years and a control group of 3,899 siblings of the cancer survivors [adapted from Mulrooney et al. 2009 [29]].

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42