Curr Oncol Rep (2016) 18:22

DOI 10.1007/s11912-016-0510-4

CARDIO-ONCOLOGY (EH YANG, SECTION EDITOR)

Cardiomyopathy in Childhood Cancer Survivors: Lessons

from the Past and Challenges for the Future
Matthew J. Ehrhardt 1 & Joy M. Fulbright 2 & Saro H. Armenian 3

# Springer Science+Business Media New York 2016

Abstract Childhood cancer survivors are at substantial risk Keywords Childhood cancer survivors . Cardiomyopathy .
for cancer treatment-related cardiomyopathy. Identification of Anthracyclines . Mediastinal radiation . Treatment .
those at highest risk has presented a longstanding challenge Prevention . Risk stratification . Screening
for survivorship researchers. To date, risk stratification ap-
proaches to screening and subsequent intervention have large-
ly been driven by demographic and treatment-related expo- Introduction
sures, possibly missing an opportunity for a more personalized
approach. A growing body of literature suggests associations Improvements in childhood cancer therapy have led to a
between cardiomyopathy and a number of genetic and ac- growing number of long-term survivors of childhood cancer.
quired risk factors, supporting a need to incorporate these data It is estimated that there are over 450,000 survivors of child-
into existing surveillance and intervention approaches. Efforts hood cancer living in the USA today, and that number is
to reduce or eliminate modifiable cardiovascular risk factors projected to exceed 500,000 by the year 2020 [1]. However,
are needed; however, the impact of these modifications re- surviving cancer does not necessarily translate into full resto-
mains to be seen. Moreover, challenges surrounding identifi- ration of health. Many childhood cancer survivors are at risk
cation of effective cardiomyopathy treatment strategies in can- for developing chronic and debilitating health-related condi-
cer survivors are ongoing. Despite these uncertainties, more tions such as second cancers, cardiopulmonary dysfunction,
accurate identification of those at highest risk and implemen- endocrine disorders, and neurocognitive impairment [2–4].
tation of early and effective interventions for those with dis- These conditions often do not become clinically apparent until
ease will lead to improved outcomes for childhood cancer years after completion of therapy and are strongly associated
survivors. with cancer-related therapeutic exposures [2–4].
Cardiovascular complications (such as coronary artery dis-
ease, stroke, and especially cardiomyopathy/heart failure
This article is part of the Topical Collection on Cardio-oncology (HF)) are a leading cause of morbidity and mortality in long-
Matthew J. Ehrhardt and Joy M. Fulbright contributed equally to this term survivors of childhood cancer [5–8]. In fact, childhood
work. cancer survivors are at a 15-fold increased risk of developing
HF compared to age-matched controls [2]. There is a strong
* Saro H. Armenian dose-dependent relation between anthracycline exposure and
[email protected]
HF risk; the risk is higher among younger patients and those
exposed to chest radiation [9–12]. This anthracycline-related
1
Department of Oncology and Epidemiology and Cancer Control, St. cardiotoxicity represents a continuum from asymptomatic
Jude Children’s Research Hospital, Memphis, TN, USA structural or functional cardiac abnormalities detected on im-
2
Division of Hematology, Oncology and Bone Marrow aging studies (stage B (American College of Cardiology/
Transplantation, Children’s Mercy Hospital, Kansas City, MO, USA American Heart Association; ACC/AHA)), to clinically
3
Department of Population Sciences, City of Hope Comprehensive symptomatic HF (ACC/AHA stage C/D) [13–15]. A recent
Cancer Center, 1500 East Duarte Rd, Duarte, CA 91010-3000, USA report found that as many as 11 % of all childhood cancer
22 Page 2 of 7 Curr Oncol Rep (2016) 18:22

survivors will develop stage B disease by 40 years of age [16], these factors at an organizational level. Presently, asymptom-
a number comparable to that anticipated for individuals atic survivors are urged to undergo routine echocardiographic
75 years of age and older within the general population [17]. screening at frequencies that range from annually to every
The incidence of clinically overt HF (stage C/D) is <5 % with 5 years, according to individual risk status.
cumulative anthracycline exposure of <300 mg/m 2 ap- However, the risk stratification strategy advocated by the
proaches 20 % at doses between 300 and 600 mg/m2 and COG has lacked prospective validation. Therefore, the ability
exceeds 30 % for doses >600 mg/m2 [5, 9, 11–13]. The out- to confidently predict cardiomyopathy risk at an individual
come following anthracycline-related HF is poor; 5-year over- level has remained limited. In response, Chow and colleagues
all survival rate is <50 % [18, 19]. Nearly 60 % of all child- [28••] recently developed cardiomyopathy prediction models
hood cancer survivors carry a history of prior anthracycline structured around incremental degrees of treatment-related da-
exposure [12, 20], representing a large and growing popula- ta available to most providers at the time of survivor entry into
tion of survivors at risk for significant cardiovascular morbid- a variety of long term follow-up settings. These investigators
ity over time. identified 13,060 survivors enrolled in the Childhood Cancer
In anthracycline-treated childhood cancer survivors, there Survivor Study (CCSS), who were free of cardiovascular dis-
is often a long latency between asymptomatic (stage B) and ease after the completion of cancer therapy and routinely
clinically evident (stage C/D) diseases. Longitudinal and screened for cardiomyopathy until 40 years of age, as directed
cross-sectional studies [11, 21] in these survivors have re- by the guidelines endorsed by COG. Risk factors for HF were
vealed characteristic changes of left ventricular (LV) remod- identified and integrated into a risk-based scoring system that
eling that can precede declines in established measures of was subsequently used to develop predictive models. The
cardiac function such as LV ejection fraction (EF). Typically, models were then validated across three independent cohorts,
there is a decrease in the LV wall thickness (LVWT) and an including the Emma Children’s Hospital, National Wilms
increase in LV dimension (LVEDD), expressed as a decreased Tumor Study, and St. Jude Lifetime Cohort. The result was a
LV Thickness-Dimension Ratio (LV T-D). This decrease in strongly predictive model (ccss.stjude.org/chfcalc; C-statistics
LV T-D and subsequent increase in LVend-systolic wall stress 0.68 to 0.81) with the ability to identify those individuals at
(ESWS) are a critical component of cardiac remodeling and highest risk for late-occurring cardiomyopathy for which ag-
neurohormonal imbalance that precedes changes in conven- gressive surveillance may be most beneficial [23].
tional systolic echocardiographic indices such as EF [11, 22]. As we enter a new era of precision medicine, it becomes
The well-recognized long latency between initial cardiotoxic particularly important to be able to communicate with cancer
exposure and clinically overt disease provides opportunities survivors, with some level of accuracy, the absolute as well as
for implementation of early screening and prevention strate- relative risk of cardiovascular disease over time. To this end,
gies in survivors at highest risk for developing therapy-related future risk prediction models will need to incorporate infor-
HF. mation from a growing body of literature on genomic predic-
tors of cardiovascular disease risk [29]. A number of studies
have now reported on germline single nucleotide polymor-
Risk Stratification and Efficacy of Early Screening phisms that may be contributing to the development of
anthracycline-induced cardiomyopathy [30–32]. However,
Leading long-term follow-up organizations have endorsed a additional validation is needed prior to widespread dissemina-
number of surveillance strategies centered on early detection tion of these findings into routinely used predictive models
of subclinical cardiac dysfunction [23–26]. In an effort to and surveillance strategies. At present, nearly 6000 survivors
align these evidence-based and expert recommendations, the have provided specimens for which completed genotyping is
International Late Effects of Childhood Cancer Guideline now available for investigation with the CCSS (https://ccss.
Harmonization Group systematically reviewed existing data stjude.org/biospecimens.html). Such resources will play a
surrounding several key aspects of early screening [27••]. critical role in refining our understanding of the implications
They found that although all groups recommend echocardiog- of known and novel mutations, ultimately facilitating future
raphy as the primary screening modality, whom and with what incorporation of these data into detection and prevention
frequency to screen remain quite discordant. Much of this strategies.
variation revolves around heterogeneity in resource availabil- As the risk for cardiomyopathy/HF in cancer survivors be-
ity, risk stratification for cumulative cancer treatment expo- comes increasingly evident, critical appraisals into the cost-
sures, and subsequent interpretation of risk benefit ratios at effectiveness of existing and future surveillance approaches
an organizational level. Consequently, the Children’s are imperative. Yet, longitudinal assessments designed to an-
Oncology Group (COG) in the USA and similar leading co- swer these clinical questions are precluded by cost, clinical
operative groups worldwide have made tailored, risk-based resource availability, and delays to meaningful result
recommendations for long-term surveillance that balance reporting. To address these limitations, two recent studies
Curr Oncol Rep (2016) 18:22 Page 3 of 7 22

utilized Markov modeling in order to simulate long-term car- population-based screening of asymptomatic disease.
diomyopathy outcomes in childhood cancer survivors using Consequently, investigators have sought to improve the sen-
the best currently available clinically predictive data [33••, sitivity and specificity of traditional two-dimensional echocar-
34••]. Both studies simulated the lifetime risk for diography through the use of a three-dimensional approach.
cardiomyopathy/HF in separate cohorts of 5-year childhood However, as seen in a recent study, improved sensitivity can
cancer survivors, in order to determine the incremental cost- come at a cost of nearly 50 % reduction in the positive pre-
effectiveness ratio per quality-adjusted life-year gained. The dictive value of the test, limiting the use of three-dimensional
first, by Wong et al. applied the risk-based surveillance ap- echocardiography for routine screening [37]. Other ap-
proach endorsed by the COG to a cohort of 4365 proaches such as myocardial contrast echocardiography may
anthracycline-exposed survivors for which they had access be especially helpful for individuals for whom the endocardi-
to both cumulative anthracycline and radiation doses. The um is not adequately visualized. In fact, the American Society
second, by Yeh et al. applied simplified anthracycline-based of Echocardiography (ASE) consensus statement [38] on the
risk stratification to a cohort of survivors for which they did clinical applications of ultrasonic contrast agents in echocar-
not have access to cumulative radiation exposure. Despite diography recommends the use of myocardial contrast echo-
these distinct approaches, both concluded that current screen- cardiography when two contiguous LV segments from any
ing practices would be more cost-effective when performed at apical view are not seen in non-contrast images. That being
reduced intervals, particularly for subgroups at lower risk for said, limited access to these advanced imaging approaches has
developing cardiomyopathy. Within the context of cancer- precluded their widespread incorporation into population-
related cardiomyopathy, these investigations are dependent based screening strategies. As a result, two-dimensional echo-
upon critical assumptions regarding the predictive values of cardiography remains the most uniformly accepted cardiomy-
available detection methods, undescribed future risk for HF, opathy screening modality of choice for long-term survivors
and efficacy of and adherence to treatment regimens both now of childhood cancer [27••].
and in the future. However, despite these assumptions, these
models bring valuable insight to current screening practices
and highlight the need for ongoing surveillance guideline ap- Prevention and Treatment Strategies
praisal and development. After Completion of Cancer Therapy
To better understand these limitations, one must first con-
sider the relationship between the prevalence of disease, the ACC/AHA Guidelines recommend initiation of angiotensin-
sensitivity and specificity of currently available testing modal- converting enzyme (ACE) inhibitors or β-blockers in individ-
ities, and the subsequent predictive value. Ramjaun and col- uals with asymptomatic LV systolic impairment (stage B),
leagues recently highlighted the impact of prevalence on regardless of etiology [39, 40]. Thus, pharmacologic interven-
screening efficacy by identifying risk factors for sustained tion can be considered standard of care for childhood cancer
(true positive) vs. transient (false positive) echocardiographic survivors with stage B disease. In fact, a survey [41] of
abnormalities in childhood cancer survivors. Individuals ex- pediatric/medical oncologists and cardiologists performed pri-
posed to cumulative anthracycline doses ≥250 mg/m2 at youn- or to the release of the ACC/AHA recommendations revealed
ger than 5 years of age were at significantly higher risk for that two thirds of respondents would initiate pharmacologic
sustained echocardiographic abnormalities compared to those therapy for stage B patients, with ACE inhibitors or β-
treated at older ages with lower doses of anthracyclines (54 vs. blockers being the most common treatments employed.
5 %, respectively; p = 0.01), emphasizing the impact of under- However, it is important to note that the rationale for initiating
lying disease prevalence (cardiomyopathy) on a test’s pharmacotherapy in this setting is based largely on random-
(echocardiography) predictive value for disease (sustained ized clinical trials in non-oncology adult populations where
ventricular dysfunction) [35]. These findings underscore the the pathophysiology and mechanism of cardiac injury are like-
critical role of risk group identification in the development of ly to be quite different than that seen in children with cancer.
efficacious surveillance strategies. Study participants in these adult clinical trials (e.g., SOLVD,
Equally important to effective screening strategies is the SAVE, and TRACE trials [42]) typically had markedly abnor-
ability of the surveillance test to accurately identify the abnor- mal EF (e.g., <40 %), and the vast majority had LV dysfunc-
mality in question. In this light, cardiac magnetic resonance tion due to myocardial dysfunction, resulting in changes in the
(CMR) imaging has emerged as the reference standard for myocardium that may be different than that seen in childhood
detecting LV dysfunction in a variety of oncology and non- cancer. Importantly, small studies in long-term cancer survi-
oncology populations, due to its superior sensitivity and spec- vors [43, 44] have shown that initiating pharmacotherapy after
ificity, non-invasiveness, and avoidance of ionizing radiation structural changes have been detected (stage B) may fail to
[36]. Yet, despite its superiority, the cost and limited availabil- halt progression of cardiac remodeling after anthracycline ex-
ity of CMR currently precludes its widespread use for posure. Lipshultz et al. [44] reported that while the use of
22 Page 4 of 7 Curr Oncol Rep (2016) 18:22

enalapril in stage B childhood cancer survivors can improve anthracyclines. However, due to the small number of partici-
cardiac parameters of remodeling (LV chamber diameter/vol- pants in the high-dose anthracycline group (N = 37/arm), in-
ume, wall stress), these changes are short-lived, and nearly all vestigators were unable to make conclusive recommendations
patients develop progressive cardiac dysfunction within regarding prevention of HF with enalapril. Thus, there re-
6 years of initiation of therapy. As such, it is especially impor- mains a gap in knowledge regarding preventive strategies in
tant to consider treatment strategies prior to the onset of echo- childhood cancer survivors at highest risk of HF.
cardiographic changes in LV structure in childhood cancer Demonstrating treatment efficacy in this setting would result
survivors. in a paradigm shift in current clinical practice for this growing
The concept of initiating interventions prior to LV func- population of survivors.
tional impairment (e.g., in individuals with normal LV EF) Recent studies in adult cancer patients provide insight into
in populations at high risk for developing heart failure is not alternative preventive strategies that may be worth exploring
without merit. Much like in anthracycline-exposed childhood in the childhood cancer survivor population. Cardinale and
cancer survivors, children with the Duchene muscular dystro- colleagues reported on a randomized study whereby patients
phy (DMD) are at high risk for developing dilated receiving cardiotoxic chemotherapy who had an elevation in
cardiomyopathy/heart failure as they age. In these individuals, serum Troponin I during cancer therapy were randomized to
pathophysiologic cardiac remodeling first manifests as minor enalapril or no enalapril shortly after the completion of che-
echocardiographic abnormalities at a young age, evolves to- motherapy [43]. Those enrolled in the control (no enalapril)
ward LV dilation, and subsequently results in a reduced EF group had a significant increase in cardiac events and 43 %
[45]. Early pharmacologic intervention, prior to detectable LV had a decrease in EF greater than 10 % units from baseline.
functional impairment, has been shown to improve long-term The investigators noted that individuals in the control group
cardiac outcomes in children with DMD [46, 47], a strategy who had persistent elevation in Troponin I experienced a
that may be worth pursuing in a subset of childhood cancer greater decrease in EF than those who did not have persistent
survivors at highest risk for developing HF. elevation. These results provide insight into markers that can
There are currently no recommendations for secondary pre- potentially be used for surveillance and initiation of pharma-
vention in asymptomatic anthracycline-exposed childhood cotherapy during cancer treatment. A subsequent study in
cancer survivors with preserved EF. A previous clinical trial adults evaluated the efficacy of both ACE inhibitors and β-
[48] randomized childhood cancer survivors with preserved blockers, initiated prior to chemotherapy, for the prevention of
EF (using a wide range of anthracycline dose: 75-738 mg/m2) EF decline in patients receiving intensive therapy for a hema-
to an ACE inhibitor (enalapril) vs. placebo. The study found tological malignancy [49]. Patients in the treatment group had
that individuals treated with high-dose anthracyclines stable EFs, while those in the placebo group experienced de-
(≥300 mg/m2) derived the most benefit from enalapril—six clining EFs, demonstrating a possible benefit to early, combi-
out of seven cardiac events occurred in the placebo arm and nation therapies exploiting different pharmacologic mecha-
nearly all were among those treated with high-dose nisms of action for HF risk reduction.

Fig. 1 Conceptual schematic of

cardiomyopathy risk and
modifiers in childhood cancer
survivors. Factors designated by
an asterisk are under active
investigation (knowledge gaps).
HTN hypertension, DM diabetes
mellitus
Curr Oncol Rep (2016) 18:22 Page 5 of 7 22

Role of Modifiable Risk Factors development of the next generation of cancer treatment clini-
cal trials. That being said, the growing number of childhood
In non-oncology populations, it is well-established that reduc- cancer survivors already exposed to potentially cardiotoxic
tion of modifiable risk factors, such as obesity, smoking, hy- therapies represents a vulnerable population in need of early
pertension, diabetes, and dyslipidemia, can result in signifi- screening and intervention. Therefore, innovative approaches
cant improvement in cardiovascular disease risk later in life integrating information obtained from non-oncology as well
[50, 51]. Childhood cancer survivors are at a higher risk of as adult cancer survivor populations are needed, setting the
developing many of these conditions, including hypertension, stage for multidisciplinary collaborative research endeavors
diabetes, and dyslipidemia, when compared to the general seeking to reduce the cardiovascular burden in long-term
population [52, 53]. In animal models, there is evidence that childhood cancer survivors.
hypertension may accelerate LV myocardial remodeling
known to occur following anthracycline exposure [54].
More recently, Armstrong and colleagues identified hyperten- Compliance with Ethical Standards
sion as an independent modifiable risk factor for HF in survi-
Conflict of Interest Matthew J. Ehrhardt, Joy M. Fulbright, and Saro
vors exposed to chest-directed radiotherapy (RR, 19.4; 95 % H. Armenian declare that they have no conflict of interest.
CI, 11.4 to 33.1) and anthracycline chemotherapy (RR, 12.4;
95 % CI, 7.5 to 20.1) [55••]. These results underscore the Human and Animal Rights and Informed Consent This article does
importance of risk-based screening for cardiomyopathy, in- not contain any studies with human or animal subjects performed by any
cluding direct assessment of hypertension in survivors already of the authors.
at substantial risk for cardiovascular events. It is important to
note, however, that the impact of early intervention for hyper-
tension and other modifiable risk factors in cancer survivors is
not known, and addressing this gap in knowledge remains an
important research priority for the childhood cancer survivor- References
ship community.
Finally, there is considerable evidence supporting the ad- Papers of particular interest, published recently, have been
vantages derived from regular, moderate exercise and fitness highlighted as:
in the general population [56, 57]. The current joint guidelines •• Of major importance
from the AHA and the American College of Sports Medicine
recommend at least 30 min of aerobic exercise five times per 1. Robison LL, Hudson MM. Survivors of childhood and adolescent
week and strength training twice per week [56]. Studies in cancer: life-long risks and responsibilities. Nat Rev Cancer.
2014;14:61–70.
limited numbers of childhood cancer survivors have found 2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health condi-
that despite having lower exercise capacity, evidenced by low- tions in adult survivors of childhood cancer. N Engl J Med.
er peak myocardial oxygen consumption [58, 59], survivors 2006;355:1572–82.
can attain significant improvements in muscle strength and 3. Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of
flexibility, cardiopulmonary fitness, and overall physical func- health outcomes among adults treated for childhood cancer. JAMA.
2013;309:2371–81.
tion when engaged in routine aerobic activity [60, 61]. Larger 4. Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year
studies in adult breast cancer patients have demonstrated an survivors of childhood cancer: a summary from the Childhood
overall improvement in cardiovascular disease risk, including Cancer Survivor Study. J Clin Oncol. 2009;27:2328–38.
a reduction in individual cardiovascular risk factors such as 5. Yahalom J, Portlock CS. Long-term cardiac and pulmonary com-
plications of cancer therapy. Hematol Oncol Clin N Am. 2008;22:
hypertension and dyslipidemia [62, 63]. Studies are needed in
305–18. vii.
childhood cancer survivors to determine the long-term effica- 6. Moller TR, Garwicz S, Barlow L, et al. Decreasing late mortality
cy of exercise to arrest or even improve cardiac function long among five-year survivors of cancer in childhood and adolescence:
after completion of cardiotoxic therapy. a population-based study in the Nordic countries. J Clin Oncol.
2001;19:3173–81.
7. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in
five-year survivors of childhood and adolescent cancer: the
Conclusion Childhood Cancer Survivor Study. J Clin Oncol. 2001;19:3163–72.
8. van der Pal HJ, van Dalen EC, Kremer LC, et al. Risk of morbidity
The past three decades of survivorship research have in- and mortality from cardiovascular disease following radiotherapy
creased our awareness of the long-term cardiovascular disease for childhood cancer: a systematic review. Cancer Treat Rev.
2005;31:173–85.
burden faced by children treated for cancer at a young age. 9. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and
Ongoing efforts are needed to integrate the information ob- radiation-associated cardiomyopathies: implications for screening
tained from these survivorship studies (Fig. 1) into the and prevention. Pediatr Blood Cancer. 2005;44:600–6.
22 Page 6 of 7 Curr Oncol Rep (2016) 18:22

10. Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and drug cardiomyopathy risk in cancer survivors. These models should
dose as risk factors for late cardiotoxic effects of doxorubicin ther- be utilized when developing future surveillance strategies.
apy for childhood cancer. N Engl J Med. 1995;332:1738–43. 29. Armenian SH, Bhatia S. Chronic health conditions in childhood
11. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cancer survivors: is it all treatment-related—or do genetics play a
cardiac dysfunction years after doxorubicin therapy for childhood role? J Gen Intern Med. 2009;24 Suppl 2:S395–400.
acute lymphoblastic leukemia. J Clin Oncol. 2005;23:2629–36. 30. Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, et al.
12. van Dalen EC, van der Pal HJ, Kok WE, et al. Clinical heart failure Genetic polymorphisms in the carbonyl reductase 3 gene CBR3
in a cohort of children treated with anthracyclines: a long-term and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in pa-
follow-up study. Eur J Cancer. 2006;42:3191–8. tients who developed anthracycline-related congestive heart failure
13. Giantris A, Abdurrahman L, Hinkle A, et al. Anthracycline-induced after childhood cancer. Cancer. 2008;112:2789–95.
cardiotoxicity in children and young adults. Crit Rev Oncol 31. Blanco JG, Sun CL, Landier W, et al. Anthracycline-related cardio-
Hematol. 1998;27:53–68. myopathy after childhood cancer: role of polymorphisms in carbon-
14. Grenier MA, Lipshultz SE. Epidemiology of anthracycline yl reductase genes—a report from the Children’s Oncology Group.
cardiotoxicity in children and adults. Semin Oncol. 1998;25:72–85. J Clin Oncol. 2012;30:1415–21.
15. Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and 32. Wang X, Liu W, Sun CL, et al. Hyaluronan synthase 3 variant and
risk factors of anthracycline-induced clinical heart failure in chil- anthracycline-related cardiomyopathy: a report from the Children’s
dren: a systematic review. Ann Oncol. 2002;13:503–12. Oncology Group. J Clin Oncol. 2014;32:647–53.
16. Mulrooney DA, Armstrong GT, Huang S, et al. Cardiac outcomes 33.•• Wong FL, Bhatia S, Landier W, et al. Cost-effectiveness of the
in adult survivors of childhood cancer exposed to cardiotoxic ther- Children’s Oncology Group long-term follow-up screening guide-
apy: a cross-sectional study. Ann Intern Med. 2016;164:93–101. lines for childhood cancer survivors at risk for treatment-related
17. Redfield MM, Jacobsen SJ, Burnett Jr JC, et al. Burden of systolic heart failure. Ann Intern Med. 2014;160:672–83.
and diastolic ventricular dysfunction in the community: appreciat- Cardiomyopathy simulation models suggest that safe and effi-
ing the scope of the heart failure epidemic. JAMA. 2003;289:194– cacious screening reductions are possible for select groups of
202. cancer survivors.
18. Armenian SH, Sun CL, Shannon T, et al. Incidence and predictors 34.•• Yeh JM, Nohria A, Diller L. Routine echocardiography screening
of congestive heart failure after autologous hematopoietic cell trans- for asymptomatic left ventricular dysfunction in childhood cancer
plantation. Blood. 2011;118:6023–9. survivors: a model-based estimation of the clinical and economic
19. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and effects. Ann Intern Med. 2014;160:661–71. Cardiomyopathy sim-
long-term survival in patients with initially unexplained cardiomy- ulation models suggest that safe and efficacious screening re-
opathy. N Engl J Med. 2000;342:1077–84. ductions are possible for select groups of cancer survivors.
20. Krischer JP, Epstein S, Cuthbertson DD, et al. Clinical 35. Ramjaun A, AlDuhaiby E, Ahmed S, et al. Echocardiographic de-
cardiotoxicity following anthracycline treatment for childhood can- tection of cardiac dysfunction in childhood cancer survivors: how
cer: the Pediatric Oncology Group experience. J Clin Oncol. long is screening required? Pediatr Blood Cancer. 2015;62:2197–
1997;15:1544–52. 203.
21. Armenian SH, Gelehrter SK, Vase T, et al. Screening for cardiac 36. American College of Cardiology Foundation Task Force on Expert
dysfunction in anthracycline-exposed childhood cancer survivors. Consensus D, Hundley WG, Bluemke DA, et al. ACCF/ACR/
Clin Cancer Res. 2014;20:6314–23. AHA/NASCI/SCMR 2010 expert consensus document on cardio-
22. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of vascular magnetic resonance: a report of the American College of
dexrazoxane as a cardioprotectant in doxorubicin-treated children Cardiology Foundation Task Force on Expert Consensus
with high-risk acute lymphoblastic leukaemia: long-term follow-up Documents. J Am Coll Cardiol. 2010;55:2614–62.
of a prospective, randomised, multicentre trial. Lancet Oncol. 37. Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors
2010;11:950–61. of childhood cancer for cardiomyopathy: comparison of echocardi-
23. Children’s Oncology Group: Long-term follow-up guidelines for ography and cardiac magnetic resonance imaging. J Clin Oncol.
survivors of childhood, adolescent, and young adult cancers. 2012;30:2876–84.
www.survivorshipguidelines.org. 38. Plana JC, Galderisi M, Barac A, et al. Expert consensus for
24. Sieswerda E, Postma A, van Dalen EC, et al. The Dutch Childhood multimodality imaging evaluation of adult patients during and after
Oncology Group guideline for follow-up of asymptomatic cardiac cancer therapy: a report from the American Society of
dysfunction in childhood cancer survivors. Ann Oncol. 2012;23: E c ho c a r d i og r a p hy an d t h e Euro pe a n Ass oci a t i o n o f
2191–8. Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27:911–39.
25. Wallace WH, Thompson L, Anderson RA, Guideline DG. Long 39. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update
term follow-up of survivors of childhood cancer: summary of up- incorporated into the ACC/AHA 2005 guidelines for the diagnosis
dated SIGN guidance. BMJ. 2013;346:f1190. and management of heart failure in adults: a report of the American
26. United Kingdom Children’s Cancer Study Group Late Effects College of Cardiology Foundation/American Heart Association
Group. Therapy based long term follow up: practice statement. Task Force on Practice Guidelines developed in collaboration with
2005. http://www.cclg.org.uk (accessed November 2, 2015). the International Society for Heart and Lung Transplantation. J Am
27.•• Armenian SH, Hudson MM, Mulder RL, et al. Recommendations Coll Cardiol. 2009;53:e1–90.
for cardiomyopathy surveillance for survivors of childhood cancer: 40. Hunt SA, American College of C, American Heart Association
a report from the International Late Effects of Childhood Cancer Task Force on Practice G. ACC/AHA 2005 guideline update for
Guideline Harmonization Group. Lancet Oncol. 2015;16:e123–36. the diagnosis and management of chronic heart failure in the adult:
Discordant practices exist between leading survivorship orga- a report of the American College of Cardiology/American Heart
nizations. Collaborative efforts to harmonize these practices are Association Task Force on Practice Guidelines (writing committee
ongoing. Future investigations are needed to optimize clinical to update the 2001 Guidelines for the Evaluation and Management
care for cancer survivors. of Heart Failure). J Am Coll Cardiol. 2005;46:e1–82.
28.•• Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart 41. van Dalen EC, van der Pal HJ, Reitsma JB, et al. Management of
failure among childhood cancer survivors. J Clin Oncol. 2015;33: asymptomatic anthracycline-induced cardiac damage after treat-
394–402. Newly developed models can reasonably predict ment for childhood cancer: a postal survey among Dutch adult
Curr Oncol Rep (2016) 18:22 Page 7 of 7 22

and pediatric cardiologists. J Pediatr Hematol Oncol. 2005;27:319– cancer survivor study. Cancer Epidemiol Biomarkers Prev.
22. 2010;19:170–81.
42. Goldberg LR, Jessup M. Stage B heart failure: management of 53. Oeffinger KC, Adams-Huet B, Victor RG, et al. Insulin resistance
asymptomatic left ventricular systolic dysfunction. Circulation. and risk factors for cardiovascular disease in young adult survivors
2006;113:2851–60. of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009;27:
43. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose 3698–704.
chemotherapy-induced cardiotoxicity in high-risk patients by 54. Herman EH, el-Hage AN, Ferrans VJ, Ardalan B. Comparison of
angiotensin-converting enzyme inhibition. Circulation. 2006;114: the severity of the chronic cardiotoxicity produced by doxorubicin
2474–81. in normotensive and hypertensive rats. Toxicol Appl Pharmacol.
44. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Long-term enalapril 1985;78:202–14.
therapy for left ventricular dysfunction in doxorubicin-treated sur- 55.•• Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors
vivors of childhood cancer. J Clin Oncol. 2002;20:4517–22. and major cardiac events among adult survivors of childhood can-
45. Connuck DM, Sleeper LA, Colan SD, et al. Characteristics and cer. J Clin Oncol. 2013;31:3673–80. Modifiable cardiovascular
outcomes of cardiomyopathy in children with Duchenne or risk factors potentiate the risk for cardiomyopathy in at risk
Becker muscular dystrophy: a comparative study from the cancer survivors. The impact of detection of and early interven-
Pediatric Cardiomyopathy Registry. Am Heart J. 2008;155:998– tion for these acquired risk factors should be the focus of future
1005. investigations.
46. Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardio- 56. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public
myopathy in Duchenne muscular dystrophy: a randomised, double- health: updated recommendation for adults from the American
blind, placebo-controlled trial. Lancet Neurol. 2015;14:153–61. College of Sports Medicine and the American Heart Association.
47. Duboc D, Meune C, Pierre B, et al. Perindopril preventive treatment Circulation. 2007;116:1081–93.
on mortality in Duchenne muscular dystrophy: 10 years’ follow-up.
57. Thompson PD, Franklin BA, Balady GJ, et al. Exercise and acute
Am Heart J. 2007;154:596–602.
cardiovascular events placing the risks into perspective: a scientific
48. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac
statement from the American Heart Association Council on
function decline in long-term survivors of pediatric cancer exposed
Nutrition, Physical Activity, and Metabolism and the Council on
to anthracyclines. J Clin Oncol. 2004;22:820–8.
Clinical Cardiology. Circulation. 2007;115:2358–68.
49. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for
58. De Caro E, Smeraldi A, Trocchio G, et al. Subclinical cardiac dys-
preventing chemotherapy-induced left ventricular systolic dysfunc-
function and exercise performance in childhood cancer survivors.
tion in patients with malignant hemopathies: the OVERCOME trial
Pediatr Blood Cancer. 2011;56:122–6.
(preventiOn of left Ventricular dysfunction with Enalapril and
caRvedilol in patients submitted to intensive ChemOtherapy for 59. Hoffman MC, Mulrooney DA, Steinberger J, et al. Deficits in phys-
the treatment of Malignant hEmopathies). J Am Coll Cardiol. ical function among young childhood cancer survivors. J Clin
2013;61:2355–62. Oncol. 2013;31:2799–805.
50. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guide- 60. Huang TT, Ness KK. Exercise interventions in children with can-
line for assessment of cardiovascular risk in asymptomatic adults: a cer: a review. Int J Pediatr. 2011;2011:461512.
report of the American College of Cardiology Foundation/ 61. Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and
American Heart Association Task Force on Practice Guidelines. physical activity guidelines for cancer survivors. CA Cancer J
Circulation. 2010;122:e584–636. Clin. 2012;62:243–74.
51. Smith Jr SC, Collins A, Ferrari R, et al. Our time: a call to save 62. Jones LW, Liang Y, Pituskin EN, et al. Effect of exercise training on
preventable death from cardiovascular disease (heart disease and peak oxygen consumption in patients with cancer: a meta-analysis.
stroke). J Am Coll Cardiol. 2012;60:2343–8. Oncologist. 2011;16:112–20.
52. Meacham LR, Chow EJ, Ness KK, et al. Cardiovascular risk factors 63. Kirkham AA, Davis MK. Exercise prevention of cardiovascular
in adult survivors of pediatric cancer—a report from the childhood disease in breast cancer survivors. J Oncol. 2015;2015:917606.