Elsevier

The Lancet Oncology

Volume 16, Issue 3, March 2015, Pages e123-e136
The Lancet Oncology

Review
Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

https://doi.org/10.1016/S1470-2045(14)70409-7Get rights and content

Summary

Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

Introduction

Advances in treatment strategies for childhood cancer have resulted in great improvements in survival, with 5-year survival approaching 80%.1 However, this improvement in outcome has been compromised by the occurrence of long-term morbidities of therapy. The cumulative incidence of severe or life-threatening chronic health disorders exceeds 40% for survivors of childhood cancer who are still alive 30 years after primary diagnosis.2, 3 These chronic health disorders include second malignant neoplasms, endocrine disorders, cardiopulmonary dysfunction, cardiovascular complications, renal dysfunction, and neurosensory impairment.2, 3

Cardiovascular complications—eg, coronary artery disease, stroke, and especially congestive heart failure—have emerged as a leading cause of morbidity and mortality in long-term survivors of childhood cancer.4 Compared with the general population, survivors of childhood cancer are at a 15-fold increased risk of developing congestive heart failure2 and at a seven-fold increased risk of premature death due to cardiac causes.5 There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and risk of congestive heart failure, and the risk is further increased in those who have been exposed to chest radiation.4 The incidence of congestive heart failure is less than 5% with cumulative anthracycline exposure of less than 250 mg/m2; approaches 10% at doses between 250 mg/m2 and 600 mg/m2; and exceeds 30% for doses higher than 600 mg/m2 for survivors of childhood cancer.4,6–8 Nearly 60% of all survivors of childhood cancer have had exposure to either anthracycline chemotherapy, or chest radiation, or both.9, 10

The American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the diagnosis and management of congestive heart failure describe heart failure as a progressive disorder, with a variable period of asymptomatic cardiac dysfunction that precedes clinically overt signs and symptoms.11 For anthracycline-exposed survivors, the asymptomatic stage is often characterised by thinning of the left ventricular wall, enlargement of left ventricular diameter, and subsequent increase in left ventricular wall stress, a clinical diagnosis similar to dilated cardiomyopathy.4, 12 These subclinical changes can result in impairment of left ventricular systolic function, manifesting as either a decrease in ejection fraction (EF), decrease in shortening fraction (SF), or decrease in both.4, 12

Anthracycline-exposed survivors could also, over time, develop restrictive cardiomyopathy, resulting in abnormal E/A ratio (peak early atrial velocity divided by peak late atrial velocity), or prolonged isovolumic relaxation time (IVRT) in the setting of preserved EF and SF.4, 12 Individuals who receive chest radiation could be at an especially high risk of developing combined dilated and restrictive cardiomyopathy that results from myocardial fibrosis, mainly due to radiation effects on the supporting vasculature.4, 12

In survivors of childhood cancer, a long latency period often occurs between cardiotoxic exposure and clinically evident disease.4, 12 North American and European groups have independently published clinical practice guidelines to facilitate early detection and treatment of asymptomatic cardiomyopathy.13, 14, 15, 16 These guidelines differ in their definitions of at-risk populations, surveillance modality, surveillance frequency, and recommendations for interventions, which could, in turn, hinder the effective implementation of screening across a wide spectrum of clinical settings. In 2010, recognition regarding the potential benefits of collaboration resulted in an international endeavour to harmonise clinical practice guidelines for survivors of childhood cancer and young adult cancer. The result was the International Late Effects of Childhood Cancer Guideline Harmonization Group.17

Here, we describe briefly the principles of the harmonisation process and present a summary of the evidence and recommendations for cardiomyopathy surveillance in survivors of childhood cancer treated with either anthracycline chemotherapy, chest radiation, or both. We conclude by identifying outstanding issues that need to be addressed to minimise the burden of cardiovascular disease in survivors of paediatric malignancies.

Section snippets

International guideline harmonisation

A detailed description of the international guideline harmonisation endeavour and method is provided elsewhere.17 Representatives from the North American Children's Oncology Group (COG),13 the Dutch Childhood Oncology Group (DCOG),14 the Scottish Intercollegiate Guidelines Network (SIGN),16 and the UK Children's Cancer and Leukaemia Group (UKCCLG)15 prepared the cardiomyopathy surveillance recommendations. These recommendations encompassed published guidelines that were developed following

Discordances and concordances between the recommendations for cardiomyopathy surveillance

Table 1 summarises the discordances and concordances between the recommendations. Concordance was found across guidelines for the following statements: survivors of childhood cancer treated with anthracyclines (including mitoxantrone) or chest radiation are at increased risk of cardiomyopathy; surveillance using echocardiography should be lifelong and performed at a minimum of every 5 years; in view of the increased cardiometabolic demand on the heart of the mother during pregnancy, closer

Who needs cardiomyopathy surveillance?

Children and adolescents treated with anthracyclines or radiation are at an increased risk of developing cardiomyopathy. These individuals and their health-care providers should be aware of the increased risk of developing cardiomyopathy following completion of therapy (strong recommendation). There is an exponential increase in risk of cardiomyopathy with increasing lifetime cumulative dose (figure 2A and figure 2B).19, 26, 27 The risk is especially high in children treated with 250 mg/m2 or

Discussion

The growing population of long-term survivors of childhood cancer has brought to the fore a host of chronic health-related disorders that can substantially affect the overall quality of life and length of survival.98 Cardiovascular complications such as congestive heart failure contribute increasingly to the long-term morbidity and mortality of these individuals.4 Here, we have summarised the international harmonised cardiomyopathy surveillance recommendations for survivors of childhood cancer

Search strategy and selection criteria

We searched Medline (through PubMed), from January, 2002, to December, 2012, using the search terms “childhood”, “adolescent”, “cancer”, “survivor”, “heart”, “anthracyclines”, “radiotherapy”, “echocardiogram, “magnetic resonance imaging”, “radionuclide ventriculography”, “biomarkers”, and “treatment” (detailed search strategies are provided in the appendix). Only reports published in English were reviewed. We critiqued references supporting the existing recommendations and contacted experts in

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