Cardiovascular Toxicology

, Volume 7, Issue 2, pp 122–128

Anthracycline cardiotoxicity in long-term survivors of childhood cancer

Authors

  • Rebecca E. Scully
    • Department of Pediatrics, Division of Pediatric Clinical ResearchUniversity of Miami Miller School of Medicine
    • Department of Pediatrics, Mailman Center for Child DevelopmentUM Miller School of Medicine
    • Holtz Children’s Hospital of the University of Miami/Jackson Memorial Medical Center
    • Sylvester Comprehensive Cancer Center
Article

DOI: 10.1007/s12012-007-0006-4

Cite this article as:
Scully, R.E. & Lipshultz, S.E. Cardiovasc Toxicol (2007) 7: 122. doi:10.1007/s12012-007-0006-4

Abstract

Anthracycline chemotherapy is a widely-used and effective treatment for a wide spectrum of childhood cancers. Its use is limited by associated progressive and clinically significant cardiotoxic effects. Onset can be acute, early, or late. While acute onset is rare, long-term survivors have significantly elevated rates of cardiac morbidity and mortality. Major complications include cardiomyopathy, coronary artery disease, and atherosclerosis. Means of prevention and treatment continue to be explored including limiting cumulative anthracycline dose, controlling the rate of administration, and using liposomal preparations and novel anthracycline analogues. Dexrazoxane prior to anthracycline chemotherapy has been shown to significantly lower rates of elevated serum cardiac troponin levels, a marker of myocyte injury, indicating a cardioprotective effect. Pilot studies indicate that exercise interventions may also be beneficial in long-term survivors with cardiac damage. Support and study of this population to decrease the morbidity and morality associated with anthracycline-induced cardiotoxicity is indicated in a time sensitive fashion.

Keywords

AnthracyclinesCardiotoxicityTreatment effectsCardiomyopathySurvivorshipChildhood cancer

Introduction

Anthracycline chemotherapeutic agents including doxorubicin and daunorubicin are cytotoxic agents with broad activity against a variety of childhood malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), Hodgkin’s Disease, and Non-Hodgkin Lymphoma. Advances in treatment, including the use of anthracyclines alone and in combination, have lead to a 5-year survival rate of nearly 80% for children diagnosed with cancer before age 15 [1]. Thus, while pediatric patients account for only approximately 1% of all those newly diagnosed with cancer, there are approximately 270,000 long-term survivors in the US today and, fortunately, this number continues to increase [2]. When survivors of adult onset cancer are included, the number of cancer survivors in the US in 2002 was over 10 million [3]. This therapeutic success is tempered by the wide spectrum of negative late effects and chronic treatment-related morbidity borne by long-term survivors, a focus of much recent discussion and research [2, 49]. A population-based study of 5-year survivors in Nordic countries found a standardized mortality ratio (SMR) of 5.8 for cardiac death and 3.9 for sudden, presumed cardiac death [10]. Results from the Childhood Cancer Survivor Study (CCSS) show that 15–25 years after diagnosis, survivors of childhood cancer have 8.2-fold higher rates of cardiac death as compared to the age and sex matched national average [11]. These rates do not decrease with increased length of follow-up [1113].

Recent results from the CCSS cohort have also revealed that compared to siblings, long-term survivors are three times as likely to develop a chronic condition and eight times as likely to develop a severe or life-threatening condition. The cumulative incidence of chronic conditions reached 73% 30 years after therapy, over 40% of which were severe (disabling, life-threatening, or fatal) and included cardiovascular disease, stroke, pulmonary fibrosis, kidney failure or a second malignancy [2]. When compared to controls, LTS had 15-fold increased rates of congestive heart failure, 10-fold higher rate of cardiovascular disease, and 9-fold higher rates of stroke [2].

Mechanisms of damage

While the mechanisms of anthracycline-related cardiac toxicity are not yet fully understood, evidence implicates free radicals generated during treatment both enzymatically and through the formation of anthracycline-iron complexes (see Fig. 1) [14]. Cardiac cells are more susceptible than other tissues to free radical damage due to their high metabolic activity, relatively weak defenses against oxidative damage, and high concentration of cardiolipin, a mitochondrial membrane-bound phospholipid critical to cell respiration for which anthracyclines have a high affinity [15]. The cardiac mitochondrial respiratory chain is implicated by studies which show mtDNA alterations and respiratory chain defects lead to increased concentrations of reactive oxygen species persisting outside the presence of anthracyclines, which may help to explain the potentially prolonged latency of anthracycline-induced cardiotoxicity [16]. Anthracyclines can also induce cardiac mitochondriopathies leading to the accumulation of mitochondrial DNA mutations and respiratory chain defects related to chronic cardiomyopathy [17]. It is probable that damage to the myocardium and eventual chronic cardiotoxicity are the result of not only the actions of those mechanisms discussed but also their interaction with multiple other anthracycline-induced cellular changes including the inhibition a wide variety of cell functions including nucleic acid and protein synthesis, expression of certain genes, membrane binding, calcium homeostatis, and enzymatic activity and the induction of apoptosis and nitric oxide production [18].
https://static-content.springer.com/image/art%3A10.1007%2Fs12012-007-0006-4/MediaObjects/12012_2007_6_Fig1_HTML.gif
Fig. 1

Mechanisms of anthracycline antitumor and cardiotoxic effects

The pathology of chronic anthracycline cardiotoxicity includes loss of myofibrils within myocytes, vascular and mitochondrial degradation, and interstitial fibrosis [19]. Late-onset cardiac failure may also be the result of the inability of this reduced number of healthy myocytes to fulfill the demands of normal growth and development.

Progression

Anthracycline-induced cardiotoxicity is categorized by time of onset as (i) acute, occurring during therapy, (ii) early, within 1 year of therapy, or (iii) late, occurring one or more years after therapy (see Table 1) [20]. Though defined temporally, the characteristics of cardiotoxicity also vary by type. Incidence of acute clinically significant cardiac toxicity in anthracycline-treated children is low, usually <1% on cumulative-anthracycline-dose-limited front line protocols [21]. Symptoms often manifest as disturbances in intracardiac conduction and arrhythmias [2123]. Symptoms appear to resolve with discontinuation of therapy, though patients may suffer permanent damage.
Table 1

Anthracycline-induced cardiotoxicity, characteristics and course

Characteristics

Acute cardiotoxicity

Early-onset, chronic progressive cardiotoxicity

Late-onset, chronic progressive cardiotoxicity

Onset

Within the first week of anthracycline treatment

<1 year after the completion of anthracycline treatment

≥1 year after the completion of anthracycline treatment

Risk factor dependence

Unknown

Yesa

Yesa

Clinical features in adults

Transient depression of myocardial contractility

Dilated cardiomyopathy

Dilated cardiomyopathy

Clinical features in children

Transient depression of myocardial contractility

Restrictive cardiomyopathy and/or dilated cardiomyopathy

Restrictive cardiomyopathy and/or dilated cardiomyopathy

Course

Usually reversible on discontinuation of anthracycline

Can be progressive

Can be progressive

Data from Giantris et al [21] and Grenier and Lipshultz [58].

From Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005; 44(7):600–606. Reprinted with permission from John Wiley & Sons, Inc

Both early- and late-onset cardiotoxicity are characterized by progressive LV dysfunction that may lead to CHF. The early incidence of CHF ranges from 1% to 16% and continues to increase with length of follow-up [12, 13, 24, 25]. Further, in a study of 115 LTS of childhood ALL (mean = 6.4 years post treatment), 57% of patients had impaired left ventricular afterload, as measured by end-systolic wall stress, or contractility, as measured by stress-velocity index [13].

Risk factors, including cumulative anthracycline dose received, dose rate, female sex, younger age at treatment, and longer length of follow-up significantly increase the incidence of anthracycline-induced cardiotoxicity (see Fig. 2) [12, 13, 26, 27]. Variation in susceptibility of patients with similar risk factors and treatment regimens suggests a genetic component to an individual’s response to anthracyclines [28].
https://static-content.springer.com/image/art%3A10.1007%2Fs12012-007-0006-4/MediaObjects/12012_2007_6_Fig2_HTML.gif
Fig. 2

Risk factors related to decreased LV function in long-term survivors who received anthracyclines. From: Wouters KA, Kremer LCM, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. British Journal of Haematology, 2005. 131, 561–578. Reprinted with permission from Blackwell Publishing

Pathways

Two pathways of late anthracycline cardiotoxicity in long-term survivors of childhood cancer have been identified [12, 13, 26, 27]. The first pathway is one that may be common in older patients as well. This pathway is characterized by depressed left ventricular function as measured by fractional shortening related to depressed left ventricular contractility (unhealthy cardiac muscle) and is related to both cumulative anthracycline dose and female gender.

The second pathway may be more specific to childhood survivors and is characterized by increased left ventricular afterload. In this second pathway, depressed left ventricular fractional shortening relates to increased left ventricular afterload (wall stress). The increased left ventricular wall stress is related to reduced left ventricular wall thickness relative to body-surface area. This inadequate left ventricular wall thickness and left ventricular mass for body-surface area appears to be related to younger age at anthracycline treatment and longer length of follow-up.

This cascade places anthracycline-treated long-term survivors at an increased risk of late cardiac dysfunction from anthracycline cardiotoxicity. These individuals are at risk for developing late congestive heart failure and having excess cardiac mortality from pump failure and sudden death. The Cardiovascular Status in Childhood Cancer Survivors Study found elevated cholesterol, LDL-cholesterol, apolipoprotein, C-reactive protein, and homocysteine levels in survivors of childhood cancer as compared to sibling controls indicating an elevated global risk for premature cardiac disease and accelerated atherosclerosis [29]. This suggests that the global cardiac risk of premature symptomatic disease is increased in this high-risk population from a variety of mechanisms [29].

In many survivors of childhood cancer, dilated cardiomyopathy often seen during the first year post therapy will progress over several years to a restrictive cardiomyopathy with diastolic dysfunction and elevated LV filling pressure [12,13]. Thus, heart failure may occur in individuals with only mild systolic dysfunction. This is similar to heart failure with preserved ejection fraction or diastolic heart failure, a condition increasingly recognized in the general population. In non-oncology patients, survival rates similar to heart failure with reduced ejection fraction, have remained the same during an era which has seen improvement in treatment of heart failure with reduced ejection fraction. The continual increase in incidence of diastolic heart failure from 1987 through 2001 indicates a need for increased study of this condition to improve and expand therapeutic options [30, 31].

Prevention and treatment

Due to the severity of this issue and its impact on both treatment and survivorship, several prevention and treatment strategies have been explored in this population. Recent reviews detail the full scope of these options, including those highlighted below [32, 33].

Continuous infusion, which limits peak anthracycline levels at the expense of prolonged exposure as compared to bolus administration, was proposed as a method of reducing anthracycline-related cardiac effects in children. However, in a randomized study of high-risk ALL patients (n = 121, dose = 360 mg/m2), 48-h continuous infusion of doxorubicin did not offer a cardioprotective advantage as compared to bolus infusions of doxorubicin over less than one hour [34].

Liposomal preparations of anthracyclines, the most commonly used of which is pegylated liposomal doxorubicin, not only have high anti-neoplastic activity, but also they appear to be less cardiotoxic, related in part to a reduced tendency to accumulate in myocardial cells [35, 36]. Novel anthracycline analogues, including epirubicin, idarubicin, and mitoxantrone have also been explored as options to reduce cardiotoxicity during treatment, though all have been shown to induce cardiac damage [3743].

In spontaneously hypertensive rats (SHR) challenged with the anthracycline doxorubicin, administration of dexrazoxane, a bis-dioxopiperazine free radical scavenger, lead to a decrease in both the incidence of elevated cardiac troponin T (cTnT), a marker of myocardial injury, and the severity of cardiac lesions on histological exam [44]. In humans, pediatric high risk ALL patients were randomized to receive 300 mg/m2/dose dexrazoxane 30 min before each doxorubicin dose (cumulative doxorubicin dosage <300 mg/m2, dox n = 76, dox/dex n = 82) had significantly lower incidence of elevated cTnT levels than patients who received doxorubicin alone (see Fig. 3). Further, dexrazoxane administration did not inhibit doxorubicin’s anti-tumor action [45, 46].
https://static-content.springer.com/image/art%3A10.1007%2Fs12012-007-0006-4/MediaObjects/12012_2007_6_Fig3_HTML.gif
Fig. 3

The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. From: Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145–153. Copyright © 2004 Massachusetts Medical Society. All rights reserved

Angiotensin converting enzyme (ACE) inhibitors, such as captopril and enalapril, significantly reduce the incidence of congestive heart failure and decrease mortality in the non-cancer setting and have been proposed as a treatment option in long-term cancer survivors [47, 48]. A retrospective study of 18 childhood cancer survivors found that enalapril treatment resulted in initial improvements in patients with asymptomatic left ventricular dysfunction. However, over 6–10 years of therapy, patients returned to pre-enalapril levels of myocardial function and structure [49, 50]. Similarly, treating this population with enalapril when they had developed congestive heart failure resulted in early improvement but by 3–5 years all patients needed cardiac transplantation or died of cardiac death [49, 50]. However, a recent study in an adult population receiving high-dose chemotherapy at high risk for developing cardiotoxicity, as identified by elevated troponin I levels, found that early treatment with enalapril was associated with preserved LV ejection fraction and volume [51]. Whether these results will perpetuate long-term is not yet known.

Growth hormone replacement therapy has also been suggested as a potential means of improvement of cardiac function in this population. Prolonged GH administration in survivors of childhood ALL (n = 34, control = 86, mean GH therapy = 3 years) resulted in improvement toward more normal LV wall thickness and blood pressure [52]. However, left ventricular function continued to deteriorate progressively over time.

Monitoring

In light of the potentially progressive and/or delayed clinical onset of anthracycline-induced cardiotoxicity, the cardiac status of long-term survivors of childhood cancer, particularly those who received anthracycline chemotherapy or radiation to the heart or chest, should be monitored throughout their lives (see Table 2) [20]. All survivors, regardless of treatment regimen, should be monitored during cardiotaxing events including but not limited to pregnancy and birth, initiating novel exercise regimes, viral infection or invasive surgery [20].
Table 2

Screening recommendations

Screening modality

Late effects

Indication

Echocardiogram

Cardiomyopathy

Anthracycline therapy and radiation therapyb

LV shortening fraction, contractility wall stress, and wall thickness

Systolic dysfunction

 

Systolic indices, LV chamber size, LV mass, and peak E/A ratioa

Diastolic dysfunction

 

Doppler echocardiography

Valvar disease

 

Wall thickness and visualization of pericardium

Pericarditis

 

Radionuclide ventriculography (RNA)

Cardiomyopathy

Anthracycline therapy and radiation therapyb

LV ejection fraction

Systolic dysfunction

 

Peak flow rate of filling

Diastolic dysfunction

 

Exercise stress test

 

Anthracycline therapy and radiation therapyb

With or without imaging (echocardiogram or RNA)

Coronary artery disease

 

With imaging

Cardiomyopathy (systolic dysfunction only)

 

Electrocardiogram and 24 h ECH

Arrhythmia and conduction disturbances

Anthracycline therapy and radiation therapyb

Lipid profile

Dyslipidemia

All Survivors, but especially those with known cardiac dysfunction and with radiation to the heart, head, or neck

aE/A ratio, peak early to peak late filling of the left ventricle during diastole

bRadiation therapy that potential included the heart in the treatment field

From Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005; 44(7):600–606. Reprinted with permission from John Wiley & Sons, Inc

Several modalities provide information on the cardiovascular status and function of long-term survivors of childhood cancer. The American Heart Association recommends that both children and adults receiving potentially cardiotoxic chemotherapy undergo echocardiography at baseline and re-evaluation recurrently to monitor for changes in cardiac function [53]. Serial monitoring of serum cardiac troponin T (cTnT), a protein found in the sarcomere of the cardiac myocyte, has been shown to accurately reflect the level of myocardial injury in children receiving anthracycline chemotherapy [45]. While levels of brain natriuretic peptide (proBNP), a marker of cardiac dilation, may be confounded by other factors that influence the volume or pressure load of the left ventricle, they do provide clinically important information on the global cardiac status of an individual [54]. Recent study has shown proBNP to predict cardiovascular morbidity and mortality independent of other prognostic markers in individuals with Coronary Heart Disease [55].

Conclusion

For long-term survivors, already years removed from therapy and potentially suffering its late effects, pilot studies indicate that comprehensive physical activity interventions may be beneficial [56]. Further, following these long-term survivors in a comprehensive clinical program focused on late effects has also been effective. Despite the time commitment involved on the part of the patient, recruitment at the Long-Term Survivor Clinic was high, suggesting a willingness to enroll in a clinic-, rather than phone or interview, based follow-up model, a model that would allow for increased research contact and study of this population [57]. As the population of long-term survivors of childhood malignancy continues to increase in number and years, the identification of effective means of their monitoring and support is increasingly time-sensitive.

Acknowledgments

This paper has been supported in part by grants from the National Cancer Institute (CA68484-SL, CA34183-SL, CA79060-SL, CA06516-SL), National Heart, Lung, and Blood Institute (HL69800-SL, HL53392-SL, HL59837-SL, HL53392-SL), the Lance Armstrong Foundation (SL), and the Children’s Cardiomyopathy Foundation (SL).

Copyright information

© Humana Press Inc. 2007