search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shankar, S. M. Articles by Rosenthal, D. Search for Related Content PubMed PubMed Citation Articles by Shankar, S. M. Articles by Rosenthal, D. Related Collections Tumors

Monitoring for Cardiovascular Disease in Survivors of Childhood Cancer: Report From the Cardiovascular Disease Task Force of the Children's Oncology Group

^a Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee
^b Division of Pediatric Hematology/Oncology, Department of Pediatrics
^k Division of Pediatric Cardiology, Stanford University, Palo Alto, California
^c Pediatric Hematology/Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
^d Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
^e Division of Epidemiology, Community and Preventive Medicine, University of Rochester, Rochester, New York
^f Division of Population Sciences, City of Hope Cancer Center, Duarte, California
^g Children's Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles, Los Angeles, California
^h Division of Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, Massachusetts
ⁱ STAR Survivorship Program, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois
^j Division of Pediatric Cardiology, University of Minnesota, Minneapolis, Minnesota

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Curative therapy for childhood cancer has improved significantly in the last 2 decades such that, at present, 80% of all children with cancer are likely to survive 5 years after diagnosis. Prevention, early diagnosis, and treatment of long-term sequelae of therapy have become increasingly more significant as survival rates continue to improve. Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer. The Children's Oncology Group Late Effects Committee and Nursing Discipline and Patient Advocacy Committee have recently developed guidelines for follow-up of long-term survivors of pediatric cancer. A multidisciplinary task force critically reviewed the existing literature to evaluate the evidence for the cardiovascular screening recommended by the Children's Oncology Group guidelines. In this review we outline the clinical manifestations of late cardiovascular toxicities, suggest modalities and frequency of monitoring, and address some of the controversial and unresolved issues regarding cardiovascular disease in childhood cancer survivors.

Key Words: cardiomyopathy • anthracyclines • radiation therapy • cancer • survivor

Abbreviations: COG—Children's Oncology Group • CHF—congestive heart failure • FS—fractional shortening • EF—ejection fraction • LVSD—left-ventricular systolic dysfunction • HL—Hodgkin's lymphoma

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Five-year survival rates approaching 80% for the majority of pediatric malignancies^1,2 have resulted in an increasing focus on the late effects of therapy and quality of life in the growing population of childhood cancer survivors. The term "late effect" refers to a late-occurring or chronic outcome, either physical or psychological, that persists or develops beyond 5 years from the diagnosis of cancer. Approximately 2 of every 3 childhood cancer survivors will experience 1 late effect, and 40% may develop a severe, disabling, or life-threatening condition 30 years after cancer diagnosis.³

Cardiotoxicity is 1 of the most serious chronic complications of cancer therapy. Mortality related to cardiac causes is 10-fold higher among childhood cancer survivors as compared with age-matched control subjects.⁴ Cardiopulmonary diseases are the third leading cause of death in this population, with recurrence of primary cancer and second malignancies being the 2 most common causes.^4,5

Cardiotoxicity may manifest as cardiomyopathy, pericarditis, congestive heart failure, valvular heart disease, or premature coronary artery disease. Anthracycline chemotherapy and mediastinal and neck radiation are the most common causes of therapy-related cardiovascular complications in childhood cancer survivors, although a variety of other chemotherapeutic agents, such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, mechlorethamine, and mitomycin, have also been associated with cardiotoxicity. Cardiac events have also been reported with paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladarabine, asparaginase, tretinoin, and pentostatin.⁶ However, no association of these agents with late cardiotoxicity has been established.

The following sections review the clinical manifestations of cardiovascular toxicity after mediastinal radiation and anthracycline therapy and critically evaluate the evidence for the cardiovascular screening recommended by the Children's Oncology Group (COG) guidelines for survivors of childhood, adolescent, and young adult cancers.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
In 2003, the COG released risk-based, exposure-related guidelines, specifically designed to direct follow-up care for patients who were diagnosed and treated for pediatric malignancies.⁷ The long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers represent a set of comprehensive screening recommendations that are clinically relevant and can be used to standardize and direct the follow-up care for this group of cancer survivors with specialized health care needs.

To ensure that the COG guidelines reflect the most current evidence-based recommendations supported by medical literature, multidisciplinary task forces have been organized within the COG Late Effects Committee to monitor the literature and recommend changes to the guidelines as new information becomes available. The Guideline Taskforce on Cardiovascular Complications performed an extensive review of the literature via Medline (National Library of Medicine, Bethesda, MD), encompassing the years 1985–2005. Key words included "childhood cancer therapy," "cardiomyopathy," "coronary artery disease," "valvular heart disease," "carotid stenosis," "stroke," "anthracycline," and "radiation therapy." References from the bibliographies of selected articles were used to broaden the search.

The multidisciplinary task force used a modified version of the National Comprehensive Cancer Network Categories of Consensus system to score the guidelines.⁸ Each score reflects the expert panel's assessment of the strength of evidence from the literature linking cardiovascular disease to specific therapeutic exposures during childhood cancer, coupled with an assessment of the appropriateness of the screening recommendation based on the expert panel's collective clinical experience. "High-level evidence" was defined as evidence derived from high-quality case-control or cohort studies with adequate sample size and sufficient power to prove the hypothesis. "Lower-level evidence" was defined as evidence derived from nonanalytic studies, case reports, case series, and clinical experience. A total of 500 studies published from 1985 to 2005 were evaluated. The recommendations were scored based on the level of evidence as described in Table 1.

	ANTHRACYCLINE-INDUCED CARDIOMYOPATHY

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

Three distinct forms of anthracycline-induced cardiotoxicity have been described: acute or subacute, chronic, and late onset.¹⁵ Acute or subacute toxicity occurs immediately after administration of anthracyclines and may manifest as transient arrhythmia, pericarditis-myocarditis syndrome, or left-ventricular failure. Such toxicity is rarely observed with current therapies and is generally reversible. Chronic anthracycline cardiomyopathy often manifests within a year of treatment with anthracyclines. Late-onset cardiotoxicity manifesting as ventricular dysfunction and arrhythmias in a previously asymptomatic individual develops years to decades after completion of therapy with anthracyclines.¹⁶ Both chronic and late-onset cardiotoxicity are dose dependent. In 1 study of adults, the incidence of CHF and cardiomyopathy rose from 4% at a cumulative dose of 500 to 550 mg/m² of doxorubicin to 18% at 551 to 600 mg/m² and 36% for cumulative doses of >600 mg/m².⁹ Lower cumulative doses of anthracyclines have been observed to place children at increased risk for chronic cardiac compromise,¹⁷ with an 11-fold increased risk of CHF with a cumulative dose 300 mg/m² as compared with a dose of <300 mg/m².

Younger age (<5 years) at exposure, female gender, black race, combination therapy with other agents (cyclophosphamide or amsacrine),^5,18 mediastinal radiation, previous cardiac disease (coronary, valvular, or myocardial), hypertension, hyperthermia, and liver disease are associated with increased risk of anthracycline-related cardiomyopathy.^19–22 Although early reports in adults have suggested a reduction in the prevalence of cardiotoxicity with continuous infusion of anthracyclines when compared with bolus administration,²³ recent reports in pediatric patients demonstrate that the method of administration affords no cardioprotection.^24,25 Cardiomyopathy can occur many years after completion of therapy (15–20 years), and onset may be spontaneous or coincide with severe exertion, pregnancy, general anesthesia induction, or growth hormone therapy.²⁶

Late subclinical cardiomyopathy or left-ventricular dysfunction, defined as the presence of echocardiographic features of cardiac dysfunction in the absence of clinical symptoms, is frequently noted in individuals who have been treated with anthracyclines. Abnormal systolic function on echocardiography or radionuclide angiocardiography and increased afterload on echocardiography are used as measures of subclinical cardiotoxicity. Although most studies have used echocardiography to make a diagnosis of left-ventricular dysfunction, assessment methods and thresholds for determining abnormality have been variable.^{16,22,27–29} Left-ventricular fractional shortening (FS) and left-ventricular ejection fraction (EF) are the most commonly used parameters.

Higher cumulative doses of anthracyclines are associated with a higher incidence of subclinical dysfunction. One study observed subclinical dysfunction in 11%, 23%, 47%, and 100% of patients treated with cumulative anthracycline doses of <400, 400 to 599, 600 to 799, and >800 mg/m², respectively.¹⁶ In another study of survivors of acute lymphocytic leukemia treated with doses of anthracyclines between 90 and 270 mg/m², 23% of the cohort developed subclinical cardiac dysfunction.³⁰ Longer follow-up of this cohort has shown that patients who received <240 mg/m² exhibited improved cardiac performance, and those with higher doses had progressive deterioration in function as assessed by echocardiography.³¹ Lipshultz et al²⁷ reported progressive elevation of afterload or depression of left-ventricular contractility in 75% of childhood cancer survivors who had received a median doxorubicin dose of 334 mg/m². A review of anthracycline-related subclinical cardiotoxicity noted a frequency varying from 0% to 57% in 25 studies with doses of anthracyclines varying from 45 to 1275 mg/m².³²

The long-term consequences of subclinical cardiac dysfunction after cancer therapy are not known. In community-based observational studies, asymptomatic left-ventricular systolic dysfunction (LVSD) in adults has been associated with increased cardiovascular mortality,³³ all cause mortality,^33,34 and nonfatal cardiovascular events, such as myocardial infarctions and stroke.^33–35 Little is known about the rate of progression of asymptomatic LVSD to overt CHF. One study in adults reported an annual incidence of CHF at 3% in elderly individuals with LVSD without coronary artery disease.³⁶ Angiotensin-converting enzyme inhibitors have been shown to reduce the incidence of CHF in adult patients with LVSD.^37,38 In the absence of longitudinal studies of cardiovascular and other outcomes in childhood cancer survivors with subclinical cardiac dysfunction, it is difficult to make treatment recommendations at this time.³⁹ The role of angiotensin-converting enzyme inhibitors in the management of subclinical cardiomyopathy among cancer survivors, therefore, remains controversial.^25,39–41 However, appropriate cardiac follow-up with serial echocardiography is recommended.⁴²

In view of the limited and suboptimal therapy for anthracycline-induced cardiomyopathy, prevention represents an important focus of active research. Contemporary treatment regimens for children with favorable risk malignancies that routinely restrict cumulative anthracycline dosage and reduce radiation treatment doses and volumes are likely to decrease the incidence of cardiomyopathy. However, anthracyclines remain critical agents for many pediatric malignancies because of their positive therapeutic profile. In particular, cumulative doses remain substantial (300 mg/m²) for pediatric patients with sarcomas and high-risk hematologic malignancies. Clinical trials of dexrazoxane have been conducted in children, with encouraging evidence of short-term cardioprotection and no adverse effects on antitumor activity.^43,44 The long-term avoidance of cardiotoxicity with the use of this agent still needs to be determined. There is some concern regarding the association of secondary leukemia with dexrazoxane.⁴⁵ Additional studies are needed to confirm this association.

	CARDIOVASCULAR EFFECTS OF RADIOTHERAPY

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Approximately 5% of patients have been shown to have symptomatic heart disease 10 years after mediastinal radiotherapy for Hodgkin's lymphoma (HL).⁴⁶ Mantle-field radiation typically delivers radiation to the coronary arteries, most valves, and a significant volume of the myocardium, conducting system, and pericardium. Constrictive pericarditis, cardiomyopathy, valvular heart disease, coronary artery disease, and conduction defects have been known to occur after mediastinal and chest radiation.^47–50 The morphologic changes in radiation-induced coronary artery disease are similar to those observed in spontaneous atherosclerosis.⁵¹ Coronary ostia and the left anterior descending artery are frequently involved. The exact mechanism by which radiation produces atherosclerosis is not well understood, but it is likely that endothelial injury secondary to radiation initiates the process. Generation of reactive oxygen species secondary to ionizing radiation and inflammation in response to endothelial injury leading to decreased availability of nitric oxide may also contribute to the development of atherosclerosis.⁵² Although radiation may initiate or promote atherosclerosis, radiation-associated atherosclerotic heart disease rarely happens in the absence of other cardiovascular risk factors, such as dyslipidemia, hypertension, smoking, and obesity.

	RADIATION-ASSOCIATED CORONARY ARTERY AND CEREBROVASCULAR DISEASE

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Although most studies have evaluated adult patients who have a higher baseline risk and more conventional risk factors,^53–56 the highest relative risk estimates for future fatal myocardial infarction is in those treated as children. In a recently published study, symptomatic coronary artery disease developed in 10% of patients at a median of 9 years after mediastinal radiation, whereas 7.4% of patients developed carotid and subclavian artery stenosis at a median of 17 years after irradiation.⁵⁷

Cardiotoxicity seems to be increased by higher doses of radiation or treatment techniques that increase the cardiac dose.^47,57,58 In addition, coronary artery disease after exposure to radiation occurs predominantly in patients with known cardiac risk factors,^53,57 although myocardial infarction after receiving mediastinal radiotherapy has been described in young children treated with radiation doses higher than those used in contemporary treatment protocols.⁵⁹ Conventional cardiac risk factors confer a greater risk of clinically significant heart disease among survivors who received mediastinal radiotherapy than among the general population.⁵⁵

High-dose radiotherapy to the neck has been associated with premature atherosclerosis and stroke in survivors treated for head and neck cancer. In adult patients with head and neck cancer treated with radiotherapy a 10-fold increased risk of carotid artery occlusive disease and stroke has been reported.⁶⁰ In a study of long-term survivors of HL, survivors were found to have a fivefold increased risk of stroke compared with sibling control subjects.⁶¹ A significantly increased risk of stroke has also been reported among survivors of childhood leukemia and brain tumors, particularly those who received cranial radiation dose of 30 Gy.⁶²

	RADIATION-ASSOCIATED CARDIOMYOPATHY AND VALVULAR HEART DISEASE

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Valvular disease is common and increases with increasing time after mediastinal radiation. With an average follow-up of 15 years postradiation, 1 study found that 29% of irradiated patients exhibited a significant degree of subclinical valvular disease for which endocarditis prophylaxis should be considered; the proportion of survivors with valvular dysfunction increased with longer latency from radiation.⁶³ Patients who received radiation >20 years before evaluation had significantly more aortic regurgitation, tricuspid regurgitation, and aortic stenosis than those who received irradiation within 10 years.⁶³ In another study clinically significant valvular disease was noted in 6.2% of patients at a median of 22 years after radiation, and aortic stenosis was the most common lesion.⁵⁷ The risk factors for valvular dysfunction are not well established, although longer follow-up and higher dose seem to increase the risk.

Myocardial dysfunction after radiation is secondary to myocardial fibrosis leading to restrictive cardiomyopathy. Diastolic dysfunction is a predominant abnormality in survivors treated with radiation alone. In contrast, systolic dysfunction is common in survivors treated with anthracyclines. Although clinically evident heart failure is rare in survivors treated with radiotherapy alone, subclinical changes are common and may be progressive.^64,65 In a recent study of survivors of adolescent or young adulthood HL, at a median 14.2 years after diagnosis, treated with an average dose of 40 Gy, 37.2% had an abnormal measure of left-ventricular mass and/or end diastolic dimension suggestive of restrictive cardiomyopathy.⁶⁵ These survivors also had a high frequency of abnormally low maximum oxygen consumption on an exercise stress test.

Cardiac dysfunction with a decreased maximal cardiac index on an exercise test, higher estimated posterior wall stress on echocardiography, and abnormal Q waves on electrocardiography have also been reported after spinal irradiation during childhood.⁶⁶ Less commonly, these changes have also been reported in children after left flank radiation.⁶⁶

	RADIATION-ASSOCIATED PERICARDITIS

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
The pericardium is the most commonly affected structure of the heart after radiotherapy. With older techniques, 20% to 40% of patients receiving radiation to the chest at higher doses developed pericarditis.^67,68 Pericardial injury may present as pericardial effusion (may resolve spontaneously), acute fibrinous pericarditis, or chronic constrictive pericarditis, which may develop several years after completion of radiotherapy. Diagnosis is made by characteristic ST-T changes and decreased QRS voltage on electrocardiogram and the presence of effusion or pericardial thickening on echocardiography. Rarely, constrictive pericarditis requiring pericardiectomy has been reported in the absence of demonstrable pericardial thickening on echocardiography.⁶⁹ Restricting total dose, subcarinal blocking, weighting anterior and posterior fields equally, and decreasing daily fraction size have resulted in a significant decrease in incidence of pericarditis.⁶⁷

	MONITORING FOR CARDIOVASCULAR DISEASE AFTER COMPLETION OF THERAPY

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Collectively, the frequency and severity of adverse cardiovascular outcomes reported in childhood cancer survivors suggest that specific diagnostic and treatment groups may benefit from screening and early intervention. The recommendations derived from the long-term follow-up screening guidelines developed by the COG for patients at risk for cardiovascular disease after completion of therapy for cancer are summarized in Table 2. ⁷ Although numerous studies of childhood cancer survivors have established the potential for cardiovascular toxicity after therapy, the size of the survivor population, as well as the prevalence and latency of cardiovascular toxicity, precludes undertaking clinical studies to evaluate the impact of screening guidelines on mortality and morbidity related to such late effects of therapy. It is, therefore, not currently possible to validate the recommendations for screening included in these guidelines. Instead, the guidelines provide conservative recommendations for periodic screening based on age, treatment, and cumulative doses of radiation and anthracyclines. Knowledge gained from continued monitoring of survivors is anticipated to refine future recommendations.

Exposure to cardiotoxic chemotherapeutic agents is an indication for baseline and subsequent reevaluation of cardiac function according to the guideline update for clinical applications of echocardiography by the American Society of Echocardiography.⁷⁰ Transthoracic echocardiography and radionuclide angiocardiography have been used to detect subclinical deterioration of cardiac function.³² Echocardiography is noninvasive and has the added advantage of evaluating structural changes in the valves and pericardium that may develop secondary to radiotherapy. Diastolic function can be assessed by echocardiography or radionuclide imaging, although the actual measurements differ. In individuals with large body habitus, echocardiogram can be technically difficult and may not provide satisfactory results. The left-ventricular ejection fraction (EF) measured by radionuclide angiocardiography has excellent reproducibility and has been well studied in adults. It is clearly very useful in individuals in whom good echocardiograms cannot be obtained. It is less operator dependent than echocardiography.

Several parameters, such as FS, EF, velocity of fiber shortening corrected for heart rate, stress velocity index, and end-systolic wall stress, have been used to assess left-ventricular function on echocardiography. Of these, FS and EF are the most frequently used parameters. The lower limit of normal for FS is usually 28%.³² Diastolic function should be indirectly measured by measuring the ratio of peak early filling to peak late filling of the left ventricle during diastole on Doppler echocardiography. The lower limit of normal EF varies between 50% and 55% in various studies. The FS obtained by echocardiogram and EF obtained by radionuclide angiocardiography are not directly convertible.

Tissue Doppler imaging is a noninvasive echocardiographic technique that can assess myocardial contractility. It has been studied predominantly in adults with ischemic heart disease. Studies of tissue Doppler imaging among cancer survivors are limited.⁷¹

Few studies have evaluated MRI for assessment of cardiac dysfunction after anthracyclines.^72,73 Although this may be a sensitive modality, more studies are needed to establish its use as a screening method for late cardiotoxicity among cancer survivors.

Prolongation of QTc has been reported in long-term survivors after anthracycline therapy.⁷⁴ However, changes in the ST-T segment and QRS complex on electrocardiography are frequently late in the course of cardiac toxicity. Thus, electrocardiography is not a useful test for the detection of early toxicity. A baseline 12-lead electrocardiogram is recommended at the end of therapy. Patients with prolonged QTc should be counseled about the use of medications such as tricyclic antidepressants, macrolide antibiotics, antifungal agents, and metronidazole, which can cause further prolongation of QTc. A detailed evaluation by a cardiologist should be considered for patients with prolonged QTc and subclinical left-ventricular dysfunction.

Exercise stress testing can reveal abnormalities that are not seen on resting studies. Both anthracycline-induced cardiomyopathy and radiation-induced cardiovascular disease are associated with exercise-associated decompensation. Signs of ischemia and significant coronary artery disease were found to be highly prevalent on stress imaging of adult survivors of HL treated with mediastinal radiation of 35 Gy.⁷⁵ Stress echocardiography and radionuclide perfusion imaging can identify asymptomatic individuals at high risk for acute myocardial infarction or sudden death.⁷⁵ Exercise stress test with or without imaging (echocardiography or radionuclide angiocardiography) is, thus, a useful screening tool. In patients treated with mediastinal radiotherapy with symptoms suggestive of cardiopulmonary dysfunction that can not be traced to poor systolic function or other causes, measurement of maximum oxygen consumption on exercise testing and pulmonary function tests should be strongly considered.

Serum Markers of Cardiac Injury
Serum cardiac troponin I levels have been reported to have high specificity and sensitivity for acute myocardial infarction and coronary ischemic events in adults. The usefulness of serum markers of myocardial injury in patients receiving high-dose chemotherapy remains under investigation. Both adult and pediatric studies have shown an association of elevated levels after receiving chemotherapy with increased incidence of subclinical cardiac dysfunction.^76,77 However, some other studies have failed to show any correlation of early elevation of cardiac troponin T and serum cardiac troponin I with cardiac dysfunction at a later stage.^78,79 Elevated levels of serum brain natriuretic peptide have been found in asymptomatic individuals who have been treated with anthracyclines⁸⁰ and preceded development of frank CHF in patients who received high-dose cyclophosphamide for conditioning for hematopoietic cell transplantation.⁸¹ The measurement of these serum markers of cardiac injury as predictors of future cardiac dysfunction remains investigational at this time.

Lipid Disorders, Metabolic Syndrome, and Other Risk Factors
Several metabolic abnormalities have been reported in survivors of childhood cancer. A cluster of metabolic disorders, including central obesity, insulin resistance or glucose intolerance, hyperinsulinemia, dyslipidemia, and hypertension, is defined as the metabolic syndrome and is associated with increased cardiovascular mortality. In particular, survivors of acute lymphoblastic leukemia are at increased risk of developing metabolic syndrome. Female gender, exposure to cranial radiation, therapy with steroids, and genetic predisposition increase the risk for metabolic syndrome.⁸² Growth hormone deficiency that follows radiation-induced damage to the hypothalamic pituitary axis secondary to cranial radiation or total body irradiation has also been associated with abnormalities of metabolism, body composition, bone mineralization, impaired cardiac muscle function, central obesity, and an unfavorable lipid profile.^82–85 Rarely, growth hormone deficiency has also been reported after chemotherapy without exposure to cranial radiation.⁸⁶ Thus, metabolic syndrome may develop in such individuals without exposure to cranial radiation and should be considered as a possibility in appropriate clinical setting. Notably, long-term survivors of hematopoietic cell transplantation are at increased risk of developing insulin resistance, type 2 diabetes, and hypertriglyceridemia.⁸⁷ Pancreatic dysfunction after hematopoietic cell transplantation may occur in the setting of normal BMI. Type 2 diabetes mellitus has also been reported after abdominal radiation for Wilms' tumor.⁸⁸

Periodic determination of serum triglycerides, low-density lipoprotein, and high-density lipoprotein cholesterol, and serum glucose is recommended for the evaluation of metabolic syndrome and assessment of risk of cardiovascular disease among childhood cancer treated with modalities predisposing to these complications.

Frequency of Monitoring Cardiac Function
Although several factors, such as young age at treatment, higher cumulative dose of anthracyclines, and combined modality therapy, have been correlated with the risk of cardiovascular dysfunction, there are no studies that can be used to guide the recommendations for frequency of follow-up studies. Thus, COG guideline recommendations reflect a consensus opinion of late-effects experts based on evidence from literature of the potential for cardiovascular disease after specific treatment modalities. The frequency of monitoring cardiac function is influenced by the age at therapy, dose of anthracyclines, and whether combined modality therapy was used. The equivalent doses of commonly used anthracyclines based on substitution rules and hematologic toxicity are shown in Table 3. ⁸⁹ The recommended frequency of cardiovascular screening in childhood cancer survivors as described in the long-term follow-up screening guidelines developed by COG can be viewed at www.survivorshipguidelines.org.⁷ These recommendations are comparable to the recommendations for long-term follow-up made by the late-effects group of the United Kingdom Children's Cancer Study Group⁹⁰ and the Scottish Intercollegiate Guidelines Network.⁹¹

For patients treated with radiation as a single modality, in doses of <30 Gy at 5 years of age, cardiovascular function should be monitored every 5 years. Patients receiving higher doses of anthracyclines and those receiving combined modality therapy are at a higher risk, and, thus, more frequent monitoring of systolic function is recommended. Echocardiography is preferable to radionuclide angiocardiography for patients treated with radiotherapy to evaluate for structural defects of the valves in addition to myocardial dysfunction. Patients with evidence of valvular disease on echocardiography should be counseled regarding the need for prophylaxis for bacterial endocarditis.

Because cardiac dysfunction may first become apparent among female survivors during pregnancy, evaluation by a cardiologist before or during early pregnancy should be considered in women who have been treated during childhood with combined modality therapy, thoracic radiation in doses of >30 Gy, or anthracyclines in doses of >300 mg/m².

Evaluation for carotid and subclavian artery stenosis should be considered in patients treated with radiation fields, including these vessels at doses of 40 Gy. A carotid Doppler study at 10 years after radiotherapy may be helpful in detecting such vascular abnormalities or establishing a baseline for future follow-up.

Health Counseling
Patient education and counseling are critical parts of preventing disease and promoting health in this vulnerable population. Counseling regarding heart healthy lifestyles is particularly important for the prevention of coronary artery disease. The majority of patients developing coronary artery disease after exposure to radiation have other cardiovascular risk factors. Although studies have not been performed that demonstrate a reduction in the rate of adverse events after risk factor modification among patients who received cardiac radiation, extrapolation of results from noncancer populations supports the potential benefits of such interventions. Therefore, we recommend interventions to reduce modifiable risk factors, such as obesity, smoking, hypertension, and dyslipidemia. Patients should be advised to maintain healthy weight and exercise regularly to promote cardiovascular health. Aerobic exercise should be encouraged. Patients beginning an exercise regimen for the first time should be encouraged to promptly report to their physician symptoms of tiredness or difficulty in breathing that do not resolve with rest. Intensive isometric exercise, such as weight lifting, has anecdotally been reported to cause cardiac decompensation. Evaluation and ongoing monitoring by a cardiologist and exercise physiologist may be beneficial to individuals who choose to pursue more aggressive weight training and aerobic activities. Also, dietary counseling and pharmacologic interventions for individuals with hypercholesterolemia who do not respond to lifestyle modification should be considered. The National Cholesterol Education Program recommendations provide guidelines for screening and treatment that should be offered to all adults and should be followed for this patient population.⁹³ Radiation exposure to the heart should be considered an independent risk factor when using these guidelines.

Because the risk of cardiovascular disease increases with longer follow-up, screening is recommended for several decades after completion of therapy. It is particularly important that physicians involved in the care of survivors are cognizant of their patients' increased vulnerability to cardiovascular disease so that symptoms suggestive of cardiac dysfunction (eg, fatigue, deterioration in exercise tolerance, or chest pain) precipitate investigations to evaluate cardiac function. It is hoped that standardization of monitoring outlined in the COG guidelines will facilitate identification of significant changes in cardiac function and determine the usefulness of frequent monitoring. The entire set of guidelines, with associated health links, can be downloaded from www.survivorshipguidelines.org.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 
Following are the key elements for providing cardiovascular care to survivors of childhood cancer: (1) assess individualized risk for cardiovascular disease by obtaining detailed treatment histories regarding cumulative dose and type of anthracyclines used, field and dose of radiation, and age at time of therapy; (2) assess additional cardiovascular risk factors, such as dyslipidemia, hypertension, obesity, smoking, and family history of coronary artery disease; (3) obtain a detailed review of symptoms related to cardiovascular disease, such as effort intolerance, chest pain, palpitations, and dyspnea; (4) monitor cardiac function at baseline and periodically using the modalities outlined by the COG guidelines; the same modality for evaluation of systolic function should be used for follow-up evaluations for comparison with previous results; (5) counsel regarding weight management, regular physical activity, smoking abstinence, and heart-healthy dietary practices; and (6) monitor cardiac function with pregnancy and general anesthesia.

	FOOTNOTES

 
Accepted Jun 15, 2007.

Address correspondence to Sadhna M. Shankar, MD, MPH, Division of Pediatric Hematology/Oncology, 397 PRB, 2220 Pierce Ave, Nashville, TN 37232-6310. E-mail: sadhnamd{at}gmail.com

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS ANTHRACYCLINE-INDUCED... CARDIOVASCULAR EFFECTS OF... RADIATION-ASSOCIATED CORONARY... RADIATION-ASSOCIATED... RADIATION-ASSOCIATED... MONITORING FOR CARDIOVASCULAR... CONCLUSIONS REFERENCES

 

1. Reis LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1973–1998. Bethesda, MD: National Cancer Institute; 2001
2. National Cancer Institute. SEER Cancer Statistics Review, 1973–1999. Bethesda, MD: National Cancer Institute; 2002
3. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15) :1572 –1582
4. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol. 2001;19(13) :3163 –3172
5. Green DM, Hyland A, Chung CS, Zevon MA, Hall BC. Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol. 1999;17(10) :3207 –3215
6. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4) :263 –302
7. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-term Follow-up Guidelines From the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol. 2004;22(24) :4979 –4990
8. Winn RJ, Botnick WZ. The NCCN Guideline Program: a conceptual framework. Oncology (Williston Park). 1997;11(11A) :25 –32
9. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32(2) :302 –314
10. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339(13) :900 –905
11. Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, Dombernowsky P. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol. 1998;16(11) :3502 –3508
12. Nielsen D, Jensen JB, Dombernowsky P, et al. Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer. J Clin Oncol. 1990;8(11) :1806 –1810
13. Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J. 1990;4(13) :3076 –3086
14. Goormaghtigh E, Huart P, Praet M, Brasseur R, Ruysschaert JM. Structure of the adriamycin-cardiolipin complex. Role in mitochondrial toxicity. Biophys Chem. 1990;35(2–3) :247 –257
15. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996;125(1) :47 –58
16. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991;266(12) :1672 –1677
17. Kremer LCM, van Dalen EC, Offringa M, Otenkamp J, Voute PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. 2001;19(1) :191 –196
18. Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol. 1997;15(4) :1544 –1552
19. Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM. Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med. 1977;62(2) :200 –208
20. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5) :710 –717
21. Praga C, Beretta G, Vigo PL, et al. Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat Rep. 1979;63(5) :827 –834
22. Pihkala J, Saarinen UM, Lundstrom U, et al. Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation. Eur J Cancer. 1996;32A(1) :97 –103
23. Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96(2) :133 –139
24. Levitt GA, Dorup I, Sorensen K, Sullivan I. Does anthracycline administration by infusion in children affect late cardiotoxicity? Br J Haematol. 2004;124(4) :463 –468
25. Lipshultz SE, Giantris AL, Lipsitz SR, et al. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 acute lymphoblastic leukemia protocol. J Clin Oncol. 2002;20(6) :1677 –1682
26. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005;44(7) :600 –606
27. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubiocin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324(12) :808 –815
28. Silber JH, Jakacki RI, Larsen RL, Goldwein JW, Barber G. Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol. 1993;21(7) :477 –479
29. Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol. 1998;16(2) :545 –550
30. Sorensen K, Levitt G, Bull C, Chessells J, Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. J Clin Oncol. 1997;15(1) :61 –68
31. Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer. 2003;97(8) :1991 –1998
32. Kremer LC, van der Pal HJ, Offringa M, van Dalen EC, Voute PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. 2002;13(6) :819 –829
33. Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med. 2002;137(8) :631 –639
34. McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart. 2001;86(1) :21 –26
35. Lauer MS, Evans JC, Levy D. Prognostic implications of subclinical left ventricular dilatation and systolic dysfunction in men free of overt cardiovascular disease (the Framingham Heart Study). Am J Cardiol. 1992;70(13) :1180 –1184
36. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol. 2001;37(4) :1042 –1048
37. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5) :293 –302
38. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327(10) :669 –677
39. Lipshultz SE, Colan SD. Cardiovascular trials in long-term survivors of childhood cancer. J Clin Oncol. 2004;22(5) :769 –773
40. Silber JH, Cnaan A, Clark BJ, et al. Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors. Am Heart J. 2001;142(4) :577 –585
41. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol. 2004;22(5) :820 –828
42. Wang TJ, Levy D, Benjamin EJ, Vasan RS. The epidemiology of "asymptomatic" left ventricular systolic dysfunction: implications for screening. Ann Intern Med. 2003;138(11) :907 –916
43. Bu'Lock FA, Gabriel HM, Oakhill A, et al. Cardioprotection by ICRF187 against high dose anthracycline toxicity in children with malignant disease. Br Heart J. 1993;70(2) :185 –188
44. 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(2) :145 –153
45. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007;25(5) :493 –500
46. Lund MB, Ihlen H, Voss BM, et al. Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin's disease: an echocardiographic study. Heart. 1996;75(6) :591 –595
47. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA. 1993;270(16) :1949 –1955
48. Stewart JR, Fajardo LF. Radiation-induced heart disease: an update. Prog Cardiovasc Dis. 1984;27(3) :173 –194
49. Slama MS, Le Guludec D, Sebag C, et al. Complete atrioventricular block following mediastinal irradiation: a report of six cases. Pacing Clin Electrophysiol. 1991;14(7) :1112 –1128
50. Warda M, Khan A, Massumi A, Mathur V, Klima T, Hall RJ. Radiation-induced valvular dysfunction. J Am Coll Cardiol. 1983;2(1) :180 –185
51. Stewart JR, Fajardo LF, Gillette SM, Constine LS. Radiation injury to the heart. Int J Radiat Oncol Biol Phys. 1995;31(5) :1205 –1211
52. Jurado J, Thompson PD. Prevention of coronary artery disease in cancer patients. Pediatr Blood Cancer. 2005;44(7) :620 –624
53. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, van Putten WL, Levendag PC. Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol. 1999;51(1) :35 –42
54. Chronowski GM, Wilder RB, Tucker SL, et al. Analysis of in-field control and late toxicity for adults with early-stage Hodgkin's disease treated with chemotherapy followed by radiotherapy. Int J Radiat Oncol Biol Phys. 2003;55(1) :36 –43
55. Glanzmann C, Kaufmann P, Jenni R, Hess OM, Huguenin P. Cardiac risk after mediastinal irradiation for Hodgkin's disease. Radiother Oncol. 1998;46(1) :51 –62
56. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol. 1993;11(7) :1208 –1215
57. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. 2003;290(21) :2831 –2837
58. Byhardt R, Brace K, Ruckdeschel J, Chang P, Martin R, Wiernik P. Dose and treatment factors in radiation-related pericardial effusion associated with the mantle technique for Hodgkin's disease. Cancer. 1975;35(3) :795 –802
59. Tötterman KJ, Pesonen E, Siltanen P. Radiation-related chronic heart disease. Chest. 1983;83(6) :875 –878
60. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol. 2002;20(1) :282 –288
61. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2005;23(27) :6508 –6515
62. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006;24(33) :5277 –5282
63. Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42(4) :743 –749
64. Constine LS, Schwartz RG, Savage DE, King V, Muhs A. Cardiac function, perfusion, and morbidity in irradiated long-term survivors of Hodgkin's disease. Int J Radiat Oncol Biol Phys. 1997;39(4) :897 –906
65. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol. 2004;22(15) :3139 –3148
66. Jakacki RI, Goldwein JW, Larsen RL, Barber G, Silber JH. Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol. 1993;11(6) :1033 –1038
67. Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin's disease: an analysis of technique, tumor eradication, and complications. Cancer. 1976;37(6) :2813 –2825
68. Pohjola-Sintonen S, Totterman KJ, Salmo M, Siltanen P. Late cardiac effects of mediastinal radiotherapy in patients with Hodgkin's disease. Cancer. 1987;60(1) :31 –37
69. Talreja DR, Edwards WD, Danielson GK, et al. Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation. 2003;108(15) :1852 –1857
70. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 Guideline Update for the Clinical Application of Echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc Echocardiogr. 2003;16(10) :1091 –1110
71. Kapusta L, Thijssen JM, Groot-Loonen J, Antonius T, Mulder J, Daniels O. Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines. Ultrasound Med Biol. 2000;26(7) :1099 –1108
72. Perel RD, Slaughter RE, Strugnell WE. Subendocardial late gadolinium enhancement in two patients with anthracycline cardiotoxicity following treatment for Ewing's sarcoma. J Cardiovasc Magn Reson. 2006;8(6) :789 –791
73. Wassmuth R, Lentzsch S, Erdbruegger U, et al. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study. Am Heart J. 2001;141(6) :1007 –1013
74. Gupta M, Thaler HT, Steinherz L. Presence of prolonged dispersion of qt intervals in late survivors of childhood anthracycline therapy. Pediatr Hematol Oncol. 2002;19(8) :533 –542
75. Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol. 2007;25(1) :43 –49
76. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22) :2749 –2754
77. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96(8) :2641 –2648
78. Kremer LC, Bastiaansen BA, Offringa M, et al. Troponin T in the first 24 hours after the administration of chemotherapy and the detection of myocardial damage in children. Eur J Cancer. 2002;38(5) :686 –689
79. Mathew P, Suarez W, Kip K, et al. Is there a potential role for serum cardiac troponin I as a marker for myocardial dysfunction in pediatric patients receiving anthracycline-based therapy? A pilot study. Cancer Invest. 2001;19(4) :352 –359
80. Pinarli FG, Oguz A, Tunaoglu FS, Karadeniz C, Gokcora N, Elbeg S. Late cardiac evaluation of children with solid tumors after anthracycline chemotherapy. Pediatr Blood Cancer. 2005;44(4) :370 –377
81. Snowden JA, Hill GR, Hunt P, et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000;26(3) :309 –313
82. Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab. 1996;81(8) :3051 –3055
83. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 1993;77(6) :1671 –1676
84. Gibney J, Wallace JD, Spinks T, et al. The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients. J Clin Endocrinol Metab. 1999;84(8) :2596 –2602
85. Link K, Moell C, Garwicz S, et al. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood. J Clin Endocrinol Metab. 2004;89(10) :5003 –5012
86. Rose SR, Schreiber RE, Kearney NS, et al. Hypothalamic dysfunction after chemotherapy. J Pediatr Endocrinol Metab. 2004;17(1) :55 –66
87. Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. 2000;356(9234) :993 –997
88. Teinturier C, Tournade MF, Caillat-Zucman S, et al. Diabetes mellitus after abdominal radiation therapy. Lancet. 1995;346(8975) :633 –634
89. Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol. 2003;21(6) :1074 –1081
90. Skinner R WW, Levitt GA, eds. Therapy based long term follow up: practice statement. UK Children's Cancer Study Group. Available at: www.ukccsg.org.uk/public/followup/PracticeStatement/index.html. Accessed September 15, 2006
91. Scottish Intercollegiate Guidelines Network. Long term follow up of survivors of childhood cancer: a national clinical guideline. Available at: www.sign.ac.uk/pdf/sign76.pdf. Accessed October 26, 2006
92. van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. 2006;42(18) :3191 –3198
93. Stone NJ, Bilek S, Rosenbaum S. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am J Cardiol. 2005;96(4A) :53E –59E

This article has been cited by other articles:

				S. H. Armenian and S. Bhatia Cardiovascular disease after hematopoietic cell transplantation - lessons learned Haematologica, August 1, 2008; 93(8): 1132 - 1136. [Full Text] [PDF]

				K. A. Meeske and M. B. Nelson The Role of the Long-Term Follow-up Clinic in Discovering New Emerging Late Effects in Adult Survivors of Childhood Cancer Journal of Pediatric Oncology Nursing, July 1, 2008; 25(4): 213 - 219. [Abstract] [PDF]

This Article Abstract