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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 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

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 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 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 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 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 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 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 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

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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

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