Late Effects of the Cardiovascular System
Radiation, chemotherapy, and biologic agents, both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer; in fact, cardiovascular death has been reported to account for 26% of the excess absolute risk of death by 45 or more years from diagnosis in adults who survived childhood cancers, and is the leading cause of noncancer mortality in select cancers such as Hodgkin lymphoma (HL).[1,2] During the 30 years after cancer treatment, survivors are eight times more likely to die from cardiac causes and 15 times more likely to be diagnosed with congestive heart failure (CHF) than the general population.[3,4] Therapeutic exposures conferring the highest risk are the anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone) and thoracic radiation. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.
The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, several reports do allow some segregation of the effects of radiation from those of chemotherapy. Of note, the pathogenesis of injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[5,6] Late effects of radiation to the heart include the following:[7-9]
- Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.
- Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Myopathy (in the absence of significant pericardial disease).
- Coronary artery disease (CAD), usually involving the left anterior descending artery.
- Functional valve injury, often aortic.
- Conduction defects.
These cardiac toxic effects are related to total radiation dose, individual radiation fraction size, and the volume of the heart that is exposed. Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to the higher radiation doses. This may translate into a reduced risk for adverse cardiac events.
- Female gender.
- Cumulative doses greater than 200 mg/m2 to 300 mg/m2.
- Younger age at time of exposure.
- Increased time from exposure.
Among these factors, cumulative dose appears to be the most significant in regard to risk of CHF, which develops in less than 5% of survivors after anthracycline exposure of less than 300 mg/m2, approaches 15% at doses between 300 and 500 mg/m2, and exceeds 30% for doses greater than 600 mg/m2.[5,12,23-25]
Emerging evidence suggests that genetic factors, such as polymorphisms that impact drug metabolism and distribution, may explain the heterogeneity in susceptibility to anthracycline cardiac injury.[22,26] Pharmacogenetic studies of this type, if consistently replicated across diverse study populations, may ultimately facilitate identification of newly diagnosed individuals at high risk of cardiac toxicity for whom anthracyclines should be avoided, and long-term survivors who may benefit from heightened surveillance after treatment with anthracyclines. Further study of genetic risk profiling of anthracycline injury is needed to integrate such pharmacogenetic data into clinical practice.
Schedule of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48 hour) versus bolus (1 hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of acute lymphoblastic leukemia (ALL) and found no difference in the degree or spectrum of cardiac toxic effects in the two groups. Because the follow-up time in this study was relatively short, whether the frequency of progressive cardiomyopathy differs between the two groups over time is not yet clear. Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. The incidence of cardiac dysfunction in the divided-dose and single-dose infusion groups did not differ significantly. Earlier studies in adults have shown decreased cardiac toxic effects with prolonged infusion; thus, further evaluation of this question is warranted.
Prevention or amelioration of doxorubicin-induced cardiomyopathy is important because the continued use of doxorubicin is required in cancer therapy. Dexrazoxane is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with doxorubicin.[29-33] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy. A single-study experience suggested a possible increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; other studies do not show an increased risk of malignancies.[33-36] At this time, however, these findings should not preclude treatment with dexrazoxane.[37,38]
Two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma (HL) [38,39] measured myocardial toxicity clinically and sequentially over time by echocardiography and electrocardiography, and by determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.[32,40-44] Long-term outcomes for these patients are not yet available.
The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced left ventricular dysfunction. Although a transient improvement in left ventricular function and structure was noted in 18 children, left ventricular wall thinning continued to deteriorate; thus, the intervention with enalapril was not considered successful. For this reason, studies to date in doxorubicin-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.[30,31]
A number of studies have examined cardiac function after radiation therapy and doxorubicin exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms.[45-49] In addition to subclinical abnormalities of systolic function observed by conventional echocardiography, diastolic dysfunction (impaired ventricular relaxation) has also been observed, which may precede impairment of systolic function. Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of left ventricular contractility. An increased prevalence of diastolic dysfunction has also been reported in childhood cancer survivors, consistent with the hypothesis of increased vascular and ventricular stiffness associated with precocious cardiovascular aging. It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiac toxic effects can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores.[53,54] Additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.
Prevalence, Clinical Manifestations, and Risk Factors for Cardiac Toxicity
Several investigations have described cardiac outcomes in adults treated for cancer during childhood. The methods used to assess cardiac outcomes in these studies range from self-report of clinically manifested cardiac disease to prospective medical assessment of cardiac function. Collectively, study results support dose-relationships of cardiac toxicity associated with anthracycline usage and radiation therapy impacting cardiac structures. However, these data may not reflect outcomes after contemporary approaches using lower cumulative doses of cardiac toxic treatment modalities and radiation technologies that facilitate protection of normal tissues.
- Childhood Cancer Survivors Study (CCSS) investigators detailed dose-response evaluations for both radiation therapy and anthracycline administration to analyze risks (self-reported) of CHF, myocardial infarction (MI), pericardial disease, and valvular abnormalities (see Figure 2). Cardiac radiation exposure of 15 Gy or more increased the risk of CHF, MI, pericardial disease, and valvular abnormalities by twofold to sixfold compared with nonirradiated survivors. Exposure to 250 mg/m2 or more of anthracyclines also increased the risk of CHF, pericardial disease, and valvular abnormalities by two to five times compared with the risk in survivors who had not been exposed to anthracyclines. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from about 2% to slightly over 4% overall.
- A study of 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom also demonstrated an association between radiation dose and risk of cardiovascular mortality. The risk of dying from cardiac diseases was significantly higher in individuals who had received a cumulative dose of anthracyclines greater than 360 mg/m2 (relative risk [RR], 4.4; 95% confidence interval [CI], 1.3–15.3) and after an average radiation dose exceeding 5 Gy (RR, 12.5 for 5–14.9 Gy and RR, 25.1 for >15 Gy) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (excess RR at 1 Gy, 60%).
- Dutch investigators evaluated subclinical cardiac function of adult 5-year childhood cancer survivors. Among 601 eligible survivors, 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF). Subclinical cardiac dysfunction (LVSF <30%) was associated with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF.
- In a Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors diagnosed between 1966 and 1996 (median attained age, 29.1 years; median follow-up time from diagnosis, 22.2 years), the 30-year cause-specific cumulative incidence of symptomatic cardiac events was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3–10.3), after anthracyclines (7.3%; 95% CI, 3.8–10.7), and after cardiac irradiation (4.0%; 95% CI, 0.5–7.4) compared with other treatments. Study results indicate an exponential relationship between cumulative anthracycline dose, cardiac irradiation dose, and risk of cardiac event.
Cardiovascular Disease in Select Cancer Subgroups
Hodgkin lymphoma (HL) continues to be the pediatric malignancy associated with the greatest risk of cardiovascular disease, with a 13.1 excess absolute risk per 10,000 person years for cardiovascular death. Newer treatment approaches are specifically designed to reduce exposure to cardiac toxic agents (e.g., total anthracycline dose) and radiation dose and volume. Moreover, newer trials explore the safe elimination of radiation from primary therapy.
Data from the German-Austrian DAL-HD studies show a dose response for cardiac diseases in children treated for HL with combined radiation and anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg/m2). The 25-year cumulative incidence of cardiac diseases was 3% with no radiation therapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy. An older study of 635 patients treated for childhood HL confirms the risks that occur after higher-dose radiation therapy. The actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute MI; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. In an analysis of 48 asymptomatic patients treated for HL from 1970 to 1991 with mediastinal therapy (median dose 40 Gy) and screened for the presence of subclinical cardiac abnormalities, 43% had unsuspected valvular abnormalities, 75% had a conduction abnormality or arrhythmia, and 30% had reduced VO2 during exercise tests. These abnormalities were noted at a mean of 15.5 years posttherapy suggesting that survivors of HL treated with high doses of mediastinal radiation therapy require long-term cardiology follow-up. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.
The risk of delayed valvular abnormalities and CAD after lower radiation doses requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD—such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia—are likely to impact the frequency of disease.[7,8,60]
Brain tumor: A study of self-reported late effects among 1,607 survivors of childhood brain tumors  showed that 18% of survivors reported a heart or circulatory late effect. Risk was highest among those treated with surgery, radiation therapy, and chemotherapy, compared with those treated with surgery and radiation therapy alone, suggesting a potential additive vascular injury from chemotherapy. Children who receive spinal radiation for treatment of central nervous system (CNS) tumors have been demonstrated to show low maximal cardiac index on exercise testing and pathologic Q-waves in inferior leads on ECG testing, and higher posterior-wall stress.
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML): In a study of ALL survivors in the CCSS cohort who reported a chronic medical condition , the risk of a cardiac condition was nearly sevenfold higher in ALL survivors than in siblings. No significant association was identified based on radiation exposure. A similar analysis among AML survivors in the cohort found the 20-year cumulative incidence of cardiac disease to be 4.7%. Adult survivors of childhood ALL have an increased prevalence of obesity and insulin resistance and may be at risk of developing diabetes, dyslipidemia, and metabolic syndrome, all of which are potent risk factors for premature cardiovascular disease.
Wilms tumor: A long-term follow-up study of Wilms tumor survivors reported a cumulative risk of CHF of 4.4% at 20 years for those who received doxorubicin as part of their initial therapy and 17.4% at 20 years when doxorubicin was received as part of therapy for relapsed disease. Risk factors for CHF in this cohort included female gender, lung irradiation with doses 20 Gy or higher, left-sided abdominal irradiation, and doxorubicin dosage of 300 mg/m2 or more.
Hematopoietic cell transplantation (HCT): Cardiac complications after bone marrow transplantation may occur, with arrhythmia, pericarditis, and cardiomyopathy predominating, although many are either acute or subacute effects. High-dose cyclophosphamide clearly is a causative agent; total-body irradiation is a secondary contributing factor.[45,60,64] In a report from the Bone Marrow Transplant Survivors Study that compared 145 HCT survivors, 7,207 conventionally treated survivors, and 4,020 siblings from the CCSS cohort, median time from HCT to study participation was 11.0 years (range, 2.3–25.9 years). The prevalence of cardiovascular conditions (grades 3–5) was 4.8% in HCT survivors, versus 3.2% in conventionally treated CCSS survivors, and it was 0.5% (for grades 3–4) in the sibling control CCSS cohort. The RR was 0.5 (95% CI, 0.1–2.5) for the conventionally treated survivors versus HCT survivors, and 12.7 (95% CI, 5.4–30.0) for the HCT survivors versus siblings.
Vascular Disease/Cerebrovascular Accident
A spectrum of vascular morbidities may occur after radiation therapy used to treat malignancies such as lymphomas, head and neck cancers, and brain tumors. Specifically, carotid artery and cerebrovascular injury occur after cervical and CNS irradiation. French investigators observed a significant association with radiation dose to the brain and long-term cerebrovascular mortality among 4,227 five-year childhood cancer survivors (median follow-up, 29 years). Survivors who received more than 50 Gy to the prepontine cistern had a hazard ratio (HR) of 17.8 (95% CI, 4.4–73) of death from cerebrovascular disease, compared with those who had not received radiation therapy or who had received less than 0.1 Gy in the prepontine cistern region. The RR for cerebrovascular accident (CVA [stroke]) in the CCSS cohort was almost tenfold higher than in the sibling control group; notably, risks were highest among the adult survivors of childhood ALL, brain tumors, and HL.[68,69] Leukemia survivors were six times more likely to suffer a CVA than were their siblings, whereas brain tumor survivors were 29 times more likely to suffer a CVA. Of the brain tumor cohort, 69 of 1,411 patients who had a history of radiation therapy reported a CVA (4.9%), with a cumulative incidence of 6.9% (95% CI, 4.47–9.33) at 25 years. Survivors exposed to cranial radiation therapy greater than 30 Gy had an increased risk for CVA, with the highest risk among those treated with greater than 50 Gy. Adult survivors of childhood HL who were treated with thoracic radiation therapy, including mediastinal and neck, had a 5.6-fold increased risk for CVA than their siblings (median dose 40 Gy). In another study from the Netherlands of 2,201 5-year survivors of HL (of whom 547 were younger than 21 years), and with median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 CVA, 31 transient ischemic attacks [TIA], and 10 both CVA and TIA), with a median age at diagnosis of 52 years. Most ischemic events were from large-artery atherosclerosis (36%) or cardiac embolism (24%). The standardized incidence ratio (SIR) for CVA was 2.2, and for TIA it was 3.1. The cumulative incidence of ischemic CVA or TIA 30 years after HL treatment was 7%. For patients younger than 21 years, the SIR for CVA was 3.8, and for TIA it was 7.6. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR, 2.5; 95% CI, 1.1–5.6) versus without radiation therapy. Treatment with chemotherapy was not associated with increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. 
A retrospective cohort study of 325 survivors of pediatric cancer treated with cranial irradiation or cervical irradiation at an age that was younger than 18 years determined that cranial irradiation puts childhood cancer survivors at a high risk of first and recurrent strokes. In this study, stroke was defined by physician diagnosis and symptoms consistent with stroke. The cumulative incidence of first stroke was 2% (95% CI, 0.01–5.3) at 5 years and 4% (95% CI, 2.0–8.4) at 10 years after irradiation. The stroke hazard increased by 5% (HR, 1.05; 95% CI, 1.01–1.09; P = .02) with each 1 Gy increase in the radiation dose. The cumulative incidence of recurrent stroke was 38% (95% CI, 17–69) at 5 years and 59% (95% CI, 27–92) at 10 years after the first stroke.
A follow-up CCSS investigation evaluated whether increased stroke risk conferred by childhood cranial radiation therapy persists into adulthood by comparing stroke risk among 14,358 5-year survivors and 4,023 sibling controls. Survivors treated with cranial radiation therapy exhibited a dose-dependent increased stroke risk, with an HR of 5.9 (95% CI, 3.5–9.9) for 30 to 49 Gy of cranial radiation and 11.0 (7.4–17.0) for 50 or more Gy of cranial radiation. The cumulative stroke incidence in survivors treated with 50 or more Gy of cranial radiation was 1.1% (95% CI, 0.4–1.8) at 10 years after diagnosis (95% CI, 2.8–5.5). Atherosclerotic risk factors increased stroke risk because hypertension advanced the stroke hazard by fourfold (95% CI, 2.8–5.5).
|Predisposing Therapy||Potential Cardiovascular Effects||Health Screening|
|DOE = dyspnea on exertion; SOB = shortness of breath.|
|Anthracyclines (daunorubicin, doxorubicin, idarubicin, epirubicin); mitoxantrone||Cardiomyopathy; arrhythmias; subclinical left ventricular dysfunction||History: SOB, DOE, orthopnea, chest pain, palpitations|
|Echocardiogram or other modality to evaluate left ventricular systolic function|
|Laboratory: lipid profile, consider troponin or brain natriuretic peptide (BNP) level|
|Radiation impacting the heart||Congestive heart failure; cardiomyopathy; pericarditis/pericardial fibrosis; valvular disease; atherosclerotic heart disease/myocardial infarction; arrhythmia||History: SOB, DOE, orthopnea, chest pain, palpitations|
|Cardiovascular exam: signs of heart failure, arrhythmia, valve dysfunction|
|Echocardiogram or other modality to evaluate left ventricular systolic function|
|Laboratory: lipid profile|
|Radiation impacting vascular structures||Carotid or subclavian artery disease||History: transient/permanent neurological events|
|Cardiovascular exam: peripheral pulses, presence of bruits|
|Laboratory: lipid profile|
|Plant alkaloids (vinblastine, vincristine)||Vasospastic attacks (Raynaud’s phenomena); autonomic dysfunction (e.g., monotonous pulse)||History: vasospasms of hands, feet, nose, lips, cheeks, or earlobes related to stress or cold temperatures|
|Exam of affected area|
|Platinum agents (cisplatin, carboplatin)||Dyslipidemia||Fasting lipid profile|
In general, survivors should be counseled regarding the cardiovascular benefits of maintaining healthy weight, adhering to a heart-healthy diet, participating in regular physical activity, and abstaining from smoking. Survivors should obtain medical clearance before engaging in extreme exercise programs.
Clinicians should consider baseline and follow-up screening as needed for comorbid conditions that affect cardiovascular health. In support of this, CCSS investigators observed significantly increased risks of major cardiac events among survivors treated with chest-directed radiation or anthracycline chemotherapy; this risk was enhanced by the presence of modifiable cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, and obesity. The risk of coronary artery disease, heart failure, valvular disease, and arrhythmia increased with increasing numbers of cardiovascular risk factors. Of the risk factors studied, hypertension appeared to have the greatest effect on potentiating cancer treatment–associated risks for adverse cardiovascular outcomes.
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for cardiovascular late effects information including risk factors, evaluation, and health counseling.
- Hudson MM, Poquette CA, Lee J, et al.: Increased mortality after successful treatment for Hodgkin's disease. J Clin Oncol 16 (11): 3592-600, 1998. [PUBMED Abstract]
- Reulen RC, Winter DL, Frobisher C, et al.: Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304 (2): 172-9, 2010. [PUBMED Abstract]
- Mertens AC, Liu Q, Neglia JP, et al.: Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 100 (19): 1368-79, 2008. [PUBMED Abstract]
- Oeffinger KC, Mertens AC, Sklar CA, et al.: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355 (15): 1572-82, 2006. [PUBMED Abstract]
- Adams MJ, Lipshultz SE: Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 44 (7): 600-6, 2005. [PUBMED Abstract]
- Berry GJ, Jorden M: Pathology of radiation and anthracycline cardiotoxicity. Pediatr Blood Cancer 44 (7): 630-7, 2005. [PUBMED Abstract]
- King V, Constine LS, Clark D, et al.: Symptomatic coronary artery disease after mantle irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 36 (4): 881-9, 1996. [PUBMED Abstract]
- Adams MJ, Lipshultz SE, Schwartz C, et al.: Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 13 (3): 346-56, 2003. [PUBMED Abstract]
- Galper SL, Yu JB, Mauch PM, et al.: Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117 (2): 412-8, 2011. [PUBMED Abstract]
- Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001. [PUBMED Abstract]
- Ewer MS, Jaffe N, Ried H, et al.: Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Med Pediatr Oncol 31 (6): 512-5, 1998. [PUBMED Abstract]
- Giantris A, Abdurrahman L, Hinkle A, et al.: Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol 27 (1): 53-68, 1998. [PUBMED Abstract]
- Krischer JP, Epstein S, Cuthbertson DD, et al.: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15 (4): 1544-52, 1997. [PUBMED Abstract]
- Lipshultz SE, Lipsitz SR, Mone SM, et al.: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332 (26): 1738-43, 1995. [PUBMED Abstract]
- 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 20 (6): 1677-82, 2002. [PUBMED Abstract]
- Nysom K, Holm K, Lipsitz SR, et al.: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (2): 545-50, 1998. [PUBMED Abstract]
- Steinherz LJ, Graham T, Hurwitz R, et al.: Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 89 (5 Pt 1): 942-9, 1992. [PUBMED Abstract]
- Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25 (4 Suppl 10): 72-85, 1998. [PUBMED Abstract]
- Pein F, Sakiroglu O, Dahan M, et al.: Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy. Br J Cancer 91 (1): 37-44, 2004. [PUBMED Abstract]
- van der Pal HJ, van Dalen EC, Hauptmann M, et al.: Cardiac function in 5-year survivors of childhood cancer: a long-term follow-up study. Arch Intern Med 170 (14): 1247-55, 2010. [PUBMED Abstract]
- Abosoudah I, Greenberg ML, Ness KK, et al.: Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors. Pediatr Blood Cancer 57 (3): 467-72, 2011. [PUBMED Abstract]
- Blanco JG, Sun CL, Landier W, et al.: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol 30 (13): 1415-21, 2012. [PUBMED Abstract]
- van Dalen EC, van der Pal HJ, Kok WE, et al.: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42 (18): 3191-8, 2006. [PUBMED Abstract]
- Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23 (12): 2629-36, 2005. [PUBMED Abstract]
- van der Pal HJ, van Dalen EC, van Delden E, et al.: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30 (13): 1429-37, 2012. [PUBMED Abstract]
- Visscher H, Ross CJ, Rassekh SR, et al.: Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol 30 (13): 1422-8, 2012. [PUBMED Abstract]
- Davies SM: Getting to the heart of the matter. J Clin Oncol 30 (13): 1399-400, 2012. [PUBMED Abstract]
- Legha SS, Benjamin RS, Mackay B, et al.: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96 (2): 133-9, 1982. [PUBMED Abstract]
- 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 22 (15): 3139-48, 2004. [PUBMED Abstract]
- 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 22 (5): 820-8, 2004. [PUBMED Abstract]
- Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20 (23): 4517-22, 2002. [PUBMED Abstract]
- Herman EH, Zhang J, Rifai N, et al.: The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48 (4): 297-304, 2001. [PUBMED Abstract]
- Lipshultz SE, Scully RE, Lipsitz SR, et al.: Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11 (10): 950-61, 2010. [PUBMED Abstract]
- Barry EV, Vrooman LM, Dahlberg SE, et al.: Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 26 (7): 1106-11, 2008. [PUBMED Abstract]
- Vrooman LM, Neuberg DS, Stevenson KE, et al.: The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer 47 (9): 1373-9, 2011. [PUBMED Abstract]
- Schwartz CL, Wexler LH, Devidas M, et al.: P9754 therapeutic intensification in non-metastatic osteosarcoma: a COG trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-8514, 2004.
- 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 25 (5): 493-500, 2007. [PUBMED Abstract]
- Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009. [PUBMED Abstract]
- Tebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer 46 (2): 198-202, 2006. [PUBMED Abstract]
- Hamm CW: Cardiac biomarkers for rapid evaluation of chest pain. Circulation 104 (13): 1454-6, 2001. [PUBMED Abstract]
- Heeschen C, Goldmann BU, Terres W, et al.: Cardiovascular risk and therapeutic benefit of coronary interventions for patients with unstable angina according to the troponin T status. Eur Heart J 21 (14): 1159-66, 2000. [PUBMED Abstract]
- Herman EH, Zhang J, Lipshultz SE, et al.: Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 17 (7): 2237-43, 1999. [PUBMED Abstract]
- Lipshultz SE, Rifai N, Sallan SE, et al.: Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96 (8): 2641-8, 1997. [PUBMED Abstract]
- 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 19 (4): 352-9, 2001. [PUBMED Abstract]
- Hogarty AN, Leahey A, Zhao H, et al.: Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr 136 (3): 311-7, 2000. [PUBMED Abstract]
- Schwartz CL, Hobbie WL, Truesdell S, et al.: Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 11 (10): 1906-10, 1993. [PUBMED Abstract]
- Pihkala J, Happonen JM, Virtanen K, et al.: Cardiopulmonary evaluation of exercise tolerance after chest irradiation and anticancer chemotherapy in children and adolescents. Pediatrics 95 (5): 722-6, 1995. [PUBMED Abstract]
- Jenney ME, Faragher EB, Jones PH, et al.: Lung function and exercise capacity in survivors of childhood leukaemia. Med Pediatr Oncol 24 (4): 222-30, 1995. [PUBMED Abstract]
- Turner-Gomes SO, Lands LC, Halton J, et al.: Cardiorespiratory status after treatment for acute lymphoblastic leukemia. Med Pediatr Oncol 26 (3): 160-5, 1996. [PUBMED Abstract]
- Alehan D, Sahin M, Varan A, et al.: Tissue Doppler evaluation of systolic and diastolic cardiac functions in long-term survivors of Hodgkin lymphoma. Pediatr Blood Cancer 58 (2): 250-5, 2012. [PUBMED Abstract]
- Poutanen T, Tikanoja T, Riikonen P, et al.: Long-term prospective follow-up study of cardiac function after cardiotoxic therapy for malignancy in children. J Clin Oncol 21 (12): 2349-56, 2003. [PUBMED Abstract]
- Brouwer CA, Postma A, Vonk JM, et al.: Systolic and diastolic dysfunction in long-term adult survivors of childhood cancer. Eur J Cancer 47 (16): 2453-62, 2011. [PUBMED Abstract]
- Cox CL, Rai SN, Rosenthal D, et al.: Subclinical late cardiac toxicity in childhood cancer survivors: impact on self-reported health. Cancer 112 (8): 1835-44, 2008. [PUBMED Abstract]
- Hudson MM, Rai SN, Nunez C, et al.: Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol 25 (24): 3635-43, 2007. [PUBMED Abstract]
- Mulrooney DA, Yeazel MW, Kawashima T, et al.: Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339: b4606, 2009. [PUBMED Abstract]
- Tukenova M, Guibout C, Oberlin O, et al.: Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 28 (8): 1308-15, 2010. [PUBMED Abstract]
- Castellino SM, Geiger AM, Mertens AC, et al.: Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 117 (6): 1806-16, 2011. [PUBMED Abstract]
- Schellong G, Riepenhausen M, Bruch C, et al.: Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. Pediatr Blood Cancer 55 (6): 1145-52, 2010. [PUBMED Abstract]
- Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11 (7): 1208-15, 1993. [PUBMED Abstract]
- Armenian SH, Sun CL, Francisco L, et al.: Late congestive heart failure after hematopoietic cell transplantation. J Clin Oncol 26 (34): 5537-43, 2008. [PUBMED Abstract]
- Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003. [PUBMED Abstract]
- Jakacki RI, Goldwein JW, Larsen RL, et al.: Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol 11 (6): 1033-8, 1993. [PUBMED Abstract]
- Gurney JG, Ness KK, Sibley SD, et al.: Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 107 (6): 1303-12, 2006. [PUBMED Abstract]
- Eames GM, Crosson J, Steinberger J, et al.: Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplant 19 (1): 61-6, 1997. [PUBMED Abstract]
- Armenian SH, Sun CL, Kawashima T, et al.: Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood 118 (5): 1413-20, 2011. [PUBMED Abstract]
- Campen CJ, Kranick SM, Kasner SE, et al.: Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 43 (11): 3035-40, 2012. [PUBMED Abstract]
- Haddy N, Mousannif A, Tukenova M, et al.: Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain 134 (Pt 5): 1362-72, 2011. [PUBMED Abstract]
- 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 23 (27): 6508-15, 2005. [PUBMED Abstract]
- 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 24 (33): 5277-82, 2006. [PUBMED Abstract]
- De Bruin ML, Dorresteijn LD, van't Veer MB, et al.: Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 101 (13): 928-37, 2009. [PUBMED Abstract]
- Mueller S, Sear K, Hills NK, et al.: Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 86 (4): 643-8, 2013. [PUBMED Abstract]
- Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013. [PUBMED Abstract]
- Armstrong GT, Oeffinger KC, Chen Y, et al.: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31 (29): 3673-80, 2013. [PUBMED Abstract]