Late Effects of the Cardiovascular System
Prevalence, Clinical Manifestations, and Risk Factors for Cardiac Toxicity
Cardiovascular Disease in Select Cancer Subgroups
Vascular Disease/Cerebrovascular Accident
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.Radiation Therapy
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.Anthracycline Therapy
- 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]
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 cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time. 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. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups. Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.
Prevention or amelioration of doxorubicin-induced cardiomyopathy is clearly 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.[27-31] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; other studies, however, do not show increased risk of malignancies.[31-34] However, at this time, this should not preclude treatment with dexrazoxane.[35,36]
Two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma (HL) [36,37] 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.[30,38-42] 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.[28,29]
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.[43-47] 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.[51,52] Clearly, 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
Children's 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).
Compared with siblings, survivors of childhood cancer were significantly more likely to report CHF (hazard ratio [HR] = 5.9; 95% confidence interval [CI], 3.4–9.6), MI (HR = 5.0; 95% CI, 2.3–10.4), pericardial disease (HR = 6.3; 95 % CI, 3.3–11.9), or valvular abnormalities (HR = 4.8; 95 % CI, 3.0–7.6). 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. There was no evidence for increased risk following doses less than 5 Gy, and slight elevations in risk were not statistically significant following doses between 5 to 15 Gy. 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 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, but to much higher cumulative percentages for those receiving the highest cardiac radiation doses and the highest cumulative dose of anthracyclines.
A study of 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom also provides evidence for an association between radiation dose and risk of cardiovascular disease. After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio was 8.3-fold (95% CI, 7.6–9.0) higher in relation to the general populations in France and the United Kingdom. Thirty-two patients had died of cardiovascular diseases, which is fivefold (95% CI, 3.3–6.7) more than expected. The risk of dying of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative dose of anthracyclines greater than 360 mg/m2 (relative risk [RR] = 4.4; 95% CI, 1.3–15.3) and following 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%).
Subclinical cardiac function was evaluated by a group from the Netherlands. Of 601 eligible adult 5-year childhood cancer survivors, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF). The median overall LVSF in the whole group of childhood cancer survivors was 33.1% (range, 13.0%–56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced 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.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 cardiotoxic 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 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.[7,8,58]Other malignancies
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 surgery and radiation therapy alone, suggesting a potential additive vascular injury from chemotherapy. Children who receive spinal radiation for treatment of central nervous system 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 reporting a chronic medical condition in the CCSS cohort, the risk of a cardiac condition was nearly sevenfold higher compared with the 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%. It is noteworthy that adult survivors of childhood ALL have an increased prevalence of obesity and insulin resistance and may be at risk for developing diabetes, dyslipidemia, and metabolic syndrome, all known to be 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.[43,58,62] 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 central nervous system 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 an 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 compared with the sibling control group; notably, risks were highest among the adult survivors of childhood ALL, brain tumors, and HL.[65,66] Leukemia survivors were six times more likely to suffer a CVA compared with 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 cardioembolism (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. It is noteworthy that hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. Table 2. Cardiovascular Late Effects
|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 impact cardiovascular health.
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.References
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