Late Effects of the Cardiovascular System
Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors.[1-5]
Evidence supports the excess risk of premature cardiovascular mortality as follows:
- Among more than 20,000 North American 5-year survivors of childhood cancer (in the Childhood Cancer Survivor Study [CCSS]) treated from 1970 to 1986, participants had a standardized mortality ratio of 7.0 (95% confidence interval [CI], 5.9–8.2) for cardiac mortality, which translated to 0.36 excess deaths per 1,000 person-years.
- All-cause circulatory disease was associated with an absolute excess risk of 3.4% (95% CI, 2.8–4.2) among nearly 18,000 5-year survivors in the British Childhood Cancer Survivor Study who were diagnosed with cancer between 1950 and 1991. Individual standardized mortality ratios for cardiac, cerebrovascular, and other circulatory diseases ranged from 3.5 to 5.2.
- All-cause cardiovascular and cardiac-specific mortality was analyzed in 4,122 5-year survivors from select centers in France and the United Kingdom, with an average follow-up of 27 years. Importantly, even radiation doses of 5 Gy to 14 Gy to the heart were associated with an increased risk of cardiac death (relative risk [RR], 12.5; P < .05).
By age 45 years, the overall cumulative incidence of severe, life-threatening, or fatal cardiac events has been reported to be approximately 5% for coronary artery disease and heart failure separately and 1% to 2% for valve disorders and arrhythmias. Compared with siblings, 5-year survivors had RRs approaching, if not exceeding, tenfold for heart failure, coronary artery disease, and cerebrovascular disease. The burden of subclinical disease is likely much greater.
The specific late effects covered in this section include the following:
- Cardiomyopathy/heart failure.
- Ischemic heart disease.
- Pericardial heart disease.
- Valve disease.
- Conduction disorders.
- Cerebrovascular disease.
The section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes in relation to these late effects, but not directly review in detail those conditions as a consequence of childhood cancer treatment. A comprehensive review on long-term cardiovascular toxicity in childhood and young adult survivors of cancer, issued by the American Heart Association, has been published.
Overall, there has been a wealth of studies focused on the topic of cardiac events among childhood cancer survivors. In addition to many smaller studies not covered in detail here, the literature includes very large cohort studies that are either hospital-based,[3,6,8-11] clinical trial based, or population-based,[2,4] many with up to several decades of follow-up. However, even with decades of follow-up, the average age of these populations may still be relatively young (middle or young adulthood). And while the risk of serious cardiovascular outcomes may be very high relative to the age-matched general population, the absolute risk often remains low, limiting the power of many studies. Among the very large studies featuring thousands of survivors, the main limitation has been inadequate ability to clinically ascertain late cardiovascular complications, with a greater reliance on either administrative records (e.g., death registries) and/or self-report or proxy-report.
While each study design has some inherent biases, the cumulative literature, based on a combination of self-reported outcomes, clinical ascertainment, and administrative data sources, is robust in concluding that certain cancer-related exposures predispose survivors towards a significantly greater risk of cardiovascular morbidity and mortality. Although late effects research often lags behind changes in contemporary therapy, many therapies linked to cardiovascular late effects remain in common use today.[13,14] Ongoing research will be important to ensure that newer targeted agents being introduced today do not result in unexpected cardiovascular effects.
Results of selected cohort studies describing the prevalence of cardiovascular outcomes include the following:
- Austrian-German investigators evaluated the development of cardiac disease (via patient self-report supplemented by physician report) in a cohort of 1,132 pediatric Hodgkin lymphoma (HL) survivors monitored for a median of 20 years. The 25-year cumulative incidence of heart disease increased with higher mediastinal radiation doses: 3% (unirradiated), 5% (20 Gy), 6% (25 Gy), 10% (30 Gy), and 21% (36 Gy). Valve defects were most common, followed by coronary artery disease, cardiomyopathy, rhythm disorders, and pericardial abnormalities.
- In a Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors (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 (congestive heart failure, cardiac ischemia, valve disease, arrhythmia, and/or pericarditis) was significantly increased after treatment with both anthracyclines and cardiac radiation (12.6%; 95% CI, 4.3–10.3), anthracyclines alone (7.3%; 95% CI, 3.8–10.7), and cardiac radiation alone (4.0%; 95% CI, 0.5–7.4) compared with other treatments. There appeared to be an exponential relationship between cumulative anthracycline dose, cardiac radiation dose, and the risk of developing a symptomatic cardiac event.
- A report from the CCSS that featured over 14,000 5-year survivors examined detailed dose-response to both radiation therapy and chemotherapy (anthracycline) in relation to self-reported (or death due to) myocardial infarction, congestive heart failure, pericardial disease, and valvular abnormalities. Cardiac radiation doses of 15 Gy or higher were associated with substantially greater risk compared with the risk seen in nonirradiated survivors, while anthracycline doses of 250 mg/m2 or more were associated with a substantially increased risk of congestive heart failure, pericardial disease, and valvular abnormalities, independent of radiation exposure. Overall, the cumulative incidence of adverse cardiac outcomes continued to rise more than 30 years after original cancer diagnosis.
- A follow-up study from the CCSS demonstrated that the cumulative incidence of these serious cardiac events continued to increase beyond age 45 years. Furthermore, the risk of these events was potentiated (i.e., beyond what would be expected by an additive model) by the presence of concurrent, but potentially modifiable, conditions such as obesity, dyslipidemia, diabetes, and, in particular, hypertension. Hypertension was independently associated with all serious cardiac outcomes (RRs, 6-fold to 19-fold), even after adjustment for anthracycline use and chest irradiation.
- Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS and data from the National Wilms Tumor Study Group, the Netherlands, and St. Jude Children’s Research Hospital), a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated, which may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy and up through age 40 years. One limitation of this estimator is that because of the young age of participants at the time of baseline prediction (5-year survival), information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated.
Treatment Risk Factors
Chemotherapy (in particular, anthracyclines and anthraquinones) along with radiation therapy both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer and are felt to be the most important risk factors contributing to premature cardiovascular disease in this population (refer to Figure 2).
Anthracyclines and related agents
Anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinones (e.g., mitoxantrone) are known to directly injure cardiomyocytes through the formation of reactive oxygen species and inducing mitochondrial apoptosis.[5,18] The downstream results of cell death are changes in heart structure, including wall thinning, which leads to ventricular overload and pathologic remodeling that over time leads to dysfunction and eventual clinical heart failure.[19-22]
Risk factors for anthracycline-related cardiomyopathy include the following:
- Cumulative dose, particularly greater than 250 mg/m2 to 300 mg/m2.
- Younger age at time of exposure, particularly children younger than 5 years.
- Increased time from exposure.
Among these factors, cumulative dose appears to be the most significant (refer to Figure 3). While it is not completely certain whether there is a truly safe lower dose threshold, doses in excess of 250 mg/m2 to 300 mg/m2 have been associated with a substantially increased risk of cardiomyopathy, with cumulative incidences exceeding 5% after 20 years of follow-up, and in some subgroups, reaching or exceeding 10% cumulative incidence by age 40 years.[9,10,17,20,22] Concurrent chest or heart radiation therapy also further increases risk of cardiomyopathy,[11,17] as does the presence of other cardiometabolic traits such as hypertension.[6,24] While development of clinical heart failure can occur within a few years after anthracycline exposure, in most survivors, even those who received very high doses, clinical manifestations may not occur for decades.
Anthracycline Dose Equivalency
It remains unclear how best to add together doses of different anthracycline agents. A variety of anthracycline equivalence formulas (in relation to doxorubicin) have been used; however, they are largely based on hematologic toxicity equivalence, and may not necessarily be the same for cardiac toxicity.[17,25,26] Most pediatric professional societies and groups have generally considered daunorubicin equivalent, or near equivalent, to doxorubicin, although historically lower ratios have been proposed as well. Other agents such as idarubicin, epirubicin, and mitoxantrone (an anthraquinone) were designed to reduce cardiac toxicity while maintaining similar antitumor effect, although data supporting this are primarily limited to adult cancer patients. Similarly, data on whether liposomal formulations of anthracyclines reduce cardiac toxicity in children also are limited.
In addition to new, less cardiotoxic agents and liposomal formulations, other cardioprotective strategies that have been explored include the following:
- Prolonged infusion time. Prolonged infusion time has been associated with reduced heart failure in adult patients but not in children.[29,30]
- Concurrent administration of cardioprotectants. A variety of agents have been tested as cardioprotectants (amifostine, acetylcysteine, calcium channel blockers, carvedilol, coenzyme Q10, and L-carnitine), but none have been definitively shown to be beneficial and are not considered standard of care.[31,32] There are more data for dexrazoxane as a cardioprotectant, but again, mainly in adult cancer patients, for whom it is approved by the U.S. Food and Drug Administration for women with metastatic breast cancer who have received 300 mg/m2 of anthracyclines and who may benefit from further anthracycline-based therapy. Pediatric data show that dexrazoxane may ameliorate some surrogate markers of cardiac toxicity.[33,34]
While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs. Late effects of radiation therapy to the heart specifically include the following:
- Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.
- Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Cardiomyopathy (in the absence of significant pericardial disease), which can occur even without anthracycline exposure.
- Ischemic heart disease.
- Functional valve injury, often aortic.
- Conduction defects.
These cardiac late effects are related to total radiation dose, individual radiation fraction size, and the volume of the heart that is exposed. Various studies have demonstrated a substantially increased risk of these outcomes with higher radiation doses, particularly doses to the heart exceeding 35 Gy.[3,10,11,16,35,36] At higher radiation doses, rates of heart failure, pericardial disease, and valvular disease have been reported to exceed 10% after 20 to 30 years. However, even doses as low as 5 Gy have been associated with an increased risk of cardiac mortality and other serious cardiac morbidity, with possibly an exponential dose relationship.[3,11] Similar to anthracyclines, manifestation of these late effects may take years, if not decades, to present. Finally, patients who were exposed to both radiation therapy affecting the cardiovascular system and cardiac toxic chemotherapies are at even greater risk of late cardiovascular outcomes.[6,11]
Cerebrovascular disease after radiation therapy exposure is another potential late effect for survivors. While brain tumor survivors have had traditionally the greatest risk, other survivors exposed to cranial radiation (≥18 Gy) and neck radiation (≥40 Gy), such as leukemia and lymphoma survivors, have also been reported to be at increased risk.[37-39] In lymphoma survivors who only received chest and/or neck radiation therapy, cerebrovascular disease is thought to be caused by large-vessel atherosclerosis and cardiac embolism.
As with cardiac outcomes, risk increases with cumulative dose received. One study (N = 325) reported that the stroke hazard increased by 5% (hazard ratio [HR], 1.05; 95% CI, 1.01–1.09; P = .02), with each 1 Gy increase in the radiation dose, leading to a cumulative incidence of 2% for the first stroke after 5 years and 4% after 10 years. Survivors who experienced stroke were then at significantly greater risk of experiencing recurrent strokes.
Results of selected studies describing prevalence of and risk factors for cerebrovascular accident/vascular disease in childhood cancer survivors include the following:
- In a multicenter retrospective Dutch study, among 2,201 5-year survivors of HL diagnosed before age 51 years (25% pediatric-aged), with median follow-up of 18 years, 96 patients developed cerebrovascular disease (cerebrovascular accidents [CVA] and transient ischemic attacks [TIA]). Most ischemic events were from large-artery atherosclerosis (36%) or cardiac embolism (24%). The cumulative incidence of ischemic CVA or TIA 30 years after lymphoma treatment was 7%. The overall standardized incidence ratio (SIR) was 2.2 for CVA and 3.1 for TIA. However, SIR estimates appeared to be greater among childhood cancer survivors, with SIRs of 3.8 for CVA and 7.6 for TIA. Iradiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR, 2.5; 95% CI, 1.1–5.6) versus no radiation therapy. Treatment with chemotherapy was not associated with increased risk. Finally, hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease.
- French investigators observed a significant association between radiation dose to the brain and long-term cerebrovascular mortality among 4,227 5-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) for 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.
- A retrospective single-center cohort study of 325 survivors of pediatric cancer treated with cranial irradiation or cervical irradiation determined that cranial irradiation put survivors at a high risk of first and recurrent strokes. The cumulative incidence of first stroke was 4% (95% CI, 2.0–8.4) at 10 years after radiation therapy. 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.
Conventional cardiovascular conditions
Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia. These conditions remain important among cancer survivors, as they do in the general population, in that they are independent risk factors in the development of cardiomyopathy, ischemic heart disease, and cerebrovascular disease.[6,38,41,42] Childhood cancer survivors should be closely screened for the development of these conditions because they represent potentially modifiable targets for intervention. This includes being aware of related conditions such as obesity and various endocrinopathies (e.g., hypothyroidism, hypogonadism, growth hormone deficiency) that may be more common among subsets of childhood cancer survivors, and if these conditions are untreated/uncontrolled, they may be associated with a metabolic profile that increases cardiovascular risk.[8,43]
Other Risk Factors
Some, but not all, studies suggest that female gender may be associated with a greater risk of anthracycline-related cardiomyopathy. In addition, there is emerging evidence that genetic factors, such as single nucleotide polymorphisms in genes regulating drug metabolism and distribution, could explain the heterogeneity in susceptibility to anthracycline-mediated cardiac injury.[44-46] However, these genetic findings still require additional validation before being incorporated into any clinical screening algorithm.
While much knowledge has been gained over the past 20 years in better understanding the long-term burden and risk factors for cardiovascular disease among childhood cancer survivors, many areas of inquiry remain, and include the following:
- Radiation may have both direct and indirect effects on vascular endothelium, contributing to vascular damage beyond the primary radiation field.
- The long-term effects of lower radiation doses, particularly in light of newer technology that allows radiation oncologists to reduce the dose to critical organs outside of the tumor field, remain to be determined.
- The long-term effects of many newer anticancer agents that are based on molecular targets remains unclear, although some of them are known to have shorter-term cardiac toxicity.
- The efficacy of cardioprotective strategies, including the use of alternative anthracycline formulations that appear promising in adults, requires further study in children.
Screening, Surveillance, and Counseling
Various national groups, including the National Institutes of Health–sponsored Children’s Oncology Group (COG) (refer to Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.[50-54] An effort to harmonize some of these guidelines is currently underway. Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring. At this point, there is no clear evidence (at least through age 50 years or 30 to 40 years posttreatment) that there is a plateau in risk that occurs after a certain time among survivors exposed to cancer treatments associated with cardiovascular late effects.[3,4,10,11,37,57] Thus, some form of life-long surveillance is recommended, even if the cost-effectiveness of certain screening strategies remains unclear.[58,59]
However, a growing amount of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines.[8,60] In these studies, for example, among adult-aged survivors of childhood cancer, evidence for cardiomyopathy on the basis of echocardiographic changes was found in approximately 6% of at-risk survivors. Overall, in a cohort of more than 1,000 survivors (median age, 32 years), nearly 60% of screened at-risk survivors had some clinically ascertained cardiac abnormality identified.
Survivors should also be counseled regarding the cardiovascular benefits of the following factors:
- Maintaining a healthy weight.
- Adhering to a heart-healthy diet.
- Participating in regular physical activity.
- Abstaining from smoking.
Survivors should obtain medical clearance before engaging in extreme exercise programs. Given the growing evidence that conventional cardiovascular conditions such as hypertension, dyslipidemia, and diabetes substantially increase the risk of more serious cardiovascular disease among survivors, clinicians should carefully consider baseline and follow-up screening and treatment of these comorbid conditions that impact cardiovascular health.[6,38,41,42]
In addition to releasing a comprehensive, publically available (online) set of guidelines, the COG has also put together a series of handouts on cardiovascular and related topics, including lifestyle choices written for a lay audience, available on the same Web site.
|Predisposing Therapy||Potential Cardiovascular Effects||Health Screening|
|aThe Children's Oncology Group (COG) guidelines also cover other conditions that may influence cardiovascular risk also exist, such as obesity and diabetes mellitus/impaired glucose metabolism.|
|bAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.|
|Any anthracycline and/or any radiation to the heart||Cardiac toxicity (arrhythmia, cardiomyopathy/heart failure, pericardial disease, valve disease, ischemic heart disease)||Yearly medical history and physical exam|
|Electrocardiogram at entry into long-term follow-up|
|Echocardiogram at entry into long-term follow-up, periodically repeat based on previous exposures and other risk factors|
|Radiation to the area (≥40 Gy)||Carotid and/or subclavian artery disease||Yearly medical history and physical exam; consider Doppler ultrasound 10 years after exposure|
|Radiation to the brain/cranium (≥18 Gy)||Cerebrovascular disease (cavernomas, Moyamoya, occlusive cerebral vasculopathy, stroke)||Yearly medical history and physical exam|
|Total-body irradiation||Dyslipidemia||Fasting lipid profile every 2 years|
|Heavy metals (carboplatin, cisplatin), ifosfamide, and methotrexate exposure; radiation to the kidneys; hematopoietic cell transplantation; nephrectomy||Hypertension (as a consequence of renal toxicity)||Yearly blood pressure and urinalysis; renal function laboratory studies at entry into long-term follow-up|
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