Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

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Late Effects of the Cardiovascular System

In This Section

• Treatment Risk Factors
  • Anthracyclines and related agents
  • Radiation therapy
  • Conventional cardiovascular conditions
• Other Risk Factors
• Heart Transplant
• Knowledge Deficits
• Screening, Surveillance, and Counseling

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 (excess risk of premature cardiovascular mortality):

1. 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.[1]
2. 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 CCSS 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.[2]

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.[6] Compared with siblings, 5-year survivors had relative risks (RRs) approaching, if not exceeding, tenfold for heart failure, coronary artery disease, and cerebrovascular disease.[7] The burden of subclinical disease is likely much greater.[8]

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.
• Venous thromboembolism.

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.[5]

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,[6,8-12] clinical trial based,[13,14] 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 (young or middle 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 overall 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 toward 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.[15,16] Ongoing research will be important to ensure that newer targeted agents being introduced today do not result in unexpected cardiovascular effects.[17]

Evidence (selected cohort studies describing cardiovascular outcomes):

1. In the CCSS, data from 24,214 5-year survivors diagnosed between 1970 and 1999 were used to assess the impacts of radiation therapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk of late-onset cardiac disease.[18]
   • The cumulative incidence of cardiac disease (any cardiac disease, coronary artery disease, and heart failure) 30 years from diagnosis was 4.8%. Male survivors were more likely to develop coronary artery disease and less likely to develop heart failure than were female survivors. Non-Hispanic black survivors were more likely to develop any cardiac disease than were non-Hispanic white survivors.
   • Low-to-moderate radiation therapy doses (5.0–19.9 Gy) to large cardiac volumes (>50% of the heart) were associated with a 1.6-fold increased risk of cardiac disease compared with survivors who did not have any cardiac radiation therapy exposure.
   • High doses (>20 Gy) to small cardiac volumes (0.1%–29.9%) were associated with an elevated rate of cardiac disease compared with unexposed survivors.
   • A dose-response relationship was observed between anthracycline exposure and heart failure, with younger children (<13 years) at the greatest risk of heart failure after comparable dosing.
2. A multicenter French cohort of 3,162 5-year survivors treated between 1942 and 1986 were monitored for a median of 26 years.[12]
   • The cumulative incidence of any cardiac disease (ischemic heart disease, heart failure, arrhythmia, or valve and pericardial diseases) by age 40 years was 11% (7% if restricted to those that warranted medical intervention).
   • Risk increased with higher anthracycline and radiation doses, particularly anthracycline doses of 250 mg/m2 or more and heart radiation doses of 15 Gy or higher.
   • A significant interaction was identified between radiation dose, anthracycline exposure, and attained age.
3. A Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors (median attained age, 29.1 years) were monitored from diagnosis for a median of 22.2 years.[11]
   • 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%–20.3%), 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.
4. The CCSS demonstrated that the cumulative incidence of serious cardiac events (myocardial infarction, congestive heart failure, pericardial disease, and valvular abnormalities) continued to increase beyond age 45 years.[6]
   • 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, particularly, hypertension.
   • Hypertension was independently associated with all serious cardiac outcomes (RRs, sixfold to 19-fold), even after adjustment for anthracycline use and chest irradiation.
5. Of 670 survivors of Hodgkin lymphoma (HL) who were treated at St. Jude Children’s Research Hospital (SJCRH) and have lived 10 or more years, 348 patients were clinically assessed in the St. Jude Lifetime Cohort Study.[19]
   • Overall, survivors had a higher cumulative burden (a novel measurement of disease burden that incorporates multiple health conditions and recurrent events into a single metric) than did community controls, with the total grade 3 to 5 cumulative burden among survivors at age 30 years being comparable to that of community controls at 50 years.
   • At age 50 years, the cumulative incidence of those survivors experiencing at least one grade 3 to grade 5 cardiovascular condition was 45.5% (95% CI, 36.6%–54.3%), compared with 15.7% (95% CI, 7.0%–24.4%) in community controls.
   • Myocardial infarction and structural heart defects were the major contributors to the excess grade 3 to grade 5 cumulative burden in survivors, whereas there was no notable difference in survivors and community controls at age 50 years for grades 3 to 5 cumulative burden of dyslipidemia and essential hypertension.
6. Another St. Jude Lifetime Cohort Study compared the prevalence of major and minor electrocardiography (ECG) abnormalities among 2,715 participants and 268 community controls.[20]
   • Major ECG abnormalities were significantly more prevalent in survivors (10.7%) than in controls (4.9%); the most common abnormalities included isolated ST-T wave abnormalities (7.2%), evidence of myocardial infarction (3.7%), and left ventricular hypertrophy with strain pattern (2.8%).
   • Treatment exposures predicting increased risk of major abnormalities were anthracycline doses of 300 mg/m2 or greater (odds ratio [OR], 1.7; 95% CI, 1.1–2.5) and cardiac radiation (OR, 2.1; 95% CI, 1.5–2.9 [1–1,999 cGy]; OR, 2.6; 95% CI, 1.6–3.9 [2,000–2,999 cGy]; OR, 10.5; 95% CI, 6.5–16.9 [≥3,000 cGy]).
   • Major ECG abnormalities were predictive of all-cause mortality (HR, 4.0; 95% CI, 2.1–7.8).
7. In the Teenage and Young Adult Cancer Survivor Study, cardiac mortality was investigated in more than 200,000 5-year survivors of adolescent and young adult cancer (aged 15–39 years).[21]
   • Age at diagnosis and type of cancer were identified as being important in determining risk of cardiac mortality.
   • The standardized mortality ratios (SMR) for all cardiac disease combined was greatest for individuals diagnosed at age 15 to 19 years (4.2), decreasing to 1.2 for individuals aged 35 to 39 years (2P for trend < .0001). This age effect was most apparent for survivors of Hodgkin lymphoma, who were also found to be at greatest risk overall.
   • Limitations of this study included lack of detailed information on exposures to radiation therapy (doses, fields), exposures to chemotherapy (primarily anthracycline dose), and cardiovascular risk factors (e.g., smoking, obesity, hypertension, diabetes, family history).

Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH), 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.[22]

In another collaborative study, data from the CCSS, Netherlands, and SJCRH were used to develop risk-prediction models for ischemic heart disease and stroke among 5-year survivors of childhood cancer through 50 years. Risk scores derived from a standard prediction model that included sex, chemotherapy exposure, and radiation therapy exposure identified statistically distinct low-risk, moderate-risk, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were less than 5%, compared with approximately 20% for high-risk groups and only 1% for siblings.[23]

Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-aged survivors of childhood cancer, as demonstrated by a CCSS investigation that constructed prediction models accounting for cardiotoxic cancer treatment exposures, combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. Risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes showed good performance (area under the receiver operating characteristic curve [AUC] and concordance [C] statistics ≥0.70) for predicting cardiovascular events in the models applied to the discovery and replication cohorts. The most influential exposures were anthracycline, radiation therapy, diabetes, and hypertension.[24]

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 considered to be the most important risk factors contributing to premature cardiovascular disease in this population (refer to Figure 4).[11]

ENLARGE

Figure 4. (A, B) Marginal (Kaplan-Meier) and (C–E) cause-specific (competing risk) cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified according to different treatment groups. (A) Marginal cumulative incidence for all CEs, stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank P < .001. (B) Marginal cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank P < .001. (C) Cause-specific cumulative incidence for congestive heart failure, stratified according to different treatment groups, log-rank P < .001. (D) Cause-specific cumulative incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX, log-rank P = .01. (E) Cause-specific cumulative incidence for valvular disease, stratified according to RTX or no RTX, log-rank P < .001. The shaded colorized background areas refer to the 95% CIs. Ant, anthracycline. Helena J. van der Pal, Elvira C. van Dalen, Evelien van Delden, Irma W. van Dijk, Wouter E. Kok, Ronald B. Geskus, Elske Sieswerda, Foppe Oldenburger, Caro C. Koning, Flora E. van Leeuwen, Huib N. Caron, Leontien C. Kremer, High Risk of Symptomatic Cardiac Events in Childhood Cancer Survivors, Journal of Clinical Oncology, volume 30, issue 13, pages 1429-1437. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

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.[5,25] 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.[26-29]

Risk factors for anthracycline-related cardiomyopathy include the following:[18,30]

• 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 5).[9] 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.[9,10,22,27,29] Concurrent chest or heart radiation therapy also further increases risk of cardiomyopathy,[11,12,22] as does the presence of other cardiometabolic traits such as hypertension.[6,31] 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.

ENLARGE

Figure 5. Risk of anthracycline-induced clinical heart failure (A-CHF) according to cumulative anthracycline dose. Reprinted from European Journal of CancerExit Disclaimer, Volume 42, Elvira C. van Dalen, Helena J.H. van der Pal, Wouter E.M. Kok, Huib N. Caron, Leontien C.M. Kremer, Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study, Pages 3191-3198, Copyright (2006), with permission from Elsevier.

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.[22,32,33] 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.[34] A large analysis of over 15,000 childhood cancer survivors who were monitored to age 40 years found that daunorubicin may be significantly less cardiotoxic than doxorubicin (equivalence ratio, 0.5 [95% CI, 0.2–0.7]).[35]

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.[36] Similarly, data on whether liposomal formulations of anthracyclines reduce cardiac toxicity in children also are limited.[36]

Anthracycline cardioprotection

Cardioprotective strategies that have been explored include the following:

• New, less cardiotoxic agents and liposomal formulations.
• Prolonged infusion time. Prolonged infusion time has been associated with reduced heart failure in adult patients but not in children.[37,38]
• 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.[39,40]
  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.[39] Pediatric data show that dexrazoxane may ameliorate some markers of early cardiac toxicity up to 5 years after therapy.[41-44] Dexrazoxane may be associated with an increased risk of acute toxicities in some regimens, however.[45] While these data suggest that dexrazoxane does protect the heart in the short term, there are not yet long-term data showing the impact of dexrazoxane on cardiac health.
  As a topoisomerase inhibitor, dexrazoxane’s association with secondary cancers, particularly secondary leukemia, remains controversial.[44,46] One report that described the use of concurrent etoposide and doxorubicin observed an increased risk of acute myeloid leukemia (AML) among patients treated with dexrazoxane.[47] However, all other pediatric randomized controlled and nonrandomized studies have not observed an increased risk of subsequent malignant neoplasms in conjunction with dexrazoxane,[44] and the risk of secondary AML was not increased among children treated with dexrazoxane who were registered in the Pediatric Health Information Systems database.[48] Another randomized trial reported an increased risk of secondary brain tumors among survivors treated with cranial irradiation, but this risk did not differ among patients who did and did not receive dexrazoxane.[43]

Radiation therapy

While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs.[5]

Cardiovascular disease

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 the following:

• Individual radiation fraction size.
• Volume of the heart that is exposed to radiation.[18]
• Total radiation dose. Various studies have demonstrated a substantially increased risk of these outcomes with higher radiation doses, particularly doses to the heart exceeding 35 Gy (refer to Figure 6).[10-12,14,49,50] At higher radiation doses, rates of heart failure, pericardial disease, and valvular disease have been reported to exceed 10% after 20 to 30 years. Although some studies suggest that doses less than 5 Gy may be associated with an increased risk of cardiovascular disease, the RR is small (i.e., 2.5) and the 95% CI is large (i.e., 0.2–41.5); moreover, the dosimetric analyses are generally estimations of incidental cardiac exposure.[3,10-12] Low-to-moderate radiation therapy doses (5.0–19.9 Gy) to large cardiac volumes (>50% of the heart) are associated with an increased rate of cardiac disease (i.e., 1.6) compared with survivors who did not have any cardiac radiation therapy exposure. High doses of radiation (>20 Gy) to small cardiac volumes (0.1%–29.9%) are associated with an elevated rate of cardiac disease (2.4).[18] Consequently, additional confirmatory data are needed for an accurate assessment of risk at very low cardiac doses.

  ENLARGE

  Figure 6. Cumulative incidence of cardiac disorders among childhood cancer survivors by average cardiac radiation dose. BMJ 2009; 339:b4606. © 2009 by British Medical Journal Publishing Group.

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 cardiotoxic chemotherapy agents are at even greater risk of late cardiovascular outcomes.[12,18]

Cerebrovascular disease

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 irradiation (≥18 Gy) and neck irradiation (≥40 Gy), such as leukemia and lymphoma survivors, have also been reported to be at increased risk.[51-54] 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.[52]

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.[55] Survivors who experienced stroke were then at significantly greater risk of experiencing recurrent strokes.

Evidence (selected studies describing prevalence of and risk factors for cerebrovascular [CVA]/vascular disease):

1. In a multicenter retrospective Dutch study, among 2,201 5-year survivors of HL diagnosed before age 51 years (25% pediatric-aged patients), with a median follow-up of 18 years, 96 patients developed cerebrovascular disease (CVA and transient ischemic attacks [TIA]).[52]
   • 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.
   • Irradiation 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.
   • Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease.
2. 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).[53]
   • Survivors who received more than 50 Gy to the prepontine cistern had an HR of 17.8 (95% CI, 4.4–73.0) 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.
3. 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.[55]
   • 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.
4. CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[56]
   • Among responding participants (329 of 443), 271 confirmed a first stroke (at median age, 19 years) and 70 reported a second stroke (at median age, 32 years).
   • Independent predictors of recurrent stroke included treatment with a cranial radiation therapy dose of 50 Gy or higher (vs. no cranial radiation therapy), history of hypertension, and age 40 years or older at first stroke (vs. age 0–17 years).
   • The 10-year cumulative incidence of late recurrent stroke was 21% overall, and 33% for those treated with 50 Gy or higher of cranial radiation therapy.
5. A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was constituted from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the Circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[57]
   • Patients who received radiation therapy had an 8.5-fold increased risk (95% CI, 6.3–11.0) of stroke in contrast to a nonelevated risk for patients not receiving radiation therapy.
   • The RR was 15.7 (95% CI, 4.9–50.2) for doses of 40 Gy or higher.
   • At age 45 years, the cumulative incidence was 11.3% (95% CI, 7.1%–17.7%) in patients who received 10 Gy or higher to the Circle of Willis, compared with 1% in the general population.
6. Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[58]
   • The investigators found that survivors of adolescent and young adult cancers had a 40% increased risk of hospitalization for cerebrovascular event compared with the general population.
   • Survivors of central nervous system (CNS) tumors (standardized hospitalization ratios [SHR], 4.6), head and neck tumors (SHR, 2.6), and leukemia (SHR, 2.5) had the highest risk of hospitalization for a cerebrovascular complication.
   • Males had significantly higher absolute excess risks than did females, especially among head and neck tumor survivors. By age 60 years, 9% of CNS tumor survivors, 6% of head and neck tumor survivors, and 5% of leukemia survivors had been hospitalized for a cerebrovascular event.
   • The risk of hospitalization for a cerebral infarction was particularly increased among survivors of a CNS tumor older than 60 years, whereas this risk was increased across all ages in survivors of head and neck tumors.

Venous thromboembolism

Children with cancer have an excess risk of venous thromboembolism within the first 5 years after diagnosis; however, the long-term risk of venous thromboembolism among childhood cancer survivors has not been well studied.[59] CCSS investigators evaluated self-reported late-onset (5 or more years after cancer diagnosis) venous thromboembolism among cohort members (median follow-up, 21.3 years). The 35-year cumulative incidence of venous thromboembolism among survivors was 4.9%, which represented a more-than-twofold-higher risk compared with a sibling cohort (RR, 2.2; 95% CI, 1.7–2.8). Risk factors for venous thromboembolism among survivors included female sex, treatment with cisplatin or asparaginase, obesity or underweight, and recurrent primary or subsequent cancer. The risk of late venous thromboembolism was higher among survivors of lower-extremity osteosarcoma treated with limb-sparing surgery compared with patients treated with any amputation, possibly resulting from alterations in peripheral vascular anatomy and homeostasis. Venous thromboembolism was associated with an almost-twofold increased risk of late mortality (RR, 1.9; 95% CI, 1.6–2.3).[60]

Conventional cardiovascular conditions

Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia.[5] 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.[6,52,61-64]

Childhood cancer survivors should be closely screened for the development of these cardiovascular 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; if these conditions are untreated/uncontrolled, they may be associated with a metabolic profile that increases cardiovascular risk.[8,65]

Other Risk Factors

Some, but not all, studies suggest that female sex may be associated with a greater risk of anthracycline-related cardiomyopathy.[5] 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.[66-71] However, these genetic findings still require additional validation before being incorporated into any clinical screening algorithm.[72]

Heart Transplant

In a study of solid organ transplants in 13,318 survivors in the CCSS, 62 survivors had end-stage heart failure that warranted heart transplants, 37 of whom received a heart transplant. At 35 years after cancer diagnosis, the cumulative incidence of heart transplant was 0.30%, and the cumulative incidence of being placed on the waiting list or receiving a heart was 0.49%. The 5-year survival rate from heart transplant was 80.6%, which is similar to the outcome in the general population of the same age range.[73]

Knowledge Deficits

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.[74]
• 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.[75]
• 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.[17]
• The efficacy of cardioprotective strategies, including the use of alternative anthracycline formulations that appear promising in adults, requires further study in children.[40]

Screening, Surveillance, and Counseling

Various national groups, including the National Institutes of Health–sponsored COG (refer to Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.[76-80] Professional groups (both pediatric and adult) have developed evidence-based health surveillance recommendations and have identified knowledge deficits to help guide future studies.[30,81] Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring.[82]

At this point, there is no clear evidence (at least through age 50 years or 30–40 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.[3,4,10,11,51,83] Thus, some form of life-long surveillance is recommended, even if the cost-effectiveness of certain screening strategies remains unclear.[30,84-86]

However, a growing amount of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines.[8,87-89] 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.[8]

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 (refer to Table 2).[6,52,61,62]

There is also emerging evidence that adoption of healthier lifestyle factors may decrease future cardiovascular morbidity in at-risk survivors.[90] Thus, similar to the general population, survivors are counseled about maintaining a healthy weight, participating in regular physical activity, adhering to a heart-healthy diet, and abstaining from smoking.

In addition to releasing a comprehensive, publicly available (online) set of guidelinesExit Disclaimer, 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 website.

Table 2. Cardiovascular Late Effectsa,b

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 CancersExit Disclaimer.
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
Radiation to the abdomen	Diabetes	Diabetes screen every 2 years
Total-body irradiation	Dyslipidemia; diabetes	Fasting lipid profile and diabetes screen 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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