Cardiovascular disease (CVD) risk stratification relies on assessment of nonmodifiable (age, sex, family history) and modifiable (weight, tobacco, physical activity, blood pressure, glucose/lipid ...levels) risk factors. Cancer therapy, itself a potential risk factor, may alter metabolism in long-term survivors of childhood cancer resulting in premature acquisition of age-related modifiable CVD risk factors. For survivors exposed to cardiotoxic therapies, the risk for CVD is significantly augmented by obesity, diabetes, dyslipidemia, and hypertension. An understanding of these risks may not be well communicated as survivors return to primary care and general population screening practices may be insufficient. Lipshultz and colleagues recruited childhood cancer survivors to return to their treating institution for a comprehensive clinical assessment. Interestingly, compared with a noncancer age-, sex-, and race/ethnicity-matched National Health and Nutrition Examination Survey population, cardiometabolic profiles were largely similar. However, cancer survivors had a higher prevalence of prehypertension/hypertension (38.4% vs. 30.1%, P = 0.04) and a lower prevalence of the metabolic syndrome (11.9% vs. 18.7%, P = 0.05). Applying general population CVD risk calculators and a cancer-specific model from the Childhood Cancer Survivor Study, risk estimates were notably higher when cardiotoxic cancer treatment exposures were included. See related article by Lipshultz et al., p. 536.
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic ...clinical assessment to determine the prevalence of chronic health conditions.
To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer.
Presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1713 adult (median age, 32 range, 18-60 years) survivors of childhood cancer (median time from diagnosis, 25 range, 10-47 years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012.
Age-specific cumulative prevalence of adverse outcomes by organ system.
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% 95% CI, 60.4%-69.8%), auditory (hearing loss, 62.1% 95% CI, 55.8%-68.2%), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% 95% CI, 59.5%-64.6%), cardiac (any cardiac condition, such as heart valve disorders, 56.4% 95% CI, 53.5%-59.2%), and neurocognitive (neurocognitive impairment, 48.0% 95% CI, 44.9%-51.0%) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% 95% CI, 10.8%-15.3%), skeletal (osteoporosis, 9.6% 95% CI, 8.0%-11.5%), renal (kidney dysfunction, 5.0% 95% CI, 4.0%-6.3%), and hematopoietic (abnormal blood cell counts, 3.0% 95% CI, 2.1%-3.9%) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition.
Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.
Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the ...cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer.
The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age-matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked-point-process regression was used for inferential cumulative burden analysis.
Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54·5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45·5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99·9% (95% CI 99·9–99·9) for grade 1–5 CHCs and 96·0% (95% CI 95·3–96·8%) for grade 3–5 CHCs. By age 50 years, a survivor had experienced, on average, 17·1 (95% CI 16·2–18·1) CHCs of any grade, of which 4·7 (4·6–4·9) were CHCs of grade 3–5. The cumulative burden in matched community controls of grade 1–5 CHCs was 9·2 (95% CI 7·9–10·6; p<0·0001 vs total study population) and of grade 3–5 CHCs was 2·3 (1·9–2·7, p<0·0001 vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1–5 CHCs at age 50 years was highest in survivors of CNS malignancies (24·2 95% CI 20·9–27·5) and lowest in survivors of germ cell tumours (14·0 11·5–16·6). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs.
The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population.
The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.
The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain ...unresolved.
We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics.
The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing.
These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Among 10,724 5-year survivors ...(median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all P(trend) < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the ...prevalence of frailty and examined associations with morbidity and mortality.
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
Abstract Background Treatment-related cardiac death is the primary, noncancer cause of mortality in adult survivors of childhood malignancies. Early detection of cardiac dysfunction may identify a ...high-risk subset of survivors for early intervention. Objectives This study sought to determine the prevalence of cardiac dysfunction in adult survivors of childhood malignancies. Methods Echocardiographic assessment included 3-dimensional (3D) left ventricular ejection fraction (LVEF), global longitudinal and circumferential myocardial strain, and diastolic function, graded per American Society of Echocardiography guidelines in 1,820 adult (median age 31 years; range: 18 to 65 years) survivors of childhood cancer (median time from diagnosis 23 years; range: 10 to 48 years) exposed to anthracycline chemotherapy (n = 1,050), chest-directed radiotherapy (n = 306), or both (n = 464). Results Only 5.8% of survivors had abnormal 3D LVEFs (<50%). However, 32.1% of survivors with normal 3D LVEFs had evidence of cardiac dysfunction by global longitudinal strain (28%), American Society of Echocardiography–graded diastolic assessment (8.7%), or both. Abnormal global longitudinal strain was associated with chest-directed radiotherapy at 1 to 19.9 Gy (rate ratio RR: 1.38; 95% confidence interval CI: 1.14 to 1.66), 20 to 29.9 Gy (RR: 1.65; 95% CI: 1.31 to 2.08), and >30 Gy (RR: 2.39; 95% CI: 1.79 to 3.18) and anthracycline dose > 300 mg/m2 (RR: 1.72; 95% CI: 1.31 to 2.26). Survivors with metabolic syndrome were twice as likely to have abnormal global longitudinal strain (RR: 1.94; 95% CI: 1.66 to 2.28) and abnormal diastolic function (RR: 1.68; 95% CI: 1.39 to 2.03) but not abnormal 3D LVEFs (RR: 1.07; 95% CI: 0.74 to 1.53). Conclusions Abnormal global longitudinal strain and diastolic function are more prevalent than reduced 3D LVEF and are associated with treatment exposure. They may identify a subset of survivors at higher risk for poor clinical cardiac outcomes who may benefit from early medical intervention.
Hypertension potentiates cardiovascular risk in survivors of childhood cancer previously exposed to cardiotoxic therapies, so it is important to determine the prevalence and risk factors for ...hypertensive blood pressure in this high-risk group.
Participants included 3,016 adult 10-year survivors of childhood cancer who had resting blood pressure measurements performed at St. Jude Children's Research Hospital (Memphis, TN). We characterized the blood pressure status of participants, calculated standardized prevalence ratios based on U.S. population rates, and examined demographic and treatment factors associated with hypertensive blood pressure using logistic regression.
The age-specific cumulative prevalence of hypertension in survivors increased sharply with age, exceeding 70% by age 50, and was substantially higher in all diagnosis groups than expected on the basis of age-, sex-, race/ethnicity-, and BMI-specific population rates. Specific cancer treatments were not significantly associated with hypertension, with the exception of nephrectomy (OR, 1.68; 95% confidence interval, 1.11-2.53). Previously undiagnosed hypertensive blood pressure was identified in 8% of survivors, and uncontrolled hypertension in 22% of those with a previous hypertension diagnosis. In a subset (
= 1,185) with longitudinal blood pressure measurements (mean interval, 3.6 years), 5% and 21% of participants with previously normal blood pressure developed hypertensive and prehypertensive blood pressure, respectively.
Survivors of childhood cancer have a higher prevalence of hypertension compared with the general population, and many have uncontrolled hypertension that may exacerbate treatment-related cardiovascular risks.
Our results suggest enhanced clinical attention to blood pressure status is warranted in all survivors, regardless of diagnosis or cancer treatment.
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Cardiovascular disease (CVD), which includes cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction, is a major concern ...for long-term survivors of childhood cancer. There is clear evidence of increased risk of CVD largely attributable to treatment exposures at a young age, most notably anthracycline chemotherapy and chest-directed radiation therapy, and compounded by traditional cardiovascular risk factors accrued during decades after treatment exposure. Preclinical studies are limited; thus, it is a high priority to understand the pathophysiology of CVD as a result of anticancer treatments, taking into consideration the growing and developing heart. Recently developed personalized risk prediction models can provide decision support before initiation of anticancer therapy or facilitate implementation of screening strategies in at-risk survivors of cancer. Although consensus-based screening guidelines exist for the application of blood and imaging biomarkers of CVD, the most appropriate timing and frequency of these measures in survivors of childhood cancer are not yet fully elucidated. Longitudinal studies are needed to characterize the prognostic importance of subclinical markers of cardiovascular injury on long-term CVD risk. A number of prevention trials across the survivorship spectrum are under way, which include primary prevention (before or during cancer treatment), secondary prevention (after completion of treatment), and integrated approaches to manage modifiable cardiovascular risk factors. Ongoing multidisciplinary collaborations between the oncology, cardiology, primary care, and other subspecialty communities are essential to reduce therapeutic exposures and improve surveillance, prevention, and treatment of CVD in this high-risk population.
Treatment-related cardiac death is the primary, noncancer cause of mortality in adult survivors of childhood malignancies. Early detection of cardiac dysfunction may identify a high-risk subset of ...survivors for early intervention.
This study sought to determine the prevalence of cardiac dysfunction in adult survivors of childhood malignancies.
Echocardiographic assessment included 3-dimensional (3D) left ventricular ejection fraction (LVEF), global longitudinal and circumferential myocardial strain, and diastolic function, graded per American Society of Echocardiography guidelines in 1,820 adult (median age 31 years; range: 18 to 65 years) survivors of childhood cancer (median time from diagnosis 23 years; range: 10 to 48 years) exposed to anthracycline chemotherapy (n = 1,050), chest-directed radiotherapy (n = 306), or both (n = 464).
Only 5.8% of survivors had abnormal 3D LVEFs (<50%). However, 32.1% of survivors with normal 3D LVEFs had evidence of cardiac dysfunction by global longitudinal strain (28%), American Society of Echocardiography-graded diastolic assessment (8.7%), or both. Abnormal global longitudinal strain was associated with chest-directed radiotherapy at 1 to 19.9 Gy (rate ratio RR: 1.38; 95% confidence interval CI: 1.14 to 1.66), 20 to 29.9 Gy (RR: 1.65; 95% CI: 1.31 to 2.08), and >30 Gy (RR: 2.39; 95% CI: 1.79 to 3.18) and anthracycline dose > 300 mg/m(2) (RR: 1.72; 95% CI: 1.31 to 2.26). Survivors with metabolic syndrome were twice as likely to have abnormal global longitudinal strain (RR: 1.94; 95% CI: 1.66 to 2.28) and abnormal diastolic function (RR: 1.68; 95% CI: 1.39 to 2.03) but not abnormal 3D LVEFs (RR: 1.07; 95% CI: 0.74 to 1.53).
Abnormal global longitudinal strain and diastolic function are more prevalent than reduced 3D LVEF and are associated with treatment exposure. They may identify a subset of survivors at higher risk for poor clinical cardiac outcomes who may benefit from early medical intervention.
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