Matthew J. Ehrhardt

Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-sectional Study

Context Information on the presence of cardiac abnormalities among adult survivors of childhood cancer is limited. Contribution This prospective study identified evidence of cardiomyopathies, conduction or rhythm abnormalities, and coronary artery and valvular diseases in substantial numbers of adult survivors of childhood cancer who were exposed to cardiotoxic therapies, many of whom were asymptomatic. Implication Prospective studies to assess the potential value of screening for cardiac abnormalities in adult survivors of childhood cancer are needed. Improvements in cancer therapies have led to an increasing number of patients living many years after successful treatment. With overall 5-year survival rates in pediatric oncology exceeding 80% (1), the number of adult survivors of childhood or adolescent cancer, which is currently estimated to be 388500 in the United States, is projected to surpass 500000 by 2020 (2, 3). This success is tempered by recognition of adverse late effects of cancer therapy and elevated mortality rates years after treatment. An 8-fold increased risk for death has been reported among 5-year survivors of childhood cancer compared with the age- and sex-matched general population (4). Historically, the leading cause of death has been cancer recurrence. However, late effects of therapy have become the leading cause of death 30 years after diagnosis, and deaths are frequently attributed to premature cardiovascular disease (5). Because of the rarity of childhood cancer and the challenges of following patients across the life spectrum, most studies have relied on self-reported outcomes (6), registry (7), or death certificate data (8) to estimate the prevalence and incidence of adverse outcomes. Few studies have directly assessed survivors or done detailed clinical evaluations (9, 10). This study aimed to report clinically evaluated cardiac outcomes among adults previously exposed to cardiotoxic therapies during treatment of childhood cancer. Methods Participants Participants for this analysis completed a baseline evaluation in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study designed to facilitate longitudinal evaluation of health outcomes among adults who previously received treatment for childhood cancer. The study design and details have been previously published (11). To be enrolled in the cohort, participants must have been diagnosed with childhood cancer and treated at St. Jude Childrens Research Hospital (Memphis, Tennessee), be 18 years or older, and have survived 10 years or more after diagnosis. This cross-sectional analysis includes data collected during the baseline evaluation. Participants (recruited from 44 states and 28 countries) must have been treated with cardiotoxic therapy (anthracycline chemotherapy or cardiac-directed radiation therapy) and completed the initial comprehensive risk-based health evaluation at St. Jude Childrens Research Hospital as of 30 April 2013. Survivors completed a detailed health questionnaire and had a medical evaluation according to the Childrens Oncology Groups Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (12). Assessments included a history and physical examination, fasting laboratory testing (blood counts, metabolic panels, insulin levels, glycosylated hemoglobin levels, and lipid panels), echocardiography, and electrocardiography (ECG). We used VIVID 7 (GE Healthcare) (n=1834) or iE33 (Philips Healthcare) (n=19) machines for 2-dimensional Doppler ultrasonography echocardiography with harmonic imaging per American Society of Echocardiography guidelines and 3-dimensional imaging for left ventricular volumes (13). All images were centrally reviewed by the echocardiography laboratory in the Department of Cardiovascular Medicine at the Cleveland Clinic (Cleveland, Ohio). A total of 1586 participants (86%) had evaluable echocardiograms sufficient for adequate determination of ejection fraction, and 1742 (94%) had echocardiograms sufficient for evaluation of cardiac valves. Twelve-lead ECGs (MAC 1200 Resting ECG System [GE Healthcare]) were obtained and centrally reviewed and coded per the Minnesota Code by the Epidemiological Cardiology Research Center at Wake Forest School of Medicine (Winston-Salem, North Carolina) (1798 participants had ECG). We abstracted medical records to capture cumulative anthracycline exposure in mg/m2, mean cardiac radiation dose, and medical events during and after therapy. We converted anthracycline doses to doxorubicin isotoxic equivalents by summing doxorubicin, daunorubicin (0.83), epirubicin (0.67), idarubicin (5), and mitoxantrone (4) doses (14). We estimated mean radiation doses in centigrays (cGy) to the heart using previously established methods by the radiation physicists at MD Anderson Cancer Center (Houston, Texas) (15). Radiation treatment details included energy source, tumor dose, and field locations. Scatter dose to the heart was estimated for each case, regardless of radiation site and target volume. The SJLIFE protocol and study documents were approved by the institutional review board, and participants provided informed consent. Outcomes Outcomes included cardiomyopathy, coronary artery disease (CAD), valve function, and conduction or rhythm defects. Medical records were obtained to validate established cardiac outcomes reported before the SJLIFE assessment. Cardiomyopathy was defined as systolic ejection fraction less than 0.50 on echocardiography. Coronary artery disease was defined as a history of myocardial infarction, evidence of wall motion defect on echocardiography, or ischemia on ECG. Valves were assessed for function (regurgitation or stenosis) and structure (thickening or calcification) on echocardiography. Only functional valve findings (graded as mild, moderate, or severe) were used in the analysis (16, 17). Conduction or rhythm disorders included major conduction abnormalities or arrhythmias (Appendix Table 1) as assessed by the Minnesota Code (18). Appendix Table 1. Conduction/Rhythm Disorders per the Minnesota Code* Covariates We assessed physical activity by asking survivors whether they participated in usual weekly vigorous activities for at least 10 minutes at a time, such as: running, aerobics, wheelchair basketball, heavy yard work, or anything else that caused large increases in breathing or heart rate; or moderate activities for at least 10 minutes, such as: brisk walking, bicycling, gardening, manual operation of a wheelchair, or anything else that caused small increases in breathing or heart rate (www.cdc.gov/nchs/data/nhanes/nhanes_09_10/paq_f.pdf). The frequency of exercise sessions per week was multiplied by the duration of each session and weighted by the standardized classification of the energy expenditure in metabolic equivalents (inactivity was defined as 450 metabolic equivalent minutes per week). Physical fitness was assessed by the 6-minute walk test (6MWT) (19) and considered abnormal if the participant walked fewer than 490 meters (20). Risky drinking was defined as alcohol consumption of 5 drinks or more on 1 occasion or 15 drinks or more per week for men and consumption of 4 drinks or more on 1 occasion or 8 drinks or more per week for women (www.cdc.gov/alcohol/faqs.htm#heavyDrinking). Survivors who reported smoking within the past month were classified as current smokers, and those who smoked at least 100 cigarettes in their lifetime but not within the past month were considered former smokers. Dyslipidemia was defined as receiving treatment for a lipid abnormality or having a low-density lipoprotein cholesterol level of 4.14 mmol/L or greater (160 mg/dL), high-density lipoprotein cholesterol level less than 1.04 mmol/L (<40 mg/dL) in men or less than 1.30 mmol/L (<50 mg/dL) in women, or triglyceride level greater than 1.70 mmol/L (>150 mg/dL). Diabetes was defined as receiving an oral hypoglycemic agent or insulin for diabetes or having a fasting blood glucose level of 6.99 mmol/L or greater (126 mg/dL) or glycosylated hemoglobin level of 6.5% or greater. Duplicate blood pressure readings were obtained in a seated position with both feet on the floor after a 5-minute rest, and the lowest reading was used for analysis. Hypertension was defined as receiving an antihypertensive agent or having a systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater. Statistical Analysis Descriptive statistics were calculated for demographic, treatment, and cardiovascular risk factors (that is, body mass index at SJLIFE assessment, smoking, drinking, physical activity, hypertension, diabetes, and dyslipidemia). Chi-square tests were used to compare demographic and treatment characteristics between study participants and nonparticipants. Frequencies of cardiac conditions reported before or diagnosed during the on-campus evaluations were ascertained, and prevalence by age at detection was reported. Multivariable logistic models were used to evaluate associations between potential risk factors and cardiac conditions detected during the on-campus evaluations, excluding participants with cardiac outcomes detected before SJLIFE participation. Results are reported as odds ratios with 95% CIs. Covariates were selected because of their known and previously reported associations with cardiac outcomes in the general population and among adult survivors of childhood cancer. Proportions of participants with poor physical fitness (6MWT result 490 meters) were calculated and associations with cardiac conditions evaluated by multivariable logistic regression with age, sex, and height as covariates. We used multiple imputation (proc MI and proc MIANALYZE in SAS, version 9.3 [SAS Institute]) to account for any missing cardiac outcomes, radiation doses (n=26), and 6MWT results (not due to a musculoskeletal cause) (n=30). Markov-chain Monte Carlo methods were used for partial imputation o

Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study

Background The magnitude of cardiovascular morbidity among survivors of pediatric, adolescent, and young adult Hodgkin lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions among Hodgkin survivors and general population controls. Methods Among 670 survivors treated at St. Jude Children’s Research Hospital, who survived ≥10 years and became 18 years old, 348 were clinically assessed in the St. Jude Lifetime Cohort Study (SJLIFE). Age-sex-frequency-matched SJLIFE community-controls (n=272) were used for comparison. All SJLIFE participants underwent evaluation for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) grading schema. Occurrences and CTCAE-grades of the conditions for 322 eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden. Findings At 50 years of age, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45.5%. The survivor cohort experienced, on average, 430·6 (95% confidence interval, 380·7-480·6) grade 1-5 and 100·8 (77·3-124·3) grade 3-5 cardiovascular conditions per 100 survivors. At age 50, the grade 1-5 and 3-5 cumulative burdens of community-controls were appreciably lower at 227·4/100 (192·7-267·5) and 17·0/100 (8·4-27·5), respectively. Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden among survivors. Higher cardiac radiation dose (≥35 Gy) was associated with an increased grade 3-5 cardiovascular burden. Interpretation The true impact of cardiovascular morbidity among pediatric Hodgkin lymphoma survivors is reflected in the cumulative burden. 50-year-old Hodgkin survivors will experience over two times the number of chronic cardiovascular health conditions compared community-controls and, on average, have one severe/life-threatening/fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach to evaluating overall morbidity and will assist clinical researchers when designing future trials and refining general practice screening guidelines.

The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE).

Background Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity among survivors, however, has not been described. Methods Among 5,522 patients treated for childhood cancer at St. Jude Children’s Research Hospital who survived ≥10 years and were ≥18 years old, 3,010 underwent prospective clinical assessment and retrospective medical validation of health records as part of the St. Jude Lifetime Cohort Study. Age- and sex-frequency-matched community-controls (n=272) were used for comparison. 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 among the 2512 survivors not clinically evaluated. Mean cumulative count and marked-point-process regression were used for descriptive and inferential cumulative burden analyses, respectively. Findings The cumulative incidence of any grade CHC at age 50 was 99·9%; 96·0% (95·3%–96·8%) for severe/disabling, life-threatening or fatal CHCs. By age 50, a survivor experienced, on average, 17·1 (16·2–18·0) CHCs including 4·7 (4·6–4·9) graded as severe/disabling, life-threatening or fatal. The cumulative burden among survivors was nearly 2-fold greater than matched community-controls (p<0·001). Second neoplasms, spinal disorders and pulmonary disease were major contributors to the excess total cumulative burden. Significant heterogeneity in CHCs among survivors with differing primary cancer diagnoses was observed. Multivariable analyses demonstrated that 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. Interpretation The burden of surviving childhood cancer is substantial and highly variable. The total cumulative burden experienced by survivors of pediatric cancer, in conjunction with detailed characterization of long-term CHCs, provide data to better inform future clinical guidelines, research investigations and health services planning for this vulnerable, medically-complex population.

Approach for Classification and Severity-grading of Long-term and Late-onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666–74. ©2016 AACR.

Obesity and Metabolic Syndrome Among Adult Survivors of Childhood Leukemia

Opinion statementTreatment-related obesity and the metabolic syndrome in adult survivors of childhood acute lymphoblastic leukemia (ALL) are risk factors for cardiovascular disease. Both conditions often begin during therapy. Preventive measures, including dietary counseling and tailored exercise, should be initiated early in the course of survivorship, with referral to specialists to optimize success. However, among adults who develop obesity or the metabolic syndrome and who do not respond to lifestyle therapy, medical intervention may be indicated to manage underlying pathology, such as growth hormone deficiency, or to mitigate risk factors of cardiovascular disease. Because no specific clinical trials have been done in this population to treat metabolic syndrome or its components, clinicians who follow adult survivors of childhood ALL should use the existing American Heart Association/National Heart Lung and Blood Institute Scientific Statement to guide their approach.

Late outcomes of adult survivors of childhood non-Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study

Survivors of childhood non‐Hodgkin lymphoma (NHL) are at increased risk for chronic health conditions. The objective of this study was to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 200 childhood NHL survivors.

Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma: Long-Term Outcomes After Auto-HCT

Autologous hematopoietic cell transplantation (auto‐HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B‐cell lymphoma (DLBCL); however, long‐term outcomes are not well described.

Chronic disease burden and frailty in survivors of childhood HSCT: a report from the St. Jude Lifetime Cohort Study

Outcomes of hematopoietic stem cell transplantation (HSCT) have markedly improved over the past 2 decades, underscoring a need to better understand the long-term health effects of this intensive treatment modality. We describe the burden of chronic medical conditions and frail health among St. Jude Lifetime Cohort Study participants treated for childhood hematologic malignancies with HSCT (n = 112) or with conventional therapy (n = 1106). Chronic conditions and frail health were ascertained clinically and classified according to a modified version of the Common Terminology Criteria for Adverse Events (version 4.03) and the Fried Frailty Criteria. Seventy-nine transplants were allogeneic (41 from a sibling donor, 34 unrelated, and 4 others from related donor). Twenty-five allogeneic donor recipients had a history of chronic graft-versus-host disease. Compared to those treated with conventional therapy, a higher percentage of HSCT survivors had severe, disabling, or life threatening (grade 3-4) chronic conditions (81.3% vs 69.2%, P = .007). By age 25 years, HSCT survivors experienced 148 grade 3-4 events/100 compared to 60 among conventional therapy survivors (P < .001). Percentages of survivors with second neoplasms (17.0% vs 7.9%, P = .003), grade 3-4 cardiovascular (19.6% vs 10.2%, P = .004) and pulmonary (16.1% vs 4.6%, P < .001) conditions, and frail health (7.1% vs 1.6%, P < .001) were higher after HSCT than conventional therapy. These results underscore the need for clinical follow-up and provide data to guide the development of prevention and/or intervention strategies for this vulnerable population.

A Case of Necrotizing Epiglottitis Due to Nontoxigenic Corynebacterium diphtheriae.

Diphtheria is a rare cause of infection in highly vaccinated populations and may not be recognized by modern clinicians. Infections by nontoxigenic Corynebacterium diphtheriae are emerging. We report the first case of necrotizing epiglottitis secondary to nontoxigenic C diphtheriae. A fully vaccinated child developed fever, poor oral intake, and sore throat and was found to have necrotizing epiglottitis. Necrotizing epiglottitis predominantly occurs in the immunocompromised host. Laboratory evaluation revealed pancytopenia, and bone marrow biopsy was diagnostic for acute lymphoblastic leukemia. Clinicians should be aware of aggressive infections that identify immunocompromised patients. This case highlights the features of a reemerging pathogen, C diphtheriae.

Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma

Children with non‐Hodgkin lymphoma (NHL) undergo treatment with central nervous system–directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors.